Clinical trial NCT02882711
Conditions: Treatment Resistant Depression Major Depressive Disorder Bipolar Disorder
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2016-11-07; Completion date: 2017-08-16
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to determine the effectiveness of serial infusions of intravenous (IV) ketamine in adults with treatment resistant depression (TRD).

Detailed description:
Thus, in the current study we want to naturalistically explore the antidepressant effects of serial slow IV infusions (40 minutes) of ketamine at a dose of 0.5 mg/kg, over a treatment period of 8 weeks in an academic psychiatric hospital. This is a minimal sedation treatment. The primary outcome measure of this study will be remission estimated based on the severity of depressive scores. After the 8 weeks of treatment, there will be a four week observational period. During the observational period, participants will receive treatment as usual and will be contacted over the phone for follow-up questions regarding their overall health status, mood and clinical state. They will also complete a neurocognitive task at the end of the 4 week observational period

Arms: arm 1: None
Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: Ketamine will be infused (slow IV infusions of ketamine (0.5 mg/kg) over 40 minutes) twice weekly over a period of 4 weeks and weekly for the following 4 weeks of the study treatment period (8 weeks total).

Protocol documents:
Prot_SAP_000.pdf: 
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IRB NUMBER: HSC-MS-16-0020 
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A naturalistic study of serial infusion of low-dose ketamine for treatment resistant 
depressive disorders in an academic psychiatric hospital: The UTHealth Ketamine 
Project 
 
NCT02882711 
 
Version Date: 9/12/2016 
 
 


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IRB NUMBER: HSC-MS-16-0020 
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Study protocol: A naturalistic study of serial infusion of low-dose ketamine for 
treatment resistant depressive disorders in an academic psychiatric hospital: The 
UTHealth Ketamine Project 
 
Principal Investigator: 
 
Salih Selek, M.D. Assistant Professor, HCPC- Department of Psychiatry and 
Behavioral Sciences, The University of Texas Medical School at Houston 2800 South 
MacGregor Way, Houston, USA Salih.Selek@uth.tmc.edu 
Co-Investigators: 
Jair C. Soares MD, PhD. Professor and Chairman of Department of Psychiatry and 
Behavioral Sciences. Director of the UTHealth Center of Excellence on Mood Disorders. 
Executive Director Harris County Psychiatric Center (HCPC), The University of Texas 
Health Science Center at Houston, TX. USA. Jair.C.Soares@uth.tmc.edu 
Joao De Quevedo, MD, PhD. Professor Department of Psychiatry and Behavioral 
Sciences. Vice-Chair, Faculty Development and Outreach, Director, Translational 
Psychiatry Program Director, Treatment-Resistant Mood Disorders Program, Department of 
Psychiatry and Behavioral Sciences The University of Texas Health Science Center at 
Houston, TX. USA. Joao.L.DeQuevedo@uth.tmc.edu 
Sudhakar Selvaraj, M.B.B.S. DPhil, Assistant Professor of Psychiatry, UTHealth Center 
of Excellence on Mood Disorders. The University of Texas Health Science Center at 
Houston. Houston, USA. Sudhakar.Selvaraj@uth.tmc.edu 
Omar F Pinjari , M.D. Assistant Professor, HCPC - Department of Psychiatry and 
Behavioral Sciences, The University of Texas Medical School at Houston 
2800 South MacGregor Way, Houston, USA. Venkata.M.Mukkavilli@uth.tmc.edu 
 
Isabelle E. Bauer, PhD, Postdoctoral Research Fellow. UTHealth Center of Excellence 
on Mood Disorders. The University of Texas Health Science Center at Houston. 
Houston, USA. Isabelle.E.Bauer@uth.tmc.edu 
Giovana Zunta-Soares, MD, Director, UTHealth Center of Excellence on Mood Disorders. 
The University of Texas Health Science Center at Houston. Houston, USA. 
Giovana.B.Zuntasoares@uth.tmc.edu 
Danielle Spiker, BA, UTHealth Center of Excellence on Mood Disorders. The 
University of Texas Health Science Center at Houston. Houston, USA. 
Danielle.E.spiker@uth.tmc.edu 
 


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1. 
Specific aims 
 
 
The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is an FDA approved 
general anesthetic with immediate calming effects (within 24 hours). Ketamine has proved to have 
great utility for emergency procedures and management of chronic pain syndromes. In psychiatry 
ketamine has been shown to induce a rapid antidepressant response in patients with Treatment 
Resistant Depression (TRD) following a 0.5 mg/kg dose administered intravenously over 40 
minutes. These benefits were maintained for approximately 1 week post-infusion (Murrough et 
al., 2011). There is also a significant body of evidence for the mood-enhancing  and anti-suicidal 
properties of ketamine in patients with bipolar and unipolar depression (Griffith et al. 2014). This 
promising area of research poses a variety of methodological challenges. The optimal dose of 
ketamine for therapeutic purposes is still unknown but previous studies have used doses of 
ketamine of up to 0.5 mg/kg (Kollmar et al., 2008; Messer et al., 2010; Murrough et al., 2011; 
Rasmussen et al., 2013; Stefanczyk-Sapieha et al., 2008; Zanicotti et al., 2012). Ketamine 
administration requires close anesthetic monitoring in most institutions. As a result, the 
administration of ketamine involves major costs that insurance companies and patients cannot 
afford (Rasmussen et al., 2013). Thus, much work is still needed to increase/maintain high 
response rates to ketamine and lower the costs associated with administration. 
 
The primary objective of our study is to determine the effectiveness of serial infusions of 
intravenous (IV) ketamine in adults with treatment resistant depression (TRD) - diagnosed with 
either Major Depressive Disorder or Bipolar Disorder - at a slower infusion time than reported in 
previous studies. We expect that this approach alongside with the presence of  a psychiatrist with 
Advanced Cardiac Life Support (ACLS) training will eliminate the need for continuing anesthetic 
monitoring during infusion, thus leading to a more cost-effective intervention. As part of this 
objective, we plan to recruit 30 individuals with Treatment Resistant Depression and conduct an 
open label, naturalistic study using slow infusions of ketamine over a time period of 40 minutes. 
The duration of this study will be 12 weeks and will include twice weekly infusions over a 
period of 4 weeks and weekly infusions for the following 4 weeks of the study treatment 
period (8 weeks). There will also be a 4 week observational period post- treatment. 
 
Our hypotheses are that patients suffering from TRD receiving weekly slow IV infusions of 
ketamine (0.5 mg/kg) over 40 minutes will: 


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1. Report similar efficacy and better tolerability than those reported with conventional schemes of 
3 infusions per week over a 12 day period. 
2. Report less psychiatric side effects measured by changes in test scores on the Montgomery- 
Åsberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology 
(QIDS) and Young Mania Rating Scale (YMRS) compared to those previously reported with 
conventional schemes of serial ketamine infusions. 
3. Report an almost immediate effect based on the PANSS and Q-LES-Q scales which will be 
administered after the 40 min infusion period. 
4. Report less suicidal ideation measured by changes in scores on the Scale for Suicide Ideations 
(SSI; Beck et al., 1979), and the Suicide Status Form (SSF; Conrad et al., 2009) scores compared 
to that previously reported with conventional schemes of serial ketamine infusions. 
5. Report a better global outcome of treatment measured by a decrease in scores on in the 
Clinical Global Impression Scale (CGI; Guy, 1976) score compared to that previously reported 
with conventional schemes of serial ketamine infusions. 
6. Experience less hemodynamic changes in blood pressure and heart rate compared to than 
those previously reported with conventional schemes of serial ketamine infusions. 
7. Experience no cognitive impairment on the Brief Assessment of Cognition in Affective 
Disorders (BAC-A) following ketamine infusions. To our knowledge this hypothesis has not been 
previously assessed after an 8-week serial ketamine infusion treatment period. 
 
Clinical relevance 
 
 
Treatment Resistant Depression (TRD) is a major public health problem that constitutes a great 
burden for patients and mental health providers because of its prevalence, impact on people’s 
quality of life and overall cost to the society (Nemeroff et al., 2007). Given the dearth of the 
research in the field of Ketamine treatment, more naturalistic follow-up studies focusing on 
ketamine’s innovative antidepressant properties are warranted. Further, the findings of this study 
will provide health professionals with additional knowledge on the antidepressant properties of 
repeated ketamine IV infusions in both resistant Major Depressive Disorder (MDD) and Bipolar 
Disorder (BD). The current study will also help characterize responders from non- responders to 
ketamine, and will enable the assessment of the response and remission rates following ketamine 
intervention. 


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2.0       Research Strategy 
 
 
A. 
Significance 
Background and Rationale 
Major psychiatric disorders such as major depressive disorder (MDD) and bipolar disorder (BD) 
are among the most disabling mental illnesses worldwide with a global social cost of $66.5 million 
and 16.8 million disability-adjusted life years (DALYs) respectively (Collins et al. 2011). MDD is a 
chronic and disabling mental illness (Kessler et al., 2005a, 2005b; Murray et al.,  2012), 
associated with increased mortality and shortened lifespan (De Hert., et al. 2011; Ferrari et al., 
2013; Whiteford et al., 2013). Likewise, BD is one of the most severe and lethal psychiatric 
disorders (Nock et al., 2009; Nordentoft et al., 2011). The lifetime prevalence of BD is 
approximately 4% in the United States (Merikangas et al., 2007) with depressive symptoms 
dominating the longitudinal course of the illness (Calabrese et al., 2008; Judd et al., 2002, 2003). 
 
A growing body of evidence has revealed that most patients with MDD who receive evidence- 
based treatments do not achieve sustained remission with first-line antidepressants (McIntyre et 
al., 2014). Treatment resistant depression (TRD) is generally defined as a reduced clinical 
response to adequate doses and duration of antidepressants (Dodd et al., 2005; Fava, 2003; 
Hauptman et al., 2008; Rush et al., 2003). Similarly, treatment resistance in bipolar depression 
refers to the lack of response to adequate trials of monotherapy with lithium or lamotrigine or the 
combinations of these two mood stabilizers with anticonvulsants or antipsychotics (Lipsman et al., 
2010) and non-remission despite receiving three adequate trials of first line medications with 
mood stabilizing properties (Malhi et al., 2012). 
 
In spite of the advances in the treatment of depression (which includes new-generation 
antidepressants and multimodal treatment strategies (combining mood stabilizers, atypical 
antipsychotics, hormone supplementation, and psychosocial interventions), treatment resistant 
depression remains a significant problem in the clinical management of MDD and BD (Gaynes et 
al., 2009; Nelson et al., 2009; Spielmans et al., 2013; Warden et al., 2007; Zarate et al., 2013b, 
Prudic et al., 2013, Rabheru et al., 2012). Furthermore, the time lag in onset of therapeutic effect 
limits treatment response and adherence in bipolar depression (Calabrese  et 


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al., 2006; Thase et al., 2006; Weisler et al., 2008). The additive effects of all these factors increase 
the overall risk for comorbidity and suicidality (Jick et al., 2004; Machado-Vieira et al., 2008). 
 
The antidepressant properties of ketamine, an anesthetic agent with N-methyl-D-aspartic acid 
receptor (NMDAR) antagonist properties has been demonstrated in MDD, bipolar depression, and 
TRD (Abdallah et al. 2012; Diazgranados et al. 2010a; Kranaster et al. 2011; Kudoh et al. 2002; 
Murrough et al. 2013a,b; Okamoto et al. 2010; Zarate et al. 2012). Further, a recently published 
meta-analysis has confirmed the efficacy of intravenously administered ketamine in depressive 
disorders independently from the severity, refractoriness or specificity of the depressive disorder 
(Fond et al., 2014). However, there is some reluctance to use ketamine in the clinical practice due 
to the potential concerns of misuse (Morgan and Curran 2011) dosage, side effects, duration of 
efficacy, and impact on suicidal ideations. 
 
The results of the largest study conducted thus far on the antidepressant effects of repeated 
ketamine infusions included twenty-four subjects with TRD who underwent a washout of 
antidepressant medication followed by a series of up to six intravenous (IV) infusions of ketamine 
(0.5 mg/kg) over 40 minutes administered open-label three times weekly over a 12- day period 
(Murrough et al., 2013b). The TRD patients meeting response criteria were monitored for 
depressive relapse for up to 83 days from the last infusion. The antidepressant effect of ketamine 
was evident very early in the course of treatment. Moreover,  ketamine exerted a broad-spectrum 
effect on individual symptoms of depression, and rapid response to the first infusion was highly 
predictive of a sustained response to subsequent infusions (Murrough et al., 2013b). Although 
preliminary, ketamine’s large and sustained effect size regarding its antidepressant properties 
seems to be carried over repetitive IV infusions. In particular, suicidal ideation (SI) rapidly 
decreases even among non-responders to repetitive ketamine IV infusions. Therefore, ketamine 
is suggested to exert a unique anti-SI effect even in the absence of a full antidepressant response 
(Murrough et al., 2013b). This finding is  consistent with previous reports highlighting the potential 
anti-SI effects of single dose infusion of IV ketamine in depressed populations (Diaz-Granados et 
al., 2010b; Larkin and Beautrais, et al 2011; Price et al., 2009). 
 
Recently, researchers at the Mayo Clinic have performed serial ketamine infusion but at a lower 
infusion rate (Rasmussen et al., 2013). Ten depressed patients were treated with twice   weekly 


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infusions of ketamine 0.3 mg/kg administered over 100 min until either remission was achieved 
or four infusions were given. Patients were naturalistically followed weekly for four weeks after 
completion of the infusions and psychiatric side effects were assessed with the Young Mania 
Rating Scale (YMRS; Young et al., 1978) and the Brief Psychiatric Rating Scale (BPRS; Overall 
and Gorman, 1988) respectively. While a 50% remission rate was documented without any 
significant increase on BPRS or YMRS measures, only two patients maintained remission at the 
4-week follow up session. Nonetheless, it seems that ketamine infusions at a lower rate than 
previously reported might produce similar efficacy, excellent tolerability, and thus may be more 
available for routine clinical care. 
 
Ketamine infusions do not appear to have negative neurocognitive sequels. In a recent study,  15 
patients with TRD underwent six IV infusions of 0.5 mg/Kg ketamine over 40 min, (three times a 
week during a 12-day period) followed by a 4-wk observational period. Following the last ketamine 
infusion the authors observed an improvement in visual memory and. working memory. These 
cognitive changes may have been due to the decrease in the severity of the depressive symptoms 
(Shiroma et al. 2014). Along the same line, Murrough et al. (2015) found no change in cognitive 
functioning 7 days post-ketamine treatment in individuals with treatment- resistant depression. 
 
To the best of our knowledge, the only published study exploring the tolerability, safety, and 
efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days) focused on 10 
medication-free symptomatic patients with TRD who had previously shown a meaningful 
antidepressant response to a single ketamine dose (Aan het Rot, et al., 2010). Patients received 
a 40-min IV infusion of ketamine (0.5 mg/kg) in an inpatient setting with continuous vital-sign 
monitoring and repeated recording of adverse events such as psychotomimetic effects. In the 
event that patients showed a 50% reduction in MADRS scores on day 2, they received five 
additional infusions on an outpatient basis on days 3, 5, 8, 10, and 12. Follow-up visits were 
conducted twice weekly for 4 weeks or until relapse. Ketamine elicited minimal transient positive 
psychotic or dissociative symptoms. Side effects during and after each ketamine infusion although 
common were reportedly mild. The response criterion was met by nine patients after the first 
infusion as well as after the sixth infusion of ketamine. MADRS scores after the sixth ketamine 
infusion were reduced by 85%, and an 89% relapse rate was reported between weeks 3 and 4 
after finishing repeated IV ketamine infusion. 


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To summarize, these findings confirm the feasibility of low concentration and slower infusion  rate 
of repeated-dose IV ketamine infusions for the acute treatment of TRD in the clinical practice (Aan 
het Rot, et al., 2010; Murrough et al., 2013b; Rasmussen et al., 2013). 
 
Thus, in the current study we want to naturalistically explore the antidepressant effects  of 
serial slow IV infusions (40 minutes) of ketamine at a dose of 0.5 mg/kg, over a treatment 
period of 8 weeks in an academic psychiatric hospital. This is a minimal sedation treatment. 
This dosage is the highest used so far in the literature and was selected because of its reported 
benefits in a psychiatric population. The dosage will be calculated using  the patient’s weight in 
kilograms. For dosing purposes, 0.5-0.9 round up to the next dose and   from 
.01-0.49, we will round down to the lower dose. The primary outcome measure of this study will 
be remission estimated based on the severity of depressive scores (MADRS). After the 8 weeks 
of treatment, there will be a four week observational period. During the observational period, 
participants will receive treatment as usual and will be contacted over the phone for follow-up 
questions regarding their overall health status, mood and clinical state using MADRS, YMRS and 
CGI. They will also complete a neurocognitive task at the end of the 4 week observational period. 
 
B. Innovation 
 
 
The approach taken in the current study is novel for two reasons: 1) we are testing a novel dosage 
and time of infusion for the administration of slow infusion, repeated IV ketamine targeting TRD; 
2) this is the first naturalistic study of repeated ketamine IV infusion for MDD and BD in a 
psychiatric setting. Furthermore, this will constitute the largest study conducted to date testing the 
antidepressant effects of repeated ketamine infusions in a combined population of MDD and BD 
patients with TRD. 
 
C. Approach 
 
 
The current project will exploit the feasibility of recruitment associated with ongoing studies at the 
University of Texas, Center of Excellence on Mood Disorder, Department of Psychiatry and 
Behavioral Science in Houston aimed at identifying the neural correlates of BD. The clinical 
sample will include individuals from various ethnic/racial backgrounds, reflecting the local 
community in the greater Houston area. We will use slow infusions of ketamine over a time 


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period of 40 minutes. We will conduct an open label, naturalistic study focusing on the 
antidepressant effects of ketamine twice a week for the first 4 weeks and then weekly 
injections up to week 8 in an academic psychiatric hospital (UTHealth Harris County 
Psychiatric Center - HCPC). Thirty patients with clinically documented TRD will be screened  for 
diagnosis with the depression and bipolar disorder subset of the Structured Clinical Interview for 
DSM-IV (SCID) (First et al., 1996) at baseline to establish the presence of a major  depressive 
episode. 
 
The administration of ketamine and urine tests will be carried out at the UTHealth Harris County 
Psychiatric Center (HCPC) in Houston, Texas. Routine blood tests and clinical/cognitive 
assessment will be done at the UTHealth Harris County Psychiatric Center (HCPC). Study drug 
will be provided in identical syringes, containing clear solutions including 1 mL of ketamine, e.g. 
100 mg/mL with 9 mL of normal saline. A syringe will be used to provide IV applications of solution 
(). An ACLS psychiatrist will monitor the patient at HCPC. The administration of ketamine will be 
initiated by the anesthesiologist. The anesthesiologist will be present during the ketamine 
administration (40 minutes) and post-procedure (until patient is awake and anesthesiologist 
deems patient is clinically stable. The infusions will be conducted in  our hospital during the 
mornings in a room set specially for this study. During the infusion, patients will  be  asked  
constantly  about  ―how  they  feel‖  and  will  receive  constant  attendance  from  a psychiatric nurse 
and the attending ACLS- trained psychiatrist. ECG and pulse oximetry monitoring will be 
maintained throughout the infusions to check for hemodynamic changes. 
 
After completion of each 40 minute infusion, patients will rest for 2 hours under observation of the 
clinical nurse before being discharged to a responsible adult who will accompany the patient 
home. Based on Zarate et al.’s (2012)’s protocol infusions will be administered twice a week, 
every 3 days for the first 4 weeks of the treatment period. 
 
Routine blood tests will be performed in fasted state before the first ketamine infusion, prior to 
infusions at week 4 and at week 8. These tests aim to test the participants’ overall health state. 
Blood samples will also be used for genetic testing and to measure levels of inflammatory 
markers. Samples will be stored at 
 
 
 
 
 
. As stated in the consent form, participants will not 
receive any medical results or genetic counseling by providing a sample. All participants will 
undergo urine drug tests before each ketamine infusion. 


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Clinical questionnaires (e.g. MADRS) will be administered at  baseline, at weeks 4, 8, and Week 
12. The PANSS and Q-LES-Q scale will be administered after each ketamine infusion is 
completed. During the course of infusions, patients will receive treatment-as-usual from their 
primary psychiatrists as would be the case in a traditional therapeutic setting. There will be no 
changes in medication regimen throughout the 8 week treatment period as well as the 4 week 
observational follow-up period. Participants will be provided with a contact card directing them to 
the nearest ER/physician in case of emergency. Participants will be contacted weekly during the 
4 week observational period to review the patient’s health status and administer clinical scales. 
Upon conclusion of the intervention patients will be offered the opportunity to come back for 
maintenance sessions. The frequency of these sessions will depend on the patient’s wishes and 
the physician’s clinical judgment. The maximum session frequency will be once every month for 
a maximum of 12 months. 
 
Assessment 
The protocol consists of two components: clinical and cognitive assessments. 
 
 
Clinical assessment 
This evaluation will obtain family history and demographic data. Copies of any recent medical 
evaluations (past medical history, physical exam, etc.) will be requested from treating clinicians 
and health care providers. We will perform a urine drug screening (UDS) to rule out recent 
undisclosed use illicit substances. Demographic information is obtained through a standardized 
form and covers: age, race, gender, education (information both on siblings and their parents), 
religion, and socioeconomic status. Participants will fill out mood questionnaires rating the severity 
of the clinical symptoms. 
-MINI Interview: This is the standard psychiatric research evaluation for ascertainment of 
psychiatric diagnosis in the context of research studies (Sheeha et al., 2016)). It is a 
comprehensive structured interview for determining axis I diagnosis according to the DSM-V. 
-Clinical Global Impression Scale (CGI): This is a clinical instrument to assess global changes in 
patients’ status in clinical studies. We will use the CGI-BD, for use with BD patients (Guy et al., 
1976). 
-Montgomery-Åsberg Depression Rating Scale (MADRS): this scale rates depressive  symptoms, 
and its psychometric properties are well-established (Montgomery et al. 1979). 


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-Young Mania Rating Scale (YMRS): This is a well-established clinical severity rating scale for 
manic symptoms that has adequate inter-rater reliability and internal consistency (Young et al., 
1978). 
- Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q): this scale is patient- 
reported and measures the degree of enjoyment and satisfaction experienced by subjects in 
various areas of daily functioning (Endicott et al., 1993). 
- 
- The Positive and Negative Syndrome Scale (PANSS) includes 30- items and was conceived as 
an operationalized, drug-sensitive instrument that provides balanced representation of positive 
and negative symptoms. It is composed of four scales measuring positive and negative 
syndromes, their differential, and general severity of illness. The Positive and Negative Syndrome 
Scale (PANSS) for Schizophrenia. Kay, Stanley R.; Flszbein, Abraham; Opfer, Lewis 
A. Schizophrenia Bulletin, Vol 13(2), 1987, 261-276.This scale will be administered following 
each ketamine infusion to assess acute changes in mood. 
 
Self-report questionnaires to assess mood and anxiety: 
1. Adult (Brief Dissociative Experiences Scale [DES-B]—Modified): Frequency: After every 
injection, to monitor the dissociative side effects, Scale features: simple, easy to use, new DSM- 
5 self-rated scale 
2. Severity Measure for Generalized Anxiety Disorder—Adult : Every 4 weeks, to measure the 
severiy of anxiety. Scale features: simple, easy to use, new DSM-5 self-rated scale 
3. Snaith–Hamilton Pleasure Scale: every 4 weeks, to measure the level of anhedonia, Scale 
features: easy to use, used before in ketamine studies, self-rated scale 
 
Cognitive assessment 
 
 
The BAC-A is based on the Brief Assessment of Cognition in Schizophrenia (BAC-S). The BAC- 
S has been validated both linguistically and psychometrically in a number of psychiatric 
populations, including patients with schizophrenia and BD (Cuesta et al., 2011; Hill et al., 2013; 
Kuswanto, Sum, & Sim, 2013; Salgado et al., 2007; Segarra et al., 2011). It has been shown to 
be as valid and sensitive as a traditional neuropsychological assessment and takes approximately 
35 minutes to administer (Keefe et al., 2004; Velligan et al., 2004). Six of the 8 subtests of the 
BAC-A match those found in the BAC-S. These tests are the Token Motor Task, Symbol  Coding,  
List  Learning,  Digit  Sequencing  Task,  Category  Instances  (Animals)   and 


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Controlled Oral Word Association Test (F and S-words), Tower of London (Keefe et al., 2004).  In 
addition to these 6 subtests the BAC-A comprises the Emotion Inhibition Test (a modified version 
of the Emotional Stroop task (LaMonica, Keefe, Harvey, Gold, & Goldberg, 2010; Williams, 
Mathews, & MacLeod, 1996)) and the affective auditory verbal learning test (Affective interference 
test). The latter task is similar to the Affective Auditory Verbal Learning Test (AAVLT) (Snyder & 
Harrison, 1997). Assessments will be conducted prior to the treatment period, 4, and 8 weeks into 
the treatment. To avoid potential learning bias we will use parallel versions of the word lists for 
the Emotion Inhibition Test, Tower of London, and the Verbal Memory Tests to assess cognitive 
changes over the course of the ketamine treatment. 
 
Study design 
We will follow an AB design and clinical/cognitive assessments will be taken at baseline, week 4, 
week 8, and week 12. Given the preliminary nature of this treatment study this open label trial 
aims to generate an effect size for a subsequent RCT and/or future grant application. No a priori 
estimates of the power/effect size were therefore calculated. 
 
 
Timeline 
After 
Each 
Infusion 
Baseline 
Week 4 
Week 8 
Weekly 
Follow-up 
Phone 
Calls 
Week 12 
SCID-I 
X 
Clinical 
scales 
(MADRS, 
CGI, YMRS) 
X 
X 
X 
X 
X 
PANAS, Q- 
LES-Q, self- 
report 
X 
BAC-A 
X 
X 
X 
X 
Blood 
tests/Sample 
X 
X 
X 
X 
Urine drug 
test 
X 
X 


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Study sample 
 
 
We will recruit adult patients aged 18-65 years with MDD or BD, with documented TRD 
(according to DSM-IV TR), and who have failed (defined as patient does not reach 
remission within the 8 week trial of an antidepressant or combination at a therapeutic dose) 
of at least two trials of first line evidence-based treatments and/or ECT. 
 
Exclusion criteria 
 
 
1) Being younger than 18 of age or older than 65. 
2) Diagnosed with intellectual disability, e.g. mental retardation (MR), neurodegenerative 
diseases, e.g. early-onset neurocognitive disturbances such as frontotemporal dementia 
(FTD) or behavioral disorders, e.g. adult onset Attention Deficit Hyperactivity Disorder 
(ADHD). 
3) Diagnosed with BD-NOS or rapid cycling BD 
4) Diagnosed with personality disorders (PD). 
5) Previously or currently diagnosed with psychosis (schizoaffective disorder - SAD) or 
schizophrenia - SCZ). 
6) Current major medical problems that affect brain anatomy, neurochemistry, or function, 
e.g., obstructive sleep apnea requiring Continuous Positive Airway Pressure (CPAP), liver 
insufficiency, kidney insufficiency, cardiovascular problems, systemic infections, cancer, 
auto-immune diseases, and any brain disorder (seizure disorder, stroke, dementia, 
degenerative neurologic diseases); history of any brain diseases, including seizures, 
stroke, meningitis, encephalitis, dementia, degenerative brain diseases, and head injury 
with loss of consciousness for any period of time. 
7) Diagnosed specifically with a cardiovascular disorders such as Arrhythmias, Chronic Heart 
Failure, Myocardial Infarction (MI) or suffering from  Chronic  Obstructive Pulmonary 
Disease (COPD) or asthma. Suffering from uncontrolled hypertension or diastolic BP over 
100. Cardiac clearance prior to enrolling in the study/medical records from physician will 
be required per patient’s PCP. (Diastolic BP must be less than 100 Systolic BP less than 165 and 
greater than 85 Heart rate less than 100.) 
8) 
Patients with thyroid condition and are not currently euthyroid or on stable treatment regimen. 
9) 
10) Patients with increased risk of laryngospasm, active upper respiratory infections, 
respiratory depression, increased intracranial pressure, hyperthyroidism, or porphyria. 


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11) Current substance abuse or dependence. Only patients who achieved stable, full 
remission for at least 6 months will be included. 
12) Pregnancy or Breast feeding. All female in reproductive age will undergo pregnancy tests. 
Female participants will be required to provide evidence of use of contraceptives during 
the course of the study. 
13) Unable to understand the design and requirements of the study 
14) Unable to sign the informed consent for any reason 
15) An assigned responsible adult has provided assent to assist in patient’s study 
participation. The responsible adult agrees to be present at each study appointment as 
well as provide transportation to study appointments for the patient. 
Non responders 
If a patient does not respond to the study treatment by their 4th treatment they will be removed 
from the study due to non-response. A successful response to study treatment will be at least a 
30% reduction in MADRS scores from screening until the 4th treatment. Again if a patient does not 
respond by the 4th treatment, they will be excluded from the study. 
 
Unanticipated Hospitalizations 
If a patient needs to be hospitalized for worsening of symptoms or for their own personal safety, 
they will be removed from their study participation and their study treatment will end at that time. 
 
Feasibility 
 
Subject recruitment: Our center has access to a large patient pool (drawing from a metropolitan 
area of about 5.5 million people) and well-established ability to recruit patients with mood 
disorders. Dr. Jair Soares is the department chair for Psychiatry and Behavioral Sciences and 
Director of the University of Texas, Center of Excellence on Mood Disorders. He successfully 
completed a large number of studies over the past 20 years with excellent recruitment of MDD 
and BD subjects at this site. We will also recruit participants through doctor referrals. Participants 
will be exclusively outpatients. 
Funding of the study: given the preliminary nature of this study we plan to use departmental 
funding for the current study and then possibly apply for a larger grant later on once we have 
collected preliminary data and calculated optimal power/effect sizes for ketamine treatment in 
individuals with TRD. 


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15 
 
 
 
 
Data analysis 
Normality assumptions for continuous variables will be examined. Where appropriate, outliers will 
be winsorised and log, square root or reciprocal transformations applied to achieve  normality if 
appropriate. If normality cannot not been achieved, either untransformed or dichotomized scores 
were used. Baseline characteristics will be compared between responders and non-responders 
with the Mann-Whitney U test for continuous variables and the chi-square test for categorical 
variables. Changes between two time-points for continuous variables were tested with paired t 
tests, and associations between continuous variables will be quantified with the Spearman 
correlation coefficient. Random effects models will be performed to quantify changes in clinical 
score and its component items over time and to compare temporal differences between eventual 
responders and non-responders. Splines will be used  to determine differences in the pattern of 
response over time among all patients and to identify the time at which there was no additional 
improvement in depressive symptoms. Additionally, the relationship between response status 
between baseline and end of study calculating sensitivity, specificity, and positive and negative 
predictive values will be reported. Time to relapse for patients who met response criteria at end 
point will be estimated with the Kaplan-Meier method. Analyses will be performed with IBM SPSS 
Statistics (version 19; SPSS, Chicago, Illinois) and SAS (version 9.2; SAS, Cary, North Carolina). 


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16 
 
 
 
 
Study timetable 
 
 
 
Activities 
Months 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
Obtain IRB approval at UTHealth and 
HCPC 
x x 
•
• 
Set up the Ketamine Ambulatory Clinic 
at HCPC 
x 
x 
Start recruiting patients and collecting 
data 
x 
x 
x 
x 
• 
Analyses of initial dataset 
x 
x 
x 
• 
Submit a poster to International 
meeting with final results 
x 
x 
x 
• 
Submit result to high-impact peer- 
reviewed journals 
x 
x 
 
Importance of the knowledge to be gained 
 
 
Our findings will enhance our understanding of the safety, tolerability and efficacy of ketamine 
infusion in adults with TRD. Further it will help us understand the feasibility of this treatment in a 
psychiatric setting. The findings of the present study will also constitute an important foundation 
for future grant proposals investigating the efficacy of this intervention as a measure of suicide 
prevention. 
 
Women and Minority Inclusion in Clinical Research 
 
 
Inclusion of Women 
The subjects will include males and females, ages 18-65 years old, from various race/ethnic 
backgrounds, as reflected in the local community in the greater Houston area. 


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17 
 
 
 
 
Inclusion of Minorities 
 
 
Our study will include minority groups in proportions that will be representative of the ethnic/racial 
composition of the local community in Houston, Texas. Our projected numbers for minority 
enrollment are detailed in the enrollment table attached. 
 
Inclusion of Children 
 
 
Children will not be included in the study. The inclusion of children at this early stage would 
increase substantially the number of subjects needed for the overall project. At this time, we will 
focus on an adult population (ages 18-65 years old), which will also allow us to limit some of the 
potential confounding factors to our brain imaging and neurocognitive findings. Depending on our 
results these investigations will be extended to children and individuals over 65 years old in future 
studies. 
 
Prisoners and pregnant women 
 
 
We are aware of the special protections afforded to prisoners per federal regulations. We will  not 
actively recruit people who are incarcerated to participate in this study. We do, however, 
acknowledge the possibility of research participants in our target population being incarcerated 
during the study. If an active participant is incarcerated for an extended period of time, 
disenrollment from the study will be necessary. No research interaction or intervention will take 
place until an incarcerated participant is released from jail. Finally, neither pregnant woman nor 
neonates will be enrolled in this study. 
 
Potential Risks 
 
 
Loss of confidentiality is a highly unlikely but potential risk associated with this study. Some 
participants may find questions annoying or intrusive and neuropsychological testing might induce 
some fatigue and sensation of boredom. The venipuncture (insertion of small IV due to need for 
IV infusion of ketamine) might produce some mild pain, bruising, bleeding, infection, and in some 
cases even induce fainting. Side effects associated with ketamine injection are rare and, if any, 
of transient duration. The most commonly reported side effects during the 4-hour period  after  
each  infusion  include  feeling  strange  or  unreal  (58.3%),  abnormal  sensations 


IRB NUMBER: HSC-MS-16-0020 
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18 
 
 
 
 
(54.2%), blurred vision (50.0%), feeling drowsy or sleepy (45.8%) (Murrough et al., 2013b) and 
headaches (30-40%) (aan her Rot et al., 2010). Based on previous evidence we do not expect 
ketamine to impair cognitive functions such as memory, attention and language (aan her Rot et 
al., 2010). 
One third of the patients exposed to standard repeated infusions of IV ketamine reported some 
kind of hemodynamic change such as elevated blood pressure (BP) and/or heart rate (Murrough 
et al., 2013b) that usually resolves shortly after the ketamine infusion (aan het Rot et al., 2010; 
Murrough et al., 2013b). It has been reported that initial hypertensive episodes and transient 
tachycardia are predictive of hemodynamic changes with subsequent repeated ketamine 
infusions (aan het Rot et al., 2010). Ventricular premature contractions, hypotension, and non- 
significant changes in oxygen saturation have also been reported with low-dose (0.5mg/kg) 
ketamine infusions over 40 minutes. 
 
Risk of other medications 
 
If patients are currently taking certain medications on a daily basis within 24 hours prior to and / 
or after receiving ketamine, they will not be able to take these medication(s) while receiving a 
ketamine infusion without clearance or approval of the physicians involved in administering 
ketamine. This is due to concerns for potential increased sedation and / or trouble breathing. 
Medications include: 
• Sedatives (e.g., clonazepam, lorazepam, alprazolam) 
• Antibiotics (e.g., azithromycin, clarithromycin) 
• Antifungal agents (e.g., ketoconazole) 
•Tramadol 
 
Potential Benefits 
 
 
There are direct potential benefits for the individual subject as a result of participating in the 
planned work. First of all, ketamine serial IV infusions will alleviate potentially disturbing, life- 
threating depressive symptoms such as suicidal ideation. Moreover, participants might be able 
not only respond but also remit from other resistant/refractory depressive symptoms that reduce 
their quality of life and everyday functional outcome. There are no direct benefits associated  with 
the completion of questionnaires, simple computer tests, and routine medical diagnostic and 
treatment procedures. Therefore we believe the risk-benefit ratio to be favorable for every subject 
involved in this naturalistic study. 


IRB NUMBER: HSC-MS-16-0020 
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19 
 
 
 
 
Potential subjects will contact the UTHealth Center of Excellence on Mood Disorders group in 
response to flyers, advertisements or recommendation from their attending psychiatrist treating 
TRD or TRBD. Potential participants will undergo a brief telephone screening. If they meet the 
eligibility criteria and are still interested in taking part in the study, a first appointment will be 
scheduled to discuss the study with the researchers. If suitable the participant will be asked to 
read and signs the consent document if all questions have been discussed and answered to the 
potential subject's satisfaction. 
 
 
 
 
 
Data and Safety Monitoring Plan 
 
 
This study will be performed in accordance as provided by law under the resolution Nº 008430 of 
1993 emitted by the Ministry of Health about medical research focused on health issues. This is 
a low-risk project in terms of ethical concerns. 
This study will acquire, use and create individually identifiable health information (known as 
Protected Health Information or PHI). Confidentiality will be protected at all times by having 
research records identified by code number only. All research information will be stored in  locked 
files at all times. Only authorized research staff will have access to the information gathered in 
this study. Only subjects capable to provide consent will be included in the study. 
As per the Health Insurance Portability and Accountability Act (HIPAA) all individuals who are 
eligible and agree to participate in this research study will be required to sign a HIPAA research 
authorization prior to participation. If an individual refuses to sign the HIPAA research 
authorization, they will not be able to participate in this study. The HIPAA form is part of the official 
consent form. 
Data will be stored separately from participants’ identifiers. Both will be stored on encrypted drives 
on computers in locked offices. Confidentiality will be protected by having research records 
identified by code number only. All research information will be stored in locked files at all times. 
Only authorized research staff will have access to the information gathered in this study. All paper 
data will be stored 
 
 
 
 
 
 in a double locked cabinet. The electronic data will be stored 
 
 
 
 
 
 
 
 
. 


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20 
 
 
 
 
An Accounting of Disclosure (AOD) will be created and maintained for any disclosure of 
individually identifiable information (III) outside the UTHSC-Houston. The manual spreadsheet 
will include the date of the disclosure, nature or description of the III disclosed purpose of each 
disclosure and the name and address of person or agency to which the disclosure was made. 
The study imparts only minimal risk to included subjects. Strict monitoring of hemodynamic and 
respiratory changes as well as psychiatric screening will be performed during each infusion of 
ketamine. 
 
 
 
 
 
Reimbursement 
 
 
Patients will pay for the ketamine treatment ($400 for each of the 12 injections that are part of the 
main treatment, $400 for each maintenance treatment) and no reimbursement will be provided 
for their participation in the study. 
 
Currently costs related to this study are not likely to be covered by insurance, and a proportion of 
eligible candidates may not be able to participate. It is however important to highlight that 
determining the effectiveness of a promising treatment for a severely ill patient group such as 
TRD-- for whom standard treatments have failed – has significant clinical relevance and needs to 
be tested in a timely fashion. 


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21 
 
 
 
 
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