Focal Electrically-Administered Seizure Therapy (FEAST): Studies at Two Enrolling Sites to Further Test and Refine the Treatment
Phase: PHASE2
Conditions: Depression
Sponsor: Medical University of South Carolina

 
 
 
Study Title: Focal Electrically-Administered Seizure Therapy (FEAST): Studies at two 
enrolling sites to further test and refine the treatment 
 
NCT02535572  
 
IRB Approved May 5, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IDE Application - Focal Electrically-Administered Seizure Therapy (FEAST): Studies at two enrolling sites 
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Institute of Psychiatry, Medical University of South Carolina 
 
FDA INVESTIGATIONAL DEVICE EXEMPTION APPLICATION 
 
DEVICE: MECTA Spectrum 5000Q FEAST Device 
 
Study Title: Focal Electrically-Administered Seizure Therapy (FEAST): Studies at two 
enrolling sites to further test and refine the treatment 
 
Original Sponsor (2005): 
Harold A. Sackeim, Ph.D. 
Department of Biological Psychiatry 
New York State Psychiatric Institute 
1051 Riverside Drive, Unit 126 
New York, NY 10032 
Current Sponsor: 
Mark S. George, MD. 
Institute of Psychiatry 
Medical University of South Carolina 
67 President Street, room 502 N 
Charleston, SC 29403 
Manufacturer: 
MECTA Corporation 
19799 SW 95th Place, Suite B 
Tualatin OR 97062 
Contact: Ms. Robin Nicol 
Phone: 503 612-6780 
Fax: 503 612-6542 
 
Original Applicant: 
Harold A. Sackeim, Ph.D. 
Department of Biological Psychiatry 
New York State Psychiatric Institute 
1051 Riverside Drive, Unit 126 
New York, NY 10032 
Phone: 212 543-5855 
Fax: 212 543-5854 
Current Applicant 
Mark S. George, MD 
Medical University of South Carolina 

IDE Application - Focal Electrically-Administered Seizure Therapy (FEAST): Studies at two enrolling sites 
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Institute of Psychiatry, Medical University of South Carolina 
Phone: 843 876 5142 
Fax: 843 792 5702 
Date of Original Submission: 5/3/05 by Harold Sackeim, PhD 
Date of Current Submission: 05/05/15 
Protocol version 1.2 
 
Table of Contents 
Focal Electrically-Administered Seizure Therapy (FEAST): Studies at two enrolling 
sites to further test and refine the treatment ............................................................................. 5 
I. INTRODUCTORY STATEMENT ....................................................................................................... 5 
II. Study Objectives ............................................................................................................................... 7 
III. Report of Prior Investigations ................................................................................................... 8 
A. Experience of the Investigators .............................................................................................................. 8 
B. Efficacy of ECT ............................................................................................................................................ 12 
B.1 Short-term Clinical Outcome ......................................................................................................................... 12 
B.2 Persistence of Benefit and Relapse ............................................................................................................. 17 
B.3 Predictors of Outcome and Indications for Use ..................................................................................... 18 
C. Adverse Effects of ECT ............................................................................................................................. 20 
C.1 Mortality ................................................................................................................................................................. 20 
C.2 Serious Medical Complications ..................................................................................................................... 21 
C.3 Systemic Side Effects ......................................................................................................................................... 24 
C.4 Psychiatric Complications ............................................................................................................................... 27 
C.5 Objective Cognitive Side Effects ................................................................................................................... 28 
D. Rationale for FEAST ................................................................................................................................. 36 
D.1 Unidirectional Stimulation ............................................................................................................................. 37 
D.2 FEAST Electrodes ............................................................................................................................................... 39 
D.3 Titrating in the Current Domain .................................................................................................................. 41 
D.4 Non-human Primate Experience.................................................................................................................. 44 
D.6 Human experience ...................................................................................................................... 47 
Experience in Ongoing Study of FEAST .............................................................................................. 56 
IV. INVESTIGATIONAL PLAN ............................................................................................................ 57 
A. Purpose ........................................................................................................................................................ 57 
B. Protocol ........................................................................................................................................................ 59 
B.1 Patient Selection ................................................................................................................................................. 59 
B.2 Inclusion Exclusion/Criteria .......................................................................................................................... 60 
B.3 Medical Work-up ................................................................................................................................................ 62 
B.4 Treatment History .............................................................................................................................................. 63 
B.5 Pretreatment Procedures ............................................................................................................................... 63 
B. 5a MRI scan .............................................................................................................................................................. 65 
B.6 FEAST Procedures .............................................................................................................................................. 67 
B.7 Ultrabrief RUL ECT Treatment Procedures ............................................................................................. 72 
B.8 Assessment of Efficacy ..................................................................................................................................... 73 

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B.9 Classification of Clinical Outcome and Dropout .................................................................................... 74 
B.10 Assessment of Function and Attitudes Toward Treatment ........................................................... 74 
B.11 Documentation of Adverse Events ........................................................................................................... 75 
B.12 Assessment of Objective Cognitive Side Effects .................................................................................. 76 
B.13 Neurophysiology .............................................................................................................................................. 78 
B.14 Quality Assurance and Data Management ............................................................................................. 79 
B.15 Statistical Analyses .......................................................................................................................................... 79 
C. Risk Analysis ............................................................................................................................................... 82 
C.1 Risks of Evaluation Procedures .................................................................................................................... 82 
C.2 Risks Unique to FEAST ..................................................................................................................................... 83 
C.3 Risks of ECT ........................................................................................................................................................... 85 
C.4 Other Risks of the Research ........................................................................................................................... 94 
C.5 Risk Analysis Summary .................................................................................................................................... 95 
D. Device and Site Safety ............................................................................................................................. 96 
D.1 Controlled Access Area .................................................................................................................................... 96 
D.2 Device Calibration and Evaluation .............................................................................................................. 96 
D.3 Screening of Subjects Prior to Treatment ................................................................................................ 97 
D.4 Conduct of FEAST ............................................................................................................................................... 97 
D.5 Adjustment of Stimulation Intensity to Individual Seizure Threshold ........................................ 97 
D.6 Protection From Excessive Electrical Dosage ........................................................................................ 97 
D.7 Supervision of Patients During Treatment Sessions ........................................................................... 98 
D.8 Emergency Medical Procedures ................................................................................................................... 98 
D.9 Fire Precautions .................................................................................................................................................. 98 
E. Device Description (Provided by the Manufacturer)................................................................... 99 
E.1 Identification of Legally Marketed Device ................................................................................................ 99 
E.2 Description of the Device ................................................................................................................................ 99 
F. Monitoring Procedures ......................................................................................................................... 102 
V. Manufacturing Information (PROVIDED BY THE MANUFACTURER) ........................ 102 
A. Software Modification ........................................................................................................................... 104 
B. Hardware Modification ........................................................................................................................ 107 
C. Details on Implementation of the Changes in the FEAST Device ........................................... 108 
D. Verification and Validation Data for the modified Spectrum 5000Q .................................. 108 
D. Feast Electrodes ...................................................................................................................................... 111 
VI. Investigator Agreement .............................................................................................................. 112 
VII. INVESTIGATOR CERTIFICATION ......................................................................................... 113 
VIII. IRB INFORMATION ................................................................................................................. 115 
IX. SECONDARY SITE(S) .................................................................................................................. 115 
X. COMMERCIALIZATION STATEMENT ..................................................................................... 115 
XI. DEVICE LABELING ...................................................................................................................... 115 
XII. INFORMED CONSENTS ............................................................................................................. 116 
XiIi. References ................................................................................................................................. 141 
 

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Focal Electrically-Administered Seizure Therapy (FEAST): 
Studies at two enrolling sites to further test and refine the 
treatment 
I. INTRODUCTORY STATEMENT 
This open label investigation further evaluates the safety, efficacy and potential 
mechanisms of action of a new form of electroconvulsive therapy (ECT). Both the 
efficacy and adverse cognitive effects of ECT are highly contingent on the 
intracerebral current paths and current density of the ECT stimulus (1993, Sackeim et 
al., 2000b, Sackeim, 2004a, McCall et al., 2000, Sackeim et al., 2008). However, the 
impedance of the skull and individual differences in skull anatomy severely limit the 
spatial targeting of stimulation, and create marked individual differences in 
intracerebral current density (Weaver et al., 1976, Sackeim et al., 1994, Deng et al., 
2009, Peterchev et al., 2010). To address these problems, we have been exploring 
various means of overcoming this limitation. One approach is to induce the seizure 
using magnetic fields [magnetic seizure therapy (MST)] (Sackeim, 1994b, Lisanby et 
al., 2001b, Lisanby et al., 2003a, Lisanby et al., 2001c, Luber et al., 2013, Kayser et al., 
2013, Hoy et al., 2013, Fitzgerald et al., 2013). MST uses high power repetitive 
magnetic stimulation to induce sufficient current flow in brain to elicit self-sustaining 
seizures. MST must overcome technological barriers as the energy transfer from 
current in a coil to that induced in brain is inefficient, and it is not clear that a form of 
MST will be developed that is sufficiently powerful to match the efficacy of ECT.  
 
An alternate approach is to modify the electrical stimulus to induce focal seizures. 
The most common methods of ECT administration in the US use a bidirectional, 
constant current, brief or ultrabrief pulse, with large (approximately 3 sq. in. surface 
area) and identically sized and shaped electrodes. In contrast, in this protocol we 
have coupled unidirectional current flow with an electrode geometry involving a 
small and large electrode that differ by more than 5:1 in surface area.  
 
Unidirectional currents were widely used in ECT during the 1940’s and 1950’s and 
continue to be used in European and American devices today (Alexander, 1955, 
Epstein and Wender, 1956, Friedman, 1949, Friedman, 1942, Hovorka et al., 1960, 
Impastato et al., 1951, Pacella, 1952, Rappa and Tanowitz, 1959). Indeed, a 
unidirectional current option is incorporated in the US marketed Thymatron System 
IV (Somatics Corp.). Transcranial electrical stimulation can be made focal by 

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stimulating with an anode-cathode arrangement (unidirectional stimulation), with 
the electrodes differing in surface area (Amassian et al., 1990, Stewart et al., 1990, 
Cracco et al., 1989, Amassian et al., 1989a, Amassian et al., 1989b). We have shown 
in nonhuman primates the capacity to produce focal frontal seizure induction under 
conditions when a unidirectional current flows from a small anterior anode (placed 
on the forehead over the nasion) to a large posterior cathode just anterior to the 
motor strip (Spellman et al., 2009). Furthermore, many of these seizures in primates 
did not result in motor convulsions. We tested this new stimulation method in 4 
nonhuman primates, who on several occasions had seizure threshold titrated with 
current either flowing from the small anterior electrode to the large posterior 
electrode or the reverse (Spellman et al., 2009). In 7 of 7 tests, EEG seizures were 
evoked at low stimulus intensity and most did not result in motor convulsion. The 
seizure threshold in the instances of an electrographic seizure without motor 
convulsion was at the first step in the titration schedule, with only 3 mC being 
administered. For each animal, seizure threshold with typical ECT parameters is 
substantially higher. These findings were remarkable and demonstrated that this 
method can produce focal frontal seizures, which we have hypothesized as key to 
therapeutic mechanisms (Sackeim et al., 1983; Sackeim, 1999, (Nobler et al., 1994, 
Sackeim et al., 1996). Furthermore, it appears that seizure threshold may be reduced 
with this approach (Sackeim, 2004a).  
 
We have recently completed preliminary open-label studies with FEAST, first at 
Columbia University, and then at the Medical University of South Carolina in 
Charleston (Nahas et al., 2013b). We have published the outcomes of the first 17 
patients studied. One patient withdrew from the study after a single titration 
session. After the course of FEAST (median 10 sessions), there was a 46.1 + 35.5% 
improvement in Hamilton Rating Scale for Depression (HRSD24) scores compared 
to baseline (33.1 + 6.8, 16.8 + 10.9; P < 0.0001). Eight of 16 patients met response 
criteria (≥50% decrease in HRSD24) and 5/16 met remission criteria (HRSD24≤10). 
Patients achieved full re-orientation (4 of 5 items correct) in 5.5 + 6.4 min (median 
time = 3.6 min), timed from when their eyes first opened after treatment. We have 
now studied 18 more patients (see results below), and we are completing the study 
in the original IDE with another two more patients still to enroll.  
 
This work allowed us to refine the treatment. For example, we selectively modified 
the electrode geometry to decrease interelectrode resistance. Additionally we 

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modified the titration schedule, now only administering a standard 800 ma 
ultrabrief pulse, and thus no longer titrating in the current domain.  
II. Study Objectives 
This study will provide preliminary evaluation of the following: 
1. Further characterization of the efficacy of FEAST and the safety of the 
treatment. 
a. The primary efficacy measure will be the 24-item Hamilton Rating 
Scale for Depression. The changes in these scores from before to 
immediately following the treatment course will be compared in 
patients treated with the FEAST methodology and matched to 
nonrandomized patients at our facilities who were treated with 
conventional ECT methods (ultrabrief right unilateral [RUL] ECT). 
b. Acute and subacute cognitive side effects following FEAST will be 
assessed with a brief neuropsychological battery. The primary acute 
measures will be the time to return of orientation following seizure 
induction. The primary subacute measures will be assessment of 
retrograde 
amnesia 
for 
autobiographical 
information. 
The 
neuropsychological measures will be compared in the patients 
treated with the FEAST methodology (under this IDE) and matched 
(but nonrandomized) patients who are treated with conventional 
ECT methods (also covered under this IDE). 
c. Safety will also be determined by examining the number and 
frequency of serious adverse advents and adverse events.  
2. Characterization of the focal nature of the seizure onset with FEAST and 
RUL ECT. We will use two main methods to address the issue of focality.  
a. Resting state fMRI before and after a course of FEAST (or 
conventional RUL ECT). We will address whether FEAST causes 
changes in hyper connected prefrontal cortical subcortical 
networks, and whether such an effect is more restricted to 
prefrontal cortex with FEAST relative to conventional RUL ECT.  
b. Peri-ictal EEG acquired immediately before, during and immediately 
after the FEAST seizure. We will acquire this in all patients at all 
treatment sessions. Again, for comparison, we will use identical EEG 
acquisition methods in patients treated with conventional RUL ECT.  
 
Section IV.B.17 describes the statistical plan for addressing these objectives.  

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III. Report of Prior Investigations 
A. Experience of the Investigators 
The original applicant, Dr. Sackeim, remains a key co-investigator on this proposal 
that is now transferred from NYSPI, Columbia University to the Institute of 
Psychiatry at MUSC. Dr. Sackeim been engaged since 1979 in research using ECT 
devices produced by the MECTA Corporation. The applicant has over 250 
publications in the area of ECT and over 425 total publications. Representative 
efficacy and safety findings from the major studies over this period are reported in 
the following: 
 
• Lisanby, S.H., Maddox, J.H., Prudic, J., Devanand, D.P., & Sackeim, H.A. (2000). 
The effects of electroconvulsive therapy on memory of autobiographical and 
public events. Archives of General Psychiatry, 57, 581-590.  
• McElhiney, M.C., Moody, B.J., Steif, B.L., Prudic, J., Devanand, D.P., Nobler, 
M.S., & Sackeim, H.A. (1995). Autobiographical memory and mood: Effects of 
electroconvulsive therapy. Neuropsychology, 9, 501-517. 
• Sackeim HA (2004): The convulsant and anticonvulsant properties of 
electroconvulsive therapy: towards a focal form of brain stimulation. Clinical 
Neuroscience Review 4:39-57. 
• Sackeim HA, Prudic J, Devanand DP, Kiersky JE, Fitzsimons L, Moody BJ, 
McElhiney MC, Coleman EA, Settembrino JM (1993): Effects of stimulus 
intensity and electrode placement on the efficacy and cognitive effects of 
electroconvulsive therapy. N Engle J Med 328:839-46. 
• Sackeim HA, Prudic J, Devanand DP, Nobler MS, Lisanby SH, Peyser S, 
Fitzsimons L, Moody BJ, Clark J (2000): A prospective, randomized, double-
blind comparison of bilateral and right unilateral electroconvulsive therapy at 
different stimulus intensities. Arch Gen Psychiatry 57:425-34. 
• Sackeim, H.A. (1986). Acute cognitive side effects of ECT. Psychopharm Bull, 
22, 482-484. 
• Sackeim, H.A., Decina, P., Kanzler, M., Kerr, B., & Malitz, S. (1987a). Effects of 
electrode placement on the efficacy of titrated, low-dose ECT. American 
Journal of Psychiatry, 144, 1449-1455. 

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• Sackeim, H.A., Portnoy, S., Neeley, P., Steif, B.L., Decina, P., & Malitz, S. (1986). 
Cognitive consequences of low-dosage electroconvulsive therapy. Annals of 
the New York Academy of Sciences, 462, 326-340. 
• Sobin, C., Sackeim, H.A., Prudic, J., Devanand, D.P., Moody, B.J., & McElhiney, 
M.C. (1995). Predictors of retrograde amnesia following ECT. American 
Journal of Psychiatry, 152, 995-1001. 
 
These publications support the efficacy of ECT and the MECTA Corporation devices 
in particular. The most recent publications (Sackeim et al., 2000, Sackeim et al. 2008) 
used the MECTA Spectrum 5000Q, which is the device modified for this protocol. 
Earlier publications reported studies using the MECTA Model D and the MECTA SR-
1. However, across these studies, fundamental characteristics of the electrical 
stimulus were kept constant throughout, including use of a bidirectional, constant 
current, brief pulse stimulus, with amplitude of 800 mA. This work has consistently 
yielded short-term remission rates on the order of 60-80% for the most effective 
forms of ECT. This work has also demonstrated that efficacy and cognitive side 
effects are determined by the current paths of the ECT stimulus (electrode 
placement) and current density, especially when assessed in terms of dosage 
relative to threshold. 
 
Contributions made by the original applicant and his collaborators to advancing the 
practice and understand of ECT include:  
(a) Invention of stimulus dose titration (Sackeim et al., 1987d), widely considered 
the most precise and optimal method for determining electrical dosing in 
ECT (American Psychiatric Association, 2001);  
(b) Establishing the safety of repeated subconvulsive stimulation as used in the 
titration technique (Prudic et al., 1994);  
(c) Establishing the correlates of seizure threshold, including gender, age, and 
electrode positioning effects and relations to dynamic impedance and EEG 
seizure manifestations (Sackeim et al., 1987d, Sackeim et al., 1987c, Sackeim 
et al., 1991);  
(d) Describing the physical properties of the ECT electrical stimulus and 
introducing the use of charge as the preferred summary dosage unit 
(Sackeim, 1994b, Sackeim et al., 1994, Weiner et al., 1987);  

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(e) Demonstrating in a set of randomized, double-blind trials that both the 
efficacy and cognitive effects of ECT are sensitive to electrical dosage, often 
in relation electrode placement, thereby overturning fundamental views 
about ECT’s mechanisms of action and offering new methods to optimize 
treatment administration (Sackeim et al., 1987b, Sackeim et al., 1993, Sackeim 
et al., 2000b, Sackeim, 2004a);  
(f) Demonstrating that ultrabrief stimuli are considerably more efficient that the 
traditional brief pulse stimulus used in ECT and result in marked cognitive 
savings relative to standard ECT techniques (Sackeim, 2004a);  
(g) Describing the effects of ECT on brain electrical (EEG) activity and on 
regional 
Cerebral 
Blood 
flow 
and 
Cerebral 
Metabolic 
rate 
and 
demonstrating that specific alterations in anatomically distinct areas are 
associated with the therapeutic and amnestic effects of the treatment 
(Nobler et al., 1993, Nobler et al., 1994, Sackeim et al., 1996, Nobler et al., 
1999, Nobler et al., 2000b, Luber et al., 2000, Nobler et al., 2000a, Perera et 
al., 2004, Sackeim and Mukherjee, 1986, Sackeim et al., 2000a);  
(h) Development of new cognitive procedures and characterization of ECT’s 
acute, short-term and long-term cognitive effects (McElhiney et al., 1995, 
Sobin et al., 1995b, McElhiney et al., 1997, Steif et al., 1986, Prudic et al., 1999, 
Sackeim et al., 1986, Devanand et al., 1991, Sackeim, 1992, Sackeim et al., 
1993, Lisanby et al., 2000, Sackeim, 2000, Sackeim et al., 2007, Sackeim, 
2014b);  
(i) Developing the methods now widely used to assess medication resistance 
(Antidepressant Treatment History Form) and determining its predictive 
value with respect to ECT immediate clinical outcome and relapse following 
remission (Sackeim et al., 1990a, Sackeim et al., 1990b, Prudic et al., 1990, 
Prudic et al., 1996, Sackeim et al., 2000b, Sackeim et al., 2001a);  
(j) Characterization of relapse rates in naturalistic studies both in research and 
community 
samples 
and 
investigation 
of 
optimal 
continuation 
pharmacotherapy following ECT, using placebo-controlled, randomized, 
double-blind designs (Sackeim et al., 1990b, Sackeim et al., 2000b, Sackeim 
et al., 2001a, Prudic et al., 2004a, Prudic et al., 2013);  
(k) Introducing and evaluating novel theories regarding the mechanisms of 
ECT’s antidepressant and adverse cognitive effects (Sackeim et al., 1983b, 
Devanand et al., 1995b, Sackeim, 1999, Nobler et al., 2001, Sackeim, 2004a);  

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(l) Providing the first modern placebo-controlled evidence of the impact of 
antidepressant pharmacotherapy on the efficacy of ECT in major depression 
(Sackeim et al., 2009) 
(n) Introducing new methods of treatment administration with the aim of 
reducing ECT’s adverse cognitive effects, including the use of dose titration, 
the use of ultra-brief electrical stimulation, reliance on high dosage right 
unilateral (RUL) ECT instead of BL ECT, use of a magnetic stimulus to elicit 
seizures (Magnetic Seizure Therapy, MST), and the topic of this IDE, the use 
of focal electrically-administered seizure therapy (FEAST) (Lisanby et al., 
2003c, Lisanby et al., 2003b, Lisanby et al., 2003a, Sackeim, 1994b, Lisanby et 
al., 2001c, Lisanby et al., 2001b, Sackeim, 2004a, Sackeim et al., 2008, 
Sackeim et al., 1993, Sackeim et al., 2000b, Nahas et al., 2013a). 
 
The MUSC team including Dr. Mark George and Dr. Baron Short, also has 
substantial experience in brain stimulation therapies and clinical research on 
treatment-resistant depression. Dr. Short is the Brain Stimulation Service director. Dr 
Mark George is a world-expert in brain stimulation research and the Editor-in-Chief 
of the journal, Brain Stimulation. He is credited with early development of both 
transcranial magnetic stimulation (George, 2002, George et al., 2010, George et al., 
1999, George et al., 1997, O'Reardon et al., 2007) and vagus nerve stimulation 
(George et al., 2002, George et al., 2005a, George et al., 2005b, Rush et al., 2005) for 
treatment-resistant depression.  
 
The GRU team consists of Dr. Vaughn McCall and Dr. Peter Rosenquist. Both are 
highly experienced clinicians in the field of ECT, with an aggregate of >20,000 ECT 
sessions. Both have participated in the design and execution of influential multi-
center studies examining the acute efficacy of ECT and the prevention of relapse 
following ECGT termination (Sackeim et al., 2009, Prudic et al., 2013). Dr. McCall has 
led the field of ECT in examining the effects of the treatment on functional 
outcomes, specifically quality of life (McCall et al., 2006, McCall et al., 2001, McCall 
et al., 2013, McCall et al., 2011a, Rosenquist et al., 2006). He and Dr. Rosenquist have 
also made seminal contributions to identification of optimal forms of ECT (McCall et 
al., 1995, McCall et al., 2002, McCall et al., 2000, McCall et al., 1993), and the 
characteristics and significance of the ictal EEG (Krystal et al., 1996a, Krystal et al., 
1996b, Krystal et al., 1993, McCall et al., 1996a, McCall et al., 1996b, McCall et al., 
1998, Rosenquist et al., 1998). Dr. McCall is the editor-in-chief of the Journal of ECT.  

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This extensive experience of the teams in carrying out seminal work that has shaped 
this field lends confidence that this study will be carried out in a highly professional 
manner, both protecting the welfare of patient participants and yielding information 
that may be critical in devising and testing a new treatment, FEAST, that will have a 
superior risk/benefit ratio relative to traditional ECT.  
B. Efficacy of ECT 
B.1 Short-term Clinical Outcome 
ECT is widely considered the most effective, short-term treatment for major 
depression. Its effectiveness in this disorder has been the subject of many reviews 
(American Psychiatric Association, 2001, Crowe, 1984, Sackeim et al., 1995, Abrams, 
2002, Royal College of Psychiatrists, 1995, Sackeim, 1989, Salzman et al., 2002) and 
formal meta-analyses (Janicak et al., 1985, Parker et al., 1992, NICE, 2003, Kho et al., 
2003, Pagnin et al., 2004). Each of these evaluations concluded that ECT exerts 
substantial short-term therapeutic effects in the treatment of major depression, with 
the conclusion also commonly reached that no other treatment has demonstrated 
short-term therapeutic effects that exceed those of ECT.  
 
Especially important are the putative effects of ECT on mortality. Large samples are 
necessary to detect any effect on mortality rates, and this issue has mainly been 
examined in naturalistic studies, often using retrospective comparisons [see Prudic and 
Sackeim (1999) for a critical review]. Post (1972) suggested that, prior to the 
introduction of ECT, elderly patients with depression often manifested a chronic course 
or died of intercurrent medical illnesses in psychiatric institutions. A number of studies 
contrasted the clinical outcomes of depressed patients who received inadequate or no 
biological treatment to those of patients who received ECT. While none of this work 
used prospective, random assignment designs, most studies indicated that ECT 
resulted in decreased chronicity and morbidity, and decreased rates of mortality (Avery 
and Winokur, 1976, Babigian and Guttmacher, 1984, Black et al., 1989, Philibert et al., 
1995, Wesner and Winokur, 1989). In much of this work, the advantages of ECT were 
particularly pronounced in elderly patients. For example, in a recent retrospective 
comparison of elderly depressed patients treated with ECT or pharmacotherapy, 
Philibert et al. (1995) found that rates of mortality and significant depressive 
symptomatology were higher in the pharmacotherapy group at long-term follow-up. 
Prudic and Sackeim (1999) noted that all but one study (Black et al., 1989) found a 
reduction in long-term mortality rates in patients treated with ECT. There is little 

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evidence that ECT has long-term impact on suicide (Milstein et al., 1986, Sharma, 1999). 
Rather, the putative benefit appears to be reduced morality due to natural causes (e.g., 
cardiovascular illness), and the mechanisms mediating such an effect are unknown.  
 
With the introduction of the tricyclic antidepressants (TCAs) and monoamine 
oxidase inhibitors (MAOIs), a series of random assignment trials were conducted in 
depressed patients. ECT was used as the “gold-standard” by which to benchmark 
the efficacy of these new medications. Three of these early studies involved random 
assignment and blinded ratings, and each found a significant therapeutic advantage 
for ECT over TCAs and placebo (Greenblatt et al., 1962, Greenblatt et al., 1964, 
Medical Research Council, 1965, Gangadhar et al., 1982). Other studies also reported 
ECT to be as or more effective than TCAs (Bruce et al., 1960, Kristiansen, 1961, Norris 
and Clancy, 1961, Robin and Harris, 1962, Stanley and Fleming, 1962, Fahy et al., 
1963, Hutchinson and Smedberg, 1963, Wilson et al., 1963, McDonald et al., 1966, 
Davidson et al., 1978) or MAOIs (King, 1959, Kiloh et al., 1960, Stanley and Fleming, 
1962, Hutchinson and Smedberg, 1963, Davidson et al., 1978). In a meta-analysis of 
this work, Janicak et al. (1985) reported an average response rate to ECT that was 
20% higher than that of TCAs and 45% higher than MAOIs. 
 
It should be noted that standards for adequate pharmacological treatment have 
changed over the decades (Quitkin, 1985, Sackeim et al., 1990a, Sackeim, 2001), and 
that, by current criteria, few of these early comparative trials used aggressive 
pharmacotherapy in terms of dosage and/or duration (Rifkin, 1988). In addition, 
these studies usually focused on depressed patients who were receiving their first 
biological treatment during the index episode. In a small study, Dinan and Barry 
(1989) randomized patients who did not respond to monotherapy with a TCA to 
treatment with ECT or the combination of a TCA and lithium carbonate. The ECT 
and the pharmacotherapy groups had equivalent efficacy, but the TCA/lithium 
combination may have had an advantage in terms of speed of response. 
 
Only one study has contrasted the efficacy of ECT with one of the newer selective 
serotonin reuptake inhibitors. Folkerts et al. (1997) studied 39 patients with major 
depression and with at least two adequate failed antidepressant trials (mean = 4.9 
trials). These patients were randomized to either paroxetine (n=18) or right unilateral 
(RUL) ECT (n=21). At the end of treatment, there was a reduction in the HAMD score of 
59% for the ECT group and of 29% for the paroxetine group (P<0.001). In the ECT 
group, 71% of subjects met response criteria (at least a 50% decrease in total HAMD 

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score). The authors concluded that ECT was superior to paroxetine in medication-
resistant major depression, both in terms of degree and speed of response. However, 
no other study has used a randomized design to compare the efficacy of ECT with 
newer antidepressant medications, including other SSRIs or medications such as 
buproprion, duloxetine, mirtazapine, nefazodone, venlafaxine, or the combination of 
an antidepressant and an atypical antipsychotic. However, no trial of any type has ever 
found an antidepressant medication regimen to be more effective than ECT.  
 
Among patients who are receiving ECT as a first-line treatment, or who have received 
inadequate pharmacotherapy during the index episode due to intolerance, response 
rates continue to be reported in the range of 80-90% (Sackeim et al., 1990b, Prudic et 
al., 1990, Prudic et al., 1996, Sackeim et al., 2000b, O'Connor et al., 2001, Petrides et 
al., 2001, Kellner et al., 2010). Among patients who have not responded to one or 
more adequate antidepressant trials, the response rate is still substantial, in the range 
of 50-60% (Sackeim et al., 2000b, Sackeim et al., 1990a, Prudic et al., 1990, Prudic et 
al., 1996). A recent meta-analysis confirmed that clinical outcome is significantly 
poorer in medication-resistant patients compared to patients who did not receive an 
adequate medication trial in the current episode prior to ECT (Heijnen et al., 2010)  
 
The time to achieve full symptomatic improvement with antidepressant medications 
is typically estimated as 4 to 6 weeks (Quitkin et al., 1984, Quitkin et al., 1996). This 
delay until response may be longer in older patients (Salzman et al., 2002). In 
contrast, the average ECT course for major depression consists of 8-9 treatments 
(Sackeim et al., 1993; Prudic et al., 1996). Thus, when ECT is administered at a 
schedule of three treatments per week, the usual schedule in the US, full 
symptomatic improvement typically occurs more rapidly than with pharmacological 
treatment (Sackeim et al., 1995, Nobler et al., 1997b). 
 
ECT is a highly structured treatment, involving a complex, repeatedly administered 
procedure that is accompanied by high expectations of therapeutic success, and 
involves an extensive consent process and period of patient education. Such 
conditions may augment placebo effects. Given this concern, a set of double-blind, 
random assignment trials were conducted in England during the late 1970’s and 1980’s 
that contrasted ‘real’ ECT with ‘sham’ ECT — the repeated administration of anesthesia 
alone. With one exception (Lambourn and Gill, 1978), real ECT was found consistently 
to be more efficacious than sham treatment (Freeman et al. 1978; Johnstone et al. 
1980; West 1981; Brandon et al. 1984; Gregory et al. 1985; see Sackeim 1989 for a 

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Figure 1. Serial HRSD scores for groups 
treated with either low dosage (1 x ST) RUL 
or BL ECT in Sackeim et al. (1987a) [Study 1] 
and Sackeim et al. (1993b) [Study 2]. Note 
the strong replication of the effects
review). Lambourn and Gill (1978) had used 
a form of real ECT, involving low stimulus 
intensity and right unilateral electrode 
placement, that is now known to be 
ineffective (Sackeim et al., 1987b, Sackeim 
et al., 1993, Sackeim et al., 2000b).  
 
Overall, 
the 
real 
vs. 
sham 
ECT 
studies 
demonstrated that the passage of an electrical 
stimulus and/or the elicitation of a generalized 
seizure were necessary for ECT to exert 
antidepressant 
effects. 
Following 
the 
randomized 
acute 
treatment 
period, 
the 
patients who participated in these studies were 
free to receive other forms of acute or 
continuation 
treatment, 
including 
ECT. 
Consequently, 
information 
regarding 
the 
duration of symptomatic improvement with real 
versus sham treatment could not be obtained in 
this research. 
 
Finally, there have been a host of studies in the treatment of major depression that 
have contrasted variations in ECT technique, manipulating factors such as stimulus 
waveform, electrode placement, and stimulus dosage. An important practical 
observation that emerged was that the efficacy of ECT is equivalent regardless of the 
use of sine wave or brief pulse stimulation, but that sine wave stimulation results in 
more severe cognitive impairments (Carney et al., 1976-, Weiner et al., 1986, Scott et 
al., 1992, Prudic et al., 2004a, Sackeim et al., 2007). More critical in establishing the 
efficacy of ECT was the series of demonstrations that the clinical outcome with ECT is 
dependent on electrode placement and stimulus dosage (Sackeim et al., 1987b, 
Sackeim et al., 1987c, Sackeim et al., 1993, Sackeim et al., 2000b, Sackeim, 2004a, 
McCall et al., 2000, Sackeim et al., 2008). These factors can dramatically impact on 
the efficacy of the treatment, with widely varying response and remission rates. For 
example, the low dosage right unilateral ECT condition in the study by Sackeim et al. 
(1993b) resulted in 17% final response rate compared to about 70% for the other 3 
conditions. As illustrated in Figure 1, this effect was highly replicable. In this figure, 
the changes in HRSD scores over time are presented for the low dose RUL and 

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bilateral (BL) ECT conditions in the 1987a and 1993b studies by Sackeim et al. The 
values per condition are virtually identical across the studies. Augmenting the 
dosage of RUL ECT substantially enhances efficacy (McCall et al., 2000). Furthermore, 
it has recently been shown that the efficacy of BL ECT can also be comprised by 
coupling ultrabrief (0.3 ms) stimulation with a dose only 2.5 times above seizure 
threshold (Sackeim et al., 2008).  
 
This 
work 
went 
beyond 
sham-controlled 
studies 
and 
provided 
powerful 
demonstrations of the intrinsic efficacy of ECT. In this set of studies, patients were 
randomized to alternative ECT conditions under strict double-masked conditions. The 
forms of ECT that differed markedly in outcome all involved general anesthesia, 
electrical stimulation of the brain, and production of a generalized seizure, using 
conservative criteria for seizure adequacy. This work established by technical factors in 
ECT administration — the form or intensity of stimulation and anatomic positioning of 
electrodes — strongly influence efficacy. 
 
Finally, another source of evidence is often overlooked. Patients form their own 
impressions regarding the treatments that have helped them the most or least. These 
subjective evaluations, while likely influenced by a variety of factors, are especially 
critical since they may impact on willingness to receive treatments in the future. Parker 
et al. (Parker et al., 1999) had 27 Australasian psychiatrists interview 341 non-psychotic 
depressed patients who rated the extent to which previous antidepressant treatments 
had been effective. ECT (both bilateral and unilateral) was judged as highly effective by 
both melancholic and non-melancholic patients. Antipsychotic medication similarly 
rated highly (but was judged as more effective by the non-melancholic than 
melancholic patients). TCAs and irreversible MAOIs were rated as more effective by the 
whole sample than several newer antidepressant classes (including SSRIs, venlafaxine, 
mianserin and moclobemide), whether effectiveness was examined dimensionally or 
categorically. Comparison of the overall tricyclic and SSRI classes indicated that any 
superior tricyclic effectiveness was specific to the melancholic patients. In short, using 
this methodology, some drug classes showed specificity to the presence or absence of 
melancholia. In contrast, regardless of this distinction, patients rated ECT as most 
effective.  In general, patient self-evaluation of the effects of ECT on depressive 
symptoms closely mirrors that of trained observers (Berman et al., 2008, Sayer et al., 
1993) 

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B.2 Persistence of Benefit and Relapse 
ECT is the only treatment in psychiatry that is usually stopped once it is found 
effective. This presents a dilemma in that it is known that without continuation 
treatment virtually all patients will relapse after achieving remission with ECT. For 
example, 
in 
the 
only 
modern 
placebo-controlled 
trial 
of 
continuation 
pharmacotherapy following ECT, Sackeim et al. (2001a) reported that 84% of 
patients randomized to placebo relapsed within 6 months of remitting with ECT. 
 
The literature on the persistence of benefit following ECT and the efficacy of 
alternative somatic continuations treatments (physical and pharmacological) in 
preventing postECT relapse were reviewed by Sackeim (1994a) and Bourgon (2000). 
A variety of studies have provided controlled or naturalistic data on relapse 
(Sackeim et al., 1993, Shapira et al., 1995, Lauritzen et al., 1996, Flint, 1997, Flint and 
Rifat, 1997, Stoudemire, 1997, Lauritzen et al., 1997, Stoudemire et al., 1998, Sackeim 
et al., 2000b, Doraiswamy and Scates, 2001, Grunhaus et al., 2001, Fox, 2001, 
Dannon et al., 2002, Flint and Gagnon, 2002, Andrade and Kurinji, 2002, Russell et 
al., 2003, Prudic et al., 2004a, Birkenhager et al., 2004, Little et al., 2004, Sackeim et 
al., 1990b, Lemstra et al., 1996, Brakemeier et al., 2014, Prudic et al., 2013, Kellner et 
al., 2006, Nordenskjold et al., 2011, Navarro et al., 2008, Youssef and McCall, 2014).  
 
It appears that in community practice, relapse rates are substantial following remission 
with ECT. Prudic et al. (2004) followed 347 patients with a depressive mood disorder 
who received ECT at 7 hospitals in the NYC metropolitan area. In this cohort, up to 
70% of patients classified as remitters following ECT relapsed during the 6-month 
follow-up period. While relapse was common, typically patients who relapsed did not 
return to the same level of symptomatology as at the start of ECT, showing some 
residual gains. While relapse rates vary considerably from study-to-study, it is a fair 
estimate that 50-70% of patients treated in an unstructured manner in community 
settings while show substantial deterioration in the first six months following ECT.  A 
similar, thought slightly less dire, conclusion was derived from a recent meta-analysis 
of studies of relapse following ECT (Jelovac et al., 2013). 
 
There appear to be two main factors that impact on the likelihood of relapse in the 
postECT period: the medication-resistant status of the patient and the form of 
continuation treatment used. Following the originally observation by Sackeim et al. 
(1990b), there have been several replications of the phenomenon that patients who 
have demonstrated clear cut medication resistance in the depressive episode prior to 

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receiving ECT are at heightened risk for postECT relapse (Sackeim et al., 1993, Sackeim 
et al., 2000b, Sackeim et al., 2001a, Shapira et al., 1995, Lauritzen et al., 1996). That 
medication resistance would have clinical significance as a relapse predictor is not 
surprising on two grounds. First, medication resistance appears to be a potent 
predictor of both difficulty in achieving response or remission regardless of the 
subsequent intervention [e.g., ECT: (Prudic et al., 1990, Prudic et al., 1996, Sackeim et al., 
2000b, Heijnen et al., 2008) and VNS: (Sackeim et al., 2001b)]. Second, it has not been 
uncommon to use as continuation therapy the very same medication strategies that 
were ineffective in the acute treatment of the depressive episode (Benbow, 1992-1993, 
Sackeim, 1994a). There is no evidence that medications that were ineffective in treating 
the acute episode are useful as continuation treatments following ECT (Sackeim et al., 
1990b).  
 
There is evidence that the form of continuation treatment used can impact on relapse. In 
a placebo-controlled, randomized, double-blind trial, we reported relapse rates over 6 
months postECT of 84%, 60% and 39% for placebo, monotherapy with nortriptyline, and 
combined nortriptyline-lithium treatment, respectively (Sackeim et al., 2001a). Similarly, 
in a naturalistic series followed for one year following ECT-induced remission, patients 
treated with combined TCA-lithium treatment had half the relapse (Sackeim et al., 
2000b). Another approach is to use ECT itself as a form of continuation treatment, and, 
indeed, for some patients, this may be the only effective from of relapse prevention 
(Decina et al., 1987). However, there is very little information on optimal schedules of 
continuation ECT and cumulative effects on cognition. A recent, NIH-supported 
supported study randomized patients to nortriptyline-lithium following ECT and an 
aggressive from of continuation ECT. No difference was detected in relapse rates, 
despite large samples(Kellner et al., 2006). Thus, at present, this form of 
pharmacotherapy is likely optimal, and recent research has shown that the same benefit 
obtains with a regimen that may be better tolerated, i.e., venlafaxine-lithium (Prudic et 
al., 2013). There is also initial evidence that the combination of an antidepressant and a 
form of psychotherapy (CBT) may protect against relapse (Brakemeier et al., 2014). This 
issue represents a critical limitation of ECT since even with what might be considered 
optimal continuation treatment relapse rates are high, about 40-50% over the first 6 
months following ECT-induced remission. 
B.3 Predictors of Outcome and Indications for Use 
There are several demographic and clinical features that show a statistical relationship 
to ECT short-term outcome [see (Nobler and Sackeim, 1996) for a review]. However, 

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none of these relationships show sufficient sensitivity and specificity to guide patient 
selection (American Psychiatric Association, 2001). 
 
As indicated, patients with demonstrated medication-resistance tend to have a poorer 
outcome with ECT than those who come to the treatment without having failed an 
adequate medication trial (Sackeim et al., 1990a, Prudic et al., 1990, Prudic et al., 1996, 
Sackeim et al., 2000b) [see (van den Broek et al., 2004) for a negative study and 
(Heijnen et al., 2010) for a meta-analysis]. However, it is likely that the rates of 
response/remission seen with ECT in medication-resistant patients (e.g., 50-60%) 
exceed that of any other treatment alternative. Consequently, the leading indication 
for the use of ECT is, in fact, medication resistance (Prudic et al., 2004a, American 
Psychiatric Association, 2001). 
 
Alternatively, a large percentage of patients are treated with ECT who have not received 
an “adequate” medication trial during the current episode. There are several reasons for 
this. First, a substantial percentage of patients treated with ECT have psychotic features, 
i.e., psychotic or delusional depression. Adequate pharmacotherapy in this subgroup 
requires combined treatment with an antidepressant and an antipsychotic medication 
(Spiker et al., 1985, Nelson and Bowers, 1978, Glassman and Roose, 1981, Sackeim, 2001). 
Prior to the widespread use of atypical antipsychotics, it was unusual for delusional 
patients to receive sufficient dosage for these combined trials to be considered 
adequate. For example, using the ATHF criteria for this condition, Mulsant et al. (1997) 
reported that only 4% of patients with psychotic depression treated at three different 
hospitals had an adequate medication trial prior to ECT. While this rate has gone up 
substantially in recent years due to better tolerability of some atypical antipsychotics, this 
rate was still only 25% in the psychotically-depressed patients represented in our recent 
study of ECT in community settings (Prudic et al., 2004a).  
 
Besides issues of tolerability, there are other reasons for primary use of ECT (in the 
absence of prior medication failure in the current episode). These issues include a 
history of poor medication response and good ECT response in prior episodes, 
urgency for rapid remission due to psychiatric (suicidality) or medical (inanition) 
reasons, and patient preference. The American Psychiatric Association Task Force 
on ECT (APA, 2001) detailed the circumstances when ECT should be considered as a 
primary (first-line) treatment and when it should be reserved for patients with 
established medication resistance. These considerations will guide patient selection 
in this protocol and the rationale for use of FEAST will be documented. 

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A factor strongly related to medication resistance is episode duration. Patients with 
more chronic episodes (longer duration) tend to have poorer outcome with ECT 
(Nobler and Sackeim, 1996). When both medication resistance and episode duration 
are considered simultaneously they make independent statistical contributions to 
outcome prediction. Age also has shown consistent relations [see (Sackeim, 2004b) for 
a review]. Surprisingly, the majority of studies have found a positive association 
between advancing age and ECT outcome, one of the few instances in medicine where 
older patients have superior outcome. Due to problems of medication tolerance with 
advanced age and the toll of severe episodes of depression, ECT is particularly likely to 
be recommended in older individuals (Olfson et al., 1998, Thompson et al., 1994).  
 
Patients with psychotic depression tend to have superior outcome with ECT than 
nonpsychotic patients (Petrides et al., 2001, Birkenhager et al., 2003), but this 
distinction is likely reflects the low level of medication resistance seen in psychotic 
depression (Prudic et al., 1990, Prudic et al., 1996). Otherwise, none of the 
phenomenological features of major depression show a consistent relationship, 
even at the statistical level, with ECT outcome. For example, severity of depressive 
symptoms, the presence of double-depression, or the presence (or absence) of 
melancholia do not have predictive value (Nobler and Sackeim, 1996, Prudic et al., 
1993, Sackeim and Rush, 1995, Fink et al., 2007). There is some evidence that 
patients with borderline personality disorder may have poorer outcomes, especially 
in the long-term (DeBattista and Mueller, 2001, Feske et al., 2004, Flint and Hill-
Johnes, 2008, Kramer, 1982, Ostergaard et al., 2014), but these effects are too weak 
to consider the presence of this disorder exclusionary. There are no biological tests 
that reliably predict ECT outcome (Scott, 1989, Nobler and Sackeim, 1996). 
C. Adverse Effects of ECT 
C.1 Mortality 
Rates of mortality attributable to ECT are difficult to determine due to 
methodological issues intrinsic to studies of medical mortality, such as uncertainty 
as to cause of death, the time frame for linking death to ECT, and variability in 
reporting requirements. The mortality rate associated with ECT is thought to be 
about the same as that associated with minor surgery (McCabe, 1985, Badrinath et 
al., 1995, Warner et al., 1993, Jan et al., 2005, Schwandner et al., 2005, Yip et al., 
2004) or childbirth (Salanave et al., 1999). Published estimates from large and 
diverse patient series over several decades report up to 4 deaths per 100,000 

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treatments (Heshe and Roeder, 1976, Fink, 1979, Babigian and Guttmacher, 1984, 
Crowe, 1984, Kramer, 1985, Abrams, 1997, Reid et al., 1998, Nuttall et al., 2004, 
Shiwach et al., 2001, Prudic and Sackeim, 1999, Ostergaard et al., 2014). Despite the 
frequent use of ECT in patients with significant medical complications (Zielinski et 
al., 1993) and in the elderly (Sackeim, 1998, Sackeim, 2004b), the mortality rate 
appears to have decreased in recent years.  
 
A reasonable current estimate is that the rate of ECT-related mortality is 1 per 
10,000 patients or 1 per 80,000 treatments (American Psychiatric Association, 2001). 
This rate may be higher in patients with severe medical conditions. The rate of 
significant morbidity and mortality is believed to be lower with ECT than with some 
types of antidepressant medication (e.g., TCAs) (Glassman et al., 1993, Roose et al., 
1998a, Zielinski et al., 1993). There is also evidence from longitudinal follow-up 
studies that mortality rates following hospitalization are lower among depressed 
patients who received ECT than among patients who received other treatment 
modalities or no treatment (Avery and Winokur, 1976, Philibert et al., 1995), 
although there is also a negative report (Black et al., 1989).  
 
Our FEAST research originated at Columbia University. Dr. Lothar Kalinowsky 
introduced ECT to the US at the Department of Biological Psychiatry, New York 
State Psychiatric Institute in September 1940. There has been no known death 
linked to ECT over this 75-year period at NYSPI. During a significant part of this 
time, NYSPI had a specialized unit for patients with serious cardiac illness and major 
depression. This unit, directed by Drs. Glassman and Roose, identified the cardiac 
effects of TCAs and SSRIs (Glassman et al., 1993, Roose et al., 1994, Roose et al., 
1998b, Roose et al., 1981), and large numbers of medication intolerant and resistant 
patients with significant cardiac disease were referred to ECT with few complications 
(Zielinski et al., 1993). 
C.2 Serious Medical Complications 
When mortality occurs with ECT, it typically happens immediately following the 
seizure or during the postictal recovery period. Cardiovascular and pulmonary 
complications are the leading cause of death and of significant morbidity (Pitts, 
1982, Burke et al., 1987, Welch and Drop, 1989, Zielinski et al., 1993, Rice et al., 1994, 
Rayburn, 1997, Nuttall et al., 2004). Despite the short-lived increases in cerebral 
blood flow and intracranial pressure, cerebrovascular complications are notably rare 
(Hsiao et al., 1987). Given that cardiac arrhythmias are common in the immediate 

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postictal period, the majority of which are benign and resolve spontaneously, it is 
important that ECG be monitored during and immediately following the procedure 
and that significant arrhythmias resolve before patients are taken to the recovery 
area. Furthermore, vital signs (pulse, systolic and diastolic pressure) should be stable 
before the patient leaves the recovery area. Patients with pre-existing cardiac illness 
are at greater risk for post-ECT cardiac complications (Prudic et al., 1987, Zielinski et 
al., 1993, Rice et al., 1994). Indeed, there is evidence that the type of pre-existing 
cardiac disease predicts the type of complication that may be encountered 
following ECT. For example, ventricular arrhythmias are more common in patients 
with pre-existing ventricular abnormalities than in patients with ischemic heart 
disease (Zielinski et al., 1993). There are hosts of treatments available to manage 
emergent cardiac complications and for prophylaxis (American Psychiatric 
Association, 2001, Saito, 2005, Saito et al., 2000). 
 
Two other possible sources of morbidity are prolonged seizures (seizures lasting 
longer than 3 minutes) and status epilepticus (continuous seizure activity lasting 
longer than 30 minutes or longer or two or more seizures occurring without return of 
consciousness between seizure activity) (Engel, 1989, Epilepticus, 1993). While there 
are no firm data on the frequency of these events in patients receiving ECT, it is clear 
that they are very rare occurrences. Failure to terminate seizures within a period of 3 
to 5 minutes may increase postictal confusion and amnesia. Inadequate oxygenation 
during prolonged seizures increases the risk of hypoxia and cerebral dysfunction, as 
well as cardiovascular complications. In animal studies, seizure activity that is 
sustained for periods exceeding 30-60 minutes is associated with an increased risk of 
structural brain damage and cardiovascular and cardiopulmonary complications, 
regardless of steps taken to maintain appropriate levels of blood gases (Meldrum et 
al., 1974, Meldrum, 1986, Post et al., 1984, Nevander et al., 1985, Siesjö et al., 1986, 
Ingvar, 1986, Devanand et al., 1994, Dwork et al., 2004). 
 
Prolonged seizures and status epilepticus may be more likely in patients with pre-
existing neurological disorders and those receiving medications or having medical 
conditions that lower seizure threshold or interfere with seizure termination. These 
include theophylline, even at therapeutic levels (Peters et al., 1984, Devanand et al., 
1988a, Fink and Sackeim, 1998), pre-existing electrolyte imbalance (Finlayson et al., 
1989), and the repeated induction of seizures within the same treatment session 
(i.e., multiple monitored ECT) (Strain and Bidder, 1971, Maletzky, 1981). The American 
Psychiatric Association Task Force on ECT (2001) discouraged the practice of 

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multiple monitored ECT, which involved eliciting as many as 6 seizures in the same 
session. With this practice, seizure duration increases with repeat seizures, probably 
reflecting dissipation of the inhibitory mechanisms responsible for seizure 
termination (Sackeim et al., 1983b, Sackeim et al., 1987c, Sackeim, 1999, Sackeim, 
2004a), and increasing the potential for prolonged seizures or status epilepticus. 
 
Nonconvulsive status epilepticus may also occur during the postictal or interictal 
period, with an abrupt onset of delirium, unresponsiveness, and/or agitation as 
distinguishing clinical features (Grogan et al., 1995, Parker et al., 2001). Cessation of 
EEG abnormalities and improved cognitive function following short-acting 
anticonvulsant treatment (e.g., intravenous lorazepam or diazepam) may prove 
diagnostic, and this condition may worsen with use of high potency antipsychotics 
(American Psychiatric Association, 2001). 
 
The concern has been raised that the rate of seizure disorder is increased following 
the course of ECT (Assael et al., 1967, Devinsky and Duchowny, 1983). However, 
follow-up studies indicate that new onset of a seizure disorder following receipt of 
ECT is very rare and probably do not differ from population base rates (Blackwood 
et al., 1980, Small et al., 1981). Indeed, due to its pronounced anticonvulsant 
properties, ECT has been used with some frequency as a last resort treatment for 
patients with intractable seizure disorder (e.g., idiopathic generalized seizures) 
(Sackeim et al., 1983b, Griesemer et al., 1997) and patients in status epilepticus 
(Lisanby et al., 2001a, Kellner and Fink, 2009, Kamel et al., 2009). 
 
Prolonged postictal apnea is a rare event that occurs primarily in patients who have 
slow metabolism of succinylcholine (Packman et al., 1978). Maintaining adequate 
oxygenation is critical in such instances, which invariably resolve spontaneously within 
10 to 60 minutes. To establish etiology, it is helpful to obtain a dibucaine number 
assay or a pseudocholinesterase level before the next treatment. At subsequent 
treatments, either a very low dose of succinylcholine may be used or a 
non-depolarizing muscle relaxant, such as atracurium, may be substituted (Hickey et 
al., 1987, Hickey, 1987, Hicks, 1987, Stack et al., 1988, Kramer and Afrasiabi, 1991, Lui et 
al., 1993-, Corominas et al., 1989). 
 
Another rare complication is the experience of being partially consciousness while 
paralyzed. This phenomenon is frightening and results from an insufficient dose of 
the anesthetic agent or an insufficient interval between administration of the 

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anesthetic and muscle relaxant. For this reason, it is preferable to establish onset of 
the anesthetic effect before administering the muscle relaxant. It is noteworthy that 
with the use of improved forms of ECT that result in rapid return of consciousness 
and orientation following seizure termination, such as administration of RUL ECT 
with an ultrabrief pulse width (<0.5 ms), the risk of such an event has increased, as 
patients awaken much more rapidly than in the past with clear consciousness. It is 
clear from our observations that FEAST shares the property of rapid reorientation. 
Anesthetic management will be carefully monitored, and especially if convulsive 
manifestations are absent or weak, reduced doses of succinylcholine will be used or 
an additional bolus of anesthetic may be administered to ensure unconsciousness 
throughout the period of respiratory paralysis. While such an event does not place 
the patient at medical risk, as they are being continuously ventilated, the 
psychological state is aversive, warranting consideration of such an event as a 
serious medical complication. 
 
To a significant extent, medical adverse events can be anticipated. Patients with 
significant pre-existing cardiac illness, compromised pulmonary status, history of CNS 
insult, or other compromising medical conditions, and those with a prior history of 
serious complications following general anesthesia or ECT are especially likely to be 
at increased risk (American Psychiatric Association, 2001, Zielinski et al., 1993). The 
steps taken in this protocol to minimize risks are discussed in Section IV.C. 
 
C.3 Systemic Side Effects 
Headache is a common side effect of ECT, and is observed in as many as 45% of 
patients during and shortly following the postictal recovery period (Devanand et al., 
1995a, Freeman and Kendel, 1980, Gomez, 1975, Sackeim et al., 1987e, Tubi et al., 
1993, Weiner et al., 1994, Dinwiddie et al., 2009). However, the precise incidence of 
post-ECT headache is difficult to determine due to methodological issues. These 
include the high baseline (pre-ECT) occurrence in patients with depression, the 
potential effects of concurrent medication or medication withdrawal, and 
differences in headache assessment across studies. Post-ECT headache appears to 
be especially common in younger patients (Devanand et al., 1995a). It is not known 
whether pre-existing headache syndromes (e.g., migraine) increase the risk of post-
ECT headache, but it is clear that ECT may exacerbate a previous headache 
condition (Weiner et al., 1994). The occurrence of post-ECT headache has not been 
found related to stimulus electrode placement (Fleminger et al., 1970, Sackeim et al., 
1987e, Tubi et al., 1993, Devanand et al., 1995a), stimulus dosage (Devanand et al., 

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1995a), or therapeutic response (Sackeim et al., 1987e, Devanand et al., 1995a). In 
most patients, the post-ECT headache is mild (Freeman and Kendel, 1980, Sackeim 
et al., 1987e), although some patients report severe pain associated with nausea and 
vomiting. Typically the headache is frontal in location with a throbbing character. 
 
The etiology of post-ECT headache is uncertain. Its throbbing character suggests a 
similarity to vascular headache, and ECT may be associated with a temporary 
change in headache quality from muscle-contraction type to vascular type (Weiner 
et al., 1994, Weinstein, 1993). ECT upregulates 5-HT2 receptors and 5-HT2 receptor 
sensitization has been associated with development of vascular headache. Other 
suggested mechanisms include electrically-induced temporalis muscle spasm or the 
acute increase in blood pressure and cerebral blood flow (American Psychiatric 
Association, 2001, Abrams, 2002). It is also possible that nitrates used to control 
blood pressure during ECT contribute to post-ECT headache (Cleophas et al., 1996, 
Tassorelli et al., 1999). 
 
Treatment of post-ECT headache is symptomatic. Typically, aspirin, acetaminophen, 
or non-steroidal anti-inflammatory drugs (NSAIDs) are highly effective, particularly 
if given promptly after the onset of pain (Hawken et al., 2001, Markowitz et al., 2001, 
Leung et al., 2003, Roth, 2004, Drew et al., 2005, Stead and Josephs, 2005). 
Sumatriptan, a serotonin 5HT1D receptor agonist, has also been effective at doses of 
6 mg subcutaneously (DeBattista and Mueller, 1995), 25-100 mg orally (Fantz et al., 
1998) or 20 mg intranasally (Markowitz et al., 2001, White et al., 2006). Most patients 
also benefit from bed rest in a quiet, darkened environment. 
 
Post-ECT headache may occur after any ECT treatment in a course, irrespective of 
its occurrence at any prior treatment. Patients who experience frequent post-ECT 
headache may benefit from prophylactic treatment, such as aspirin, acetaminophen, 
or NSAIDs (e.g., IV ketorolac) immediately after seizure induction, or immediately 
prior to the ECT treatment. In a patient with severe, resistant post-ECT headache, 
subcutaneous sumatriptan 6 mg given several minutes prior to ECT was found to 
provide effective prophylaxis (DeBattista and Mueller, 1995). 
 
Some patients report general muscle soreness following ECT. These complaints are 
most common after the first treatment, and often are not reported subsequently. 
Muscle soreness due to strong fasciculations following administration of a 
depolarizing muscle relaxant (succinylcholine) can be reduced at subsequent 

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treatments by blocking the fasciculations with a nondepolarizing agent, such as a 
small dose of curare. Alternatively, muscle soreness due to excessively vigorous 
convulsive movements can be managed by increasing the dose of the muscle 
relaxant. In either case, muscle soreness can be treated symptomatically with 
analgesic agents, such as aspirin, acetaminophen, or NSAIDs. 
 
The ECT stimulus results in direct stimulation of the pterygoid, masseter, and 
temporalis muscles. This action produces a clamping action of the jaw that is not 
attenuated by the muscle relaxant (Minneman, 1995). Firm pressure, ensuring 
closure of the teeth around the bite-block, may minimize jaw pain. Such pain can 
be treated with aspirin, acetaminophen, or NSAIDs. 
 
This clamping action of the jaw as a direct result of the electrical stimulus is responsible 
for the occasional dental complications. The greatest force is exerted on the molars 
and, with rare exception, a bite block that is constructed to absorb this force over these 
teeth should be inserted prior to electrical stimulation. In most cases, dentures should 
be removed prior to the start of treatment and before the insertion of the bite block. A 
dental consultation is advisable in patients with poor dentition and especially teeth 
vulnerable to fracture or loss (Morris et al., 2002, Faber, 1983, McCall et al., 1992, 
Weiner and McCall, 1992). 
 
Estimates of the prevalence of nausea following ECT vary from 1.4-23% of patients 
(Gomez, 1975, Sackeim et al., 1987e), but, as with headache, methodological issues 
make determination of the rate problematic. Nausea can occur secondary to 
headache or its treatment with narcotics. It may also occur as a side effect of 
anesthesia, withdrawal or institution of psychotropic medications, or through other 
mechanisms. When nausea accompanies headache, the primary treatment should 
focus on the relief of headache. Otherwise, post-ECT nausea is typically well 
controlled with dopamine-blocking agents, such as phenothiazine derivatives (e.g., 
prochlorperazine 
and 
others), 
butyrophenones 
(haloperidol, 
droperidol), 
trimethabenzamide, or metoclopramide (Cook et al., 2000). All of these agents have 
the potential to cause hypotension and motoric side effects, and may lower seizure 
threshold. If nausea does not respond to these treatments or if side effects are 
problematic, the serotonin 5HT3 receptor antagonists, ondansetron or dolasetron, 
may be useful alternatives. If nausea routinely follows the use of a particular 
anesthetic, an alternative anesthetic agent may be considered.  

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C.4 Psychiatric Complications 
At one or more treatments, a minority of patients, perhaps on the order of 5%, 
develop a postictal delirium or excitement (Devanand et al., 1989, Sackeim et al., 
1983a). This state is characterized by motor agitation, disorientation, and poor 
response to commands. For some patients, postictal delirium may occur at one or 
two treatments and never recur, or it may be manifested at all treatments. Recovery 
may take from 5 to 45 minutes, and patients are usually amnestic for the episode. 
Postictal delirium may result in physical injury if the patient thrashes against hard 
objects or injury to staff attempting to protect the patient. In addition, patients may 
dislodge the intravenous line, complicating management. Depending upon severity, 
postictal 
delirium 
may 
be 
managed 
supportively 
or 
pharmacologically. 
Pharmacological prophylaxis should be considered for patients who repeatedly 
manifest postictal delirium and usually involve administration of a rapidly acting 
benzodiazepine (midazolam, lorazepam) or administration of the anesthetic used in 
ECT (often at half the original dose). It has also been suggested that increasing the 
dose of succinylcholine can prevent postictal delirium (Swartz, 1990).There is no 
indication that methods of ECT administration (e.g., electrode placement, dosage, 
etc.) differ in likelihood of postictal delirium and this state is also commonly seen with 
emergence from general anesthesia outside the context of ECT. 
 
All known antidepressant pharmacological treatments have the potential of producing a 
switch into hypomania or mania in patients presenting with depression or a mixed state. 
Such a switch may also occur with ECT (Devanand et al., 1988b, Andrade et al., 1988, 
Andrade et al., 1990, Angst et al., 1992, Devanand et al., 1992, Saatcioglu and Guduk, 
2009). However, this phenomenon appears to be rare with ECT (Devanand et al., 1992), 
perhaps because ECT is one of the few treatments that is effective in both the treatment 
of depression and mania (Mukherjee et al., 1994, Mohan et al., 2009). When it is 
manifested, it almost invariably occurs in patients with bipolar disorder. In some 
patients, the severity of manic symptoms may worsen with further ECT treatments. In 
such cases, it is important to distinguish treatment emergent manic symptoms from 
delirium with euphoria (organic euphoria) (Devanand et al., 1988b). There are a number 
of phenomenological similarities between the two conditions. However, in delirium with 
euphoria, patients are typically confused and have pronounced memory disturbance. 
The confusion or disorientation should be continuously present and evident from the 
period immediately following the treatment. In contrast, hypomanic or manic 
symptomatology may occur in the context of a clear sensorium. In addition, states of 
delirium with euphoria are often characterized by a giddiness in mood or "carefree" 

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disposition, whereas the classical 
features 
of 
hypomania, 
racing 
thoughts, 
hypersexuality, irritability, etc., may be absent. In delirium with euphoria, resolution of 
the condition may be facilitated by increasing the time between treatments, decreasing 
the stimulus intensity, changing from bilateral to unilateral electrode placement, and 
switching to an ultrabrief pulse width.  
 
Various approaches can be used in the context of emergent hypomania or mania. 
Some practitioners continue with ECT with the view that the treatment will address 
both residual depressive symptoms and the emergent hypomania. Others may 
follow the same strategy but add a mood stabilizer (other than lithium). Still others 
may stop ECT and observe the patient. Often with this strategy the hypomanic or 
manic symptoms resolve spontaneously and depressive symptoms may or may not 
return (American Psychiatric Association, 2001).  
 
There is no evidence that ECT worsens depressive symptoms or results in an 
increase in suicidality or aggressivity in even a small number of patients. For 
example, in the recent large prospective study of ECT in community settings, Prudic 
et al. (2004) found that non-remitters to ECT (defined as HRSD > 10 after 
termination of the acute course) showed on average a 33% improvement in HRSD 
scores that was maintained over a period of 6 months. Critically, of the 347 patients 
evaluated before and after ECT, only 3 (0.9%) individuals had an increase in HRSD 
scores > 4 points, and one of these patients received only 2 ECT treatments and 
another only 4 treatments. Thus, worsening of depressive symptoms is extremely 
unlikely. While there is no evidence that ECT exerts long-term benefit in reducing 
suicide rates (Prudic and Sackeim, 1999), suicidality is one of the symptoms to show 
the most robust and earliest improvement (Prudic et al., 1989-, Kellner et al., 2005). 
C.5 Objective Cognitive Side Effects 
The cognitive side effects of ECT and its potential for relapse are the major factors 
limiting its use. The neuropsychological accompaniments and sequelae of ECT have 
been the subject of intense investigation since the 1940’s (Janis, 1948, Janis and 
Astrachan, 1951, Zubin, 1948, Zubin and Barrera, 1941, Daniel and Crovitz, 1986, Daniel 
and Crovitz, 1983b, Daniel and Crovitz, 1983a, Daniel et al., 1985, Daniel et al., 1983, 
Daniel and Crovitz, 1982, Calev et al., 1991a, Calev et al., 1989, Calev et al., 1991b, 
Zervas et al., 1993, Lerer et al., 1995, Calev, 1994, Calev et al., 1995, Shapira et al., 1998, 
Frith et al., 1987, Frith et al., 1983, Lancaster et al., 1958, Kriss et al., 1978, Pratt et al., 
1971, Warrington and Pratt, 1973, Cronholm and Ottoson, 1963, Mindus et al., 1975, 

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Cronholm and Ottosson, 1963b, Cronholm and Molander, 1957, Cronholm and 
Ottosson, 1963a, Cronholm and Ottosson, 1961, d'Elia, 1981, d'Elia et al., 1977, d'Elia et 
al., 1976, d'Elia and Raotma, 1977, d'Elia, 1976, d'Elia, 1970, Fromholt et al., 1973, 
Strömgren et al., 1976, Shimamura and Squire, 1987, Squire, 1986b, Weiner et al., 
1986, Squire et al., 1984, Squire and Slater, 1983, Spanis and Squire, 1981, Cohen and 
Squire, 1981, Squire et al., 1981a, Squire et al., 1981b, Squire and Chace, 1975, Squire et 
al., 1976a, Squire and Cohen, 1979, Squire and Miller, 1974, Squire et al., 1976b, Squire 
and Slater, 1978, Squire et al., 1976c, Squire et al., 1978, Squire et al., 1979).  
 
A particular focus of the ECT research at NYSPI has been better characterizing these 
cognitive adverse effects, determining their severity and persistence, and identifying 
the patient characteristics that predict vulnerability, and developing treatment 
techniques that can lead to their reduction, if not complete amelioration (Sackeim et 
al., 2000a, Sackeim, 1992, Sackeim et al., 1987c, Steif et al., 1986, Sackeim, 1986a, 
Sackeim et al., 1986, Sackeim et al., 1983c, Devanand et al., 1991, Sackeim et al., 1992a, 
Sackeim et al., 1991, Sackeim et al., 1992b, Prudic et al., 1994, McElhiney et al., 1995, 
Perera et al., 2004, Sackeim, 2004a, Moscrip et al., 2005, Sobin et al., 1995b, Coleman 
et al., 1996, Prudic et al., 1999, Sackeim, 2000, Sackeim et al., 1993, Lisanby et al., 2000, 
McCall et al., 2000, Sackeim et al., 2000b, Sackeim et al., 2007, Sackeim et al., 2008, 
Berman et al., 2008, Sackeim et al., 2009, Sackeim, 2014b, Sackeim, 2014c). 
 
There are four central features to the cognitive side effects of ECT (Sackeim, 1992). 
First, both the nature and severity of cognitive alterations change rapidly with time 
since the last treatment. The most severe cognitive side effects and the broadest 
range of impairment are observed in the immediate postictal period. Following 
seizure induction, patients experience a variable period of disorientation, with 
impairments in attention, language, praxis, and memory (Sackeim, 1986a). Indeed, 
the most profound deficits are seen as soon as patients can be evaluated with the 
return of spontaneous respiration and the capacity to respond to oral command. At 
this time, as with recovery from spontaneous seizures (Trimble and Thompson, 
1986), soft neurological signs may be evident and there may be gross disturbance in 
attention and language abilities, in concert with clouded consciousness (Kriss et al., 
1978, Kriss et al., 1980, Pratt and Warrington, 1972, Warrington and Pratt, 1973). 
Within minutes, neurological signs remit and there is dramatic improvement in 
orientation. Indeed, it is common in the immediate postictal period to observe 
patients progressively “return to the present,” stating that they are far younger than 
their true age, speaking perhaps only their first language, and steadily “aging” over 

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a period of minutes, as if a deep, temporally graded retrograde amnesia was rapidly 
lifting (Daniel and Crovitz, 1982, Daniel et al., 1987, Sobin et al., 1995b).  
 
This pattern pertains generally to the cognitive sequelae of ECT, which differ in their 
rates of recovery (e.g., anterograde vs. retrograde amnesia) (Squire and Miller, 1974, 
Squire and Chace, 1975, Squire, 1975, Squire et al., 1981b, Sackeim, 1992). 
Consequently, the magnitude of deficits observed during the course of ECT will be a 
function, in part, of the time of assessment relative to the last treatment, the number 
of treatments received, and the temporal dynamics of the cognitive function, as well 
as individual difference factors (Daniel and Crovitz, 1983b, Daniel and Crovitz, 1983a, 
Lerer et al., 1995, Squire and Zola-Morgan, 1985). In general, when treatments are 
applied that result in more profound cognitive deficits, such as sine wave stimulation 
and/or the use of the bilateral electrode placement, recovery may be incomplete by 
the next treatment. In such a circumstance, a pattern of progressive deterioration can 
be documented, with neuropsychological functioning deteriorating over the treatment 
course (Daniel and Crovitz, 1982, Daniel and Crovitz, 1983b, Daniel and Crovitz, 1983a). 
In the most extreme cases, the period of disorientation will become longer following 
each treatment and a continuous delirium can be produced (Summers et al., 1979, 
Miller et al., 1986). In contrast, when “softer” forms of ECT are applied the opposite 
can occur. For example, the period of disorientation in the postictal period is 
progressively briefer when low dosage, RUL ECT is applied (Sackeim et al., 1986). The 
reasons given for this counterintuitive phenomenon are that the combination of low 
dosage and RUL electrode placement minimizes untoward effects on orientation 
recovery and, critically, under these conditions, seizure duration has a significant 
association with time to orientation recovery (Sackeim et al., 1987c). Seizures are 
progressively shorter in duration over the course of ECT, reflecting one of ECT’s 
anticonvulsant properties (Sackeim, 1999). This same progressive improvement in 
speed of orientation recovery has been especially marked with the use of RUL ECT 
and ultra-brief pulse width stimulation, even though dosage was substantially 
suprathreshold in order to preserve efficacy (Sackeim, 2004a, Sackeim et al., 2008). 
 
The second general feature is that the methods used in ECT administration 
profoundly impact on the nature and magnitude of cognitive deficits. For example, 
to use the example described above, ECT treatment technique is a major 
determinant of the percentage of patients that develop delirium, characterized by 
continuous disorientation (Miller et al., 1986, Daniel and Crovitz, 1986, Sackeim et al., 
1986, Sackeim et al., 1993, Sackeim et al., 2000b, Sackeim, 2004a). In general, 

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bilateral electrode placement, sine wave stimulation, high electrical dosage relative 
to seizure threshold, use of a wide pulse width, closely spaced treatments, larger 
numbers of treatments, and high dosage of barbiturate anesthetic agents are each 
independently associated with more intense cognitive side effects compared to right 
unilateral electrode placement, brief pulse waveform, lower electrical intensity, use of 
an ultrabrief pulse width, more widely spaced treatments, fewer treatments, and 
lower dosage of barbiturate anesthesia (Miller et al., 1985, Sackeim et al., 1986, 
Sackeim et al., 1993, Sackeim et al., 2000b, Sackeim, 2004a, Weiner et al., 1986, Lerer 
et al., 1995, Shapira et al., 2000, McElhiney et al., 1995, Sackeim et al., 1992a, 
Lancaster et al., 1958, Squire and Zouzounis, 1986, Sackeim et al., 2007, Sackeim et 
al., 2008, Sackeim et al., 2009, Sackeim, 2014b). Optimization of these parameters 
minimizes short‑term cognitive side effects and likely reduces the magnitude of 
long-term changes (Sobin et al., 1995b, Sackeim, 2014b, Sackeim et al., 2007).  
 
Scores of controlled, small sample studies have documented the effects of treatment 
parameters on the short-term cognitive effects of ECT [see (Sackeim, 1992) for a 
review]. In contrast, the follow-up period has rarely been longer than 2 months and 
the sample sizes have most often been too small to detect persistent deficits. Indeed, 
there has been only one modern large scale, prospective study of the nature and 
long-term persistence of ECT’s cognitive effects. Prudic et al. (Prudic et al., 2004a) 
followed 347 patients treated with ECT at 7 different hospitals in the NYC 
metropolitan area. The sample was administered a neuropsychological battery at 
preECT baseline, following the acute ECT treatment course (mean=4 days postECT), 
and, again, 6 months later. The 7 hospitals differed in a host of cognitive outcome 
measures at the postECT time point and in Mini-Mental State Exam scores (a measure 
of global cognitive status) and retrograde amnesia scores (for autobiographical 
information) at the six-month time point (Sackeim et al., 2007). At both time points 
the differences among the hospitals in cognitive outcomes was fully attributable to 
differences in treatment technique. In particular, the use of sine wave stimulation 
resulted in a marked deficit on reaction time tasks, with this deficit persistent at 6 
months for 2 of 3 measures. The use of bilateral ECT was associated with greater 
retrograde amnesia at both time points (relative to right unilateral ECT), and this effect 
was linearly related to the number of bilateral ECT treatments. These findings 
indicated that the effects of electrode placement and stimulus waveform could be 
detected six months following the termination of ECT. In general, especially with 
respect to retrograde amnesia, deficits observed this long after ECT termination are 

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not expected to reverse. Thus, this study provided the first definitive evidence of 
persistent cognitive impairment resulting as a function of variation in ECT technique.  
 
In a recently completed study at NYSPI, patients were randomized to RUL ECT at 6 
times initial seizure threshold or BL ECT at 2.5 times initials seizure threshold. In 
addition, the groups were also randomized to use of a traditional wide pulse width 
(1.5 ms) or use of an ultra-brief pulse width (0.3 ms) (Sackeim, 2004a, Sackeim et al., 
2008). There were marked advantages for the ultra-brief pulse width in acute, short-
term and long-term cognitive outcomes. For example, a normal comparison group, 
comprised of individuals with negative psychiatric and neurological histories, 
matched to the patient sample in age, gender, education, and verbal IQ, was 
administered the same neuropsychological battery at the same time interval as given 
to patients. The Columbia University Autobiographical Memory Interview (AMI) is 
extremely sensitive to the amnestic effects of ECT in producing forgetting for past 
autobiographical events (McElhiney et al., 1995, Sackeim et al., 1993, Sobin et al., 
1995b, Lisanby and Sackeim, 2000, Sackeim et al., 2000b). Patients treated with RUL 
ultrabrief ECT did not differ from the normal comparison group in amnesia scores 
when tested a few days (mean=4 days) following the ECT course. This outcome was 
striking. In contrast, the BL ultra-brief group had a significant deficit, but was superior 
to the RUL wide pulse width group, who in turn were superior to the BL wide pulse 
width group. At the short-term time point, the deficit in the BL wide pulse width 
group was equivalent to a reduction (relative to controls and RUL ultra-brief ECT) of 
approximately 1.5 SD. This pattern was also maintained at reassessment 6 months 
following the end of ECT. Thus, these new findings suggest that some forms of ECT 
result in persistent impairment, especially in the area of retrograde amnesia, but that 
some innovations in ECT technique may minimize such deficits. The use of ultra-brief 
stimulation and the right unilateral electrode placement appears to retain efficacy 
and yet lead to the least degree of impairment. The ultimate goal of the research 
proposed in this application is to determine whether an additional modification, the 
use of FEAST to produce greater focality of stimulation, is of further benefit in 
protecting patient from adverse cognitive effects. 
 
The third general feature is that patients vary considerably in the extent and severity 
of cognitive side effects following ECT. There has been limited investigation of the 
factors that contribute to these individual differences. Among depressed patients 
without known neurological disease or insult, there is evidence that the extent of pre-
ECT global cognitive impairment, i.e., Mini-Mental State Exam (MMSE) scores, 

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predicts the magnitude of retrograde amnesia for autobiographical information at 
long-term follow-up. In these patients, ECT typically results in improved global 
cognitive status, as a function of symptomatic response. Nonetheless, these same 
patients may have greater persistent amnesia for personal memories (Sobin et al., 
1995b). Similarly, there is evidence that the duration of disorientation immediately 
following the ECT treatment is an independent predictor of the magnitude of 
retrograde amnesia for autobiographical information. Patients who require 
prolonged periods to recover orientation may be at greater risk for more profound 
and persistent retrograde amnesia (Sobin et al., 1995b). Patients with pre-existing 
neurological disease or insult (e.g., Alzheimer’s disease, Parkinson’s disease, stroke) 
may also be at increased risk for ECT-induced delirium and memory deficits (Figiel et 
al., 1991, Mulsant et al., 1991-). Magnetic resonance imaging (MRI) findings of basal 
ganglia lesions and severe white matter hyperintensities have also been linked to the 
development of an ECT-induced delirium (Figiel et al., 1990). Some medications may 
exacerbate ECT-induced cognitive side effects. These include lithium carbonate (Small 
et al., 1980, Weiner et al., 1980), and medications with marked anticholinergic 
properties, particularly in elderly patients. 
 
It has long been thought that age is a risk factor for greater adverse cognitive 
effects, although the evidence for this has been relatively weak (Zervas et al., 1993, 
Stoudemire et al., 1991, Mulsant et al., 1991-) [see Sackeim (2004b) for a review]. In 
the study of ECT in community settings (Prudic et al., 2004a, Sackeim et al., 2007), 
there were two individual difference factors that were strongly related to short- and 
long-term cognitive outcomes. Older patients generally showed greater deficits and 
those with higher premorbid IQ [assessed with the National Adult Reading Test; 
(Crawford et al., 1991)] had smaller deficits. These findings confirmed the suggestion 
that that there is great vulnerability to adverse cognitive effects with advanced age, 
and raise the possibility that higher premorbid IQ has protective effects, perhaps 
through a cognitive reserve mechanism, as seen in neurological disorders (Stern, 
2002, Legendre et al., 2003). 
 
The fourth central feature is that ECT results in highly characteristic cognitive 
changes. Across psychiatric disorders and prior to receiving ECT, many patients have 
deficits in attention and concentration that limit their capacity to learn new 
information (immediate memory) (Byrne, 1977, Pogue-Geile and Oltmanns, 1980, 
Cornblatt et al., 1984, Sackeim and Steif, 1988, Zakzanis et al., 1998, Majer et al., 2004). 
For example, patients with severe psychopathology often have deficient recall of 

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information that was just presented to them (immediate memory). In depressed 
patients, these deficits are most marked for unstructured material that requires 
effortful processing in order to impose organization (Weingartner et al., 1981, 
Weingartner et al., 1983, Weingartner and Silberman, 1984, Roy-Byrne et al., 1986, 
Burt et al., 1995, Burt et al., 2000). However, such patients are less likely to have 
deficits in retaining the new information that they do learn (delayed memory) 
(Cronholm and Ottosson, 1961, Sternberg and Jarvik, 1976, Steif et al., 1986). During 
the ECT course, deficits in attention and concentration may be accentuated (Sackeim 
et al., 1992b, Sackeim, 1992, Calev et al., 1995). In contrast, with symptomatic response 
following ECT, these deficits usually resolve. Consequently, measures of immediate 
memory are either unchanged or improved within a few days of ECT termination 
(Cronholm and Ottosson, 1961, Steif et al., 1986, Weiner et al., 1986, Rossi et al., 1990, 
Sackeim et al., 1993, Sackeim et al., 2000b, Sackeim et al., 2007).  
 
Since attention and concentration are essential to many aspects of cognitive 
function, it is not surprising that shortly following completion of the ECT course 
improvement may be observed in a wide variety of neuropsychological domains, 
including global cognitive status (Sackeim et al., 1993, Sobin et al., 1995b) and 
measures of general intelligence (IQ) (Huston and Strother, 1948, Stieper et al., 1951, 
Squire and Chace, 1975, Malloy et al., 1982, Sackeim et al., 1992a) [see (Semkovska 
and McLoughlin, 2010) for a recent meta-analysis]. There is no evidence that ECT 
results in lasting impairments of executive function (e.g., the capacity to shift mental 
sets), abstract reasoning, creativity, semantic memory, implicit memory, or skill 
acquisition or retention (Weeks et al., 1980, Frith et al., 1983, Squire et al., 1984, 
Taylor and Abrams, 1985, Abrams and Taylor, 1985, Jones et al., 1988). Indeed, the 
fundamental distinction between declarative and nondeclarative memory systems, 
as formulated by Squire, was based partly on evidence that ECT patients showed 
deficits in the retention of information consciously recalled or propositional in 
nature, while retention of procedural learning (mirror reading), classical 
conditioning, word priming, etc. was unimpaired even shortly following treatments 
(Squire, 1986a). 
 
Against this background of unchanged or improved neuropsychological performance, 
ECT selectively results in anterograde and retrograde amnesia (for declarative 
information). The anterograde amnesia is characterized by rapid forgetting of newly 
learned information (Cronholm and Ottosson, 1961, Squire, 1986b, Steif et al., 1986, 
Weiner et al., 1986, Frith et al., 1987, McElhiney et al., 1995, Sackeim, 2000, Lisanby et 

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al., 2000). As noted, compared to preECT baseline, patients tested a few days 
following ECT may recall more items from a list that was just presented. However, 
recall after a delay will often be impaired (Korin et al., 1956, Cronholm and Molander, 
1964, Squire and Miller, 1974, Squire and Chace, 1975, d'Elia et al., 1976, Robertson and 
Inglis, 1978, Steif et al., 1986, Weiner et al., 1986, Calev et al., 1989, Sackeim et al., 1993, 
Sackeim et al., 2000b, Sackeim et al., 2007). The extent and persistence of this rapid 
forgetting of newly learned information varies among patients and should be 
considered when making recommendations regarding the post-ECT convalescence 
period. Until there is substantial resolution of the anterograde amnesia, returning to 
work, making important financial or personal decisions, or driving may need to be 
restricted.  
 
 
Following the termination of ECT, the anterograde amnesia rapidly resolves. Indeed, 
no study has documented anterograde amnestic effects of ECT more than a few 
weeks following the ECT course (Strain et al., 1968, Bidder et al., 1970, Heshe et al., 
1978, Jackson, 1978, Fraser and Glass, 1980, Weeks et al., 1980, Gangadhar et al., 
1982, Frith et al., 1983, Weiner et al., 1986, Sackeim et al., 1993, Sackeim et al., 
2000b) [see (Semkovska and McLoughlin, 2010) for a recent review]. It is unlikely 
that ECT has any long-term effect on the capacity to learn and retain new 
information. 
 
Following ECT, patients also display retrograde amnesia. Deficits in recalling both 
personal (autobiographical) and public (impersonal) information are usually evident, and 
are typically greatest for events that occurred temporally closest to the treatment (Janis, 
1950, Cronholm and Molander, 1961, Strain et al., 1968, Squire and Chace, 1975, Squire, 
1975, Squire et al., 1976a, Squire et al., 1976c, Squire et al., 1981b, Weeks et al., 1980, 
Sackeim et al., 1986, Sackeim et al., 1993, McElhiney et al., 1995, Sackeim et al., 2000b, 
Sackeim et al., 2007, Sackeim, 2014b). The magnitude of the retrograde amnesia is 
greatest immediately following the treatment. A few days following the ECT course, 
memory for events in the remote past is usually intact, but there may be difficulty in 
recalling events that transpired several months to years prior to ECT. The retrograde 
amnesia over this time span is rarely complete. Rather, patients have gaps or spottiness 
in their memories of personal and public events (Donahue, 2000). Recent evidence 
suggests that the retrograde amnesia is typically greater for public information 
(knowledge of events in the world) as compared to personal information 
(autobiographic details of the patient’s life) (Lisanby et al., 2000). The emotional valence 

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of autobiographical events, i.e., memories of pleasant or distressful events, is not related 
to their likelihood of being forgotten (McElhiney et al., 1995). 
 
As time from ECT increases, there is usually a substantial reduction in the extent of 
retrograde amnesia. Older memories are more likely to be recovered earlier, if at all. 
However, the time course for this reduction in retrograde amnesia is often 
considerably more gradual than that for the resolution of anterograde amnesia. In 
many patients, the recovery from retrograde amnesia will be incomplete. While 
several authorities have contended that all the cognitive side effects of ECT are 
transient, there is now compelling evidence that ECT can result in some degree of 
persistent or permanent memory loss in some patients (Squire et al., 1981b, Weiner 
et al., 1986, McElhiney et al., 1995, Sobin et al., 1995b, Chahine et al., 2014, Sackeim 
et al., 2008, Anderson et al., 2009). In this respect, the most important evidence 
comes form the recently completed study of ECT practices in community settings, 
where the degree of retrograde amnesia six months after ECT was found to be a 
function of ECT electrode placement and number of treatments (Prudic et al., 
2004b, Sackeim et al., 2007). Indeed, there is evidence that patients’’ self-evaluation 
of the global long-term effect of ECT on their memory is associated with the extent 
of the objective autobiographical retrograde amnesia (Berman et al., 2008, 
Brakemeier et al., 2011b). Owing to a combination of anterograde and retrograde 
effects, many patients may manifest persistent loss of memory for some events that 
transpired in the interval starting several months before and extending to several 
weeks following the ECT course. There are individual differences, however, and, 
uncommonly, some patients may experience persistent amnesia extending several 
years prior to ECT (Donahue, 2000). Profound and persistent retrograde amnesia 
may be more likely in patients with pre-existing neurological impairment and 
patients who receive large numbers of treatments, using methods that accentuate 
acute cognitive side effects (e.g., sine wave stimulation, bilateral electrode 
placement). It is hoped that techniques, such as FEAST, will reduce the possibility of 
such negative outcomes.  
D. Rationale for FEAST 
Understanding of the safety of ECT has undergone substantial change. It is now 
apparent that the amnestic effects of the treatment are not always transient, and many 
patients will have some degree of permanent retrograde amnesia (Sackeim, 2000, 
Sackeim, 2014b). While for most individuals the extent of amnesia will be limited, 
patients treated with bilateral ECT, and especially when coupled with inefficient forms of 

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stimulation or excessive dosage, may experience more pronounced and persistent 
amnesia. In contrast, we have shown that right unilateral ECT, when administered with an 
ultrabrief stimulus, maintains efficacy but has marked advantages in cognitive side 
effects (Sackeim, 2004a, Sackeim et al., 2008). Indeed, with a highly sensitive measure of 
retrograde amnesia, patients receiving this modality did not differ from healthy 
comparison subjects in the amount of memory loss over the period corresponding to 
the ECT course. Thus, factors such as electrode positioning (BL vs. RUL), stimulus 
waveform (sine vs. brief pulse vs. ultra-brief pulse) and stimulus dosage relative to 
threshold have a substantial and enduring effect on the safety of the procedure. We 
hypothesize that further increasing the efficiency of the ECT stimulus, by use of 
unidirectional stimulation, will result in further reductions in cognitive side effects. 
Furthermore, increasing the focality of stimulation, and avoiding neural circuitry 
responsible for ECT’s amnestic properties, will provide additional protection. 
 
FEAST, as described in this application, differs from conventional ECT in two ways: 
electrical waveform and electrode geometry. There is no reason to believe that 
either of these factors, alone or in combination increases risk. Our experience to 
date, with 35 depressed patients (7 Columbia, 28 MUSC) having received a course 
of FEAST has confirmed this expectation. 
D.1 Unidirectional Stimulation 
The unidirectional waveform of FEAST is identical to the bidirectional stimulus of the 
marketed MECTA Spectrum 5000Q except that half the pulses are rectified. There is 
considerable experience with unidirectional stimuli in the US and abroad. For 
example, all the ECTRON ECT devices, manufactured in the UK (Mark 4, Series 2, 
Series 3, Series 5, Series 5A, Series 5B, and Series 6) deliver unidirectional stimuli, with 
the Mark 4 offering a choice of unidirectional or bidirectional stimulation (Lock, 1995). 
The Series 6 is presently marketed in the UK. A similar choice is available with the 
Neurotronic Therapy System MKII ECT device, also presently marketed in the UK by 
Sycopel Scientific Ltd. (Lock, 1995). The Siemens Konvulsator, which was 
manufactured in Germany and in widespread use especially in Scandinavian 
countries, used unidirectional partial (chopped) sine wave stimulation. In the US, from 
1940’s through 1970’s a variety of ECT devices delivered unidirectional stimulation, 
the most well documented being the Reiter devices (e.g., Reiter CW47) produced by 
Friedman and Wilcox (Epstein and Wender, 1956, Friedman, 1942, Friedman, 1949, 
Friedman, 1952, Friedman, 1953, Friedman and Wilcox, 1942, Proctor and Goodwin, 
1943, Wilcox, 1947). Indeed, Impastato, Pacella and others used unidirectional 

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stimulation with the Reiter CW47 and symmetric, round 3 cm diameter electrodes to 
deliberately produce focal seizures, much like the goal of this application. They 
demonstrated that focal seizures could be produced by, for instance, eliciting 
convulsive activity unilaterally in a limb (Blaurock et al., 1950, Impastato et al., 1953, 
Bergman et al., 1953, Pacella and Impastato, 1954). The ElCot MF-1000, marketed in 
the US by ElCot, Inc. in the late 1980’s and 1990’s had the option of delivering either 
unidirectional or bidirectional brief pulses. The currently marketed Thymatron System 
IV, by Somatics Inc., includes a unidirectional brief pulse stimulation option.  
 
Thus, there has been more than 60 years of experience with unidirectional 
stimulation in ECT, including devices marketed in the US. It had been frequently 
claimed that unidirectional stimulation results in lower seizure threshold and, thus, 
more efficient stimulation than bidirectional stimulation (Alexander, 1950, 
Alexander, 1955, Andrade et al., 2002, Epstein and Wender, 1956, Friedman, 1942, 
Friedman, 1949, Friedman, 1952, Friedman, 1953, Friedman and Wilcox, 1942, 
Liberson and Wilcox, 1945, Hovorka et al., 1960, Hyrman et al., 1985, Impastato et al., 
1951, Pacella, 1952, Proctor and Goodwin, 1943, Rappa and Tanowitz, 1959, Wilcox, 
1947, Spellman et al., 2009). While this claim has not been validated by randomized 
comparison, on neurophysiological grounds it would be anticipated that summation 
would be facilitated by unidirectional relative to bidirectional stimulation, resulting 
in greater efficiency. Further, it is established that anodal vs. cathodal stimulation 
can differ several fold in the threshold charge values that produce depolarization, 
with bidirectional stimulation at the upper end of this range (Roth, 1994, Iles, 2005, 
Rattay, 1998, Rattay, 1988, Follett and Mann, 1986). Thus, because of greater 
efficiency resulting in a net reduction in the charge administered, this component of 
FEAST should confer advantages with respect to cognitive side effects.  
 
For example, there was a dramatic reduction in the cognitive effects of ECT with the 
move from sine wave to brief pulse stimulation (Weiner, 1986). Similarly, recent data 
indicate that ultrabrief pulse stimulation results in improved safety relative to standard 
brief pulse stimulation (Sackeim, 2004a, Sackeim et al., 2008, Loo et al., 2012). Of special 
note, we have also reported that the acute cognitive side effects of magnetic seizure 
therapy (MST) are superior to that of state-of-the art ECT (Lisanby, 2002, Lisanby et al., 
2003a), although the efficacy of barely suprathreshold MST was inferior. The goal with 
FEAST is to retain the cognitive advantages of MST, through the efficiency and focality 
of stimulation, while retaining the efficacy of traditional ECT. 

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D.2 FEAST Electrodes 
Electrode shape and positioning determine the direction of current flow and the 
degree of focality (current paths) induced by FEAST. The use of a small anterior anode 
might have increased the risks if it resulted in excessive impedance (inability to deliver 
the stimulus) or elevated ST through excessively narrow current path. The 
configuration we used with primates represented an extreme test. The anterior 
electrode was very small and the inter-electrode distance was short due to the small 
size of the head (approximately 2-3"). Nonetheless, impedance was not a problem and 
in all cases dynamic impedance values were in the range obtained with conventional 
ECS in these same animals (approximately 300 ohms) and seizure threshold values 
were very low (Spellman et al., 2009).  
 
The implementation of FEAST in this proposal is conservative. The anterior electrode is 
now1.25” in diameter (increased from 0.75”). Round stainless steel electrodes with 
smaller dimensions (0.75”) were used for decades for both the anode and cathode with 
the Reiter unidirectional ultrabrief pulse ECT stimulator, which had no limit on the 
charge that could be administered (train duration was maintained indefinitely until the 
stimulus delivery button was released) (Furst and Reiter, Liberson and Wilcox, 1945, 
Summerskill et al., 1952, Pacella, 1952, Friedman, 1952, Miller et al., 1953, Pacella and 
Impastato, 1954). There was no evidence of an increase in burns with this device. 
Similarly, for decades, the standard in Europe and elsewhere has been a 1” electrode 
diameter, and this has not presented problems with respect to excessive impedance or 
burns.  
 
Nonetheless, in our first approved IDE we reduced the voltage cutoff of the device 
from 400 V to 240 V.  This was done to limit maximal current density in the case of 
excessive impedance.  As a result, impedances in excess of 300 ohms resulted in 
inability to deliver an electrical stimulus as they would exceed the 240 V cutoff (at 800 
mA constant current).  The early experience with FEAST under these conditions (Nahas 
et al., 2013a) demonstrated that we had been wrong in our expectation of low 
impedance.  Impedances were sufficiently high that passage of the electrical stimulus 
was frequently blocked.  This was unacceptable as patients were under time-limited 
general anesthesia and required treatment.  As detailed in our account of this work, we 
progressively increased the size of the circular anode (from 0.75” to 1.0” to 1.25”) as 
allowed by the IDE.  At the 1.25” diameter, we had no problems at all with impedance, 
and these values were in the range usually obtained with traditional ECT. 
Consequently, in our next iteration of the IDE we requested an increase in the voltage 

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cutoff to the value used in the commercial Spectrum 5000Q (400 V).  Since the report 
by Nahas et al. (2013), we have administered FEAST to an additional 18 patients at 
MUSC.  There have been no instances at any treatment session of burns or indeed of 
excessive impedance interfering with stimulus delivery.  In Section V.D, we provide 
current, charge, and power density values for the proposed stimulation parameters 
and electrode geometries.  
 
With respect to optimization of treatment, the key issues are the choice of sites for 
electrode positioning and the dosing strategy. In using the 1.25” diameter anterior 
electrode (as opposed to a smaller anode), the degree of focality is reduced and 
this should protect efficacy. We do not have sufficient knowledge of the functional 
neuroanatomy to justify greater focality (Nobler et al., 1994, Nobler et al., 2001, 
Seminowicz et al., 2004). Rather, at this stage, the more limited goals are to restrict 
seizure onset and expression largely to regions in the right prefrontal cortex (PFC), 
with virtually no stimulation in left PFC or left or right medial temporal lobe (MTL). 
In positioning the anode in the area of the Fp2 site in the 10/20 International EEG 
System, current density will peak broadly through the right anterior PFC. 
Furthermore, we have taken two steps to ensure that FEAST is not under-dosed. 
EEG seizures without convulsion are very rare with conventional ECT (Boylan et al., 
2001), but may be more frequent with FEAST. Research groups differ in whether or 
not motor manifestations are required in defining the seizure threshold (ST). In this 
protocol, we will note the intensity level that results in an “EEG only” seizure, but 
require that EEG seizure manifestations be clear-cut and last at least 15 s to define 
the ST value used for subsequent dosing. Second, at any point after the fifth 
treatment, a clinical evaluation team can recommend a dosage increment, up to 9 x 
ST. Thus, in this first examination of FEAST, to protect efficacy we have deliberately 
erred on the side of sacrificing the degree of focality, while also allowing some 
flexibility in dosing. With stimulation at these levels, it is very unlikely that FEAST will 
be markedly ineffective, unlike low dosage RUL ECT (Sackeim et al., 1987b, Sackeim 
et al., 1993). Rather, to determine whether there is any effect on efficacy, a 
substantial number of patients will have to be treated in a masked, randomized 
protocol (which is planned following this study). Our published data (Nahas et al., 
2013a) has demonstrated that FEAST has marked antidepressant effects. However, 
in the absence of a masked, randomized comparison with traditional ECT, 
equivalence in efficacy is unknown. This study focuses on the mechanistic issue and 
attempts to demonstrate that seizures induced by FEAST show robust 
electroencephalographic activity in frontal electrodes, but reduced activity in 

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temporal EEG leads.  The lesser involvement of medial temporal structures with the 
seizures induced by FEAST should result, in turn, in lesser amnestic effects, 
especially for autobiographical information (Sackeim et al., 2000a).  To accomplish 
this we propose to compare matched groups of patients who have elected to 
receive FEAST to non-randomized patients received regular treatment with 
ultrabrief right unilateral (UB RUL) ECT.  Since FEAST delivers an ultra-brief stimulus 
and an identical titration schedule is used in both groups, the only difference in the 
stimulation given between the groups will be the features unique to FEAST, i.e., the 
use of unidirectional stimulation and geometry and positioning of the electrodes.  
As we will carefully evaluate efficacy, this comparison will provide preliminary (but 
not definitive) data on whether efficacy is equivalent for FEAST relative to traditional 
ECT. 
 
In summary, we are confident that FEAST does not increase the risks of ECT. It is 
simply a form of ECT that is more focal and likely more efficient in seizure induction. 
We have optimized FEAST’s potential for being efficacious by limiting its degree of 
focality and ensuring that markedly suprathreshold electrical dosage can be 
administered. By using 1.25” diameter electrodes rather than the earlier 3/4” 
electrodes, we have demonstrated acceptable impedances and have had no 
instances of skin burns. 
D.3 Titrating in the Current Domain 
Another innovation was originally examined in this study. This modification was the use of 
current or pulse amplitude as the basis for titrating electrical dosage to the patient’s 
seizure threshold. As explained below, we no longer use procedures for titrating in the 
current domain as part of this study.  Our original rationale for this approach and the 
reasons we no longer include it in the procedures are explained below. 
 
The empirical titration procedure was introduced to ECT in the 1980’s by the NYSPI group 
(Malitz et al., 1982, Sackeim et al., 1987d), and has become adopted world-wide. The 
American Psychiatric Association Task Force Report on ECT noted that the method of 
limits procedure used in titration is the most precise means available to determine 
dosage (American Psychiatric Association, 2001). Farah and McCall (1993) more than a 
two decades ago conducted a survey of ECT practitioners and found that the majority 
reported routine use of titration. The titration procedure involves deliberate 
administration of subconvulsive stimuli until the convulsive threshold is reached. Prudic et 
al. (1994) demonstrated that subconvulsive stimuli that preceded convulsive stimulation 

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had no impact on the cognitive effects of ECT compared to single convulsive stimulation, 
supporting the safety of the titration procedure.  
 
Until now, it has been impossible to titrate the electrical stimulus in any parameter 
dimension other than pulse frequency or train duration. There are marked individual 
differences in ST, and the range is estimated to be at least 50-fold (keeping waveform 
constant) (Sackeim et al., 1991). Thus, any approach to titration must manipulate 
dosage over a substantial range. Of the two standard ECT devices in the US, the 
Thymatron System IV delivers a fixed 900 mA constant current, with no possibility for 
adjusting pulse amplitude. The standard MECTA Spectrum 5000Q, however,  offers a 
selectable range of 500-800 mA, partially allowing for titrating with current.  Indeed, 
our first IDE application for FEAST was approved with a modification of the MECTA 
Spectrum 5000Q broadening the range of the constant current to 100–800 mA.   
 
Why did we propose to change the titration procedure and use current as the 
principal means of dosage adjustment when quantifying seizure threshold? The 
marked individual differences in ST largely reflect differences in the extent of 
shunting of current away from brain (Sackeim et al., 1994(Peterchev et al., 2010)). Only 
a small and variable proportion of the administered current enters brain (Hayes, 1950, 
Smitt and Wegener, 1944, Weaver et al., 1976, Deng et al., 2009). For example, 
differences in skull geometry and thickness between men and women contribute to 
the large gender difference in ECT ST, whereby women require a lower electrical dose 
than men (Sackeim et al., 1987d, Sackeim et al., 1994). Thus, people differ in the 
amplitude of the current in brain (charge density per phase) when a standard pulse is 
administered transcranially. Titrating in the current domain is expected to equate 
individuals more closely in intracerebral dosage than packing more pulses into the 
same time frame (increasing frequency) or making the stimulus train longer 
(increasing duration). In other words, by compensating for differences in the degree 
of shunting away from brain, the amplitude adjustment should result in greater 
intracerebral uniformity in dosing. Indeed, the titration paradigm we used in the 
initial pilot research used the same frequency (60 Hz), pulse width (0.3 ms), and train 
duration (1 sec) across the first 4 steps of the titration schedule while varying pulse 
amplitude to titrate dosage. 
 
The increased homogeneity in intracerebral current density as a result of this approach 
to titration should (1) allow for more rigorous comparison of the effects of treatment 
and patient variables, by reducing extraneous individual differences and (2) improve 

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safety. The amplitude of the pulse is a key factor in neuronal depolarization and it 
would be expected that excessive amplitude results in adverse cognitive side effects, 
just as we have already shown that excessive pulse width increases adverse side effects. 
For example, the tolerability of vagus nerve stimulation (VNS) is principally determined 
by pulse amplitude, which is the primary parameter adjusted with this intervention 
(Sackeim et al., 2001b). This is also true of many applications of deep brain stimulation 
(DBS). The present practice of ECT results in uncontrolled difference among individuals 
in intracerebral current density. Individuals with the least degree of shunting away from 
brain will have the highest intracerebral pulse amplitudes. Therefore, this original 
modification should have resulted in improved experimental designs and superior 
safety.  
 
We continue to believe that titration in the current domain will represent an advance in 
the practice of ECT.  However, for two reasons, we abandoned this approach, and 
reverted to a traditional titration schedule.  First, it is unknown what the optimal 
intracerebral current level should be to have the most efficient electrical stimulus.  While 
we were conducting the FEAST pilot studies, research has appeared suggesting that the 
most efficient electrical stimulus has a current level (pulse amplitude) that is higher than 
that used in any US ECT device (Swartz et al., 2012, Swartz, 2011). For example, using a 
within-subject design in which patients underwent empirical titration at both the first 
and second treatment, Swartz et al. (2012) contrasted seizure threshold values when 
using a standard 900 mA current or an experimental 1150 mA. Substantially less charge 
was needed to induce a seizure with the higher current value, suggesting that higher 
current may be more efficient.  While this finding is preliminary, it highlights the fact 
that the optimal level around which one should titrate in the current domain is 
unknown.  In other words, using current values of 200, 400, or 600 mA as starting 
values for titrating in the current domain may be inappropriate if the optimal level for 
efficient stimulation is much higher. 
 
The second reason for abandoning in this IDE the notion of titrating in the current 
domain rests on the principle that current values determine the intracerebral depth 
(focality) of stimulation (Lee et al., 2010, Peterchev et al., 2010). Low pulse amplitude 
results in stimulation that is more superficial. We considered that coupling FEAST with 
low current would result in excessive focality and consequently reduced efficacy.  Thus, 
in our pilot work, we suspended the use of titration in the current domain and the 
titration and subsequent dosing schedules used in the proposed research employ a 
fixed pulse amplitude of 800 mA.  This fixed current is exactly the same as that used in 

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the vast majority of clinical applications and research studies using the MECTA devices 
over the past 35 years. 
 
D.4 Other Procedures 
The diagnostic, clinical evaluation, electrophysiological, and neuropsychological 
procedures described in this protocol have all been used in numerous previous 
controlled ECT research studies conducted by the applicant and his colleagues at 
NYSPI, MUSC and GRU. Large data sets are available to be used as references for 
contrasting the data collected in this study with the highly controlled studies 
previously conducted at the New York State Psychiatric Institute (Sackeim et al., 1987, 
1993, 2000; Sackeim, 2004), a comprehensive study of ECT in community settings 
(Prudic et al., 2004a), and national prospective trials of ECT outcome and relapse 
prevention (Sackeim et al., 2001a, Sackeim et al., 2008, Sackeim et al., 2009, Prudic et 
al., 2013).  
D.4 Non-human Primate Experience 
Two standard MECTA Spectrum 5000Qs were modified by the MECTA Corporation so 
that bi- or unidirectional stimulation is selectable as a menu option. We specified that 
unidirectional stimulation be identical to standard bidirectional stimulation other than 
the rectification of half the pulses. Using the stimulus acquisition system at NYSPI, we 
verified the output of these devices across the entire parameter range (Freq: 20-120 
Hz; PW: 0.2-2 ms; Duration: 0.1 to 8 s; Current: 0.5-0.8A; charge: 1-576 mC). This 
involved independent sampling of voltage and current at a rate of 100k samples/s or 
greater, using procedures previously described (Sackeim et al., 1994).  
 
FEAST electrodes were fabricated at NYSPI, using a disposable Thymapad adhesive 
electrode cut to the shape of an isosceles triangle with a surface area of ~1.2 cm2. 
Since neither the rhesus or bonnet monkey has a forehead, after site preparation, this 
small electrode was applied in an L-shape so that the point of the triangle was over 
nasion, and the base extended over the most anterior portion of skull by ~4.2 mm. The 
posterior electrode used in the three rhesus monkeys was a rectangular stainless steel 
bar, with a surface area of 25.4 cm2 (2.86 x 8.89 cm). This large electrode was 
tangentially centered at vertex, with the short side parallel to the sagittal plane and the 
long side extending across the right hemisphere. The ECS published methods (Dwork 
et al., 2004) used ketamine for transport, and atropine, methohexital, and 
succinylcholine for anesthesia. The FEAST and EEG electrode sites were cleansed with 
alcohol and then abraded. A conductant gel was liberally placed on the posterior 

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electrode that was bent to conform to skull curvature. EEG leads, referenced to 
ipsilateral mastoids, were placed over homologous left and right frontal regions (F7 
and F8). ECG, heart rate, respiratory rate, end-tidal CO2, O2 saturation, and blood 
pressure were monitored throughout. The “cuff technique” (Fink and Johnson, 1982) 
blocked the distribution of succinylcholine in an occluded arm, permitting observation 
of unmodified motor seizure expression.  
 
At NYSPI, 3 male, adult rhesus monkeys (3.9-5.1 kg) were studied, each on 3 occasions 
at least one week apart. Using an ABA or BAA design, ST was assessed with the 
elicitation of a motor seizure as the endpoint of re-stimulation. On two occasions each 
monkey was titrated with the anode on the small anterior electrode (nasion), and the 
cathode on the large posterior electrode (largely over supplementary motor area). On 
one occasion the direction of current was reversed. Staff involved in data collection 
were masked as to whether the anode was anterior or posterior on a given day. The 
titration schedule began with a very low charge (3 mC: 0.8A amplitude, 0.3 ms PW, at 
20 Hz for 0.4 s duration). Each titration step increased charge by doubling train 
duration. 
 
At the outset we had two major concerns about FEAST. Impedance is a function, in 
part, of electrode surface area, and with the small anterior electrode there was the 
worry that impedance would be excessive and either the device would limit voltage 
(400 V) and not deliver the specified current or, worse, it would deliver excessive 
voltage, with potential for burns. The MECTA 5000Q continuously reports “static 
impedance” and records this value just prior to stimulation. It also reports the dynamic 
impedance during stimulation. At each of the 19 stimulations in the 3 monkeys, static 
impedance was in the acceptable range (790-2,070 Ω; Mn = 1,192.2 Ω; SD=482). The 
Spectrum 5000Q will “pass” up to a static impedance of 5,000. Dynamic impedance 
during the 19 stimulations averaged 299 Ω (SD=22.87), with a narrow range (269-333 
Ω). This value is in line with what we have obtained with standard BL ECS in primates. 
While the impedance value is somewhat higher than that typically obtained in human 
ECT with standard 2” circular electrodes (220 Ω is the nominal value assumed), the 
assumed value in Europe is 300 Ω, where 1” circular electrodes are common. Dynamic 
impedance did not differ with direction of current (P=0.23). These observations 
allayed the first concern we had about FEAST. Despite use of a small anterior 
electrode, dynamic impedance was within the acceptable range (< 500 Ω for a .8 A 
pulse) and constant current could be assured. Because the cranium of the adult rhesus 

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monkey is quite small, the surface area of the electrodes must be considerably smaller 
than what we have used in the human. 
 
The extent to which current is shunted through the scalp is partly a function of 
interelectrode distance. In the rhesus monkey, the distance between the FEAST 
electrodes is much smaller than in the human. Further, the necessity of having the base 
of the disposable electrode on the same plane as the posterior electrode only 
increased shunting. Thus, the second concern was that it would be more difficult to 
evoke seizures with FEAST in the primate than the human, and that high stimulus 
intensity would be needed. Instead, we found that the ST with FEAST was among the 
lowest we ever encountered and that with anodal stimulation there was clear-cut 
evidence for greater focality in seizure expression than ever seen with routine ECT or 
ECS. 
 
On 6 of 6 occasions at NYSPI with the anode at nasion, EEG seizures were evoked at 
the first or second step of titration (3-7 mC), most without motor expression and all 
markedly asymmetric in EEG expression. The seizures without motor convulsion were 
characterized by sharp spike activity, although unilateral slow wave activity was also 
present in some cases. These asymmetric EEG seizures had duration of between 8-
35 s. On all 6 occasions titration continued and a motor convulsion occurred at a 
subsequent stimulus. These seizures were also markedly asymmetric in motor and 
EEG manifestations. Figure 2 presents a typical FEAST seizure with motor expression 
during the titration procedure. For comparison purposes a standard BL ECS (WIDE 
PW and 5 X ST) is also presented. The FEAST seizure occurred with stimulation at the 
minimum level for eliciting motor expression. The ECS seizure was with a dosage 2.5 
times this ST, the convention used in a protocol comparing BL ECS to MST (Lisanby 
et al., 2003c, Moscrip et al., 2005, Dwork et al., 2004, Dwork et al., 2009). It is evident 
that on the side of stimulation (right) robust and classic spike-and-wave activity was 
manifested with FEAST. Each of the three NYSPI monkeys had one session in which 
the direction of stimulation was reversed (posterior to anterior). All 3 animals had 
motor seizures at the second step of titration (7 mC) that appeared to be more 
symmetric in motor and EEG expression. Finally, a fourth large male bonnet monkey 
(12 kg) was titrated with FEAST at the SUNY Downstate primate facility. The same 
procedures were followed except that the posterior electrode was made from a 20 
gauge soft copper-grounding clamp (1.9 x 6.35 cm; 12.07 cm2). This smaller 
dimension allowed placement of the electrode anterior to the motor strip and the 
shorter length should further limit stimulation to temporal areas. The first two 

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Figure 2. EEG Seizure Expression with FEAST and ECS 
FEAST                                ECS 
 
stimulations resulted in asymmetric 
EEG seizure activity without motor 
expression; an asymmetric motor 
and EEG seizure was obtained at the 
third stimulation.  
 
A 
potential 
theoretical 
concern 
might 
be 
that 
FEAST 
could 
concentrate current so intensely as 
to result in damage to neuronal 
tissue (Yuen et al., 1981, Agnew et al., 
1983, Agnew and McCreery, 1987, 
McCreery et al., 1990). This concern was obviated by intracranial voltage 
measurements taken in 3 nonhuman primates, contrasting FEAST with standard 
bilateral electroconvulsive shock (Spellman et al., 2009). Using chronic, multicontact, 
indwelling electrodes (recording from 24 locations in brain), the highest recorded 
values with FEAST were within the range of those seen with BL ECS. All observations 
indicated that the BL ECS led to a more diffuse spread of current than FEAST. FEAST 
consistently showed a more marked anterior-posterior gradient than BL ECS, 
supporting its focality and an absence of excessively high current density.  
 
These data indicate that FEAST is capable of inducing focal seizure activity with 
stimulus parameters in the range or less intense than that used for traditional ECS. 
We have hypothesized that the comparable or lower dosing needs of FEAST and 
the elicitation of focal seizures should confer a superior safety profile for FEAST 
relative to traditional ECT.  
D.6 Human experience  
The original FDA IDE approved testing FEAST at NYSPI/Columbia University. The 
amendments in summer 2010 approved the testing of  additional subjects at the 
Medical University of South Carolina. Thus, feasibility of FEAST human work in 
depressed adults began at NYSPI/Columbia University and further optimization of 
the stimulation protocol continued at the Medical University of South Carolina. The 
general protocol was identical at both sites and approved by the respective 
Institutional Review Boards and under an Investigational Device Exemption from 
United States Food and Drug Administration.  The findings in these first 17 patients 
were detailed by Nahas et al. (2013). 

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Using the Structured Clinical Interview for Axis I DSM-IV Disorders, Patient Edition 
(with Psychotic Screen, Structured Clinical Interview for DSM Disorders), patients 
met DSM-IV criteria for a major depressive episode (unipolar or bipolar). They 
scored 21 or greater on the Hamilton Rating Scale for Depression (HRSD, 24-item), 
and treatment with ECT was indicated. Patients were excluded if they had a history 
of 
schizophrenia, 
schizoaffective 
disorder, 
non–mood 
disorder 
psychosis, 
neurological illness, alcohol or drug abuse within 6 months, ECT within 6 months, or 
severe medical illness.  
 
In this open-label feasibility trial, patients’ use of psychotropic medications was 
discontinued before starting FEAST, other than lorazepam given as needed (up to 3 
mg/d). There was no stipulated minimum or maximum number of treatments for 
patients to be classified as provisional responders; the aim was to achieve maximal 
improvement. Treatment continued until patients were asymptomatic or had 
plataeued in improvement over at least two treatments. As a precaution expressly 
for this preliminary trial, patients who showed less than 40% improvement following 
4 treatments (later amended to 6 at MUSC) were withdrawn from the study and 
offered traditional ECT (UB RUL ECT). Methohexital (0.75-1.0 mg/kg) and 
succinylcholine (0.75-1.0 mg/kg) were used as anesthetic medications with pre-
administration of atropine (0.4-0.6 mg) or glycopyrrolate (0.2-0.4 mg).  
 
FEAST was administered with a modified MECTA spECTrum 5000Q device (MECTA 
Corp, Tualatin, Oregon). It relies on a relatively small (reduced surface area) frontal 
and large posterior electrode to induce focal seizures. Smaller electrodes however 
can lead to increased dynamic impedance, and failed treatment delivery if the ECT 
device voltage limit is exceeded or could produce superficial skin burn. When this 
clinical study was first proposed with a ¾ inch diameter anode electrode, the 
expectation was that the resulting dynamic impedances would remain in the 200-
300 Ω range, but that the likelihood of skin burns could increase due to reduced 
electrode surface area. To mitigate this risk, the spECTrum voltage shut down limit 
was reduced from 400 Volts to 240 Volts, thus reducing the allowed dynamic 
impedance upper limit (at 800 mA) from 500 to 300 Ω. Thus stimulating electrodes 
consisted of a small (0.75 inch) anterior round stainless steel electrode and a larger 
posterior oblong stainless steel electrode (1 x 2.5 in) that attaches in a standard 
manner to the MECTA remote-treat stimulus cables. The smaller electrode was 
placed anteriorly, with the lower boundary just above the center of the right 

IDE Application - Focal Electrically-Administered Seizure Therapy (FEAST): Studies at two enrolling sites 
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eyebrow. The larger posterior electrode was concave in shape to better couple to 
the scalp. The posterior electrode was placed tangential to the midline and 
extended across the right supplementary motor cortex. The medial position of this 
electrode was adjacent to the line connecting the nasion and inion and with the 
posterior boundary 1.0 inch anterior to the vertex, with the lateral portion extending 
over the right hemisphere.  
 
As the study began it became apparent that this 300 Ohm limit on dynamic 
impedance was too restrictive (there were frequent aborted stimuli due to the 
voltage limit being exceeded). To solve this practical issue in stimulus delivery, the 
anode electrode size was increased, first to 1 inch and then to 1.25 inches (MUSC). 
The posterior electrode size was also increased to 2 x 3 inches. 
 
FEAST treatments were given in the morning, 3 times per week. The criterion for an 
adequate seizure was ≥ 20 s motor duration. Subconvulsive stimuli, which occurred 
only during titration sessions, were followed 20 s later by restimulation. At the first 
treatment, the empirical titration procedure was used to estimate seizure threshold 
(ST) (Sackeim et al., 1987c, Sackeim et al., 1987d, Sackeim et al., 1991). Dosing at 
subsequent treatments was substantially above seizure threshold (6xST) as it is now 
commonly adopted for UB RUL ECT (Sackeim et al., 2008, Loo et al., 2008). Given 
insufficient clinical progress, this dosage was increased in some instances to up to 
approximately 9xST prior to terminating use of FEAST.  
 
The titration schedule we used combined 5 parameters, with a range of charge 
from 5.4 to 43.2 mC. (See Appendix II for the titration table and dosing schedule for 
the proposed study.) If a patient did not have an adequate seizure at the highest 
titration setting (43.2 mC) they exited the protocol and received conventional ECT. 
However all patients had adequate FEAST induced seizures by this titration step and 
none exited prior to receiving FEAST. Thus, the highest dosage that was used in this 
pilot study was 384.0 mC, 66.7% the maximal output of a standard US Spectrum 
5000Q (576 mC).  

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Seventeen 
unmedicated 
depressed adults (7, NYSPI: 
10, 
MUSC) 
participated. 
There were 5 men and 3 
bipolar affective disorder 
patients with an average 
age of 53±16 years. The 
length 
of 
the 
current 
depressive 
episode 
and 
lifetime depressive illness 
were 
225.7±257.3 
weeks 
and 
20.1±11.2 
years, 
respectively. The average 
number of FEAST treatment 
sessions per patient was 8.8, 
the median was 10, with a 
range 4-14.  
 
There was a notable 42.1±38.3% improvement after FEAST compared to baseline in 
HRSD24 (32.7±6.8, 17.7±11.2; p=0.0004) and IDS-SR (55±6.5, 28.1±16, p=0.003) 
scores. At the end of the course, 8 of 17 (47.1%))  patients met response criteria and 
5 of 17 (29.4%) met remission criteria. The extent of improvement and likelihood of 
remission appeared to increase, perhaps because of increases in the size of the 
anode electrode and use of a fixed pulse amplitude of 800 mA (as opposed to 
titrating in the current domain). Only 1 of the first 9 patients achieving remission, 
compared to 4 of the last 8. Two patients presented with severe suicidal ideation 
but had their Suicidal Scale Inventory scores drop from 26 and 31 at baseline, to 7 
and 0 at end of treatment.  
 
The average duration of seizures as recorded on EEG was 57±47 seconds. This 
value is comparable to that observed with routine ECT. 
 
 
Note how, with improvements in technique, the percent 
improvement and number of FEAST remitters has increased 
with time (left, first patient, right, recent). Early patients had 
lower currents and smaller electrodes

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Cognitive markers: Time 
to 
return 
of 
full 
orientation 
in 
the 
postictal period is highly 
sensitive 
to 
ECT 
technique 
and 
is 
predictive of long-term 
amnestic effects (Sobin 
et al., 1995b). Patients 
achieved 
full 
re-
orientation in 16.9±7.5 
minutes from stimulus 
delivery 
or 
7.3±9.6 
minutes 
(median=3.6) 
from when their eyes 
first opened in the postictal period. This average value for orientation recovery 
compares favorably with traditonal ECT, even the use of ultrabrief RUL stimulation 
(Sackeim et al., 2008) .One subject exposed to both FEAST and UB RUL had a 
substantially shorter time to orientation recovery with FEAST (14.7±6.8 min versus 
21.6±6.5).  
 
Importantly, other measures of cognition showed no change after a full course of 
FEAST. MMSE scores at baseline and end of treatment were 28.4±1.2 and 29.1±1.3 
(p=0.33), respectively. Similarly, AMI-SF scores were 53±4.9 and 51.5±5.1 (p=0.6); 
RBANS were 90.3±4.2 and 86.2±14.2 (p=0.56).  
 
Adverse Events:  There were 2 first-degree burns at the anterior site of stimulation 
with the smaller 0.75” electrode. One patient exhibited a drop in RBANS score 
immediately after treatment but recovered by 2 months follow-up and was 
substantially improved by 4 months. 
 
 
Average positive change from baseline (LOCF) in IDS-SR score 
with more FEAST sessions (n=10 patients from MUSC). Mean 
values  ±SEM. 

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FEAST technical development for improved feasibility and safety: With successive 
increases in electrode sizes and thus surface area, the average dynamic impedance 
dropped from an 
average of 350 to 
250 ohms and the 
heat flux through 
the skin decreased 
by a factor of 2.77 
times. 
 
 
The 
following 
discussion presents 
the rationale and 
supporting data for 
the 
changes 
in 
electrode size (to 
1.25 “) and the increase in voltage cutoff (to 400 V) that were approved in the last 
IDE submission on FEAST. 
 
In the original IDE proposal (2005), arguments were based primarily upon Power 
Density concerns. We now believe that this approach was incorrect, and that Energy 
Density is the correct measure for evaluating safety. The use of Power Density relies 
upon the fundamental assumption that the skin can conduct heat away in time 
frames of a few seconds, whereas Energy Density assumes much longer time frames 
are involved. Research data for fire fighters strongly supports the latter view, that 
conduction of heat by the skin is a slow process, involving tens of seconds up to 
minutes. The following analysis will include both Power and Energy Density values 
for comparison. 
Another issue that was not addressed in the original IDE is that of dissimilar 
electrodes. MECTA’s product line utilizes two, 2” diameter electrodes, so the energy 
absorption is split evenly between the two, thus doubling the effective area and 
reducing the power densities at the skin. FEAST uses differently sized electrodes, a 
smaller circular electrode on the forehead and a larger rectangular electrode 
posteriorly located, above the temple. Analysis shows that rather than the power or 
energy densities splitting evenly, the densities are substantially higher at the smaller 
 
Dynamic impedance function of electrode size. Note that at 800mA 
stimulus intensity, impedance values greater than 300 Ω lead to failed 
delivery as voltage exceeds the machine upper limit of 240 V. 
 

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electrode. Thus, density calculations need to consider this, and assume the 
maximums will occur at the smaller anterior (anode) electrode. The effective area 
may be calculated as: 
Aeffective = Asmall(1+Asmall/Alarge) 
When the small and large electrodes are equal in area, the effective area is the sum 
of the two areas (twice either one). Otherwise, the effective area approaches that of 
the smaller electrode as the ratio of areas gets smaller. 
A significant problem in the FEAST study was the inability to treat at 800 mA due to 
high patient dynamic impedance (above the 300 ohm limit imposed by the 240 V 
cutoff.) Hence, it was desirable to raise this voltage limit. Graph 1 shows the 
measured dynamic impedances for the 1.25 inch diameter electrodes. The values 
above 300 ohms for 800 mA were all attempted treatments that failed. In order to 
treat at all, the current was dropped back to 600 mA where the effective impedance 
limit is 400 ohms (240 volts divided by 600 mA.) Nearly every treatment at that level 
was successful, but there were concerns that efficacy may be reduced at lower pulse 
amplitude. Indeed, virtually all modern ECT has used 800 or 900 mA pulse 
amplitudes, so the routine use of lower current values introduced additional 
uncertainty. 
 
Thus, it was important that the voltage limit be increased to allow dynamic 
impedances of 500 ohms or less, equivalent to a standard commercial ECT device. 
This translates to a voltage limit of 400 V. 
 
 

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Table 1 presents electrical parameter sets for the domestic and international 
commercial Spectrum devices and those proposed in the original IDE and its 
subsequent iterations.  The last set of parameters (Third FEAST IDE) were those last 
approved and have been used in the last 18 patients at MUSC.  When comparing 
values to the original approved IDE, submitted by Dr. Sackeim in 2005, the Power 
Densities for the parameters used in the currently approved study and now 
unchanged in this proposal are lower than in the original IDE submission due to 
inclusion of the second electrode area and the effective area calculations.  In 
essence, the likelihood of high impedance and/or skin burns has been reduced. 
The data submitted with the original FEAST IDE data showed approximately the 
same power density as obtain with the International spECTrums. However, under 
our updated calculations, it is evident that these values were twice as high (6.87 vs. 
2.84), while the energy density was nearly 5 times higher (54.96 vs. 11.37). This 
accounts for the skin burn, which had a slightly higher power density than the 
International device (3.43 vs. 2.84), but a much larger energy density (27.48 vs. 
11.37). Further, two safe FEAST deliveries are shown in the Table, each with power 
densities a little below and energy densities above the international machine 
maximums. 

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Table 1 
  
Max 
PW 
ms 
Max 
Freq 
Hz 
Max 
Dur 
Sec 
Max 
Cur 
mA 
Max 
Volts 
Anode 
Radius 
cm 
Cathode 
Area     sq 
cm 
Effective 
Electrode 
Area         sq 
cm 
Power 
Density 
W/sq 
cm 
Total 
Charge 
mC 
Total 
Energy 
J@220 
Ohms 
Max 
Dynamic 
Impedance 
Allowed 
Energy @ 
max 
Impedance 
Energ
Density   
cm 
2011 
Domestic 
spECTrum 
100 J 
  
2.00 
60 
3 
800 
400 
2.54 
20.27 
40.5367 
1.89 
576.0 
101.38 
500 
230.40 
5.68
2011 
International 
spECTrum 
200 J 
1.50 
120 
4 
800 
400 
2.54 
20.27 
40.5367 
2.84 
1152.0 
202.75 
500 
460.80 
11.37
Original 
FEAST IDE 
1.00 
60 
8 
800 
240 
0.95 
16.13 
3.3539 
6.87 
768.0 
135.17 
300 
184.32 
54.96
Second 
FEAST IDE 
0.30 
120 
8 
800 
280 
1.59 
38.71 
9.5367 
1.69 
460.8 
81.10 
350 
129.02 
13.53
Third 
FEAST IDE 
  
0.50 
90 
8 
800 
400 
1.59 
38.71 
9.5367 
3.02 
576.0 
101.38 
500 
230.40 
24.16
FEAST 
Deliveries 
with no 
burns 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
2 deliveries 
0.30 
60 
7 
800 
240 
0.95 
16.13 
3.3539 
2.06 
201.6 
35.48 
300 
48.38 
14.43
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
FEAST 
Delivery 
with burn 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
1 delivery 
0.50 
60 
8 
800 
240 
0.95 
16.13 
3.3539 
3.43 
384.0 
67.58 
300 
92.16 
27.48
 
The formulae used in the preceding table are as follows: 
Effective Electrode Area (Aeff) = Anode area (1 + Anode area / Cathode area) 
Power density = 2 x I x V x P x F / Aeff 
Total Charge = 2 x I x P x F x T 
Total Energy at 220 ohms = 2 x I x I x 220 x P x F x T 
Max Dynamic Impedance = V / I 
Energy at Max Impedance = 2 x I x I x Max Impedance x P x F x T 
Energy Density = Energy at max impedance / Aeff 
 
Where I is current, V is max volts, P is pulse width, F is frequency, and T is duration. 
The 2 in various formulae accounts for 2 pulses per cycle. 
The table above also shows Third FEAST IDE Parameters. These were the 
parameters approved for the current IDE and proposed again for the new study. 
These include a 400 V limit thus allowing 500 ohm dynamic impedances. They use 
1.25 inch diameter anterior electrodes and 2 inch by 3 inch posterior electrode.  The 

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resulting Power Densities are comparable to MECTA’s international units (2.69-3.02 
vs. 2.84) and less than half the originally approved FEAST device capabilities (2.69-
3.02 vs. 6.87). The energy densities are about twice the international units and 10 to 
15% below the one FEAST burn stimulus. These parameters will allow treatment of 
all patients at 800 mA,. 
In summary, we propose to continue the following changes, which were modified 
from the original IDE and have been in use at MUSC for the past two years: 
1. 
Increase the front electrode diameter to 1.25 inches (2.77 times increase in 
area)  
2. 
Decrease the maximum energy delivery at maximum allowed impedance 
from 184 Joules to 154 Joules (16% drop in maximum energy)  
3. 
Increase the voltage limit from 240 Volts to 400 Volts to allow 500 Ohms 
dynamic impedances at 800 mA (1.67 times increase in dynamic impedance.) 
When compared to approved domestic machines, the proposed changes 
would adhere to the 100 Joule limit, but would utilize smaller electrodes, thus 
increasing the burn risk some. However, experience with these smaller 
electrodes, and with our 200 Joule international machines, indicates that the 
burn risk should remain small. This has been confirmed in the 18 patients 
treated with these parameters (see below).  
Experience in Ongoing Study of FEAST 
 
The data presented above derive from the first 17 patients treated with forms 
of FEAST (7 from NYSPI and 10 at MUSC) under the originally approved IDE. These 
have been published in Nahas et al, 2013. (Nahas et al., 2013b) The ongoing FEAST 
study was conducted under an IDE with Dr. George at MUSC as the sponsor.  In this 
ongoing study, 18 of a maximum of 20 patients have been enrolled and treated.  
Analysis of the data from these additional patients is ongoing, but essential 
observations are reported below. 
 
 
The 18 patients who have completed the protocol received an average 9.8 
treatments (range 3-14), or a total of 168 FEAST administrations.  There have been 
no instances of skin burn.  Indeed, in this second cohort there have been no 
instances of excessive dynamic impedance and consequent inability to deliver the 
electrical stimulus.  There had been 2 burns and frequent instances of inability to 

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deliver treatment in the first cohort.  Thus, the change in the electrode geometry 
and device electrical parameters proposed in the ongoing study appear to be major 
improvements and enhance the reliability and safety of the procedure. 
 
 
One patient was discovered in the 3rd week of treatment to have been 
misdiagnosed and was diagnoses with lupus cerebritis. We have excluded her from 
the analysis. After stopping ECT, she received a course of steroids for her lupus and 
her depression improved remarkably. The remaining 17 patients had average 
baseline HRSD24 scores of 36.7 and postFEAST scores of 16.7, representing an 
average 59.4% reduction.  Of these 18 patients, 13/17 (76%) met response criteria (≥ 
50% score reduction) and 9 (53%) met remission criteria (postFEAST HRSD24 score ≤ 
10).  Thus, it appeared that the improved efficacy seen in the patients treated at the 
end of the first cohort was maintained and even amplified in the second cohort.  
Response and remission rates with ECT vary considerably among institutions. It is 
not possible to determine whether the observed rates are equivalent to what would 
be obtained at the same facility in patients receiving traditional ECT.  Consequently, 
the next study in this series will include a non-randomized, non-masked 
comparison to patients receiving UB RUL ECT.  The primary goal of the next study is 
to contrast the groups in focality of seizure onset EEG measures, and the lack of 
randomization and masking should have little impact on these measures.  While this 
is more of a concern for the efficacy measures, the comparison of clinical outcomes 
in the next study, conducted at two centers, should still be informative. 
 
 
The average time to reorientation was determined for the second cohort.  
Averaging across all treatments per patient, it took 11.4 minutes to recover full 
orientation (timed since seizure termination).  This value again suggests that FEAST 
is especially cognitively sparing.  Comparison of the cognitive effects of FEAST and 
UB RUL ECT is of keen interest in this field. 
 
IV. INVESTIGATIONAL PLAN 
A. Purpose 
The protocol presented in this new IDE will be performed at two clinical sites (MUSC 
and GRU). At each site 20 patients will be recruited to receive treatment with FEAST, 
or a total of 40 FEAST patients across the sites. A contemporaneous group of 20 
patients will be identified at each site who are receiving standard clinical treament 
with UB RUL ECT. These pateints will be matched to the FEAST sample (within site) 

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in the distribution of gender and diagnosis (unipolar vs. bipolar), and the mean, 
variance and shape of the distributions of age and baseline modified mini-Mental 
State score (mMMS) (Stern et al., 1987). This RUL cohort is also included under this 
IDE. [We considered but ultimately abandoned having a formal, blind 
randomization of patients to FEAST or RUL. While we ultimately hope to perform 
such a study, the data with FEAST are quite limited at present. There thus may not 
be true clinical equipoise. Similarly, although the FEAST side effects appear benign, 
there have still been less than 50 patients total ever treated with FEAST. We thus 
have settled on a non-randomized but loosely matched comparison group. This 
group is important for the analysis of the EEG and MRI data, and can also be used 
for rough comparison of efficacy and cognitive side effects. It is our hope that 
following this trial, there might be sufficient evidence of efficacy to enable a formal 
randomized definitive trial.  
 
We will be applying to the NIH for funding to support the conduct of this protocol. 
This IDE will serve to gather important pilot data and will serve as the IDE for the 
NIH study, if it is funded.  
 
In an open label study, the investigators intend to test the feasibility, safety and 
efficacy of a new form of electroconvulsive therapy (ECT), referred to as focal 
electrically-administered seizure therapy (FEAST). A modified MECTA Spectrum 
5000Q device will be used. This device will be capable of delivering unidirectional, 
ultrabrief stimulation with a montage involving a small circular electrode (anode, 
1.25” diameter) and a larger rectangular electrode (cathode, 2” x 3"). The primary 
objective in using unidirectional stimulation with this electrode geometry is to 
increase the precision of anatomical targeting. FEAST should enhance the capacity 
to concentrate current density in regions implicated in therapeutic processes and 
minimize exposure of areas in which stimulation results in adverse cognitive effects.  
As an expression of this objective, FEAST is expected to result in therapeutic 
seizures with focal onset and limited generalization.  This hypothesis will be tested 
by comparing the FEAST and UB RUL ECT samples in focality of seizure onset as 
assessed by EEG ictal measures. A four-lead EEG montage will be employed at 
every treatment with the expectation that FEAST treatments result in reduced 
seizure expression in left and right temporal leads compared to traditional UB RUL 
ECT.  In addition, fMRI measures of resting connectivity will be collected before and 
immediately following the ECT course (24-96 hours post-treatment).  It is 

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hypothesized that FEAST results in greater focality inconnectivity alterations, with 
primarily a right frontal locus of effects. 
 
A second hypothesis is that FEAST will represent a more efficient form of seizure 
induction. The FEAST patients in this protocol should have a lower seizure threshold 
(expressed in the minimal charge to elicit a seizure) compared to the contemporaneous 
matched reference group.  
 
A third hypothesis is that FEAST should be of similar therapeutic potency with a superior 
side effect profile when compared to standard UB RUL ECT, the form of traditional ECT 
with the most benign adverse effect profile and robust efficacy (Loo et al., 2012).  
 
The study is expected to be completed 3 years after the approval of this IDE.  
B. Protocol 
B.1 Patient Selection 
Across the sites 60 patients will be enrolled to achieve 40 FEAST patients who will fully 
complete this study at the MUSC Institute of Psychiatry, Brain Stimulation Service (BSS) 
in Charleston, SC, and at GRU in Augusta, GA and Aiken, SC.  At both MUSC and GRU, 
roughly matched 30 patients (each) will also be recruited from those scheduled to 
receive UB RUL ECT to obtain a cohort of 40 RUL comparison patients.  The FEAST 
and UB RUL ECT groups must meet identical inclusion/exclusion criteria and will 
undergo identical evaluation procedures.  The only difference between the groups will 
be that one receives FEAST and other UB RUL ECT. The treatment received by the UB 
RUL ECT group will not be affected by participating in this protocol. This is an open 
label, non-randomized, non-masked study.  Separate consent forms will be used in 
each group. We are thus asking FDA permission to study 60 patients with FEAST. An 
additional 60 patients will be studied who receive conventional ECT. Even though they 
are getting conventional ECT, they are covered by this FDA IDE as their data will be 
used for comparison purposes with FEAST.  
 
Patients will be selected from those referred for ECT for the treatment of major 
depressive episode. To verify diagnosis, the SCID-P will be admiinsitered to derive 
DSM-V diagnosis (unipolar or bipolar major depressive episode) and relevant 
subtypes and specifiers (American Psychiatric Association, 2013). 
 

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Inclusion and exclusion criteria are presented in Table 2. Briefly, patients will be 
between the ages of 18 and 90 years and will provide informed consent. Exclusions 
include: history of schizophrenia, schizoaffective disorder or any non-mood disorder 
psychosis, rapid cycling bipolar disorder, central nervous system illness other than 
conditions associated with psychotropic exposure, alcohol or substance abuse or 
dependence in the past 3 months, pregnancy, epilepsy, inability to have stable 
medications, and ECT within the past six months.  
 
There is no evidence that gender or minority status is related to response to ECT or by 
extension to FEAST (Nobler and Sackeim, 1996). Patient recruitment will reflect the 
referral patterns to MUSC and GRU. Given the gender difference in the prevalence of 
major depressive episode it is expected that approximately two-thirds of the sample will 
be female. It is expected that the sample composition will be approximately 85% 
Caucasian, 14% African-American, 1% Hispanic or other ethnic group in line with the 
historical referral basis for the MUSC ECT service and the  GRU ECT services. 
B.2 Inclusion Exclusion/Criteria 
Table 2 presents the inclusion/exclusion criteria for the next FEAST study.  These 
criteria have been consistent since the original FEAST IDE with the following 
exceptions.  First, all psychiatric diagnoses now are based on DSM-V instead of 
Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) or DSM-IV. The second 
change is more substantive.  In the previous iterations of this IDE, we required that 
patients be medication free during the FEAST course, other than lorazepam (up to 3 
mg/d).  Maintaining this medication-free status was deemed untenable.  There is 
now randomized, blinded, placebo-control evidence from a large multi-center 
study that the efficacy of traditional ECT is enhanced by the co-administration of 
antidepressant medication (Sackeim et al., 2009). Thus, medication-free status 
presents an ethical dilemma as it may diminish the likelihood of clinical benefit.  
Second, in clinical practice ECT patients commonly receive concomitant 
psychotropics. Continuing to require medication-free status in the FEAST group 
would introduce a fundamental confound in comparison with the UB RUL ECT 
group.  The approach we now take excludes exposure to medications that may 
interfere with ECT efficacy (anticonvulsants, higher doses of anxiolytics) or present a 
safety risk (e.g., lithium), while permitting medications that may augment clinical 
efficacy (antidepressants, atypical antipsychotics).  Medication status will be carefully 
tracked and explicitly compared in the two groups.  
 

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Table 2. Inclusion and exclusion criteria for study participation 
 
Inclusion Criteria 
Age between 18 and 90 years (inclusive) 
 
Diagnosis of major depressive episode 
SCID to derive DSM-V 
Pretreatment HRSD score ≥ 21 
Hamilton 
Rating 
Scale 
for 
Depression (24-item) 
ECT indicated 
Physician evaluation  
Willing and capable of providing informed 
consent 
Physician evaluation 
 
Exclusion Criteria 
History 
of 
schizophrenia, 
schizoaffective 
disorder, other functional psychosis, or rapid 
cycling bipolar disorder 
SCID to derive DSM-V; rapid cycling 
defined as ≥ four episodes in past 
year 
History of central nervous system illness or 
insult other than conditions associated with 
psychotropic 
exposure 
(e.g., 
tardive 
dyskinesia) 
Physician 
evaluation; 
medical 
history 
Alcohol or substance abuse or dependence 
in the past year (DSM-V) 
Physician evaluation 
Secondary diagnosis of a delirium, dementia, 
or amnestic disorder (DSM-V), pregnancy, or 
epilepsy 
Physician evaluation 
Requires especially rapid antidepressant 
response 
due 
to 
suicidality, 
psychosis, 
inanition, psychosocial obligations, etc. 
Physician evaluation 
 No anticonvulsant mood stabilizers (e.g., 
Depakote, Tegretol, Lamictal); 
No lithium; 
No psychostimulants (e.g., Ritalin, Adderall); 
 
Allowed medications during FEAST/ECT: 
Antidepressants, including buproprion 
Atypical antipsychotics;  
Hypnotics for sleep; 
Anxiolytics 
(limited 
to 
up 
to 
3 
mg 
equivalents/day lorazepam) 
  
Treatment history and physician 
evaluation 

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ECT in the past six months 
Physician 
evaluation; 
medical 
history 
 
Patients with a history of schizophrenia, schizoaffective disorder, or any other (non-
mood disorder) psychotic condition, or substance abuse within the past year are 
excluded. At screening, patients will be administered the Hamilton Rating Scale for 
Depression (24-item version) (Hamilton, 1967) and must have a score of at least 21. 
Patients who meet these conditions and the other inclusion/exclusion criteria in Table 2 
will be considered for participation. Informed consent will be obtained from all study 
participants. Capacity to provide consent will be independently documented by a 
member of the patient’s treatment team not involved in the research (likely at MUSC), 
or have the patient successfully complete a document that shows that they have the 
capacity to consent to participate (likely at GRU).  
 
The inclusion criteria includes a physician evaluation that ECT is indicated. 
Medication resistance constitutes but one indication for the use of ECT. The CRF 
that documents this determination is based on the American Psychiatric Association 
Task Force Report on ECT (2001) statement of the conditions that justify the primary 
or secondary use of ECT. The considerations that are weighed in determining 
whether ECT is indicated include the following:  
a. Previous positive response to ECT as ascertained by history.  
b. Failure to benefit from adequate pharmacological treatment in the present 
episode.  
c. Presentation of severe symptomatology (e.g., debilitating psychiatric or 
medical conditions) requiring a prompt antidepressant response.  
d. Complicating medical conditions (e.g., heart disease) that could be 
worsened by the use of psychotropic medications.  
e. Complicating adverse reactions to psychotropic medications (e.g., delirium, 
urinary retention) that contraindicate or limit their use.  
The conditions that resulted in recommendation of ECT for each particular patient is 
documented by the study physician. 
B.3 Medical Work-up 
At screening, a medical history will be obtained. In patients who have consented to 
protocol participation, a physical and neurological examination, and EKG will be 
performed, and blood work-up (Chem20, thyroid function, CBC) and urinalysis will be 

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obtained. In women of childbearing potential, a pregnancy blood test will be obtained. 
All patients are evaluated by an internist.  
B.4 Treatment History 
Life-time exposure to psychiatric treatments is charted, including the medication and 
ECT trials, and the type, frequency, and duration of psychotherapy. Using the ATHF 
(Sackeim et al., 1990b, Prudic et al., 1990, Prudic et al., 1996, Mulsant et al., 1997, Sackeim, 
2001) the duration, oral dosage, blood levels, compliance, and clinical outcome of each 
medication trial during the index episode are assessed. These ratings based on 
information derived from interviews with patients, family members, and treating 
physicians, and from pharmacy and medical records.  
B.5 Pretreatment Procedures 
A psychotropic (antidepressants, anxiolytics, mood stabilizers, sedatives, barbiturates, 
etc.) stabilization period of at least 5 days will be completed prior to the start of FEAST 
= as it is standard practice in clinical ECT delivery.  We allow the as needed 
administration of lorazepam (up to 3mg/d PRN). Lorazepam is used as a rescue 
medication for patients in whom insomnia and/or anxiety are intolerable. Baseline 
evaluation procedures will be conducted after completion of the psychotropic 
stabilization period.  
 
Table 3 lists the research procedures completed at baseline, prior to the start of FEAST 
or UB RUL ECT.  
 
TABLE 3. PRETREATMENT ASSESSMENT BATTERY 
 
Clinical Status and Characteristics  
1. Structured Clinical Interview for DSM-V (SCID-P) 
2. Past and Current Medication and ECT History (Antidepressant Treatment History Form) 
(Sackeim, 2001, Sackeim et al., 1990b) 
3. Clinical Global Impression: Severity & Improvement (CGI:S, CGI:I) (Guy, 1976) 
4. Global Assessment Scale (GAS) (Endicott and Spitzer, 1978) 
5. Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1967) 
6. Montgomery-Åsberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 
1979) 
7. Inventory for Depressive Symptoms (IDS-SR) (Rush et al., 1985) 
8. Medical Outcomes Study - SF36 (MOS-SF36) (Wells et al., 1992, McHorney et al., 1993) 
9. Demographics (age, education, race, martial status) and handedness  

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Baseline Measures in Cognitive Battery 
Global Cognitive Function 
1. Modified Mini-Mental State Exam (mMMS) (Stern et al., 1987, Mayeux et al., 1981) 
Retrograde Memory 
1. Columbia University Autobiographical Memory Interview – Short Form (AMI) 
(McElhiney et al., 2001, McElhiney et al., 1995, Sobin et al., 1995b, Sackeim et al., 1993, 
Sackeim et al., 2000b, Sackeim, 2014b) 
Anterograde Memory 
 
I. Buschke Selective Reminding Test (BSRT) 
Patient Attitudes 
1. ECT Attitude Interview (Berman et al., 2008, Brakemeier et 
al., 2011b) 
 
The measures of Clinical Status and Characteristics in Table 3 are essentially unchanged 
since the original IDE. The cognitive battery is considerably reduced. This was done 
since the primary goal of this study is the comparison of the groups in EEG 
manifestations of seizure, with comparisons of efficacy and side effects secondary.  
Second, none of the dropped measures showed significant change with FEAST 
administration in our prior analyses, and the literature on traditional ECT has only 
shown persistent deficits for retrograde memory for autobiographical events (Sackeim, 
2014b).  The measures that were retained serve a particular purpose: (1) the mMMS at 
baseline is used for sample characterization and matching of the two groups. A 
significant difference between the groups would denote an effect pertaining to global 
cognitive status. This is not expected. (2) Orientation recovery will be assessed at each 
treatment (but obviously not at preFEAST baseline). This measure has been extremely 
sensitive to differences in ECT treatment modalities (sine wave vs. brief pulse; ultrabrief 
vs. brief pulse, BL ECT vs. RUL ECT, etc.) and has been found to predict long-term 
deficits in autobiographical memory (Sobin et al., 1995b). We expect the FEAST group 
to manifest faster recovery of orientation than the UB RUL ECT group, even though the 
latter has manifested remarkably rapid recovery compared to other ECT modalities 
(Sackeim et al., 2008).  (3) The most critical measure is the CUAMI-SF. This measure has 
repeatedly shown differences between modalities and has the strongest evidence for 
persistent defict following ECT.  While effects of UB RUL ECT on this measure have 
been slight (compared to retested normal controls), nonetheless we predict an 
advantage for FEAST in this measure of autobiographical amnesia. (4) The Attitudes 
Interview collects patient self-report on the effects of the treatment course on mood 

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and memory.  A global assessment is given by the patient, akin to a clinical global 
impression (CGI) for each domain.  Recent research has shown that these are the only 
self-report measures in the history of ECT research to show significant covariation with 
objective cognitive deficits and with type of ECT modality (Berman et al., 2008, 
Brakemeier et al., 2011b). We predict that the FEAST and UB RUL ECT groups will be 
equivalent in self-report of effects on mood, but the FEAST group will report less 
deleterious impact on memory.    
 
B. 5a MRI scan 
Prior to the first ECT treatment all patients in both groups will be offered an MRI scan. 
The scanning at MUSC will be done on a research dedicated 3T Siemens scanner 
across the street from the Institute of Psychiatry. At GRU scanning will be done on a 3-
T Philips Scanner. In addition to a high resolution structural scan (to be used for 
potential modelling of current flow), patients will also have an 8 minute resting BOLD 
scan for assessing functional connectivity. The entire non-contrast scan will take about 
30 minutes. This will be repeated as well within 24-96 hours of the last ECT session of 
the course. MRI scanning details follow, although these may change over time as the 
technology advances without requiring an ammended IDE as they pose no safety issue.  
 
High-resolution 
structural 
images 
will 
be 
acquired 
using 
T1-weighted 
magnetization-prepared rapid-acquisition gradient echo (MPRAGE; FOV 256mm by 
256 mm; voxel size: 1x1x2mm, with 0 mm gap; TR=7.5s, TE=3.7ms, ﬂip angle=8°). 
 
T2-weighted functional images will be acquired with a gradient-echo echo-planar 
imaging (EPI) sequence (TR=2 sec, TE=29 ms, flip angle=75, 64x64 acquisition 
matrix, 3.75 x 3.75 x 4.55 mm voxel size, FOV=240 mm, 3.5mm slice thickness, 1mm 
gap).  Resting state scans will be acquired over a minimum of 5 min, 16 s in duration 
(158 volumes).  
 
Subjects will be instructed to keep their eyes open during the scan and stare 
passively at a fixation cross. Their head will be restricted with foam cushions in 
order to minimize head motion.   
 
fMRI Image processing and motion correction 

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Artifact Detection Tools (ART, http://www.nitrc.org/projects/artifact_detect) software 
will be used for automatic detection of the global mean and motion outliers in the 
functional data.   
We will exclude from the analyses individual volumes from the time series if head 
displacement from the median head position was greater than 1.5 mm, or if head 
rotation from the median head position was greater than 0.5 degrees.   The 
functional 
images 
will 
be 
pre-processed 
with 
SPM8 
(http://www.fil.ion.ucl.ac.uk/spm/).  Slice timing correction will be applied to the 
data to remove signal variation due to slice acquisition temporal onset differences. 
The first functional image volume of each participant will be used to determine 
parameters for spatial normalization into Montreal Neurological Institute (MNI) 
standardized space employed in SPM8 using non-linear transformation.  
 
Functional Connectivity Analysis 
Two approaches can be used to perform functional network connectivity: a model-
free method and a model-dependent method using seed-based correlational 
techniques. The first method enables the exploration of connectivity patterns 
without the need of defining an a priori seed region. In contrast to seed-based 
methods, model-free methods are designed to look for general patterns of (unique) 
connectivity across brain regions. We will first proceed with a model-free method 
(Independent Component Analysis (ICA)) and then guided by the results we will 
perform a seed-based method to confirm those results 
 
Independent Component Analysis (ICA) 
As a model-free method, we will use Group ICA (Calhoun et al., 2001). It will be 
performed using the Group ICA fMRI Toolbox (GIFT) to identify distinct brain 
regions with temporally coherent (functionally connected) hemodynamic signal 
change (Calhoun et al., 2008).   
                      
Time Series 
As a seed-based method, using an in house program in Matlab or the resting state 
version 
of 
the 
Matlab-based 
cross-platform 
software 
CONN 
(http://www.nitrc.org/projects/conn), time series from the resting state scans will be 
extracted from specific ROIs based on the ICA analysis results by averaging the time 
series of all voxels in the ROIs. After scaling and filtering steps performed across all 

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brain voxels, the resulting times series will be correlated with the resting-state time-
series of all other voxels, resulting in a functional connectivity map (fcMap). 
 
Statistical Analysis 
As correlation analysis, we will correlate the change in functional connectivity 
measures with the change in symptom measures for all subjects. 
A two-factor MANCOVAs analysis will be conduct with Site and Treatment Group as 
between-subject factors, age as a covariate, and time (pre-post) and connectivity 
values in a priori brain regions as repeated measures factors.   
Hypotheses 
In contrasting resting fMRI data, we hypothesize that both connectivity methods will 
show that both FEAST and UB RUL ECT treatments significantly reduce connectivity 
between frontal cortex structures, replicating previous findings (Perrin et al., 2012, 
Abbott et al., 2013).  However, we hypothesize that this effect is especially focal within 
the FEAST group (that is, FEAST patients will show a greater reduction in hyper-
connectivity than will UB RUL, and these changes will be more restricted to right frontal 
regions.   
B.6 FEAST Procedures 
Medication Status. Patients will be stabilized on their medications for 7 days 
and will be withdrawn from lithium and anticonvulsants for at least 5 days.  ECT starts 
after completion of the baseline battery, usually after an additional 1-2 days. PRN 
lorazepam is limited to 3 mg/d, and is withheld approximately 10 hr before a 
treatment. A daily log is kept of all medications (psychotropic or otherwise) patients 
receive. Introduction of any medication during the FEAST (or UB RUL ECT) will be 
considered a protocol violation but will not lead to termination from the study. 
 
General Treatment Technique. After completion of the pretreatment assessment 
battery, treatment with FEAST will begin. FEAST will be administered only with the 
modified Spectrum 5000Q device approved with this IDE application. Treatments are 
given in the morning, 3 times per week. Pharmacological agents are standardized: 
atropine (0.4 mg IV), methohexital (0.75 mg/kg) and succinylcholine (0.75-1.0 mg/kg). [If 
methohexital is unavailable, thiopental is substituted (2.0 mg/kg).] Patients are 
oxygenated by mask (100% O2) prior to anesthesia and until resumption of 

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spontaneous respiration. Standardized procedures are used to reduce impedance at 
FEAST and EEG electrode sites. The impedance of the EEG electrodes is kept ~ 5k ohms.  
 
The "cuff technique" assists in monitoring the duration of ictal motor activity (Fink and 
Johnson, 1982). The EEG sites are left and right frontal (F7 and F8) and a custom 
placement for the left and right temporal leads (to avoid overlap with the RUL ECT 
electrodes). Each EEG site is referenced to the ipsilateral mastoid (Weiner and Krystal, 
1993). A detailed manual is available that describes detailed procedures for preparing 
the FEAST or RUL ECT electrode sites and the EEG sites. As indicated the primary 
hypothesis tested in this study concerns the ictal EEG collected at every treatment. We 
predict that seizure onset will be more restricted to the right frontal site with FEAST 
compared to UB RUL ECT.  
 
The criterion for an adequate seizure is ≥ 20 s EEG duration. Subconvulsive stimuli, 
which occur only during titration sessions, are followed 20 s later by restimulation. Up 
to 5 stimulations are permitted at titration. Using these criteria, across our two of our 
recent studies, only 3 out of 1,372 treatment sessions were terminated without an 
adequate seizure (all due to very high thresholds at the first treatment). Additional 
monitoring includes continuous display of three channels of ECG (leads I, II, IV), heart 
rate, blood pressure, and pulse oximetry. At each treatment, the 4 EEG channels are 
digitized and along with treatment parameters automatically entered into a database 
using the MECTA EMR (electronic Medical Record) software. The intervals to return of 
spontaneous respiration and eyes opening upon command are also recorded. 
 
 
FEAST Stimulus Dosing. After completion of the pretreatment assessment 
battery, treatment with FEAST will begin. FEAST will be administered using a 
modified spECTrum 5000Q device. In this study, stimulation parameters at titration 
will be restricted to an ultrabrief electrical stimulus (0.3 ms pulse width) and 
unidirectional administration. The amplitude of the constant current during each 
pulse will also be fixed at 800 mA. Train duration (1.5-8 s) and pulse frequency (30-
80 Hz) will be the primary parameters manipulated to adjust dosage relative to 
seizure threshold (see Table 4). [One suprathreshold setting involves increasing 
pulse width to 0.5 ms]. 
 
At the first treatment, the empirical titration procedure is used to estimate ST 
(Sackeim et al., 1987c, Sackeim et al., 1987d, Sackeim et al., 1991). This procedure at 
the first session ensures that the lowest charge needed to evoke a seizure is 

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identified for each individual patient (Sackeim et al., 1994, American Psychiatric 
Association, 2001). Dosing at subsequent treatments will be substantially above 
seizure threshold. With traditional ECT and a RUL electrode placement, a dose of at 
least 6 times the initial seizure threshold (6xST) has been shown to be maximally 
effective (McCall et al., 2000, Sackeim et al., 2000b), with lower dosage resulting in 
reduced efficacy (Sackeim et al., 1987b, Sackeim et al., 1993). This is also the case 
when an ultrabrief stimulus is used with the RUL electrode placement (Sackeim, 
2004a, Sackeim et al., 2008, Loo et al., 2012). Thus, the minimum dosage for FEAST 
will be approximately 6xST in treatments administered after the first session [see 
Table 4]. Given insufficient clinical progress after at least 5 treatments, this dosage 
may be increased to up to approximately 9XST prior terminating use of FEAST. Since 
the seizure thresholds with an ultrabrief stimulus are very low (Sackeim, 2004a, Loo et 
al., 2012), and are expected to be lower still with the use of FEAST, the absolute 
dosage administered will in almost all cases be well below that commonly 
administered with routine treatment in the community.  
 
The criterion for determining ST will be EEG determined. In the past 28 patients at 
MUSC we are now sufficiently confident that FEAST seizures can be seen on EEG. We 
will also record motor movement cessation in the leg that has the BP cuff inflated. 
 
Table 4. Titration and Dosing Schedule 
 
Titration and Dosing Schedule 
 
 
 
 
 
 
 
 
 
Pulse 
Frequency 
(Hz) 
Pulse 
Width (ms) 
Train 
Duration    
(s) 
Current    
(mA) 
Total 
Charge 
(mC) 
Dose 
Relative to 
Initial ST 
 
 
 
 
 
 
20 
0.3 
1 
800 
9.6 
 
20 
0.3 
2 
800 
19.2 
 
20 
0.3 
4 
800 
38.4 
 
20 
0.3 
8 
800 
76.8 
 
40 
0.3 
8 
800 
153.6 
 
80 
0.3 
8 
800 
307.2 
 
 
 
 
 
 
 
Subsequent Dosing: 6 X ST 
 
 
 
20 
0.3 
6 
800 
57.6 
6 
30 
0.3 
8 
800 
115.2 
6 
60 
0.3 
8 
800 
230.4 
6 
90 
0.4 
8 
800 
460.8 
6 
90 
0.5 
8 
800 
576 
3.75 
 
 
 
 
 
 
Subsequent Dosing: 9 X ST 
 
 
 

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30 
0.3 
6 
800 
86.4 
9 
60 
0.3 
6 
800 
172.8 
9 
90 
0.3 
8 
800 
345.6 
9 
90 
0.5 
8 
800 
576 
7.5 
 
The titration schedule to be used in the study and the prescribed dosing at treatments 
following the initial titration session are presented in Table 4. The titration schedule 
starts with a dose of 9.6 mc, which is nearly the lowest ever used in clinical or research 
use of ECT, reflecting the expectation that seizure thresholds will be very low.  
 
Only 6 parameter combinations will be used at initial titration, with a range of charge 
from 9.6 to 307.2 mC. If a patient does not have an adequate seizure at the highest of 
these settings (307.2mC) they will exit the protocol and be offered conventional ECT. 
[This has not occurred in any of the patients who have received FEAST.] The highest 
dosage that can be used in this study is 576 mC, the same as the maximal output of a 
standard domestic Spectrum 5000Q (576 mC).  
 
The stimulating electrodes consist of a small (1.25”) round stainless steel electrode 
and a larger poster stainless steel electrode (2 x 3”) that attaches in a standard 
manner to the MECTA remote-treat or standard stimulus cables. This smaller 
electrode will be placed anteriorly with the lower boundary just above the center of 
the right eyebrow. The larger posterior electrode is concave in shape to better 
couple to the scalp. The posterior electrode will be placed tangential to the midline 
and extend across the right supplementary motor cortex. The medial position of 
this electrode will be adjacent to the line connecting the nasion and inion and with 
the posterior boundary 1.0” anterior to the vertex, with the lateral portion extending 
over the right hemisphere. A self-adhesive locator will be used to position the 
anterior anode electrode, ensuring restiriction of any conductant gel to the 
geometry of the anode. 
 
Unless otherwise contraindicated, all patients will be premedicated with atropine 
(0.4 mg IV) to block the parasympathetic effects of electrical stimulation 
(approximately 2 minutes prior to anesthetic induction). As indicated, methohexital 
(1.0 mg/kg) will be used as the general anesthetic and succinylcholine (0.75 mg/kg) 
will serve as the muscle relaxant. Dosing of these agents after the first treatment will 
be based on anesthetic response. Patients will be oxygenated from prior to the 
induction of anesthesia until the return of spontaneous respiration. 

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At MUSC, ECT sessions will be conducted in a dedicated ECT suite on the fifth floor 
of the Institute of Psychiatry. At GRU, ECT sessions can be either inpatient or 
outpatient, depending upon the patient’s needs, and can occur either at Georgia 
Regents Medical Center in Augusta , Georgia, or at Aiken Regional Hospital in 
Aiken, South Carolina, depending upon patient preference. The custom device used 
for FEAST will not be used for any other purpose. [Patients receiving UB RUL ECT 
will be treated with a standard commercial MECTA Spectrum 5000Q.  After the 
patient is medically stabilized following the administration of FEAST he/she will be 
moved by stretcher to an adjacent recovery room where she/he will complete 
neuropsychological testing (recovery of orientation, if not already obtained). 
Patients leave the recovery room only after being cleared by medical staff. 
 
 
RUL ECT Stimulus Dosing. For the matched  RUL sample, we will use the 
same MECTA device, but with conventional ECT settings. We will not use the FEAST 
electrodes, but instead will use conventional ECT electrodes. Seizure threshold will 
be determined at the first session, and subsequent treatments will be performed at 
6 times seizure threshold. As this is a rough clinical comparison sample, all aspects 
of ECT treatment in these individuals will follow what is now routine clinical practice 
at MUSC and GRU. These details are outlined in the landmark paper regarding RUL 
ECT (Sackeim et al, 2008). 
 
Number of Treatments. Duration of treatment will determined by a clinical 
evaluation team at each site. ECT is typically dynamically adapted to each person, 
attempting to deliver the necessary treatments for that patient, and no more. We 
incorporate that model in this IDE, similar to our algorithm in the first IDE. At MUSC 
that team is composed of Dr. Mark George, Dr Baron Short, and Ms. Carol Burns, 
Senior Nurse and ECT specialist. At GRU the ECT delivery team consists of Dr. W. 
Vaughn McCall and Dr. Peter Rosenquist, while depression severity, quality of life 
and cognitive ratings will be performed by Dr. Laryssa McCloud, Mary Anne Riley, 
MS, Chelsea Hodges, MS or Brittany Gubosh. 
 
There is no stipulated minimum or maximum treatments for patients to be classified 
as provisional responders; the aims are to achieve maximal improvement in each 
patient without exposing them to unnecessary treatment. In patients who have 
shown substantial benefit (>40% improvement in HRSD24 score), treatment is 
continued until there is a plateau over at least two treatments (i.e., change in 

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HRSD24< 3 points) or it is judged that maximal improvement has been achieved (ie, 
HRSD24≤ 5). In patients who have shown more than 40% improvement, a minimum 
of 10 treatments will be required before classification as a nonresponder. In patients 
with <40 % improvement, treatment may be stopped when a plateau in 
improvement has obtained and the patient has received at least 6 treatments.  After 
5 treatments, there is the option of increasing electrical dose from 6xST to 9xST.  
Thus, the trajectory of symptomatic change is closely monitored. These criterion 
ensure an adequate trial of ECT (Sackeim, 1986b) before declaring nonresponse, 
while not exposing patients who respond rapidly or patients who show no benefit 
to excessive treatment.  
 
Non-responders to FEAST will be offered a course of traditional ECT, first using high 
dosage RUL with a standard pulse width (i.e., 0.5-1.0 ms), and, if necessary, 
switching to bilateral ECT. The efficacy evaluation procedures will be repeated after 
this second (Mode 2) course.  
 
Participation in this protocol terminates following the acute completion of the final 
assessments (clinical, neuropsychological, and fMRI). Patients will be followed up at 
2,4, and 6 months. At that 6 month visit they are fully terminated from the study. Of 
note, after the acute phase is over, FEAST patients resume fully standard care at the 
discretion of the ECT team and the referring physicians. We will document 
medication changes and whether they require additional ECT during the 6 month 
followup. 
 
 
B.7 Ultrabrief RUL ECT Treatment Procedures 
FEAST and ultrabrief RUL ECT patients will be treated identically except as noted 
below. The traditional d’Elia electrode placement will be used for UB RUL ECT 
(American Psychiatric Association, 2001), with the frontotemproal electrode 
tangential to the midpoint of the line connecting the right auditory tragus and the 
canthus. The posterior electrode will be tangential to the vertex (midpoint of line 
connecting nasion and inion). Standard stainless steel 2” diameter electrodes will be 
used. If it is deemed that patients require a change in ECT modality, a switch to 
either brief pulse RUL or BL ECT will be implememnted, as clinically indicated.     

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B.8 Assessment of Efficacy 
 
Clinician ratings. Instruments include the HRSD (24-item) (Hamilton, 1967), 
MADRS (Montgomery and Asberg, 1979), CGI (severity and improvement) (Guy, 
1976), and the GAS (Endicott and Spitzer, 1978). A clinical evaluation team 
independently completes these scales on the basis of conjoint interviews, both at 
set time points (preECT baseline, 1-2 days after ECT termination) and the HRSD 
alone is also completed at spaced intervals (weekly during the ECT course). 
Interviews usually take place between 10 AM-12 PM to minimize variability due to 
diurnal variation. 
 
 
The HRSD is the "gold standard" in MDE treatment trials (Depression Guideline Panel, 
1993). The 3 additional items on helplessness, hopelessness, and worthlessness in the 
HRSD24 are especially relevant in ECT samples. The HRSD24 has provided the primary 
efficacy outcome measures for the previous ECT trials at NYSPI (Sackeim, 2004a, 
Sackeim et al., 1987b, Sackeim et al., 1993, Sackeim et al., 2000b, Sackeim et al., 2008), 
the national multisite trials that we have organized (Sackeim et al., 2001a, Prudic et al., 
2004a, Sackeim et al., 2009), as well as single-site (McCall et al., 2000, Bailine et al., 
2000) and multi-site ECT trials conducted by others (O'Connor et al., 2001, Petrides et 
al., 2001). Thus, consistency with the literature and the large databases available 
dictated this choice. We have demonstrated near perfect inter-rater reliability in its use 
(ICCs > .98) (Sayer et al., 1993, Sackeim et al., 1993), and have reported on its internal 
reliability, factor structure, sensitivity to change, and relations with self-report measures 
in ECT samples (Sayer et al., 1993). Nonetheless, studies using traditional factor analytic 
methods (Sayer et al., 1993, Fleck et al., 1995) or normal item response theory (IRT) 
models (Gibbons et al., 1993) have shown that the HRSD has several limitations. Medical 
illness in the elderly can contaminate HRSD scores, which are influenced by somatic 
symptoms (Koenig et al., 1993, Fleck et al., 1995, Legrand et al., 1995). Keeping this in 
mind, total HRSD scores are the primary measure in efficacy analyses. Secondary 
analyses will be performed on response and remission rates and on MADRS, CGI and 
IDS-SR scores. Dr. Sackeim has authored a detailed, structured, combined interview for 
the HRSD and MADRS, with new and explicit anchors for each item. A different version 
of this interview is used when symptoms are assessed over a one-week time frame (e.g., 
preECT, follow-up visits), and when the HRSD is administered twice weekly during the 
ECT course. In several large multisite studies of rTMS, VNS, ECT, and pharmacotherapy, 
ICCs between clinical raters and time-blind ratings of videotapes at NYSPI have 
exceeded 0.96 (Sackeim et al., 2001a). 
 

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Self-Report ratings. The Inventory of Depressive Symptoms (IDS-SR) (Rush et 
al., 1985) is completed at baseline, and following completion of the course. This 
instrument has shown strong psychometric properties and is especially broad in its 
coverage of depressive symtpoms. It has been used in many  MDE treatment trials, 
including STAR*D (Rush et al., 2006).  
B.9 Classification of Clinical Outcome and Dropout 
Dropout. If, for any reason, there is a lapse of 3 scheduled treatments during a 
FEAST course (e.g., intercurrent illness, withdrawal of consent), the course is considered 
terminated. If, for any reason, the patient receives a prohibited psychotropic they are also 
considered to have dropped out. Patients who withdraw consent for research 
participation are immediately withdrawn from the research. The Principal Investigator or 
the Study Physician may withdraw a patient from the protocol at any time if it is deemed 
in the patient’s interest to do so. Examples include emergence of a complicating medical 
condition, discovery of a previously undiagnosed exclusion criterion, etc. 
 
 
Response Criteria. Remission is the categorical outcome that has precedence 
for efficacy determination. However, response status denotes that substantial, but 
incomplete, benefit has obtained. The a priori criteria for response are consistent 
across virtually all MDE clinical trials. Based on an assessment 1-2 days following ECT, 
patients are responders if they have a ≥50% reduction in HRSD24 scores relative to 
preECT baseline. All other patients are nonresponders.  
 
 
Remission Criteria. Especially when ECT is the treatment modality, the goal is 
remission and not response (Thase, 2003, Paykel, 2002, McCall, 2014, McCall, 2013). 
Remitters in this study must satisfy final response criteria and have a 1-wk postECT 
HRSD ≤ 10. The remitter criteria are stringent, given the use of the 24-item HRSD 
and the severity of illness at study entry. 
B.10 Assessment of Function and Attitudes Toward Treatment 
 
Health-Related Quality of Life (HRQOL). We hypothesize that the reduced 
side effect burden of FEAST translate into a HRQOL advantage. We will use the 
Medical Outcomes Study SF-36 (MOS SF-36) (Ware and Sherbourne, 1992). While 
there are depression-specific HRQOL scales (Grégoire et al., 1994, Turner, 1994), the 
MOS SF-36 was selected because of its widespread use (including treatment studies 
of MDD) (Lonnqvist et al., 1995, Lonnqvist et al., 1994), brevity, data on reliability 
and validity (McHorney et al., 1993), and its sensitivity to change with the treatment 

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of MDD (Miller et al., 1998). Its 8 dimensions have internal reliability estimates 
ranging from .77 to .98, and strong relative precision values compared to the full 
scale. The MOS SF-36 is completed at preECT baseline, and during the week 
following ECT. Dr. McCall ahs shown that ECT samples are especially impaired in 
MOS SF-36 scores at baseline, and that sustained remission following ECT results in 
profound improvement, with scores of remitted patients virtually indistinguishable 
from normative values (Rosenquist et al., 2006, McCall et al., 2013, McCall et al., 
2011b, McCall et al., 2006).  
 
 
 
Expectations and Attitudes Toward Treatment. A structured interview is conducted 
at baseline and during the week following FEAST/ECT. At baseline, this interview queries 
expectations regarding the effects of the impending course on mood and cognition. The 
postECT interviews is structured to make the same inquiries about the completed ECT 
course. Patients provide a global self-evaluation of the impact of the treatemnt on mood 
and memory using a 9-point Likert-type scale (i.e, +4 very much improved, 0 no change, 
-4 very much worsened. Post-ECT patient reports using this interview have shown strong 
relations with clinical outcome, extent of retrograde amnesia, and treatment modality 
(Brakemeier et al., 2011a, Berman et al., 2008).  
B.11 Documentation of Adverse Events 
Following FDA guidelines and IRB recommendations, we define an adverse event 
(AE) as any detrimental or unintended event involving a research subject. A serious 
adverse event (SAE) is any event that results in death, life threatening experiences, 
hospitalization or prolongation of hospitalization, disability or incapacitation, 
overdose, congenital anomalies or other serious events that may jeopardize the 
subject or require medical or surgical intervention to prevent any of the outcomes 
listed in this definition. An unexpected adverse event is any event that is not 
anticipated as a risk in the IRB-approved protocol and consent form, or occurs at a 
greater frequency or intensity than anticipated. 
 
Identification of an AE will trigger completion of an AE Report. The CRF will indicate 
whether this is the initial report or a follow-up. It will include an event description, 
start date, stop date or statement that the AE is continuing, rating of frequency (once, 
continuous, intermittent), grade (mild, moderate severe), whether it is considered a 
SAE (triggering a SAE report), relationship to FEAST (definite, possible, probable, not 
related), relationship to other study procedures (e.g., anesthesia), and description of 

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actions taken. Any occasion in which a medication is administered to treat an 
emergent side effect or complication (e.g., headache, arrhythmia) will be considered 
an AE. However, administration of medication for prophylactic purposes will not, in 
itself, constitute an AE. 
B.12 Assessment of Objective Cognitive Side Effects 
 
Overview. For the reasons outlined above, the cognitve battery is much reduced 
in this study. Four key measures will be collected.  The hypotheses concerning each of 
these measures were presented above. 
 
Oreintation recovery time will be assessed at every treatment session. The most 
profound cognitive effects of ECT are expressed in the postictal period (Daniel and 
Crovitz, 1983a, Daniel and Crovitz, 1983b, Sackeim, 1986a). The repeated assessment 
(every treatment) strongly enhances reliability of measurement, and allows for 
examination of progressive change over the treatment course (Calev et al., 1991a, Calev 
et al., 1991b, Sackeim et al., 1986). The measurement of orientation recovery has been 
particularly sensitive to variation in ECT electrode placement, waveform, and dosage. 
Further, it has been been repeatedly found to be a potent predictor of the degree of 
retrograde amnesia following the ECT course, even in the long-term (Sobin et al., 1995b).  
Following seizure termination, orientation (5 items) is assessed continuously until the 
criterion for full recovery is met or 90 min elapse. The critierion for recovery is correct 
response to 4 of the 5 items. The 5 questions pertain to name, birth date, age, place, 
and day of the week. 
 
The mMMS, Buschke Selective Reminding Test (BSRT) and CUAMI-SF will be 
administered at baseline and at follow-up (during the week following FEAST or UB RUL 
ECT).  The modified form of the MMS provides a total socre of 57 (as opposed to 30 with 
the original version) and broader coverage of gross cognitive abilities (Mayeux et al., 
1981, Stern et al., 1987). The primary use of the mMMS is sample characterization, 
epsecially since there is evidence that low baseline scores predict more severe short- 
and long-term retrograde amnesia (i.e., cogntively-compromised paitents are more 
vulnerable to the key adverse effect on memory) (Sobin et al., 1995a). No change is 
expected in mMMS scores in either group.  However, as a safety measure, the two 
groups will be compared in change in mMMS scores to verify this assumption and 
assure that there was no change in global congtive status. 
 

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Anterograde verbal learning and memory will be assessed with the BSRT (Hannay & 
Levin, 1985). Impairments in verbal earning have been demonstrated with this instrument 
when administered during the ECT course, with impairments in retention (delayed recall) 
most evident shortly following the treatment course (Steif et al., 1986).  BSRT scores 
during and immediately following ECT have been sensitive to differences in ECT 
electrode placement (e.g., Sackeim et al., 1993; Sackeim et al., 2007). Versions A and B 
(Hannay & Levin, 1985) will be used in an ABAB or BABA format over the 4 time periods, 
with assignment to either order randomly determined.  The BSRT will follow standard 
scoring using a 6 trial acquisition phase, and free recall tested after a 30 min retention 
interval.  Indeed, an invariant order of testing will be used at each time point, starting 
with the mMMS, then the 6-trtial acquisition phase of the BSRT, followed by 
administration of the CUAMI-SF during the delay interval, followed by the free recall trial 
of the BSRT.  The dependent measures derived from the BSRT will be total recall over the 
6-trial acquisition phase (learning) and the delayed total recall score (retention).  We 
expect that the FEAST group will have superior scores on the delayed recall score 
relative to the comparison group at the immediate postECT time point. We do not 
expect group differences at the later time points, since persistent deficits following ECT 
on this task have not been identified (e.g., Sackeim et al., 1993; Sackeim et al., 2007). 
 
Retrograde amnesia for autobiogrpahical information will be assessed with the CUAMI-
SF (McElhiney et al., 2001). Although there has been some controversey about the 
reliability and validity of the measure (Semkovska and McLoughlin, 2010, Semkovska and 
McLoughlin, 2013, Semkovska et al., 2012{Semkovska, 2014 #23089)}, the CUAMI-SF has 
been remarkably sensitive to both short- and long-term effects of ECT (Sackeim, 2014a), 
showing, for example, long-term differences in amnesia scores as a function of electrode 
placement, stimulus waveform, and number of treatments (Sackeim et al., 2007, Sackeim 
et al., 2008). The CUAMI-SF is also the only neuropsycholopgical instrument to show 
signifcant covariation with pateints’ subjective report of the effects of ECT on their 
memory (Berman et al., 2008, Brakemeier et al., 2011a).  Accordingly, we expect post-
course CUAMI-SF scores to be superior in the FEAST relative to the UB RUL ECT group. 
 
Table 5: Schedule of Procedures/Assessments 
 
Assessment or 
Measurement 
Screening 
Visit (s) 
MRI 
Visit 
ECT Weekly 
Assessments 
End  
Of 
Acute 
Study 
MRI 
Visit 
#2 
2 month, 
4 month, 
6 month 
follow-up 

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Informed Consent 
X 
 
 
 
 
 
Study Information 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical Workup 
X 
 
 
 
 
 
SCID and other 
treatment 
assessment 
battery (table 3) 
X 
 
 
X 
No 
SCID 
 
 
HRSD 24 
X 
 
X 
X 
 
X 
ATHF/medications 
X 
 
 
X 
 
X 
Cognitive Battery 
X 
 
 
X 
 
X 
MRI scan 
 
X 
 
 
X 
 
 
B.13 Neurophysiology 
Four-Channel Ictal EEG. At each treatment, 4 channels of EEG are recorded with 
the MECTA Spectrum amplifiers (1.4-48 Hz bandpass, -3dB, 12 dB/octave), and 
digitized and archived with MECTA EMR software. The spatial positioning of the 
frontal and temporal EEG electrodes, the preparation of each electrode site, and the 
referencing to ipsilateral linked mastoid EEG electrodes are detailed in a study manual. 
At each session, impedance of the each referenced pair is determined to be below 5k 
ohms.  
 
The 4-channel EEG recordings are manually artifacted to remove non-
encephalopathic signals. Expert visual inspection is used to define for each session the 
temporal periods characterized as preictal baseline (20 seconds prior to stimulus 
delivery), tonic phase (post-stimulus to onset of prominent low wave activity), clonic 
phase (end of tonic until offset of seizure activity in all channels) and postictal period 
(20 s following the termination of the seizure). These 4-channel ictal recordings are 
analyzed in a fashion identical to the procedures we have previously employed, but 
with the addition of measures of coherence (Luber et al., 2000, Nobler et al., 2000a). 
Power spectral analyses will be conducted, using a moving Hanning window and 
apply a Fast Fourier Transform to yield power and coherence data for each electrode 
site and measurement period for delta, theta, alpha, and beta frequency bands. The 4-
channel recordings allow averaging across treatments to enhance reliability of 
measurement, and examination of cumulative effects (Krystal et al., 1998, Krystal et al., 
1996a, Krystal et al., 1997, McCall et al., 1996a).   

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The primary aim of this study is to contrast FEAST and UB RUL ECT in these EEG 
measures of seizure onset and propagation. Specifically, we expect FEAST to show 
greater focality of seizure onset than UB RUL ECT, with seizure onset most manifest in 
the right frontal EEG with FEAST, and far greater activity in the left and right temporal 
leads with UB RUL ECT. 
B.14 Quality Assurance and Data Management 
A highly experienced rater will provide clinical ratings throughout the treatment 
period. Accuracy of the output of the FEAST device will be tested (Sackeim et al., 
1994), and calibration signals regularly applied to the EEG recordings. The stimulus 
parameters used with the modified Spectrum 5000Q will both be recorded 
electronically and transferred to a database using the Spectrum’s automatic EMR 
logging software. An experienced psychometrician will review all neurocognitive data. 
Data will be entered on digital forms using automatic flags for out-of-range and 
missing values. Any correction to a data record will be recorded in an audit notebook. 
The study database will be backed-up regularly. 
B.15 Statistical Analyses 
 
Data Screening. Data will be reviewed for extreme values. When distributional 
assumptions are not met, data will be transformed or nonparametric procedures used. 
Prior to statistical analyses, the study sites (MUSC vs. GRU) and treatment groups 
(FEAST vs. UB RUL ECT) will be compared in the baseline sociodemographic and clinical 
features, using ANOVA and log-linear analyses, with a liberal threshold to detect 
inequality (P < 0.2).  
 
 
Hypothesis Testing. Even though this is a preliminary investigation, yielding 
effect sizes by which to power a subsequent randomized study, it is important to 
protect the Type I error rate by limiting primary analyses to a restricted and clearly 
specified set of hypotheses and outcome measures. The primary analyses will test the 
hypotheses stated below which address the objectives described in Section II. The 
major areas of investigation are effects on seizure threshold, electrophysiological 
(EEG) activity, efficacy, function, objective changes in cognition and subjective 
cognitive changes. The primary efficacy analyses will be conducted in the intent-to-
treat sample. 
 
 

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Hypothesis 1.FEAST is substantially more efficient (i.e., lower ST) than traditional 
ECT, even when both use an ultrabrief (0.3 ms) pulse width. 
 
An identical titration schedule is used at the first treatment in all patients. Seizure 
threshold, quantified at the first treatment (in mC) will be log10 transformed to 
achieve normal distributions, with adequacy of fit tested. An ANCOVA will be 
conducted on these values with Site (MUSC vs. GRU) and Treatment Group (FEAST vs. 
UB RUL ECT) as between-subject factors, and age and gender as covariates. Second 
order interactions will be modeled for the covariates. Gender and age were selected 
since they have repeatedly shown association with ST (Boylan et al., 2000, Krueger et 
al., 1993, Sackeim et al., 1987c, Sackeim et al., 1987d, Sackeim et al., 2008). 
 
Hypothesis 2. In quantitative 4-lead ictal EEG measures, FEAST results in (a) less 
intense seizure expression (i.e., reduced amplitude especially in low frequency bands) 
and (b) less postictal suppression, than UB RUL ECT. In addition, the FEAST group will 
manifest (c) marked asymmetry in the ictal EEG as expressed in greater amplitude 
(total power) in right relative to left hemisphere leads. With EEG leads over traditional 
frontal sites and novel temporal sites, FEAST will show a pattern of (d) greatest EEG 
seizure expression at the right prefrontal site. In contrast, the group treated with a 
bidirectional stimulus and a conventional electrode configuration (UB RUL ECT) will 
have (e) less of a gradient between the hemispheres and in the anteroposterior 
plane. Quantitative measures of (f) seizure expression and postictal suppression have 
no or weak relations with efficacy.  
 
The four-lead EEG digitized at each treatment will be subjected to a FFT after 
artifacting, and power computed in 4 frequency bands, as well as total power across 
bands. The baseline, tonic, clonic and postictal epochs will be averaged separately. 
After testing for multivariate normality, MANCOVAs will be applied to the ictal and 
postictal power (log10) values, using Site and Treatment Group as between-subject 
factors, and age as a covariate. Hypotheses 2a and 2b call for opposite main effects 
in the ictal and postictal analyses. Hypotheses 2c and 2e predict an interaction 
between Treatment Group and the laterality repeated measures factor. Thus, an 
asymmetry index [(r-l)/(r+l)] will be greater with FEAST than conventional stimulation. 
Similarly, Hypotheses 2d and 2e calls for an interaction between Treatment Group 
and frontal vs. temporal lead placement. Finally, Hypothesis 2f states that measures 
of ictal and postictal power have at most weak relations with efficacy. Percent change 

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in HRSD24 scores will be added to the MANCOVAs as a covariate. Main effects of 
clinical improvement and first and second-order interactions will be modeled. 
 
Hypothesis 3. In contrasting resting fMRI data, both FEAST and UB RUL ECT 
result in a reduction of (heightened) frontal connectivity, replicating previous findings 
(Abbott et al., 2013, Beall et al., 2012, Perrin et al., 2012).  However, this effect is 
especially focal within the FEAST group, and more restricted to right frontal regions.   
 
MANCOVAs will be conducted with Site and Treatment Group as between-subject 
factors, age as a covariate, and time (pre-post) and connectivity values in a priori brain 
regions as repeated measures factors.    
 
Hypothesis 4. Efficacy as assessed immediately following the treatment course 
does not differ between the FEAST and UB RUL ECT groups. 
 
The primary analysis for Hypothesis 4 will use all available HRSD24 data (i.e., the intent-
to-treat data) from the FEAST and UB RUL ECT samples. A random regression model 
will be used to examine the relationship between HRSD24 scores and treatment group. 
Time will be the within-subjects repeated measures factor, site and treatment group 
the between-subjects factors, with medication-resistance classification and baseline 
HRSD24 serving as covariates. All interactions with time will be modeled. In secondary 
analyses, we will also include age, gender, age-at-onset of illness, and duration of 
current episode as covariates, if pre-screening indicates utility. We will investigate 
whether HRSD24 scores are linear in time or quadratic, cubic, or piece-wise linear (e.g., 
hockey-stick shaped). Indeed, in a study comparing several different statistical methods 
in their sensitivity to ECT treatment groups differences in rate of clinical improvement, 
we found that the HRSD24 scores over time were frequently nonlinear (Nobler et al., 
1997a). The type of analysis conducted on HRSD24 scores will be repeated for 
secondary analyses with the MADRS, IDS-SR, and CGI-S.  
 
FEAST and UB RUL ECT will also be compared in the categorical outcomes of final 
remission status (HRSD24 of 10 or less at post-treatment) in a secondary analysis to 
gauge generality of the effect and clinical significance. Nominal logistic regression 
analysis will be used to compare the treatment groups in covariate-adjusted odds of 
remission. Remission status will be the dependent variable. The independent 
variables will be the treatment group indicator, along with site, medication resistance, 
and baseline HRSD24.  

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Hypothesis 5. In two primary cognitive measures, orientation recovery time 
and CUAMI-SF scores, FEAST will have a significant advantage relative to UB RUL ECT. 
 
The cognitive measures were described in Section B.12. Orientation time will be 
averaged within each patient across all treatments. An ANCOVA will be conducted on 
these values with Site and Treatment Group as between-subject factors, and age and 
number of treatments in the average as covariates. A similar ANOCA will be 
conducted on CUAMI- 
SF scores, with Site and Treatment Group as between-subject factors, and age, 
number of treatments, and baseline CUAMI-SF score as the covariates. 
 
Hypothesis 6. FEAST will have a significant advantage in the subjective global 
evaluation of the effects of ECT on memory. 
 
An ANCOVA will be conducted on scores at the postECT time point. Site and 
Treatment Group will be the between-subject factors and age, percentage change in 
HRSD24 scores and percentage change in CUAMI-SF scores will be covariates.. 
 
C. Risk Analysis 
It is now clear that with our experience in 35 patients, that FEAST is a relatively well 
tolerated procedure.  Our preliminary data suggest that its cognitive side effect 
profile is equal if not lower that one observed with ultrabrief pulse right unilateral 
ECT.  In turn UB RUL ECT is now a widely, internationally used ECT modality. It is 
established to have a superior risk profile compared to traditional forms of ECT 
using bilateral or bifrontal electrode placement and/or brief pulse or sine wave 
stimulation (Loo et al., 2008, Loo et al., 2011, Loo et al., 2012, Loo et al., 2013, Loo et 
al., 2007, Sackeim et al., 2008).  Thus, this study contrasts an established ECT 
modality with a superior side effects profile (UB RUL ECT) to an experimental 
treatment (FEAST) that is expected to have a further improved side effect profile. 
C.1 Risks of Evaluation Procedures 
The research evaluation procedures include interviews to determine diagnosis and 
psychiatric symptomatology, medical exams, cognitive tests, self-report questionnaires 
(depressive symptoms, function, subjective evaluations of mood and memory effects, 
etc.), electrophysiological measures (ictal EEG), and fMRI measures. These evaluation 
procedures involve no risks to subjects.  

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C.2 Risks Unique to FEAST 
The major risks of the research, beyond those associated with ECT in general, are those 
associated with the administration of FEAST. This new modality is a form of ECT and is 
expected to have reduced risk of cognitive impairment compared to traditional forms of ECT. 
In particular, the use of a 0.3 ms pulse width is thought to markedly reduce the side effects of 
traditional brief pulse ECT, without impact on efficacy (Sackeim, 2004a, Sackeim et al., 
2008, Loo et al., 2012). Furthermore, the FEAST condition will be administered in such a 
way that cognitive side effects should be less intense and/or persistent than that which 
regularly occurs with older methods that do not take into account variation in seizure 
threshold. The use of a unidirectional current and focal stimulation should additionally 
contribute to further reductions in cognitive side effects. 
 
We do not anticipate that this form of ECT (unidirectional, ultrabrief pulse with 
spatial targeting) will have an adverse impact on efficacy, although this is not 
certain. Potential lack of efficacy likely constitutes the most significant risk of FEAST. 
Precautions have been taken in this protocol to mitigate this risk. First, patients who 
do show sufficient benefit after 5 treatments may receive a dosage increment, 
increasing the stimulus dose from 6xST to 9xST. In the community, dosing of UB 
RUL ST is often 8xST or more (e.g., (Loo et al., 2012)). Second, any patient who 
completes the research phase as a nonremitter will be offered a course of 
traditional ECT (UB RUL ECT, high dose RUL or BL ECT).  Our preliminary experience 
in 35 patients clearly indicates that FEAST has potent antidepressant properties.  We 
cannot, however, say with assurance that these properties are equivalent to 
traditional forms of ECT, without explicit comparison.  This study provides important 
data in this respect, involving the first cotemporaneous comparison of FEAST and 
UB RUL ECT, albeit in a non-randomized and non-masked fashion. It is anticipated 
that the findings obtained here will provide the foundation for a subsequent RCT. 
 
The protocol involves monitoring of objective and subjective side effects and includes 
provision for alternative treatment for patients who do not respond clinically. Although a 
large number of procedures are conducted, other than ECT, they are all noninvasive. 
Patients who consent to the protocol have the option of declining participation in specific 
procedures (e.g., fMRI studies), but can retain participation in the remaining procedures.  
 
Finally, FEAST might present with two theoretical risks: superficial skin burn and 
intracerebal damamge to excessive current density). The use of an electrode with small 
surface area could increase the impedance in the circuit and result potentially in skin burn or 
prevent the passage of the stimulus. This theoretical risk is minimized by the fact that the 
ECT device voltage limits and immediately aborts stimulus delivery when excessive 
impedance in encountered. In this protocol, we are requesting that  the voltage/impedance 

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limit be maintained at 400 V (500 ohm) for the maximal current (0.8 A). The maximal 
charge administered in this protocol is 576 mC. This is the same as the maximal output 
of a standard Spectrum 5000Q (576 mC). As indicated in Section V.D, the maximal 
power density with these values and the 1.25” electrode is comparable or below that 
commonly used in ECT.  
 
The 2 skin burns observed in the FEAST human studies were likely a function of the 
electrode sizes and asymmetries rather than total energy delivered. The standard 
electrode sizes in Europe and many countries outside the US are approximately 1” 
diameter, providing an effective area of 1.57 square inches (sum of the two areas). The 
burns in this study occurred while using an anode of 0.75 inch diameter and cathode 
of  1” X 2.5”. The combined effective area (see calculations elsewhere) is only 0.52 
square inches, resulting in energy densities at the anode three times higher than for 1” 
diameter electrodes. 
 
The second theoretical concern is that the degree of focality obtained with FEAST is so 
substantial that very high current densities could be achieved that may be injurious. This 
concern is obviated by intracranial measurements taken in nonhuman primates, contrasting 
FEAST with standard bilateral electroconvulsive shock (Spellman et al., 2009). The highest 
recorded values with FEAST were within the range of those seen with BL ECS. All 
observations indicated that BL ECS led to a more diffuse spread of current than FEAST. 
FEAST consistently showed a more marked anterior-posterior gradient than BL ECS, 
supporting its focality and an absence of excessively high current density. Furthermore, 
reviews of current density estimates with ECT (Weaver et al., 1976, Devanand et al., 1994) 
indicate that the values, even in the context of extremely high applied dosage, are not in the 
range associated with tissue injury (Agnew and McCreery, 1987, Agnew et al., 1983, 
McCreery et al., 1990, Yuen et al., 1981). We completed the most extensive study to date of 
potential neuropathological effects of ECS in non-human primates, using a randomized, 
double-blind, sham-controlled design. There was no histological evidence of tissue injury 
after 5 weeks of daily high dosage bilateral ECS (Dwork et al., 2004). Indeed, exacting glial 
and neuronal counts using stereological methods, failed to provide evidence of cell loss with 
ECS (Dwork et al., 2009).  
 
One of the 4 nonhuman primates died 8 days after participating in the FEAST studies. This 
event was judged to be unrelated to the research procedures as the animal had chronic 
indwelling electrodes and postmortem examination revealed that he had developed an 
infection along the track of one of the electrodes. Infection is not an uncommon occurrence 
in animals with chronic implantation. There is no evidence that electrical stimulation from 
FEAST or ECS could cause or contribute to an infectious process. Subsequent FEAST 
procedures have been successfully completed in another subject with implanted electrodes 
with no observed ill effects. 

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The 35 patients treated with FEAST at NYSPI and MUSC have shown no evidence of any 
serious adverse event.  All have tolerated the procedure well.  
 
Thus, there is no evidence to suggest that FEAST presents an electrical danger to 
patients. All the safeguards of modern ECT and the Spectrum 5000Q are preserved, and 
the intensity of electrical stimulation is expected to be markedly less than with traditional 
ECT techniques. 
C.3 Risks of ECT 
The potential adverse effects of ECT, and the steps that can be taken to reduce risk or 
manage complications, were described in III.C. These risks include death, medical 
complications (principally cardiovascular, pulmonary, and neurological), dental injury, 
fracture, dislocation, muscle soreness, headache, and nausea. In addition, there can be 
acute, short-term and long-term adverse cognitive effects and a set of risks associated with 
the premedication and anesthetic agents used in ECT. 
 
Medical Complications and Death. The risks of medical complications and death 
are heightened in individuals with serious and unstable medical conditions or who present 
with medical conditions known to markedly increase the risks of ECT, such aortic 
aneurysm (Devanand et al., 1990, American Psychiatric Association, 2001). Several steps 
are taken in this protocol to minimize these risks. First, patients believed to be at 
especially elevated risk for ECT induced complications are excluded. For example, 
history of neurological insult or disease is an exclusion, as are secondary diagnosis of a 
delirium, dementia, or amnestic disorder (DSM-V), pregnancy, or epilepsy. Second, all 
patients undergo an extensive physical and neurological exam, including blood workup, 
and are medically evaluated expressly for the purpose of evaluating the safety of ECT. 
Specialized medical consultations (i.e., cardiology consultation) are ordered as clinically 
indicated. Any recommendations of the medical consultant for enhancing the safety of 
ECT/FEAST, such as altering medication regimens, will be followed. Third, FEAST will 
be administered by experienced psychiatric attendings at MUSC and GRU, and by 
members of the Anesthesia departments at MUSC and GRU. The anesthesiologists, 
responsible for life support during FEAST, are privileged at each institution and each has 
considerable experience in the care of patients receiving ECT. In particular, residents will 
not be directly involved in the provision of FEAST. Fourth, the FEAST protocol is 
compatible with the administration of medications intended to reduce the risk of 
complications or the manage complications if they emerge. For example, in patients who 
manifest sustained hypertension prior to or following seizure induction, the 
anesthesiologist could recommend pretreatment with a beta-blocker, such as esmolol or 
labetalol, a common practice in ECT (Drop and Welch, 1989, Castelli et al., 1995).  
 
Dental Complications. Dental injury from ECT is rare and unusually occurs in the 
context of compromised dentition and/or improper use of a mouth guard (bite block) 

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(Minneman, 1995, Morris et al., 2002). A dental exam prior to ECT will be required for 
patients of any age who present with significant dental vulnerability (e.g., loose or fractured 
teeth, dentures, gum disease, etc.). Recommendations, such as the use of a custom bite block, 
will be followed. 
 
Fractures and Dislocations. With the use of muscle paralyzing agents, fracture 
and dislocation are extremely rare complications of ECT. Succinylcholine is the agent 
used in this protocol to reduce the intensity of convulsive movements. Several 
precautions are taken to further minimize the risk of skeletal injury. First, during the 
passage of the electrical stimulus there is contracture of the masseter and temporalis 
muscles due to direct stimulation. This could result in a vigorous clamping action of the 
jaw, creating dental or skeletal injury. The anesthesiologist presses upward on the chin, 
keeping the jaw closed and the bite block in place. Second, in case of inadequate 
succinylcholine dose or timing, especially at the first treatment, the patient’s limbs are 
gently held by nursing staff to prevent excessive movement. Third, in instances where 
there is uncertainty about the effectiveness of the muscular paralysis (.e.g., rapid 
metabolism), a nerve stimulator is used to gauge the degree of relaxation. Fourth, the cuff 
technique is used to monitor convulsive movements in a limb in which the distribution of 
succinylcholine has been blocked. This can result in fracture in elderly patients with 
marked osteoporosis if the cuff is placed high on a limb. In this protocol, the cuff is 
placed on the left ankle, avoiding the possibility of such injury. 
 
Muscle Soreness. Muscle soreness is either a consequence of excessive vigorous 
convulsive motor activity or intense fasciculations due to the depolarizing muscle relaxant 
(American Psychiatric Association, 2001). This complication is usually reported after the 
first treatment and commonly is not experienced again even if no change is made in 
treatment technique. Therefore, conservative management of this complication involves 
assessment of its source (fasciculations vs. excessive convulsive movements) and its 
severity. Mild or moderate soreness after the first treatment might result in careful 
observation for recurrence at the next treatment without a change in technique. Recurrent 
and/or severe complaints may result in (a) an increase in the muscle relaxant if excessive 
convulsive movements are causal; (b) premedication with a non-depolarizing agent such as 
curare to reduce the intensity of fasciculations; or (c) switch to a non-depolarizing agent. 
 
Headache and Nausea. Postictal headache and nausea are common sequelae of 
ECT. Prediction of individuals at risk is not possible, although determining previous 
response to general anesthesia and ECT may be helpful. Furthermore, although not 
established empirically, most practitioners believe that individuals predisposed to 
migraine may be likely to experience headaches following ECT.  
 
Treatment of post-ECT headache is symptomatic. Typically, aspirin, acetaminophen, 
or non-steroidal anti-inflammatory drugs (NSAIDs), are highly effective. If postECT 

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headache is severe, sumatriptan should prove effective. PostECT nausea is typically 
well controlled with the serotonin 5HT3 receptor antagonists, ondansetron. 
 
Cognitive Side Effects. In several respects, the cognitive alterations are the 
most concerning risks of ECT. While it had been frequently contended that all the 
cognitive side effects were transient, it is now evident that many patients will 
experience some degree of persistent, and likely permanent, retrograde amnesia 
(Sackeim, 2000, American Psychiatric Association, 2001, Sackeim, 2014b). 
Furthermore, in some exceptional individuals, this retrograde amnesia will be 
profound extending back several years and involving loss of memory for substantial 
personal experiences and knowledge of the external events (Donahue, 2000, 
Lisanby et al., 2000, Sackeim, 1992, Freeman et al., 1980).  
 
There is no empirical evidence that ECT results in long-term deficits in cognitive 
domains other than memory for past events (retrograde amnesia) (Sackeim, 1992, 
Semkovska and McLoughlin, 2010). However, in the acute and subacute period, ECT 
often has a deleterious effect on the retention of newly learned information 
(anterograde amnesia), and may acutely disrupt a variety of cognitive processes, 
including attention and concentration (Sackeim, 1992, Sackeim, 1986a). At its most 
intense, ECT can result in an organic brain syndrome (OBS) in which the patients is 
continuously disoriented (Miller et al., 1986). It may take several days or more for OBS 
to resolve after the termination of ECT (Summers et al., 1979). Consequently, the 
severity and persistence of the cognitive effects of ECT determine, in part, the 
duration of the period of convalescence that follows the treatment, during which 
patients should refrain from driving, use heavy equipment, or make important 
financial or life decisions (American Psychiatric Association, 2001). 
 
Both patient and treatment variables are predictive of the severity and persistence of 
cognitive side effects. Fortunately, factors that are associated with less severe acute 
side effects are also predictive of less severe and persistent long-term side effects. 
Thus, the cognitive response of the patient to the administration of ECT during the ECT 
course is a strong indicator of the likelihood of long-term persistent amnesia. For 
example, Sobin et al. (1995b) demonstrated that the duration of disorientation in the 
immediate postictal period was predictive of the magnitude of retrograde amnesia two 
months following the completion of ECT. Thus, patients show unusually intense 
cognitive side effects during the receipt of ECT are especially likely to have more 
severe and/or persistent deficits. The predictive value of orientation recovery for 

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retrograde autobiographical amnesia was recently replicated in Australia by Loo and 
colleagues. Identifying such patients and altering methods of ECT administration, such 
as reducing the frequency of treatment, switching from BL to RUL ECT, or adopting use 
of an ultrabrief pulse width may reduce the risk of persistent impairment. 
 
Patients with preexisting neurological or cognitive impairment appear to be at 
increased risk for ECT-induced cognitive side effects (Sobin et al., 1995b, Sackeim, 
2004b, Sackeim et al., 2007). Consequently, the exclusion of patients with a history 
of neurological disease or insult should aid in mitigating against excessive cognitive 
side effects. Several factors in the administration of ECT also impact on the 
magnitude of cognitive side effects. The most important of these variables are: (a) 
electrode placement or the anatomical positioning of electrodes; (b) stimulus 
waveform; (c) stimulus dosage relative to seizure threshold; (d) spacing of 
treatments; (e) number of treatments; and (f) anesthetic dosage.  
 
It is well established by the traditional bifrontotemporal (bilateral) electrode 
placement results in broader and more severe cognitive side effects than the right 
unilateral placement (Valentine et al., 1968, Lancaster et al., 1958, Costello et al., 
1970, Bidder et al., 1970, Strain et al., 1968, Weiner et al., 1986, d'Elia and Perris, 1970, 
Lisanby et al., 2000, McElhiney et al., 1995, Sackeim et al., 1986, Sackeim et al., 1993, 
Sackeim et al., 2000b). Furthermore, our recent evidence, form the largest 
prospective long-term study of ECT cognitive side effects, indicates that severity of 
persistent retrograde amnesia is greater six months following ECT in patients 
treated with the BL than RUL electrode placement. Indeed, the number of BL 
treatments was linearly related to amnesia scores at this time point, while there was 
no relation to the number of RUL treatments (Sackeim et al., 2007). 
 
There is substantial evidence that waveforms inefficient in producing neuronal 
depolarization result in more severe cognitive side effects without any advantage 
with respect to efficacy. Thus, compared to brief pulse stimulation, sine wave 
stimulation is especially likely to produce organic brain syndromes and greater 
deficits in a variety of cognitive domains, and recent evidence suggests that some 
of these untoward effects may be persistent (Scott et al., 1992, Weiner et al., 1986, 
Spanis and Squire, 1981, Weaver et al., 1977). In turn, the use of ultrabrief stimulation 
has been shown recently to have dramatic savings with respect to cognitive side 
effects relative to standard brief pulse stimulation, and this effect also appears to be 
persistent for some cognitive measures (Sackeim et al., 2008). In our most recent 

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randomized trial at NYSPI, coupling RUL ECT with ultrabrief pulse stimulation 
resulted in retrograde amnesia scores that were indistinguishable from those of 
healthy participants studied at comparable time intervals. In other words, there was 
no evidence that RUL ultrabrief ECT produced retrograde amnesia a few days 
following ECT.  This makes the choice of UB RUL ECT as the contrast condition 
especially challenging and clearly minimizes the risks of study participation. It is 
noteworthy that the cognitive savings associated with ultrabrief stimulation have 
been widely replicated (Loo et al., 2012, Sienaert et al., 2010). 
 
The absolute dose (charge) administered in ECT shows little relation to cognitive side 
effects. In contrast, consistent relations have been observed when quantifying the 
extent to which dosage exceeds seizure threshold (Sackeim et al., 1987c, Sackeim et 
al., 1993, McCall et al., 2000). This reflects the fact that a large component of the 
delivered dose is shunted away from brain and it is likely that dose relative to 
threshold provides a better index of intracerebral charge density than absolute dose 
(Sackeim et al., 1994, Deng et al., Lee et al., 2010, Peterchev et al., 2010). Treatment 
techniques that do not quantify the seizure threshold and which administer an 
arbitrary fixed dose to all patients can result in patients receiving stimulus intensities 
that exceed threshold by 20-50 fold (Sackeim et al., 1991). Excessive cognitive side 
effects are expected under these circumstances.  
 
There is consistent evidence that treatment schedules that are closely spaced (e.g., 5 
times per week) result in greater cognitive side effects, while greater spacing of 
treatments results, at times, in a slower rate of improvement, but with less severe postECT 
cognitive impairment (Lerer et al., 1995, Shapira et al., 1991, Shapira et al., 1998, Shapira et 
al., 2000). Thus, in patients who develop excessive cognitive side effects, reducing the 
treatment frequency from three to two treatments per week can be protective. 
 
The findings that the number of BL ECT treatments is linearly related to the magnitude 
of retrograde amnesia at 6-month follow-up (Sackeim et al., 2007), exemplify the fact 
that longer treatment courses are associated with more negative cognitive outcomes. 
This is especially the case for forms of ECT that result in more severe acute cognitive 
changes (sine wave, BL placement, etc.), as recovery of function may be incomplete by 
the time of the next treatment, resulting in a pattern of progressive deterioration that 
deepens with extended treatment (Daniel and Crovitz, 1983a). 
 
Finally, there is some evidence that excessive anesthetic dose also results in more 

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severe cognitive side effects, at least in the acute postictal period (Miller et al., 1985).  
 
Each of these factors was considered when designing FEAST and the procedures 
used in this protocol. The guiding philosophy was to utilize knowledge of these 
factors to minimize adverse cognitive effects. Specifically: 
 
1. 
FEAST uses a form of RUL ECT. Given the fact that it is more focal 
than traditional RUL ECT, with sparing of right medial temporal lobe 
areas expected, the electrode position should have advantages 
relative to both BL and traditional RUL ECT.  
2. 
FEAST not only uses the 0.3 ms pulse width (ultrabrief) found to 
result in marked cognitive savings, but also uses a unidirectional 
waveform that is expected to confer additional advantages due to 
greater efficiency.  
3. 
Stimulus dosage in this protocol is adjusted relative to the seizure 
threshold determined for each patient. The dosage relative to 
seizure threshold was selected based on evidence that this is the 
dose at which traditional RUL exerts maximal efficacy. A further 
dosage increment (9xST) is permitted only in the context of 
insufficient improvement. 
4. 
FEAST will be administered at a schedule of three treatments per 
week. If patients show clinical benefit, but side effects are severe, the 
study physician may order that treatment frequency be reduced to 
twice per week. 
5. 
The number of treatments administered is regulated. Treatment is 
continued until there is a plateau in improvement over two 
treatments. For patients with substantial clinical improvement (≥ 
40% change in HRSD24 scores) a minimum of 10 treatments is 
required before declaring nonresponse. In patients with more 
modest improvement (< 40% change in HRSD24 scores) the 
minimum is reduced to 6 treatments.  Patients who manifest 
remission or plateau after substantial  improvement can exit 
treatment at any time.  Thus, the number of treatments is titrated to 
the clinical progress of patients and lack of further improvement 
over two treatments results in termination of the treatment course. 
These methods minimize the number of treatments administered 

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while simultaneously allowing each patient ample opportunity to 
attain 
remission. 
The 
same 
guidance 
will 
apply 
to 
the 
cotemporaneous UB RUL ECT sample. 
6. 
Anesthetic dosage is adjusted for each patient. At the first 
treatment, the dose of methohexital is set at 1.0 mg/kg. Based on 
anesthetic response, this dose is then adjusted for the subsequent 
treatments. 
 
Thus, this protocol attempts to minimize the risks of adverse cognitive effects by 
both attending to the patient and treatment factors that impact on cognitive 
outcomes. The fact that participants in this protocol will be under close observation 
and supervision provides another set of safeguards, allowing for rapid and sensitive 
detection of adverse effects and early intervention. 
 
Psychiatric Adverse Effects. The major psychiatric adverse effects, as 
discussed at length in Section III.C, are the emergence of postictal delirium or 
agitation and a switch to hypomania or mania. As noted, it cannot be predicted 
which patients will manifest postictal delirium, and this state may be seen at any 
treatment in the course. It may occur only once or twice or it may be manifest at all 
treatment sessions. Depending on the severity and persistence of the agitation, 
various interventions will be considered. First, the patient should be made safe such 
that thrashing movements or attempts to leave the stretcher can be restrained 
without harm. Second, the IV line needs to be secured so that IV access is not lost if 
the agitation becomes more profound. Third, the amount of environmental 
stimulation should be limited, and the patient monitored in a quiet, dimly light area. 
Fourth, if pharmacological intervention is needed, the preferred agent is IV 
midazolam, although other benzodiazepines and the anesthetic agent may be 
used. 
 
The induction of hypomania or mania is a relatively rare complication, almost 
invariably seen in patients known to have bipolar illness. There is no consensus in 
the field about how to manage such patients. We take a conservative approach and 
suspend ECT when emergent hypomania or mania is seen. Commonly, within a few 
days, these symptoms subside spontaneously and the depressive disorder is 
manifest. If the interruption is less that 3 scheduled treatments, such patients can 
return to the research protocol. On the other hand, if the symptoms are sufficiently 
prominent and concerning that immediate institution of a mood stabilizer is 

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warranted, these patients will be dropped from the protocol and treated on an open 
clinical basis. 
 
 
As noted in Section III.C, worsening of depression and increased suicidality 
are virtually never seen during a course of ECT. Nonetheless, it is noted that all 
outpatient participants regularly seen at BSS and GRU will be required to have a 
support network and someone living with them at home responsible of monitoring 
them and bringing them to their treatments. Patients who do not meet remission 
criteria following the FEAST research phase will be offered a second course of 
treatment, using traditional ECT methods. Furthermore, our commitment to patients 
is to take all reasonable steps in treating their major depression. Thus, if patients do 
not benefit sufficiently from FEAST/ECT, they will be offered a series of medication 
trials. 
 
 
 
Social Consequences of ECT.  
The review of our first application (2005) noted 
that we did not address the “social implications of seizure” and potential effects on 
employability, insurability, and driving licensure. The review also recommended that 
patients be given a letter documenting that their seizures were “experimentally 
produced.”  
 
The applicant knows of no instance in which the employability, insurability, or 
driving licensure of a patient was threatened due to the receipt of ECT. While it is 
undoubtedly the fact that there is a social stigma associated with this treatment, its 
receipt alone would never justify denial of employment, insurance, or driving 
privileges. On the other hand, providing patients with a letter documenting that 
they had ECT and seizures were produced for therapeutic (not experimental) 
purposes would likely cause more concern and distress in some patients by raising 
an issue that has no basis in fact.  
 
The FEAST/ECT program involves considerable one-on-one counseling with 
patients about how to address the issue of their treatment and hospital stay with 
friends, family, employers, and medical documentation. Patients are informed about 
how others have dealt with these issues and the fact that ECT-induced seizures are 
distinct from the seizures of epilepsy. If documentation is needed, the directors of 
the ECT services at MUSC and GRU will readily provide it. 
 
 
Premedication and Anesthesia Effects. In addition to the risks of ECT noted 

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above, there are additional risks to the premedication and anesthetic agents used in 
the procedure. Atropine is administered approximately two minutes prior to 
anesthetic induction to block the vagal (parasympathetic) outflow that results from 
electrical stimulation (independent of seizure induction). The principal reason for 
this agent is that subconvulsive stimulation results in vagal outflow and bradycardia, 
and in the absence of the catecholamine surge that accompanies the seizure, 
asystole may result (Decina et al., 1984, McCall, 1996). However, in patients who are 
tachycardic or hypertensive, atropine has the theoretical potential of aggravating 
these conditions. To mitigate this risk, we note that the dose of atropine that is used 
(0.4 mg) is the lowest reported in the field and we have found this dose to be 
entirely satisfactory in providing sufficient vagal blockade. This low dose also 
mitigates against anticholinergic effects on cognitive function. Furthermore, the 
anesthesiologists do a thorough examination prior to the first treatment and review 
the medical history and the medical exam and tests. In rare cases, due to elevated 
baseline heart rate or pressure, and especially in non-titration sessions, the atropine 
may be withheld based on the anesthesiologist’s clinical judgment. 
 
 
Allergic reactions to the muscle relaxant or the anesthetic agent are 
extremely rare. If the patient manifest prolonged apnea following seizure induction 
due to slow catabolism of the succinylcholine, they will be re-anesthetized and their 
respiration supported until spontaneous breathing returns. A pseudocholinesterase 
level will be obtained and the determination made for subsequent treatments to 
either use a very small dose of succinylcholine (e.g., 5 mg) or to switch to a non-
depolarizing muscle relaxant.  
 
 
The experience of being awake while still paralyzed is frightening and is 
especially likely to occur with treatments that result in rapid return of orientation 
following seizure termination. We have seen some instances of this phenomenon 
with Magnetic Seizure Therapy that were managed by administering an additional 
(half) dose of the anesthetic after seizure 
termination. The possibility of such a 
phenomenon will be closely monitored in the FEAST patients as it is expected that 
they have especially rapid return of orientation. In such circumstances, we will 
determine whether increasing the anesthetic dose prior to the electrical stimulation 
or giving a second post-seizure dose is the most effective strategy. 

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C.4 Other Risks of the Research 
 
Three aspects of the research may involve other risks. These are the 
medication restrictions prior to and during the FEAST trial, the potential delay in the 
start of pharmacotherapy or continuation ECT following the end of the FEAST trial, 
and the confidentiality of the data. 
 
 
Medication Washout.  There is a 5-day medication washout of lithium or other 
anticonvulsants or stimulants prior to the start of the research evaluation procedures. 
All other  psychotropic medications are held stable other than PRN use of lorazepam 
(up to 3 mg/d). The holding steady of psychotropic medications and the stopping of 
some medications (anticonvulsants, lithium, stimulants, excessive anxiolytic) may lead 
to an increase in depressive and related symptomatology, either as a withdrawal 
reaction or as a worsening of the psychiatric condition. Stopping lithium and 
anticonvulsants is standard practice for ECT, however. We limit the risks of the 
medication washout in the following manner. First patients who it is believed cannot 
tolerate medication withdrawal are excluded from the study (see Table 2). Second, any 
patient who finds the medication withdrawal intolerable will be withdrawn. Third, any 
patient who on clinical grounds requires mood stabilizers or changes in medications 
during the trial are withdrawn and offered the requisite treatment. Patients are in close 
contact with the MUSC and GRU clinicians and their primary psychiatrists. We have 
used these procedures in several hundred patients in our ECT clinical services and in 
previous ECT research at MUSC and GRU and rarely have patients had to be withdrawn 
from the study due to intolerance of the washout or related factors. 
 
 
Delay in Start of Alternative or Continuation Therapy. Two or three days may 
elapse between completion of the FEAST/UB RUL ECT course and the completion of 
post-course research evaluations (e.g., cognitive measures, fMRI, etc.). This interval 
will occur regardless of clinical outcome of the FEAST/ECT course.  At maximum, 
this delay may extend to 5 days if there are scheduling difficulties. This delay of at 
most 5 days before starting alternative acute treatment or continuation therapy has 
the theoretical risk of contributing to or accelerating later relapse. However, it 
should be noted that in many of our prior research studies we have routinely used a 
one-week medication-free interval following ECT in order to certify response and/or 
remission status (Sackeim et al., 2008, Sackeim et al., 1987a, Sackeim et al., 1993, 
Sackeim et al., 2000b, Sackeim et al., 2009).  No untoward effect of this practice was 
noted. However, more critically, during the short delay, patients will not be 
medication free.  They will continue on the medication regimen that was stabilized 

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before FEAST/ECT and maintained during the FEAST/ECT course.  This should 
mitigate against potential clinical worsening due to the delay in instituting 
alternative acute treatment (e.g., nonresponders) or continuation therapy (e.g., 
remitters). 
 
 
Confidentiality of the Data. It is always important to protect patient 
confidentiality, and especially so in the treatment of individuals with severe 
psychiatric disorders. Several steps will be taken to preserve confidentiality. When 
research papers are written, no participant identifying information will be reported. 
All records will be kept in locked files and kept confidential to the extent permitted 
by law. Electronically stored or transmitted information (computerized data) will not 
contain the name or other identifiers of participants. Participants will be identified in 
the electronic data by an arbitrary numeric code. The master list linking these 
numbers to participants’ names will be kept in locked files. Any electronic 
transmission of information about participants will not contain the name or other 
personal identifiers and will be encrypted. 
 
C.5 Risk Analysis Summary 
The major risks of the research are those associated with receipt of ECT. The 
experimental treatment condition used here, FEAST, should have reduced risk of 
cognitive impairment compared to traditional forms of ECT. The use of a 0.3 ms 
pulse width has been shown to markedly reduce the cognitive side effects of ECT, 
with little impact on efficacy (Sackeim, 2004a, Sackeim et al., 2008, Loo et al., 2012). 
FEAST will be administered in such a way that cognitive side effects should be less 
intense and/or persistent than that which regularly occurs with older methods that 
do not take into account variation in seizure threshold (American Psychiatric 
Association, 2001). The use of a unidirectional current and focal stimulation should 
contribute to further reductions in cognitive side effects, although this is not certain. 
 
We do not anticipate that this form of ECT (unidirectional, ultrabrief pulse with 
spatial targeting) will have an impact on efficacy. Were there an effect, it is 
anticipated that this form of treatment would confer lesser benefit. Given this 
possibility, provision has been made to identify early patients who do not benefit 
sufficiently from FEAST and offer them alternative treatment. That treatment will 
intensify in a stepwise manner the form of ECT administered. Specifically, as 
clinically indicated, patients who show insufficient benefit will have the dosage of 

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the unidirectional, ultrabrief pulse stimulus increased (from 6xST to 9xST), followed 
by a switch to high dosage RUL ECT with wide pulse width (1 ms), followed by use 
of traditional bilateral ECT. Thus, the protocol involves close monitoring of objective 
and subjective side effects and includes provision for alternative treatment for 
patients who do not respond clinically to initial treatment assignment. All of the 
assessment procedures are noninvasive, with several specifically  geared to track the 
effects of treatment on cognition. Patients who consent to the protocol have the 
option of declining participation in specific procedures (e.g., fMRI), but can retain 
participation in the remaining procedures. Explicit provisions have been made to 
identify and manage complications.  
 
Patients in the comparison group are selected from those referred for ECT and 
scheduled to start with ultrabrief, right unilateral (UB RUL) treatment.  This 
treatment is routine in the US and internationally, and is considered to manifest the 
least short- and long-term cognitive side effects compared to other ECT modalities.  
Participation in this protocol presents no additional risks. 
D. Device and Site Safety 
Several procedures will be in place to enhance safety in use of the device at the 
Institute of Psychiatry at MUSC and the two facilities at the GRU (Augusta, GA and 
Aiken, SC) . 
D.1 Controlled Access Area 
The device will be used only in the dedicated area used for the delivery of ECT at 
the Institute of Psychiatry at MUSC on the fifth floor.  When not in use, the 
Spectrum 5000Q FEAST device will be shut off and the room and suite housing it is 
locked. Identical precautions will be taken in the GRU ECT suites in Augusta, GA and 
Aiken, SC. 
D.2 Device Calibration and Evaluation 
All the quality control procedures recommended by the manufacturer in the testing 
and calibration of the Spectrum 5000Q will be followed, including verifying the 
correct operation of the circuitry that determine whether bidirectional or 
unidirectional stimulation is delivered.  These assessments of device integrity and 
calibration will be conducted on each device at each site prior to first use and then 
again at least every 6 months. 

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D.3 Screening of Subjects Prior to Treatment 
 
As described above, the screening assessment of potential subjects will identify 
and exclude from participation individuals with current or past medical conditions 
that may place them at increased risk for adverse effects from ECT or who are 
unlikely to benefit. Screening will involve physician evaluation, physical examination, 
and blood work. 
D.4 Conduct of FEAST 
The conduct of FEAST is detailed in Section IV.B.6. The procedures are described 
with respect to all aspects of the administration of FEAST, including management of 
concomitant medications, provision of anesthesia, stimulus dosing, physiological 
monitoring, and data logging. Prior to study initiation, training sessions will be held 
in the use of the Spectrum 5000Q FEAST device with all Study Psychiatrists. The 
study monitor and sponsor will regularly attend treatment sessions to document 
compliance with study procedures. 
D.5 Adjustment of Stimulation Intensity to Individual Seizure Threshold 
The most important factor determining the safe use of the device is the dosing of the 
electrical stimulus. Determining the seizure threshold and adjusting the dose relative to 
this threshold is concerned the most precise method for stimulus delivery in ECT 
(American Psychiatric Association, 2001). Stimulus dosing based on the empirical titration 
(method of limits) method is routine practice at the MUSC and the GRU, and was 
introduced to the field by Dr. Sackeim. The titration schedule specific to the use of FEAST 
was presented above (Section IV.B.6). An identical titration schedule will be used at first 
treatment in the UB RUL ECT group. The maximum dosage (charge) to be administered 
in this protocol with this device is 576 mC (see Table 4 - titration schedule), the same as 
the maximal output of the US marketed Spectrum 5000Q  
D.6 Protection From Excessive Electrical Dosage 
The Spectrum 5000Q FEAST device retains all the safety features of the commercial 
Spectrum 5000Q. These features include internal tests of the integrity of device 
operation and the accuracy of stimulus output when the device is powered on and 
following the completion of each treatment. A continuous static impedance 
measurement is provided, and the device will not arm for stimulus delivery if static 
impedance is below 100 or above 5,000 ohms. Under situations of inadequate 
electrode contact (e.g., slippage), the device automatically terminates stimulus 
delivery when the delivered voltage be would above the cutoff of 400 V. Each of the 
stimulus parameters is measured during delivery. If any parameter exceeds 

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specified tolerances, stimulus delivery is automatically terminated. The operator 
(Study Psychiatrist) can terminate stimulus delivery at any moment by releasing the 
treatment button.  
D.7 Supervision of Patients During Treatment Sessions 
Treatment sessions will be conducted under the supervision of trained personnel 
already privileged in the delivery of ECT at the MUSC and GRU, and further trained 
in the delivery of FEAST. These personnel include the Study Psychiatrist, 
Anesthesiologist, a nurse attending to the patient in the treatment room and 
another nurse attending to the patient in the recovery room. These personnel will 
be in visual and auditory contact with the patients at all times. The study 
procedures prescribe physiological monitoring of EEG, ECG, pulse oximetry, and 
blood pressure. The procedures for the provision of FEAST and the monitoring of 
patients exceed the standards recommended in the last report of the American 
Psychiatric Association Task Force on ECT (American Psychiatric Association, 2001). 
D.8 Emergency Medical Procedures 
Each treatment area is equipped and staffed to handle medical emergencies that 
may arise during or following the conduct of ECT.  A standard crash cart is available 
in the treatment room. During the administration of FEAST, patients are attended to 
by an experienced Study Psychiatrist (credentialed in the administration of ECT at 
the site), an anesthesiologist, and a registered nurse.  Nursing personnel are 
responsible for recovery room care. At each site, emergency medical facilities are 
readily available, if needed.  
D.9 Fire Precautions 
Fire extinguishers are available and easily accessible in the treatment and recovery 
areas. Fire precautions are in accordance with the regulations of the Institute of 
Psychiatry at MUSC and the Department of Psychiatry, GRU. 
 
D.10 Environmental Impact Claim for Exclusion 
We claim categorical exclusion for this study as provided for in 21 CFR section 25.24 
(e) 7. The device shipped under the Investigational Device Exemption is intended to 
be used for clinical studies in which waste will be controlled or the amount of waste 
expected to enter the environment may reasonably be expected to be nontoxic. 

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E. Device Description (Provided by the Manufacturer) 
E.1 Identification of Legally Marketed Device 
The legally marketed devices, the MECTA Spectrum 5000 and 4000 series, are the 
current generation of MECTA Spectrum 5000 and 4000 devices. The FDA 510 K # is 
K965070, the regulatory class is III, and the product code is 84GXC.  
E.2 Description of the Device 
The MECTA Spectrum 5000* and Spectrum 4000* ECT devices are the fourth 
generation of MECTA ECT devices and continue technically to be the state-of-the-
art ECT devices, while also continuing to offer even more safety and efficacy 
clinically. The 5000 devices offer up to six channels of monitoring of ECG and EEG 
and one Optical Motion Sensor, while the 4000 devices contain only the ECT 
module of the 5000 devices. As such, they are upgradeable to the 5000 series units. 
The 5000 Q and 4000 Q offer the user flexibility to manipulate four stimulus 
parameters to vary energy and charge. The 5000 M and 4000 M offer the user 
greater simplicity, with one single Stimulus Intensity knob, which varies all four 
stimulus parameters simultaneously, thus varying energy and charge.  
 
The touch screen provides the user with an interface to set pre-treatment 
parameters. This provides the user with more flexibility as he can access all menus 
by simply touching a screen. The LCD, which illuminates the touch screen, provides 
the user with alphanumerics that guide her/him through self-test, treatment, and 
monitoring of the EEG, ECG, and OMS. The LCD/touch screen includes choices of 
eight set-up menus in the 5000 series and one menu in the 4000 series that can 
help to individualize each patient's treatment. The LCD/ touch screen also provides 
the user with more data that can be recorded on the patient's record regarding the 
self-test and treatment to ensure greater safety. Also, up to four channels of 
physiological monitoring can be seen on the LCD-touch screen.  
 
 
The two-channel thermal chart recorder provides the user with a hard copy of the 
self test and treatment parameters. The simplicity of the chart recorder only 
requires the user to set two gain knobs as the self-test and treatment results are 
printed automatically. The manual on/off push button offers the user the option of 
also manually controlling printing. The printout provides two channels of 
monitoring and also provides the user with elapsed time, date, time of treatment, 
and patient name. The four stimulus parameters on the M series and Q series are 
also shown on the LCD/Touch Screen and the continuous updating of the percent 

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energy on the M series also helps to increase efficacy of treatment.   
 
The hinged cover on the Stimulus Control push button prevents the user from 
accidentally treating. The Stimulus Status LED is illuminated to offer the user a visual 
confirmation that the Spectrum is enabled, that the stimulus is being delivered and 
finally indicates if there is a stimulus delivery fault.  The three warning tones during 
self-test and the constant tone during treatment delivery offer the user enhanced 
safety during the treatment process. The continuous self-test offers the user far 
greater accuracy in avoiding aborted or missed seizures as this bio-feedback 
provides him with acceptable ranges continuously.  
 
The EEG Data Analysis** feature provides analyses on seizure adequacy and allows 
the clinician to better assess the quality and presumed efficacy of each individual 
seizure. The Optical Motion Sensor (OMS) allows the user to monitor motor 
movement during the seizure and provide further valuable information in assessing 
seizure duration and strength. The event timer, and the leads off information all 
provide added information for the clinician that allows him/her to better assess and 
improve clinical efficacy. The event timer is printed on the chart recorder as a 
permanent record. The leads off feature documents that the EEG or ECG leads are 
off and notifies the user by providing a message on the LCD Touch Screen.  
 
Ultrabrief ECT uses the parameter of 0.3 milliseconds ultrabrief pulse width which 
sharply reduces seizure threshold, thus allowing treatments to be given at much 
lower electrical dosage than had been previously possible. Most critically, when 
compared to standard brief pulse stimulation, use of ultrabrief parameters results in 
a profound reduction in cognitive side effects. In many domains, this advantage for 
ultrabrief stimulation is as large or larger than the difference between bilateral and 
right unilateral ECT in their cognitive effects. Right unilateral ultrabrief ECT is a clear 
advance for the field as patients show improvement with little sign of cognitive 
deficit.  
 
The additional feature of ECT Data Management Software is provided with the 
devices as external software to use with a stand-alone PC. MECTA Electronic 
Medical Record (MEMR) software allows the clinician to view all of the traces of 
physiological monitoring from the Spectrum (up to four EEGs, 1 ECG, and OMS) on 
an external PC monitor. Up to eight traces can be displayed. These traces of 
monitoring are viewed in real time throughout the treatment. They can then be 

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stored on in a MEMR patient database that allows the clinician to store, sort, select, 
query, print and export multiple patient- and treatment-related variables. This 
software will automatically record all the treatment parameters administered in a 
FEAST/ECT session. It will automatically account for multiple stimulations, as often 
occurs in a titration session.  Thus, the EMR software sued in this study will track the 
treatment parameters administered at each stimulation, as well as the 
accompanying 
physiological 
recordings 
and 
patient 
information. 
 
Two features that offer the user enhanced safety are thorough device internal testing 
before deliveries and continuous monitoring of every pulse during delivery. All of the 
above features demand the most advanced technical design, as did the 
commitment to design to the most stringent domestic and international standards 
UL 60601, and IEC 60601-1, 60601-1-2, 60601-2-25, 60601-2-26 all of which resulted 
in far greater safety in the 4000 and 5000 devices to comply with these standards. 
These standards require that these devices include extensive redundant hardware 
and software testing and verification to confirm that they are operating correctly. 
The safety of these devices is unparalleled and as such are an advance that has 
impacted the safety and efficacy of the ECT treatment dramatically. The regulatory 
agency approvals that have been granted to the spECTrums are both domestic and 
international: cUL, UL, TUV Annex II Article 3, Health Canada, EN ISO 13485:2012, EN 
ISO 
9001:2008, 
KFDA, 
SDA. 
 
 As the technical advances have been a result of the field's demand for greater 
information, efficacy, and safety, the clinical advances have primarily been ongoing 
in the field over the last 35 years of MECTA's device history. Therefore, the MECTA 
5000, 4000 series are used in a clinical setting with modified ECT. The 5000/4000 
series continues to use the constant current bi-directional square waveform and the 
starter kit items accompanying these devices remains the same with the exception 
of the hand-held electrodes that have been redesigned with the same redundant 
safety requirements. The patents that have been issued on the above devices and 
features 
are 
identified 
with 
an 
asterisk. 
 
*U.S. Patent #5,755,744-U.S. Patent #6,014,587- U.K> Patent #GB 2 307 413 B 
**Duke U.S. Patent #5,626,627-Duke U.K. Patent #2 304 196 B (Under exclusive 
license from Duke University)  
 
A patent has also recently been approved for FEAST. 

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F. Monitoring Procedures 
The study monitor will be Dr. Mark George, Professor, Departments of Psychiatry, 
Neurology, and Radiology, MUSC. Dr. George is highly experienced in the conduct 
of ECT and clinical trials. He will ensure the quality of the study and establish that 
the investigators are complying with the signed agreement, the investigational plan, 
and FDA and IRB regulations. Prior to the conduct of the study, the monitor will 
establish that the investigators understand the investigational status of the device 
and the requirements for accountability, the nature of the protocol and 
investigational plan, the obligations to obtain informed consent, and to comply with 
FDA and IRB regulations. The study monitor will also establish the feasibility of 
conducting the study at the site. Throughout the investigation, the monitor will be 
in regular contact with investigators at each site and will conduct monitoring no less 
frequently than every 4 mo. The monitor will ensure that the facilities being used 
continue to be acceptable for the purposes of the study, that the investigational 
plan is being followed, that any changes to the protocol have received IRB approval 
and have been reported to the sponsor, that accurate, complete, and current 
records are maintained, that accurate, complete and timely reports are made to the 
sponsor and the IRB, and that the investigators are carrying out their agreed-upon 
duties and are not delegating responsibilities to unspecified staff. 
 
As indicated, in addition to the study monitor, the Brain Stimulation Service 
Director, Dr. Short, will review each research chart for completeness and accuracy. 
He will provide independent confirmation that inclusion and exclusion criteria have 
been met for each patient enrolled and that there is compliance with all other 
aspects of the investigational plan and the investigator agreement. Similarly, Dr. 
Rosenquist at the GRU will also review each research chart for completeness and 
accuracy. He will provide independent confirmation that inclusion and exclusion 
criteria have been met for each patient enrolled and that there is compliance with 
all other aspects of the investigational plan and the investigator agreement. 
 
V. 
Manufacturing 
Information 
(PROVIDED 
BY 
THE 
MANUFACTURER) 
In the FDA review of the original Spectrum 5000Q FEAST Device IDE application 
(6/8/05) a number of deficiencies were listed. Several of these related to the 
modified Spectrum units to be used in the study. These deficiencies are again 
addressed specifically in Sections V.C, V.D, and V.E. 

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Because of our preliminary work in humans, we have changed the specifications for 
the FEAST units from the original application. The modifications to the standard 
Spectrum for the FEAST IDE will include the following: 
 
• Change voltage limits from 10-400 Volts  
 
This change was approved and included in the ongoing IDE. As noted above, since 
increasing the voltage cutoff to 400 V there have been no untoward events, 
including no skin burns.  
  
The 0.3 ms pulse width has been available as part of the standard marketed units 
since July, 2003 and thus does not constitute a modification or change for the 
FEAST units. See notes in Section V.C. 
 
Reliability and validity of the manufacturing of these devices is ensured by testing 
each unit to validate the output of the device. The verification that the Current, 
Duration, Pulse Width and Frequency are within the acceptable ranges are all 
tested, recorded and validated in the Manual Test for each device.  
 
Methods of manufacturing are determined by UL, cUL, TUV, ISO 9001 and FDA 
approvals and are identical to current methods used to manufacture, process, 
package, store, and install the Spectrum devices. 
 
Facilities and Controls are determined by the UL, cUL, TUV, ISO 9001 and FDA 
approvals of the device and facility and are identical to current facilities and controls 
to manufacture, process, package, store and install the Spectrum devices. 
 
RERERENCE 
APPROPRIATE 
SECTIONS 
AND 
APPENDICES 
FOR 
FURTHER 
DISCUSSION 
OF 
THE 
FOLLOWING 
DESIGN 
AND 
MANUFACTURING 
REQUIREMENTS: 
 
Design/engineering drawing of device—Reference Appendix A.1 Block 
Diagram 
 

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Rationale for device design—MECTA has been asked to design a 
modification to the existing approved Spectrum 5000Q for a research study 
of FEAST. 
 
Device 
and 
Performance 
specifications—The 
Spectrum 
hardware 
specifications are identical with the exception of the rectifier on the stimulus 
output and a small change to allow delivery currents down to 100mA. See 
Section 
V.D 
for 
new 
verification 
and 
validation 
data. 
Reference Appendix A.2 and Hardware Modification Section (Section V.B).  
 
Description of Materials- Reference Hardware Modification Section 
(diodes and electrodes) (Sections V.B and V.E) 
 
Description of Function- Reference Appendix A.2 Block Diagram 
 
Validation Testing for Subsystems and Main System- Reference Appendix A.3 
and Section V.D. 
 
Manual Test – which verifies and validates all of the settings. 
 
A. Software Modification 
The devices used for the FEAST research are modified versions of MECTA’s standard 
Spectrum 5000 Q product. The Spectrum unit itself has been modified to allow 
delivery of a unidirectional pulse train (all pulses have current flow in the same 
direction) and to change the lowest delivery current from 500 mA down to 100 mA. 
The details of the hardware modifications are covered in a separate document. This 
document describes the software changes to the Spectrum 5000 Q units. 
 
The software changes provide control and support for the following: 
 
1. Enabling or disabling the hardware unidirectional feature (addition of a menu 
option), and 
2. Extending the lower end of the delivery current range from 500 mA down to 100 
mA, and 
3. Change the lower voltage limit from 50 down to 10 V. 
 

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The addition of a new software “button” in the main menu screen of the Spectrum 
toggles the unidirectional setting between ON and OFF. The setting is saved in non-
volatile memory so that it is retained while the power is off. The software simply 
controls the hardware line that activates the relay that controls the unidirectional 
feature. The software was verified by using an oscilloscope to display the delivered 
voltage across a load resistor for the ON and OFF settings and cycling of the power. 
 
The changes to allow lower currents are more extensive and include the following: 
 
1. Changes of the parameter selection settings to include currents down to 100 
mA. 
2. Recalibration of the current setting Pulse Width Modulator (PWM) control. 
3. Changing the minimum treatment voltage limit from 50 Volts to 10 Volts. 
4. Increasing the tolerance on the internal 300 Load impedance measurement from 
10 % to 20%. 
5. Disabling one of the redundant Energy monitor circuits. 
 
Changes one and two were simple changes to internal tables that specify the 
allowed range of treatment current and duration. These allow the study to use 
much lower charge and energy levels than are possible on a standard spECTrum. 
 
 
The delivered current circuitry utilizes a PWM to set the desired current. In a 
standard Spectrum, the allowed range is from 500 mA to 900 mA. A linear equation 
is used to determine the proper PWM setting for the desired current. Extension 
down to 100 mA required minor changes to the slope and offset of the linear 
equation (change 3). 
 
 
The standard Spectrum requires that the delivered voltage be at least 50 Volts (this 
guarantees that the patient impedance is at least 100 Ohms). This feature detects 
and notifies the operator when the treatment paddles are shorted together or the 
current path is too low an impedance due to too much conducting gel etc. Delivery 
of 100 mA into 100 Ohms requires 10 Volts, so the lower voltage limit has been 
dropped to 10 Volts (change 4). Before delivery to a patient, the Spectrum delivers 
energy to an internal 300 Ohm load and verifies that the proper current, voltage, 

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pulse width, frequency and duration all occur. Dividing the delivered voltage by the 
delivered current provides a measurement of the 300 Ohm load resistance. For the 
standard spECTrum, the measured value must be within 10% of 300 Ohms. The 
PWM allows current to be set in 4 mA steps. This resolution in current constitutes a 
5 times larger contribution to measurement error at 100 mA than it does at 500 mA. 
Similar concerns apply to the voltage measurement circuitry as well, which has a 
resolution of 0.5 volts. This requires somewhat larger tolerance on the measured 
values during this delivery test. The allowed impedance measurement variation has 
been increased to 20% in the FEAST units (change 5). This still puts the unit well 
within the required regulatory energy measurement specifications of 30% (energy is 
proportional to impedance). 
 
 
Finally, the Spectrum includes multiple methods to ensure that excess energy is not 
delivered to a patient including: 
 
1. Software monitoring of voltage, current, pulse width, frequency and duration 
during deliver, including verification of all of these measurement functions 
before treatment of each patient. 
2. Independent hardware monitoring of pulse width, frequency, duration and 
energy, including verification of all of these functions before treatment of each 
patient.  
3. Another software counter that monitors the energy delivery to ensure it does 
not exceed the expected delivery settings. 
 
The energy monitoring in items 2 and 3 both derive from a hardware circuit that 
generates a pulse train whose frequency is proportional to delivered power. 
Counting these pulses measures the energy. The hardware counts the pulses and 
ensures that the energy does not exceed predetermined safety thresholds. The 
software (item 3) also counts the pulses as a redundant backup.  
 
When the current setting is much lower than 500 mA, this hardware circuit fails to 
provide pulses for counting. As a result, the energy measurement is 0. This causes 
the software backup counter to register an error, since it checks for both too much 
and too little energy delivery. The hardware counter continues to function as an 
energy limiting device according to its original design. For FEAST units, the software 
energy counter has been disabled. This does not compromise the safety, since the 

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software continues to verify that current, pulse width, frequency and duration are all 
as specified (within a few percent for each), and that the voltage does not exceed 
the limit of 400 volts. This is equivalent to measuring the delivery energy. The 
software counter was originally included as a means to provide a simple measure of 
the delivered energy. This is done in the FEAST units by calculating the delivered 
energy from the previously mentioned parameters including the measured delivery 
voltage. 
 
It is our belief that these changes provide a unit suitable for the FEAST studies, 
without compromising the safety features of the standard Spectrum product.  
 
These changes simply continue the changes of the previously approved IDE. Even 
though the new FEAST protocol will use only 800 mA, we have maintained the 100 
mA minimum rather than develop new FEAST software and hardware. This decision 
eliminates the need to change existing FEAST devices. 
 
B. Hardware Modification 
The modifications to the Spectrum Hardware are the addition of a full wave bridge 
on the output and a relay to switch between unidirectional (output passes through 
the bridge) and bidirectional (output bypasses the bridge). Dynamic current, 
voltage, impedance, pulse width and frequency are still all constantly measured 
during delivery. 
The full wave bridge consists of four 1N4005 diodes connected in a standard bridge 
configuration. These parts are rated 1 Amp 600 PIV each. (Spectrum output is 
limited to 800mA at 400V peak for FEAST devices). The stimulus output of the 
spectrum is connected to a DPDT relay that connects either the rectified output of 
the bridge or the bi-directional output of the standard Spectrum to the stimulus 
connector. The stimulus connector is connected so the negative output (cathode) 
connects to the remote treat handle of the standard hand-held stimulus cable. The 
Anode connection will be to the anterior electrode. The relay is switched by writing 
a bit to a latch on the backplane of the Spectrum. An indication of “UNI” for 
unidirectional and “BI” for bidirectional mode is displayed on the LCD display of the 
spectrum. Output is verified by observing the output across a fixed resistor with an 
oscilloscope. 
 

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C. Details on Implementation of the Changes in the FEAST Device 
Item 21 in the FDA review (6/8/05) addressed the implementation of two parameter 
changes: lowering of the minimum pulse width and lowering of the minimum 
current from 500 to 100 mA. The FDA requested specific details on how these 
changes would be implemented. 
 
Regarding the 0.3 ms pulse width, we mistakenly included this as a new feature for 
the FEAST IDE. This has been a part of our standard product since July of 2003, 
both in the U.S. and abroad. FDA reviewed documentation on this change in 
preparation for the FDA two day audit of MECTA on 9/4/03 and 9/8/03. This 
change has been widely accepted and used throughout the world (including the 
U.S.A.) since then with beneficial results and no reported adverse affects. 
 
The minimum current setting is controlled by table values in both the 386 and 
80C592 processors. The minimum current setting in each table has been changed in 
the code for each processor and recompiled. The hardware was originally designed 
to operate from well below 500 mA current output to 1000 mA current output, even 
though the original specifications were for 500-800 mA. During testing of the 
desired 100 mA setting, it was found that the lowest usable current setting was 
about 140 mA. An op-amp used to provide a full output swing from 0 to 5 volts to 
cover the output current range of 0 to 1 Amp was not providing rail to rail outputs 
when operated between 0 and 5 Volts. The solution was to change the op-amp 
lower rail voltage to -5. This allowed current settings all the way down to 100 mA 
without problems. See the attached circuit changes for details. 
 
D. Verification and Validation Data for the modified Spectrum 5000Q 
Item 22 in the FDA review (6/8/05) requested verification and validation data for the 
modified Spectrum units. 
 
Since the Spectrum is a mature product, and the change for the FEAST IDE is very 
minor, the verification and validation activities have been limited to the specific 
changes made. The FEAST units will go through our standard manual and 
automated testing done for every unit shipped (modified slightly for the different 
current range). This testing, coupled with the extensive internal testing done by 
each unit before each patient treatment, guarantees that each unit is functioning 

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properly, including all of its backup safety circuits. A copy of the Overall Quality 
Plan is attached. (Appendix A.4) 
 
Verification activities for the lower current limit change were straight forward 
including: 
 
1. Measurement of various delivered currents (100-400 mA) into various load 
impedances (100-600 ohms) (see data below). The delivered currents were 
calculated from measurements of the load impedances with a DMM and 
delivered voltages with a Tektronix TDS 320 digital storage oscilloscope. 
These were compared to the specified delivery current and required to be 
within 10%.  
2. Standard automated final testing. One of the automated tests verifies 
accurate calibration of the delivery current.  
3. Standard internal testing done by the instrument prior to every patient 
treatment verifies that correct currents are being delivered 
 
The following representative data was all taken with a 0.5 second duration setting. 
The voltages were measured with Tektronix TDS 320 digital oscilloscope. The Load 
resistances were measured with a Fluke 87 True RMS Multi-meter. The worst case 
delivery current error is 5.0% for 100 mA into 605 Ohms for 0.3 ms. 
 
Table VD. Representative Data Testing Accuracy of FEAST Device Output 
Pulse 
Width 
Freq. 
Load 
Resistance 
Volts/Current 
@ 100 mA 
Volts/Current 
@ 300 mA 
Volts/Current 
@ 500 mA 
Volts/Current 
@ 600 mA 
Volts/Current 
@ 800 mA 
0.3 ms 
60 Hz 
90 Ohms 
Won’t 
allow 
treatment 
Won’t 
allow 
treatment 
Won’t 
allow 
treatment 
Won’t 
allow 
treatment 
Won’t 
allow 
treatment 
0.3 ms 
60 Hz 
104 Ohms 
10.8/104 
31.2/300 
51.2/492 
62.4/600 
82.0/788 
0.3 ms 
60 Hz 
201 Ohms 
20.4/101 
59.2/295 
98.0/488 
118/587 
158/786 
 
Notes: 
 
 
Worst-case conditions occur for shortest pulse width at highest frequency. 
 
The Spectrum uses adaptive current setting. During the delivery of the first 3 
pulses, the delivery current is adjusted to make it as accurate as possible and 
must be within 22% of the expected value. After the first 3 pulses, the current 
must be within 10% of the expected value. If the current is more than 10% off 
on any delivered pulse, the Spectrum automatically terminates delivery and 

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notifies the operator of an error situation. Further, correct current delivery is 
checked by the Spectrum before each patient treatment by delivering into an 
internal 300 ohm resistor and verifying that the delivered voltage across the 
resistor is correct based upon the delivered current (within 8% of expected 
voltage). If this test fails, patient treatments are inhibited until this and all other 
internal tests pass. 
 
These verification activities ensure that the modified Spectrum operates correctly in 
the 100-400 mA range.  
 
Possible faults in the delivered current level and their consequences include: 
 
1. Delivery system fails to turn off current pulse. Hardware pulse width limiter 
will automatically turn the pulse off after 2.4 ms and force the Spectrum into 
its error mode which notifies the operator, forces an internal testing cycle, 
and inhibits further treatments until all internal tests pass. This backup circuit 
is automatically tested by the unit before every patient treatment and must 
be working properly before a treatment will be allowed. 
2. Delivery current level is wrong (including being too high). Delivered current is 
measured on every pulse and must be within tolerance or the delivery will be 
stopped, the operator will be notified, an internal test cycle will be started, 
and further treatments will be inhibited until all internal tests pass. The 
current measurement circuit is tested by the unit before every patient 
treatment and must be working properly before a treatment will be allowed. 
3. Current measurement circuit fails. Delivered current is measured on every 
pulse and must be within tolerance or the delivery will be stopped, the 
operator will be notified, an internal test cycle will be started, and further 
treatments will be inhibited until all internal tests pass. The current 
measurement circuit is tested by the unit before every patient treatment and 
must be working properly before a treatment will be allowed. This includes a 
test at two different currents, both of which must pass. 
 
Verification activities for the voltage limit changes are straight forward including: 
 
1. Verifying the modified Spectrum will not allow any delivery into static 
impedances below 100 Ohms. 

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2. Verifying that the modified Spectrum successfully delivers 100 mA into 104 
Ohms (10.4 Volts). 
 
See the above data table summarizing these results. These verification activities 
ensure that the modified Spectrum operates correctly over the required voltage 
range and will not deliver when the voltage is outside of that range.  
 
Possible faults in the delivered voltage level and their consequences include: 
 
1. Delivered voltage too high (broken delivery cables, poor skin prep, etc.). The 
Spectrum measures the voltage on every delivered pulse and when it is out 
of range it will terminate the delivery, notify the user, force an internal test 
cycle, inhibit further treatments until all internal tests pass. The voltage 
measurement circuit is tested by the unit before every treatment. 
2. Voltage measurement circuit fails and reports a value between 10 and 400 
Volts (very unlikely failure mode). The voltage measurement circuit is tested 
by the unit before each treatment and must read the voltage within 8% of 
the expected value or treatments will be inhibited. This failure would not be 
detected until the next internal test cycle after the patient treatment is 
finished. It is then checked at two different voltage readings. This failure, in 
conjunction with a poor patient electrode contact, could result in a skin burn 
for that single treatment. 
3. Voltage measurement circuit fails and reports a value below 10 or above 400 
Volts. The Spectrum measures the voltage on every delivered pulse and 
when it is out of range it will terminate the delivery, notify the user, force an 
internal test cycle, inhibit further treatments until all internal tests pass. The 
voltage measurement circuit is tested by the unit before every treatment. 
 
As noted under Section V.C above, no changes were made related to the pulse-
width, so no additional verification or validation activities have been done in this 
regard for the FEAST units. 
D. Feast Electrodes  
The anode electrode will be made of the same material as the conventional 
Spectrum electrodes (stainless steel) and will be 1.25” in diameter. The commercial 
Spectrum electrodes are circular and 2” in diameter. The cathode electrode will 
connect to the handle of the current Spectrum hand held stimulus cable. It will be 

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made of stainless steel and be rectangular in shape (except for radius corners) and 
it will be 2” wide and 3” long. It will be made malleable so it can be bent to conform 
to the relative shape of the patient’s head. Standard jell and paste will be used to 
improve patient contact (just as in the current Spectrum). See Appendix 4 
(Electrode shapes) 
 
The updated information related to the risk of skin burns was addressed earlier. 
 
VI. Investigator Agreement 
 
A signed Investigator Agreement by each of the active investigators is 
included in Appendix B. These agreements describe each investigator’s 
qualifications. A copy of each investigator’s curriculum vitae is attached. These 
agreements have been signed by: 
 
Mark S. George, MD 
Baron Short, MD 
Vaughn McCall, MD 
Peter Rosenquist, MD 
Harold A. Sackeim, Ph.D. 
 
 
A blank sample agreement is presented below: 
 
I have examined the protocol designed by Dr. Mark George, entitled, Focal Electrically-
Administered Seizure Therapy (FEAST) and have fully discussed the objectives of this trial 
and contents of this protocol with Dr. George, Sackeim and the rest of the Executive Committee. 
I agree to conduct this investigation in accordance with the agreement, the investigational plan, 
Part 812 and other applicable FDA regulations, and conditions of approval imposed by the 
reviewing IRB and FDA. 
 
I understand that, should the decision be made to terminate prematurely or suspend the trial at 
any time for whatever reason, such decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the trial I will communicate immediately in writing 
to Dr. George. 
  
I also certify that I have never been terminated from other investigational projects. If so, an 
explanation of the circumstances that led to termination and a statement of commitment will be 
attached. 
 
Investigator Name (Please Print) ___________________________________________ 
 

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Investigator Address ____________________________________________________ 
 
  ___________________________________________________ 
 
 
Telephone Number______________________ Fax Number ___________________ 
 
Investigator Qualifications _________________________________________________ 
 
______________________________________________________________________ 
 
______________________________________________________________________ 
 
 
Signature ______________________________________Date  _______________      
 
VII. INVESTIGATOR CERTIFICATION 
 
 
I certify that all personnel participating in the investigation have agreed to 
follow the applicable clinical investigational protocol contained in this application. I 
have submitted the written protocol to the Institutional Review Board. All 
investigators participating in this investigation understand that they are bound to 
adhere to it as a condition of IRB approval, when granted. I certify that the list of 
investigators in this application identifies all current investigators. Additional 
participating investigators in the investigation will be added to the investigation 
only when they have obtained IRB approval and have signed an investigator 
agreement. 
 
 
________________________ 
 
___2/12/15_____________________ 
Signature 
 
 
 
 
 
Date  
 
 
 
 
 
Mark S. George, MD 
Name (print) 
 
 
 
Investigators who have signed the agreement: 
 
Mark S George, M.D. 

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Harold A. Sackeim, Ph.D. 
Baron Short, M.D. 
Vaughn McCall, M.D. 
Peter Rosenquist, M.D. 
 
Mark George, Vaughn McCall, Peter Rosenquist, Harold A. Sackeim., or Baron Short will not 
promote or commercialize the device in the US during clinical investigation. There will be no 
charge to the subjects for use of the MECTA Spectrum 5000Q FEAST stimulator during this 
study. 
 
Mark George certifies that all investigators who will take part in the study for the MECTA 5000Q 
FEAST stimulator will read and sign the Investigator Agreement and Certification before 
participating in the study. No investigator will participate in the investigation until the agreement 
has been signed. 
 
 
Mark S. George, MD 
 

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VIII. IRB INFORMATION 
MUSC IRB -I 
IX. SECONDARY SITE(S) 
 
Georgia Regents University (GRU)  
 
X. COMMERCIALIZATION STATEMENT 
 
The device is not commercialized. No sale will take place and no site will be 
charged for its use. 
 
XI. DEVICE LABELING 
 
The modified Spectrum 5000Q FEAST Stimulators used in this study are donated to 
the Institute of Psychiatry at MUSC and the Department of Psychiatry, GRU by the 
MECTA Corporation. These devices were obtained for research purposes and will 
not be sold. We request permission for investigational human use for the protocol 
described in this application. When IDE approval is obtained this device will be 
labeled, “CAUTION—Investigational Device. Limited by Federal (or United States) 
law to investigational use.” Research subjects will not be charged for the costs of 
the device or for any other aspect of the research. Subject payments in this protocol 
are limited to reimbursement for travel expenses and time devoted to follow-up 
evaluations after discharge from the hospital. 
 
 

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XII. INFORMED CONSENTS 
(We include two informed consents for MUSC, one for the FEAST patients and one 
for the matched RUL patients. GRU researchers will modify them slightly to conform 
to GRU language and verbiage but the elements will be the same across the two 
sites.) 
 
Medical University of South Carolina Informed Consent Form 
Focal Electrically-Administered Seizure Therapy (FEAST): 
Studies at two enrolling sites to further test and refine the treatment 
 
A. PURPOSE AND BACKGROUND: 
 
Your doctor has recommended that you receive treatment with electroconvulsive therapy 
(ECT). You have been asked to participate in a research study. The study examines the 
effects of a new form of ECT on mood and thinking. For ECT to work, doctors have to 
induce a seizure during treatment. Work over the past 20 years has greatly reduced the 
amount of electricity needed to induce a seizure, and where the current goes in the brain. 
This new type of ECT attempts to restrict the brain seizure to the frontal lobe. This new type 
of ECT is called Focal Electrically-Administered Seizure Therapy (FEAST). Your participation 
in this study is purely voluntary. You are being asked to participate in this study because 
you have major depression that has not responded to other depression therapies. The 
principal investigator is Dr. Mark George (843 876 5142). This study is taking place at two 
sites – MUSC and Georgia Regents University and will involve 60 patients, about 30 of 
whom will come from MUSC.  
You have been told that besides FEAST there are other treatments for depression, which 
include medication, psychotherapy, transcranial magnetic stimulation (TMS) and 
conventional forms of ECT. These alternative treatments have their own benefits and risks. 
The question of whether FEAST or an alternative treatment is most appropriate for you 
depends on your prior experience with these treatments, the nature of your psychiatric 
condition, and other considerations. Why ECT has been recommended for your specific 
case has been explained to you. ECT is available at many hospitals and you do not have to 
participate in this research study to receive ECT.  
PROCEDURES: 
 
If you agree to be in this study, the following will happen: 

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Overall, this study investigates FEAST in the same manner that you would normally receive 
conventional ECT. So, the only additional time or procedures that are purely for research 
are some questionnaires at the beginning and weekly through your acute course, and the 
2,4 and 6 month followup visits (and the MRI scans if you elect to do those). The 
procedures and risks below pertain to ECT in general, as well as to the new form of ECT 
that we are researching, called FEAST.  
In general, you can stay on most of your medications that would normally be allowed with 
ECT. We may suggest some changes in your medications (if any) that were used to treat 
your psychiatric at least five days before you receive FEAST. This is part of standard ECT 
practice. If there are medications that you are taking that are not allowed in this research 
study and you need to stop taking them in order to be in the trial, we will discuss the 
specific risks associated with that. The procedures used in FEAST will be identical to those 
used in conventional ECT except that the current will flow in one (unidirectional) instead of 
two directions (bidirectional) and special electrodes will be used to concentrate the current 
to the right frontal lobe. You will receive treatments at a rate of three a week, usually for 
two to six weeks, depending on your doctor's clinical judgment of what would be best for 
you. 
During this period, if your depressive condition does not respond to treatment with FEAST, 
your doctor may change the treatment you receive to a traditional form of ECT. If the type 
of treatment is changed, all the testing procedures described below will be administered 
before the change, as well as following the ECT course. 
At each treatment, you will be under the care of an anesthesiologist, a psychiatrist, and a 
nurse. To receive each treatment you will be brought to a specially equipped room. The 
treatments are given in the morning, before breakfast. Because the treatments involve 
general anesthesia, you will have had nothing to drink or eat for at least eight hours before 
each treatment. When you come to the treatment room, before beginning the treatment, in 
order to spare you the discomfort from many “needle sticks”, a thin plastic tube (an “IV line” 
or catheter) will be placed in your arm so that medications can be given to you. You will be 
given an anesthetic drug that will quickly put you to sleep. You will be given a second drug 
that will relax your muscles. Because you will be asleep, you will not experience pain or 
discomfort during the procedure. You will not feel the electrical current, and when you 
wake up you will have no memory of the treatment. 
To prepare for the treatments, monitoring sensors will be placed on your head and other 
parts of your body. A blood pressure cuff will be placed on one of your limbs. This is done 
to monitor your brain waves, your heart, and your blood pressure. These recordings involve 
no pain or discomfort. After you are asleep, a small, carefully controlled amount of 
electricity will be passed between two electrodes that have been placed on your head. 
When the current is passed, a generalized seizure is produced in the brain. Because you will 
have been given a medication to relax your muscles, muscular contractions in your body 
that would ordinarily accompany a seizure will be markedly softened. The seizure will last 

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for approximately one minute. Within a few minutes, the anesthetic will wear off and you 
will awaken. During the procedure your heart rate, blood pressure, and other functions will 
be monitored. You will be given oxygen to breathe. After waking up from the anesthesia, 
you will be brought to a recovery room, where you will be observed until it is time to leave 
the ECT area. 
You will be closely monitored in terms of the effects of the treatments on your symptoms 
and thinking and memory. If the evaluation team feels that you are improving at too slow a 
rate, they may recommend an increase in the electrical dosage administered or they may 
recommend that FEAST be stopped. Likewise, if excessive cognitive side effects are seen, 
FEAST may be stopped and a traditional form of ECT offered. 
Clinical Evaluation and Neuropsychological Procedures: Before starting FEAST you will 
participate in interviews and will be asked questions about your current psychiatric 
condition, any psychological problems you may have had in the past, your family's history 
of psychological problems, your medical history, and your attitudes about receiving FEAST. 
A member of your family may also be asked to participate in some interviews to provide 
further information about your psychological condition and that of members of your family. 
You will also be asked to complete questionnaires that assess your psychological state.  
During your course of treatment and during the week following this course, you will 
participate in interviews to assess changes in your symptoms. Following the acute course (4 
weeks of treatment), we will ask you to participate in clinical interviews at 2 months, 4 
months and 6 months following your recovery. If travel is a major problem, some of these 
interviews may be conducted by telephone by a member of the clinical research staff. They 
will take place at two, four and 6 months after the end of the FEAST acute course. 
To assess the effects of treatment on your cognitive abilities (thinking and memory), you 
will receive a battery of neuropsychological tests during the week before starting FEAST, 
following the sixth/seventh treatment, during the first week after treatment, and two, four, 
and six months following the completion of FEAST. Each administration of this battery will 
take about an hour. The battery includes a series of tasks to assess your memory for 
material that you will be asked to learn, for events that occurred in your life, and for public 
events. On other tasks you will be asked to repeat phrases that you have heard, solve 
puzzles, and other similar tests of thinking.  
At each treatment session, just before you receive FEAST, you will be asked to remember a 
set of information. Following each treatment, after you wake up, you will be asked to recall 
or recognize this material and you will be administered an additional set of brief 
neuropsychological tasks.  
EEG Procedures: The naturally occurring electrical activity of brain regions will be measured 
by recording the EEG (electroencephalogram). For the EEG examinations, your scalp will be 

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cleaned and sensors placed on your head and near your eyes. The sensors will not pass any 
electricity to you, but will be used to measure the brain waves that are naturally occurring. 
During this examination, measurements will be taken while you lie quietly with your eyes 
closed and while you lie quietly with your eyes open. These procedures will be conducted 
prior to treatment, at two or more of your treatment sessions, during the week following 
treatment, and at two-month follow-up sessions. 
Functional Magnetic Resonance Imaging (fMRI) Procedures: You may choose to also have 
two MRI scans done as part of this research, one before the FEAST treatments and then 
one right at the end of the acute course, about 4 weeks later on average. The time between 
the scans will depend on how rapidly you improve, and could be as little as one week or as 
long as 5 weeks apart.  
☐ Yes, I agree to participate in the MRI scans.  
☐ No, I do not wish to participate in the MRI scans.  
If you do not wish to participate in the MRI scans, you can skip the following paragraphs.  
You are being asked to provide a brain image that will be stored for future research. The 
procedure used to take the brain image is called a Magnetic Resonance Imaging (MRI) 
scan. It uses magnetic fields and radio waves, and it is completely non-invasive and not 
harmful. The scan will take pictures of the brain, which will allow investigators to measure 
the size and shapes of parts of your brain. You will be in the scanner for less than one hour.  
If you agree to participate in this fMRI part of the study, the following will happen: 
MRI Procedure:  
• 
You will first be asked questions to find out if there are any reasons as to why you 
might not be able to have an MRI. We will, for example, ask you questions about 
whether you have any metal in your body that may interfere with the scanner. This 
does not include things such as dental fillings or surgical pins that are stainless 
steel. Some people are uncomfortable in small spaces and we will also ask you 
about this. Women may not be pregnant or breastfeeding. Women must agree to 
use an effective form of birth control such as a birth control pill, birth control patch, 
or condoms. Women who are of childbearing age who may be pregnant will 
provide a urine sample for pregnancy testing.  
• 
If there are no reasons to prevent you from having an MRI scan and you agree to 
participate, your first one hour MRI scan will be scheduled. The MRI scanning will 
occur at the MUSC Center for Advanced Imaging Research MRI scanner located at 
30 Bee Street, just across the street from the Psychiatry Building.  
• 
The night before the scan session, we encourage you to have a normal night’s 
sleep. Please do not drink any coffee within 2 hours before the scan.  

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• 
Before the scan session, you will meet with a representative of the study (the doctor 
in charge or one of the research staff) to review what will happen during the scan.  
• 
Pictures of your brain will be collected using a Magnetic Resonance Imaging (MRI) 
Scanner, which involves the following:  
• 
You will be placed on a table that will slide into the scanner.  
• 
A large plastic cylinder with holes in it will surround your head. This is the part of 
the scanner which will make the pictures of your brain. 
• 
Foam or a pillow will be placed around your head to keep your head still. 
• 
After you are made comfortable on your back on the table, the table will slide into 
the MRI scanner. It is wider than your body and you can see out into the room as 
you are lying down. 
 
• 
During the scans, you will be asked to lie still and be awake. Occasionally the MRI 
tech or the research assistant will talk with you and instruct you in how to perform 
the tasks. You will be able to see the tasks on a computer screen projected into the 
scanner.    
• 
You will hear loud noises from the scanner during the imaging study. These are 
normal operating sounds that the scanner makes. You will be given earplugs to 
help soften the noise. During the imaging session you will be able to talk to the 
investigators and the MRI technician, and they will be able to talk to you.  
• 
Your scan will be labeled with a numerical code that does not directly identify you 
in any way other than that you are a research subject in this study. The scan will 
contain your age and the scan date/time. Your scan will then be stored on secure 
computers at MUSC. Your and other participants’ images will be shared with the 
FEAST investigators and collaborators for this research study.  
You may be withdrawn from this imaging study without your consent if the researchers 
believe it is in your best interest or if you fail to follow study procedures. For example, if 
there is concern that you have metal in your body we would not allow the MRI scan to 
proceed.  
Repeat Scan – About 4-5 weeks after the first scan, we will invite you back to the MRI 
center to do exactly the same things as you did on the first scanning visit. We will try and 
coordinate this scanning session with other testing that is part of the parent study. That 
may not always be possible and we will then need for you to make a separate visit. Just like 
the first visit, the second return imaging visit should not last more than one hour.  
B. DURATION: 
Participation in the study will take about 3-5 weeks during the acute treatment phase, with 
followup visits at 2,4 and 6 months following the acute course. This research is done on top 
of your clinical care. The additional time required for the research aspect is several hours at 
the beginning in terms of questions, an additional hour each week for ratings, the MRI visits 
if you choose to participate in those, and the followup visits, each of which is about 2-3 
hours. Thus the total duration and time of the research is about 24 hours over the 6 

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months.  
 
C. RISKS/DISCOMFORTS:  
Treatment Procedures: Like other medical procedures, FEAST involves some risks. The 
primary risk of treatment with FEAST is that it may not be effective. FEAST is a new ECT 
method and is still being studied and it cannot be known ahead of time whether it has the 
same beneficial effects as standard ECT. In the first 35 patients that we have treated so far, 
FEAST appears to have antidepressant effects similar to conventional ECT. However, if you 
do not benefit from FEAST, you will be offered treatment with a standard form of ECT. We 
will be monitoring your clinical response each visit and there is a formula or algorithm for 
switching you back to conventional ECT if you are not making progress. We will talk with 
you about this progress at each visit.  
A common side effect of ECT is decreased memory functioning. This may also occur with 
FEAST, although the effect on memory is expected to be less than with traditional forms of 
ECT. The degree of disruption of memory is likely to be related to the number and type of 
treatments given. A smaller number of treatments are likely to produce less memory 
impairment than a larger number of treatments. The memory difficulties with ECT have a 
characteristic pattern. Shortly following a treatment, the problems with memory are most 
pronounced. As time from treatment increases, memory functioning improves. Shortly after 
the course of FEAST, you may experience difficulties remembering events that happened 
before and while you received FEAST. Your spottiness in memory for past events may 
extend back to several months before you received FEAST, and in rare instances, to one, 
two, or more years. Many of these memories will return during the first few months 
following the FEAST course. However, you may be left with permanent gaps in memory, 
particularly for events that occurred close in time to the FEAST course. In addition, for a 
short period following FEAST, you may experience difficulty in learning and remembering 
new events. This difficulty in forming new memories should be transient and will most likely 
subside within several weeks following the FEAST course. 
Individuals vary considerably in the extent to which they experience confusion and memory 
problems during and shortly following treatment with ECT. However, in part because 
psychiatric conditions themselves produce impairments in learning and memory, most 
patients report that their learning and memory functioning is improved after ECT compared 
to their functioning prior to the treatment course. Objective tests indicate that many 
aspects of thinking are improved following ECT, but that, nonetheless, there are specific 
problems in memory, as described above. While it is expected that FEAST will have reduced 
negative effects on thinking and memory compared to ECT, this cannot be guaranteed. A 
small minority of patients treated with ECT report severe problems in memory that remain 
for months or even years. The reasons for these exceptional reports of long-lasting 
impairment are not fully understood. However, as with any medical treatment, individuals 
who receive ECT differ in the extent to which they experience side effects. Rarely, ECT may 
result in permanent and extensive gaps in memory. 

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Because of the possible problems with confusion and memory, it is important that you not 
make important personal or business decisions during the FEAST course or immediately 
following the course. This may mean postponing decisions regarding financial or family 
matters. After the treatment course, you will begin a “convalescence period,” usually one to 
three weeks, but which varies from patient to patient. During this period, you should refrain 
from driving, transacting business, or other activities for which impairment of concentration 
or memory may be problematic, until so advised by your doctor. 
When you awaken after each FEAST treatment, you may experience confusion. The 
confusion usually goes away within an hour. Shortly after the treatment, you may have a 
headache, muscle soreness, or nausea. These side effects usually respond to simple 
treatment, such as Tylenol® for muscle soreness or headache and Reglan® for nausea. 
More serious medical complications with ECT are rare, and should be very infrequent with 
FEAST. With modern anesthetic techniques, dislocations or bone fracture, and dental 
complications very rarely occur. As with any general anesthetic procedure, there is a remote 
possibility of death. It is estimated that fatality associated with ECT occurs approximately 
one per 10,000 patients treated. While also rare, the most common medical complications 
with ECT are irregularities in heart rate and rhythm, which can be effectively treated in 
nearly all cases. FEAST should have similar complications to ECT, although it is anticipated 
that their frequency and/or severity will be reduced with FEAST when compared to ECT. 
To reduce the risk of medical complications, you will receive a careful medical evaluation 
prior to starting FEAST. However, in spite of precautions there is a small chance that you 
might experience a medical complication. Should this occur, medical care and treatment 
will be instituted immediately and facilities are available to handle emergencies. 
Clinical Evaluation Procedures: There are no anticipated risks to you. You may find the 
interviews about your psychological condition upsetting, but no more so than the 
psychiatric interviews you would undergo as part of your care. 
EEG Procedures: There are no anticipated risks associated with the EEG examinations. 
fMRI Procedures:  (The following pertains only to those also doing the fMRI study).MRI tests 
are non-invasive and painless. There are no known or foreseeable risks or side effects 
associated with conventional MRI procedures except to those people who have electrically, 
magnetically, or mechanically activated implants (such as cardiac pacemakers) or to those 
who have clips on blood vessels in their brain. There are no known additional risks 
associated with high-speed MRI. Both the conventional and the high speed MRI systems 
have been approved by the U.S. Food and Drug Administration (FDA) and will be operated 
within the standards reviewed and accepted by the FDA.  
However, an MRI may cause you to feel claustrophobic (uncomfortable in a small space) or 
anxious from the banging noises made by the machine. Most subjects find the procedure 

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easy, and often fall asleep during the scanning. We ask that you try to stay awake since if 
you fall asleep and suddenly wake up, you may move and this will affect the image. 
Because the MRI machine acts like a large magnet, it could move iron-containing objects in 
the MRI room during your examination, which could in the process possibly, harm you. 
Precautions have been taken to prevent such an event from happening; loose metal 
objects, like pocket knives or key chains, are not allowed in the MRI room. If you have a 
piece of metal in your body, such as a fragment in your eye, aneurysm clips, ear implants, 
spinal nerve stimulators, or a pacemaker, you will not be allowed into the MRI room and 
cannot have a MRI. 
Having an MRI may mean some added discomfort to you. In particular, you may be 
bothered by feelings of claustrophobia and by the loud banging noise during the study. 
Temporary hearing loss has been reported from the loud noise. You will wear earplugs 
during the scan to help prevent this.  
This MRI scan will be used to answer research questions, not to examine your brain 
medically.  This MRI scan is not a substitute for one a doctor would order. It may not show 
problems that would be picked up by a medical MRI scan. Nevertheless, a neuroradiologist 
(a doctor trained in reading MRI brain scans) will review all scans and if they believe that 
there may be a medical problem in your MRI scan, we will ask your permission to contact 
your primary care physician. If you do not have a primary care physician, we will assist you 
in finding a doctor to follow up on any finding that may not be normal.  
Another risk relates to the loss of privacy as images will be shared with other scientists. 
Additional data included with the image are the date and time of the scan and your age at 
the time of the scan. We will make every effort to protect your confidentiality and make 
sure that your identity does not become known. All written information will be stored in a 
locked file cabinet, and electronic data will be encrypted. A limited number of staff 
members will have access to the data. However, there is a slight risk of a breach of security.  
Your brain scan will be labeled with a numeric code only and will not contain your name, 
initials, date of birth, social security number, or any other information that could identify 
you directly. The image will contain the date/time of your scan and your age at the time of 
the scan. The scans will be securely stored at the Center for Biomedical Imaging (CBI) 
Archive at MUSC.   
Research records will be kept confidential to the extent allowed by law. Federal Privacy 
Regulations provide safeguards for the privacy, security, and authorized access. Research 
records may be reviewed by the Institutional Review Board, the Office of Human Research 
Protection, and the Food and Drug Administration (FDA).  

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Unknown Risks: The experimental treatments may have unknown side effects to you or to 
an embryo or fetus should you become pregnant. The researchers will let you know if they 
learn anything that might make you change your mind about participating in the study. 
D. BENEFITS: 
The potential benefit of the treatment component of this study is that it may lead to 
improvement in your psychiatric condition. 
The neuropsychological procedures, the neurophysiology procedures, and the MRI 
procedures will not benefit you directly. Many people suffer from the same type of 
psychiatric condition and many people receive ECT. The information obtained from this 
study may benefit others, although there is no way to know for sure if this will be so. 
E. COSTS: 
There is no cost to participate in this research. Specifically, the MRI scans, and additional 
assessments are paid for by the study.  
ECT is a medical procedure covered by almost all insurance carriers. You or your insurance 
company will be billed for the routine clinic visits, and all standard laboratory tests (e.g. 
routine blood counts and blood chemistry tests) and ECT treatments.  You will not be billed 
for tests required for purposes of research (e.g. MRI exams).  
F. PAYMENT TO PARTICIPANTS: 
 
When you participate in the two-, four-, and six-month follow-up procedures, you will be 
paid $20.00 for each hour of time that you contribute. For each MRI scan you will be paid 
$50.00. If you discontinue your participation you will be paid for the amount of time you 
have contributed to that point. Payments will be made in cash at the visit. If you complete 
these follow-up assessments, which typically involve up to 3 hours, the total compensation 
would be $180. With two MRI scans at $50 each, the total possible would be $280. 
Payments that you receive from MUSC for participating in a research study are considered 
taxable income per IRS regulations.  Payment types may include, but are not limited to: 
checks, cash, gift certificates/cards, personal property, and other items of value.  If the total 
amount of payment you receive from MUSC reaches or exceeds $600.00 in a calendar year, 
you will be issued a Form 1099. 
G. ALTERNATIVES: 
 
If you choose not to participate in this study, you could receive other treatments for your 
condition. The standard therapies for your condition are talking therapy, medications, 
transcranial magnetic stimulation, or conventional ECT. You and your doctor have 
discussed why ECT is likely the next best treatment for you and your depression. If you elect 

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not to participate in this FEAST study, you may still receive standard clinical care and 
standard ECT.  
 
H. NEW INFORMATION: If there are significant new findings during the course of the study, 
you will be notified. 
 
I. 
RELEASE OF MEDICAL RECORDS TO ANYONE OTHER THAN THE INVESTIGATORS: You will 
be asked to sign a separate release for the release of your medical records.  
J. STUDENT PARAGRAPH: Your participation or discontinuance will not constitute an element 
of your academic performance nor will it be a part of your academic record at this 
Institution. 
K. EMPLOYEE PARTICIPATION: Your participation or discontinuance will not constitute an 
element of your job performance or evaluation nor will it be a part of your personnel 
record at this Institution. 
L. CLINICAL TRIAL REGISTRY DATABANK: A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This web site will not include 
information that can identify you. At most, the web site will include a summary of the 
results. You can search this web site at any time. 
 
Results of this research will be used for the purposes described in this study. This 
information may be published, but you will not be identified. Information that is obtained 
concerning this research that can be identified with you will remain confidential to the 
extent possible within State and Federal law. The sponsor and the Food and Drug 
Administration (FDA) will receive copies of the research records. The investigators 
associated with this study, employees of the sponsor, the FDA, and the MUSC Institutional 
Review Board for Human Research will have access to identifying information. All records in 
South Carolina are subject to subpoena by a court of law. 
In the event of a study related injury, you should immediately go to the emergency room of 
the Medical University Hospital, or in case of an emergency go to the nearest hospital, and 
tell the physician on call that your are in a research study.   They will call your study doctor 
who will make arrangements for your treatment.   If the study sponsor does not pay for 
your treatment, the Medical University Hospital and the physicians who render treatment to 
you will bill your insurance company.   If your insurance company denies coverage or 
insurance is not available, you will be responsible for payment for all services rendered to 
you. 

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Your participation in this study is voluntary. You may refuse to take part in or stop taking 
part in this study at any time. You should call the investigator in charge of this study if you 
decide to do this. The data collected on you to this point remains part of the study 
database and may not be removed.  Your decision not to take part in the study will not 
affect your current or future medical care or any benefits to which you are entitled. 
The investigators and/or the sponsor may stop your participation in this study at any time if 
they decide it is in your best interest. They may also do this if you do not follow the 
investigator’s instructions. 
Volunteers Statement 
I have been given a chance to ask questions about this research study. These questions 
have been answered to my satisfaction. If I have any more questions about my participation 
in this study or study related injury, I may contact __________________. I may contact the 
Medical University of SC Hospital Medical Director (843) 792-9537 concerning medical 
treatment.  
If I have any questions, problems, or concerns, desire further information or wish to offer 
input, I may contact the Medical University of SC Institutional Review Board for Human 
Research IRB Manager or the Office of Research Integrity Director at (843) 792-4148.  This 
includes any questions about my rights as a research subject in this study. 
I agree to participate in this study. I have been given a copy of this form for my own 
records. 
If you wish to participate, you should sign below. 
 
                                                                    
                                                                 
   
Signature of Person 
Obtaining Consent 
Date 
Signature of Participant 
Date 
                                                                 
   
  
 
 
  
  
Capacity to Consent Addendum  
 
 
I have discussed the proposed research with this patient and, in my 
opinion, this patient understands the benefits and risks and is capable of 
freely consenting to participate in this research. 

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DATE 
 
 
 
SIGNATURE                                    
 
 
Study Physician 
 
PRINT NAME                                     
 
 
Study Physician 
 
 
I have examined on _______ for the purpose of determining whether 
he/she is capable of understanding the purpose, nature, risks, benefits and 
alternatives (including non-participation) of the research, making a decision 
about participation, and understanding that the decision about participation 
in the research will involve no penalty or loss of benefits to which the 
patient is otherwise entitled, for Dr. Mark George’s research project 
“FEAST: Studies at two enrolling sites to further test and refine the 
treatment”. On the basis of this examination I have arrived at the 
conclusion that: 
 
______ A. This patient has this capacity at this time. 
______ B. There is a question about this patient’s capacity at this time. 
______ C. This patient clearly lacks this capacity. 
 
DATE 
 
 
SIGNATURE                                    
 
 
 
Member of Treatment Team 
 
(M.D. or Ph.D.; Not a co-investigator) 
 
PRINT NAME                                     
 
 
 
Member of Treatment Team 
 
 
 
 

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Focal Electrically-Administered Seizure Therapy (FEAST): 
Studies at two enrolling sites to further test and refine the treatment: 
Right Unilateral Ultrabrief ECT as a Comparison to FEAST 
 
M. PURPOSE AND BACKGROUND: 
 
Your doctor has recommended that you receive treatment with electroconvulsive therapy 
(ECT). You have been asked to participate in a research study. The study seeks to document 
your clinical progress and brain changes in order to compare a new form of ECT against 
the current state of the art. You will be receiving standard state of the art ECT. The only 
aspect of your treatment that is research are some additional questions and tests, two MRI 
scans, and followup visits at 2,4 and 6 months after treatment. The new type of ECT is 
called Focal Electrically-Administered Seizure Therapy (FEAST). YOU WILL NOT BE GETTING 
FEAST but will instead be getting standard care. Your participation in this study is purely 
voluntary. You are being asked to participate in this study because you have a diagnosis of 
major depression and you have not responded to, or have been intolerant to, other 
depression therapies. The principal investigator is Dr. Mark George. (843 876 5142) This 
study is taking place at two sites – MUSC and Georgia Regents University and will involve 
60 patients, about 30 of whom will come from MUSC.  
You have been told that besides ECT there are other treatments for depression, which 
include medication, psychotherapy, transcranial magnetic stimulation (TMS) and 
conventional forms of ECT. These alternative treatments have their own benefits and risks. 
Why ECT has been recommended for your specific case has been explained to you. ECT is 
available at many hospitals and you do not have to participate in this research study to 
receive ECT.  
N. PROCEDURES: 
 
If you agree to be in this study, the following will happen: 
Overall, this study simply follows your clinical progress as you receive ECT. So, the only 
additional time or procedures that are purely for research are some questionnaires at the 
beginning and weekly through your acute course, and the 2,4 and 6 month followup visits 
(and the MRI scans if you elect to do those). The procedures and risks below pertain to ECT 
in general. The only part that is research are the additional questionnaires and scans. 

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In general, you can stay on most of your medications that would normally be allowed with 
ECT. We may suggest some changes in your medications (if any) that were used to treat 
your psychiatric at least five days before you receive FEAST. This is part of standard ECT 
practice. If there are medications that you are taking that are not allowed in this research 
study and you need to stop taking them in order to be in the trial, we will discuss the 
specific risks associated with that. The procedures used in FEAST will be identical to those 
used in conventional ECT except that the current will flow in one (unidirectional) instead of 
two directions (bidirectional) and special electrodes will be used to concentrate the current 
to the right frontal lobe. You will receive treatments at a rate of three a week, usually for 
two to six weeks, depending on your doctor's clinical judgment of what would be best for 
you. 
During this period, if your depressive condition does not respond to treatment with right 
unilateral ultrabrief ECT (which is the current standard), your doctor may change the 
treatment so that you receive an older form of  traditional ECT. If the type of treatment is 
changed, all the testing procedures described below will be administered before the 
change, as well as following the ECT course. 
At each treatment, you will be under the care of an anesthesiologist, a psychiatrist, and a 
nurse. To receive each treatment you will be brought to a specially equipped room. The 
treatments are given in the morning, before breakfast. Because the treatments involve 
general anesthesia, you will have had nothing to drink or eat for at least eight hours before 
each treatment. When you come to the treatment room, before beginning the treatment, in 
order to spare you the discomfort from many “needle sticks”, a thin plastic tube (an “IV line” 
or catheter) will be placed in your arm so that medications can be given to you. You will be 
given an anesthetic drug that will quickly put you to sleep. You will be given a second drug 
that will relax your muscles. Because you will be asleep, you will not experience pain or 
discomfort during the procedure. You will not feel the electrical current, and when you 
wake up you will have no memory of the treatment. 
To prepare for the treatments, monitoring sensors will be placed on your head and other 
parts of your body. A blood pressure cuff will be placed on one of your limbs. This is done 
to monitor your brain waves, your heart, and your blood pressure. These recordings involve 
no pain or discomfort. After you are asleep, a small, carefully controlled amount of 
electricity will be passed between two electrodes that have been placed on your head. 
When the current is passed, a generalized seizure is produced in the brain. Because you will 
have been given a medication to relax your muscles, muscular contractions in your body 
that would ordinarily accompany a seizure will be markedly softened. The seizure will last 
for approximately one minute. Within a few minutes, the anesthetic will wear off and you 
will awaken. During the procedure your heart rate, blood pressure, and other functions will 
be monitored. You will be given oxygen to breathe. After waking up from the anesthesia, 
you will be brought to a recovery room, where you will be observed until it is time to leave 
the ECT area. 

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You will be closely monitored in terms of the effects of the treatments on your symptoms 
and thinking and memory. If the evaluation team feels that you are improving at too slow a 
rate, they may recommend an increase in the electrical dosage administered or they may 
recommend that FEAST be stopped. Likewise, if excessive cognitive side effects are seen, 
Right Unilateral ECT may be stopped and a traditional form of ECT offered. 
Clinical Evaluation and Neuropsychological Procedures: Before starting ECT you will 
participate in interviews and will be asked questions about your current psychiatric 
condition, any psychological problems you may have had in the past, your family's history 
of psychological problems, your medical history, and your attitudes about receiving ECT. 
A member of your family may also be asked to participate in some interviews to provide 
further information about your psychological condition and that of members of your family. 
You will also be asked to complete questionnaires that assess your psychological state.  
During your course of treatment and during the week following this course, you will 
participate in interviews to assess changes in your symptoms. Following the acute course (4 
weeks of treatment), we will ask you to participate in clinical interviews at 2 months, 4 
months and 6 months following your recovery. If travel is a major problem, some of these 
interviews may be conducted by telephone by a member of the clinical research staff. They 
will take place at two, four and 6 months after the end of the ECT acute course. 
To assess the effects of treatment on your cognitive abilities (thinking and memory), you 
will receive a battery of neuropsychological tests during the week before starting ECT, 
following the sixth/seventh treatment, during the first week after treatment, and two, four, 
and six months following the completion of ECT. Each administration of this battery will 
take about an hour. The battery includes a series of tasks to assess your memory for 
material that you will be asked to learn, for events that occurred in your life, and for public 
events. On other tasks you will be asked to repeat phrases that you have heard, solve 
puzzles, and other similar tests of thinking.  
At each treatment session, just before you receive ECT, you will be asked to remember a set 
of information. Following each treatment, after you wake up, you will be asked to recall or 
recognize this material and you will be administered an additional set of brief 
neuropsychological tasks.  
EEG Procedures: The naturally occurring electrical activity of brain regions will be measured 
by recording the EEG (electroencephalogram). For the EEG examinations, your scalp will be 
cleaned and sensors placed on your head and near your eyes. The sensors will not pass any 
electricity to you, but will be used to measure the brain waves that are naturally occurring. 
During this examination, measurements will be taken while you lie quietly with your eyes 
closed and while you lie quietly with your eyes open. These procedures will be conducted 
prior to treatment, at two or more of your treatment sessions, during the week following 
treatment, and at two-month follow-up sessions. 

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Functional Magnetic Resonance Imaging (fMRI) Procedures: You may choose to also have 
two MRI scans done as part of this research, one before the ECT treatments and then one 
right at the end of the acute course, about 4 weeks later on average. The time between the 
scans will depend on how rapidly you improve, and could be as little as one week or as 
long as 5 weeks apart.  
☐ Yes, I agree to participate in the MRI scans.  
☐ No, I do not wish to participate in the MRI scans.  
If you do not wish to participate in the MRI scans, you can skip the following paragraphs.  
You are being asked to provide a brain image that will be stored for future research. The 
procedure used to take the brain image is called a Magnetic Resonance Imaging (MRI) 
scan. It uses magnetic fields and radio waves, and it is completely non-invasive and not 
harmful. The scan will take pictures of the brain, which will allow investigators to measure 
the size and shapes of parts of your brain. You will be in the scanner for less than one hour.  
If you agree to participate in this fMRI part of the study, the following will happen: 
MRI Procedure:  
• 
You will first be asked questions to find out if there are any reasons as to why you 
might not be able to have an MRI. We will, for example, ask you questions about 
whether you have any metal in your body that may interfere with the scanner. This 
does not include things such as dental fillings or surgical pins that are stainless 
steel. Some people are uncomfortable in small spaces and we will also ask you 
about this. Women may not be pregnant or breastfeeding. Women must agree to 
use an effective form of birth control such as a birth control pill, birth control patch, 
or condoms. Women who are of childbearing age who may be pregnant will 
provide a urine sample for pregnancy testing.  
• 
If there are no reasons to prevent you from having an MRI scan and you agree to 
participate, your first one hour MRI scan will be scheduled. The MRI scanning will 
occur at the MUSC Center for Advanced Imaging Research MRI scanner located at 
30 Bee Street, just across the street from the Psychiatry Building.  
• 
The night before the scan session, we encourage you to have a normal night’s 
sleep. Please do not drink any coffee within 2 hours before the scan.  
• 
Before the scan session, you will meet with a representative of the study (the doctor 
in charge or one of the research staff) to review what will happen during the scan.  
• 
Pictures of your brain will be collected using a Magnetic Resonance Imaging (MRI) 
Scanner, which involves the following:  
• 
You will be placed on a table that will slide into the scanner.  
• 
A large plastic cylinder with holes in it will surround your head. This is the part of 
the scanner which will make the pictures of your brain. 

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• 
Foam or a pillow will be placed around your head to keep your head still. 
• 
After you are made comfortable on your back on the table, the table will slide into 
the MRI scanner. It is wider than your body and you can see out into the room as 
you are lying down. 
 
• 
During the scans, you will be asked to lie still and be awake. Occasionally the MRI 
tech or the research assistant will talk with you and instruct you in how to perform 
the tasks. You will be able to see the tasks on a computer screen projected into the 
scanner.    
• 
You will hear loud noises from the scanner during the imaging study. These are 
normal operating sounds that the scanner makes. You will be given earplugs to 
help soften the noise. During the imaging session you will be able to talk to the 
investigators and the MRI technician, and they will be able to talk to you.  
• 
Your scan will be labeled with a numerical code that does not directly identify you 
in any way other than that you are a research subject in this study. The scan will 
contain your age and the scan date/time. Your scan will then be stored on secure 
computers at MUSC. Your and other participants’ images will be shared with the 
ECT investigators and collaborators for this research study.  
You may be withdrawn from this imaging study without your consent if the researchers 
believe it is in your best interest or if you fail to follow study procedures. For example, if 
there is concern that you have metal in your body we would not allow the MRI scan to 
proceed.  
Repeat Scan – About 4-5 weeks after the first scan, we will invite you back to the MRI 
center to do exactly the same things as you did on the first scanning visit. We will try and 
coordinate this scanning session with other testing that is part of the parent study. That 
may not always be possible and we will then need for you to make a separate visit. Just like 
the first visit, the second return imaging visit should not last more than one hour.  
O. DURATION: 
Participation in the study will take about 3-5 weeks during the acute treatment phase, with 
followup visits at 2,4 and 6 months following the acute course. This research is done on top 
of your clinical care. The additional time required for the research aspect is several hours at 
the beginning in terms of questions, an additional hour each week for ratings, the MRI visits 
if you choose to participate in those, and the followup visits, each of which is about 2-3 
hours. Thus the total duration and time of the research is about 24 hours over the 6 
months.  
 
P. RISKS/DISCOMFORTS:  
Treatment Procedures: Like other medical procedures, ECT involves some risks. The primary 
risk of treatment with ECT is that it may not be effective.  

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A common side effect of ECT is decreased memory functioning. The degree of disruption of 
memory is likely to be related to the number and type of treatments given. A smaller 
number of treatments are likely to produce less memory impairment than a larger number 
of treatments. The memory difficulties with ECT have a characteristic pattern. Shortly 
following a treatment, the problems with memory are most pronounced. As time from 
treatment increases, memory functioning improves. Shortly after the course of ECT, you 
may experience difficulties remembering events that happened before and while you 
received ECT. Your spottiness in memory for past events may extend back to several 
months before you received ECT, and in rare instances, to one, two, or more years. Many of 
these memories will return during the first few months following the ECT course. However, 
you may be left with permanent gaps in memory, particularly for events that occurred close 
in time to the ECT course. In addition, for a short period following ECT, you may experience 
difficulty in learning and remembering new events. This difficulty in forming new memories 
should be transient and will most likely subside within several weeks following the ECT 
course. 
Individuals vary considerably in the extent to which they experience confusion and memory 
problems during and shortly following treatment with ECT. However, in part because 
psychiatric conditions themselves produce impairments in learning and memory, most 
patients report that their learning and memory functioning is improved after ECT compared 
to their functioning prior to the treatment course. Objective tests indicate that many 
aspects of thinking are improved following ECT, but that, nonetheless, there are specific 
problems in memory, as described above. A small minority of patients treated with ECT 
report severe problems in memory that remain for months or even years. The reasons for 
these exceptional reports of long-lasting impairment are not fully understood. However, as 
with any medical treatment, individuals who receive ECT differ in the extent to which they 
experience side effects. Rarely, ECT may result in permanent and extensive gaps in memory. 
Because of the possible problems with confusion and memory, it is important that you not 
make important personal or business decisions during the ECT course or immediately 
following the course. This may mean postponing decisions regarding financial or family 
matters. After the treatment course, you will begin a “convalescence period,” usually one to 
three weeks, but which varies from patient to patient. During this period, you should refrain 
from driving, transacting business, or other activities for which impairment of concentration 
or memory may be problematic, until so advised by your doctor. 
When you awaken after each ECT treatment, you may experience confusion. The confusion 
usually goes away within an hour. Shortly after the treatment, you may have a headache, 
muscle soreness, or nausea. These side effects usually respond to simple treatment, such as 
Tylenol® for muscle soreness or headache and Reglan® for nausea. More serious medical 
complications with ECT are rare, and should be very infrequent with FEAST. With modern 
anesthetic techniques, dislocations or bone fracture, and dental complications very rarely 
occur. As with any general anesthetic procedure, there is a remote possibility of death. It is 
estimated that fatality associated with ECT occurs approximately one per 10,000 patients 

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treated. While also rare, the most common medical complications with ECT are 
irregularities in heart rate and rhythm, which can be effectively treated in nearly all cases.  
To reduce the risk of medical complications, you will receive a careful medical evaluation 
prior to starting ECT. However, in spite of precautions there is a small chance that you 
might experience a medical complication. Should this occur, medical care and treatment 
will be instituted immediately and facilities are available to handle emergencies. 
Clinical Evaluation Procedures: There are no anticipated risks to you. You may find the 
interviews about your psychological condition upsetting, but no more so than the 
psychiatric interviews you would undergo as part of your care. 
EEG Procedures: There are no anticipated risks associated with the EEG examinations. 
fMRI Procedures:  (The following pertains only to those also doing the fMRI study).MRI tests 
are non-invasive and painless. There are no known or foreseeable risks or side effects 
associated with conventional MRI procedures except to those people who have electrically, 
magnetically, or mechanically activated implants (such as cardiac pacemakers) or to those 
who have clips on blood vessels in their brain. There are no known additional risks 
associated with high-speed MRI. Both the conventional and the high speed MRI systems 
have been approved by the U.S. Food and Drug Administration (FDA) and will be operated 
within the standards reviewed and accepted by the FDA.  
However, an MRI may cause you to feel claustrophobic (uncomfortable in a small space) or 
anxious from the banging noises made by the machine. Most subjects find the procedure 
easy, and often fall asleep during the scanning. We ask that you try to stay awake since if 
you fall asleep and suddenly wake up, you may move and this will affect the image. 
Because the MRI machine acts like a large magnet, it could move iron-containing objects in 
the MRI room during your examination, which could in the process possibly, harm you. 
Precautions have been taken to prevent such an event from happening; loose metal 
objects, like pocket knives or key chains, are not allowed in the MRI room. If you have a 
piece of metal in your body, such as a fragment in your eye, aneurysm clips, ear implants, 
spinal nerve stimulators, or a pacemaker, you will not be allowed into the MRI room and 
cannot have a MRI. 
Having an MRI may mean some added discomfort to you. In particular, you may be 
bothered by feelings of claustrophobia and by the loud banging noise during the study. 
Temporary hearing loss has been reported from the loud noise. You will wear earplugs 
during the scan to help prevent this.  
This MRI scan will be used to answer research questions, not to examine your brain 
medically.  This MRI scan is not a substitute for one a doctor would order. It may not show 
problems that would be picked up by a medical MRI scan. Nevertheless, a neuroradiologist 

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(a doctor trained in reading MRI brain scans) will review all scans and if they believe that 
there may be a medical problem in your MRI scan, we will ask your permission to contact 
your primary care physician. If you do not have a primary care physician, we will assist you 
in finding a doctor to follow up on any finding that may not be normal.  
Another risk relates to the loss of privacy as images will be shared with other scientists. 
Additional data included with the image are the date and time of the scan and your age at 
the time of the scan. We will make every effort to protect your confidentiality and make 
sure that your identity does not become known. All written information will be stored in a 
locked file cabinet, and electronic data will be encrypted. A limited number of staff 
members will have access to the data. However, there is a slight risk of a breach of security.  
Your brain scan will be labeled with a numeric code only and will not contain your name, 
initials, date of birth, social security number, or any other information that could identify 
you directly. The image will contain the date/time of your scan and your age at the time of 
the scan. The scans will be securely stored at the Center for Biomedical Imaging (CBI) 
Archive at MUSC.   
Research records will be kept confidential to the extent allowed by law. Federal Privacy 
Regulations provide safeguards for the privacy, security, and authorized access. Research 
records may be reviewed by the Institutional Review Board, the Office of Human Research 
Protection, and the Food and Drug Administration (FDA).  
Unknown Risks: The experimental treatments may have unknown side effects to you or to a 
fetus or embryo if you were to become pregnant during the acute phase of the study. The 
researchers will let you know if they learn anything that might make you change your mind 
about participating in the study. 
Q. BENEFITS: 
The potential benefit of the treatment component of this study is that it may lead to 
improvement in your psychiatric condition. 
The neuropsychological procedures, the neurophysiology procedures, and the MRI 
procedures will not benefit you directly. Many people suffer from the same type of 
psychiatric condition and many people receive ECT. The information obtained from this 
study may benefit others, although there is no way to know for sure if this will be so. 
R. COSTS: 
There is no cost to participate in this research. Specifically, the MRI scans, and additional 
assessments are covered by the study.  
ECT is a medical procedure covered by almost all insurance carriers. You or your insurance 
company will be billed for the routine clinic visits, and all standard laboratory tests (e.g. 

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routine blood counts and blood chemistry tests) and ECT treatments.  You will not be billed 
for tests required for purposes of research (e.g. MRI exams).  
S. PAYMENT TO PARTICIPANTS: 
 
When you participate in the two-, four-, and six-month follow-up procedures, you will be 
paid $20.00 for each hour of time that you contribute. For each MRI scan you will be paid 
$50.00. If you discontinue your participation you will be paid for the amount of time you 
have contributed to that point. Payments will be made in cash at the visit. If you complete 
these follow-up assessments, which typically involve up to 3 hours, the total compensation 
would be $180. With two MRI scans at $50 each, the total possible would be $280. 
Payments that you receive from MUSC for participating in a research study are considered 
taxable income per IRS regulations.  Payment types may include, but are not limited to: 
checks, cash, gift certificates/cards, personal property, and other items of value.  If the total 
amount of payment you receive from MUSC reaches or exceeds $600.00 in a calendar year, 
you will be issued a Form 1099. 
T. ALTERNATIVES: 
 
If you choose not to participate in this study, you could receive other treatments for your 
condition. The standard therapies for your condition are talking therapy, medications, 
transcranial magnetic stimulation, or conventional ECT. You and your doctor have 
discussed why ECT is likely the next best treatment for you and your depression. If you elect 
not to participate in this ECT study, you may still receive standard clinical care and standard 
ECT.  
U. NEW INFORMATION: If there are significant new findings during the course of the study, 
you will be notified. 
V. RELEASE OF MEDICAL RECORDS TO ANYONE OTHER THAN THE INVESTIGATORS: You will 
be asked to sign a separate release for the release of your medical records.  
W. STUDENT PARAGRAPH: Your participation or discontinuance will not constitute an element 
of your academic performance nor will it be a part of your academic record at this 
Institution. 
X. EMPLOYEE PARTICIPATION: Your participation or discontinuance will not constitute an 
element of your job performance or evaluation nor will it be a part of your personnel 
record at this Institution. 
Y. CLINICAL TRIAL REGISTRY DATABANK: A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This web site will not include 
information that can identify you. At most, the web site will include a summary of the 
results. You can search this web site at any time. 
 

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Results of this research will be used for the purposes described in this study. This 
information may be published, but you will not be identified. Information that is obtained 
concerning this research that can be identified with you will remain confidential to the 
extent possible within State and Federal law. The sponsor and the Food and Drug 
Administration (FDA) will receive copies of the research records. The investigators 
associated with this study, employees of the sponsor, the FDA, and the MUSC Institutional 
Review Board for Human Research will have access to identifying information. All records in 
South Carolina are subject to subpoena by a court of law. 
In the event of a study related injury, you should immediately go to the emergency room of 
the Medical University Hospital, or in case of an emergency go to the nearest hospital, and 
tell the physician on call that your are in a research study.   They will call your study doctor 
who will make arrangements for your treatment.   If the study sponsor does not pay for 
your treatment, the Medical University Hospital and the physicians who render treatment to 
you will bill your insurance company.   If your insurance company denies coverage or 
insurance is not available, you will be responsible for payment for all services rendered to 
you. 
Your participation in this study is voluntary. You may refuse to take part in or stop taking 
part in this study at any time. You should call the investigator in charge of this study if you 
decide to do this. The data collected on you to this point remains part of the study 
database and may not be removed.  Your decision not to take part in the study will not 
affect your current or future medical care or any benefits to which you are entitled. 
The investigators and/or the sponsor may stop your participation in this study at any time if 
they decide it is in your best interest. They may also do this if you do not follow the 
investigator’s instructions. 
Volunteers Statement 
I have been given a chance to ask questions about this research study. These questions 
have been answered to my satisfaction. If I have any more questions about my participation 
in this study or study related injury, I may contact __________________. I may contact the 
Medical University of SC Hospital Medical Director (843) 792-9537 concerning medical 
treatment.  
If I have any questions, problems, or concerns, desire further information or wish to offer 
input, I may contact the Medical University of SC Institutional Review Board for Human 
Research IRB Manager or the Office of Research Integrity Director at (843) 792-4148.  This 
includes any questions about my rights as a research subject in this study. 
I agree to participate in this study. I have been given a copy of this form for my own 
records. 

IDE Application - Focal Electrically-Administered Seizure Therapy (FEAST): Studies at two enrolling sites 
Page 138 
Institute of Psychiatry, Medical University of South Carolina 
If you wish to participate, you should sign below. 
 
                                                                    
                                                                    
Signature of Person 
Obtaining Consent 
Date 
Signature of Participant 
Date 
 
Revised: 2/11/15 
Capacity to Consent Addendum  
 
 
I have discussed the proposed research with this patient and, in my 
opinion, this patient understands the benefits and risks and is capable of 
freely consenting to participate in this research. 
 
DATE 
 
 
 
SIGNATURE                                    
 
 
Study Physician 
 
PRINT NAME                                     
 
 
Study Physician 
 
 
I have examined on _______ for the purpose of determining whether 
he/she is capable of understanding the purpose, nature, risks, benefits and 
alternatives (including non-participation) of the research, making a decision 
about participation, and understanding that the decision about participation 
in the research will involve no penalty or loss of benefits to which the 
patient is otherwise entitled, for Dr. Mark George’s research project 
“FEAST: Studies at two enrolling sites to further test and refine the 
treatment”. On the basis of this examination I have arrived at the 
conclusion that: 
 
______ A. This patient has this capacity at this time. 
______ B. There is a question about this patient’s capacity at this time. 
______ C. This patient clearly lacks this capacity. 
 

IDE Application - Focal Electrically-Administered Seizure Therapy (FEAST): Studies at two enrolling sites 
Page 139 
Institute of Psychiatry, Medical University of South Carolina 
DATE 
 
 
SIGNATURE                                    
 
 
 
Member of Treatment Team 
 
(M.D. or Ph.D.; Not a co-investigator) 
 
PRINT NAME                                     
 
 
 
Member of Treatment Team 

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Department of Biological Psychiatry, New York State Psychiatric Institute 
 
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