Clinical trial NCT01703039
Conditions: Major Depressive Disorder
Keywords: Major Depression Major Depressive Disorder Depression Riluzole Glutamate Sertraline
Sponsor: Brigham and Women's Hospital
Start date: 2013-01-01; Completion date: 2018-06-01
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators are doing a research study to find out if riluzole, when taken along with a standard antidepressant (sertraline) can help people with major depression.

This research study will compare riluzole + sertraline to placebo + sertraline. The investigators hypothesize that adding riluzole will lead to a better antidepressant response, in less time, then sertraline alone.

Detailed description:
Recent attention has focused on the glutamatergic system as a new, distinct target for depression treatment. Riluzole (Rilutek, Sanofi), an oral modulator of glutamate activity with neuroprotective and anticonvulsant properties, is currently approved by the United States Food and Drug Administration for treatment of amyotrophic lateral sclerosis (ALS). Preliminary studies using riluzole to treat depression in humans are promising, though larger, double-blinded controlled trials are needed.

Overall study population:

Adult outpatients with a current, untreated major depressive episode.

Disallowed therapies include: other psychotropic medications, including antipsychotics, mood stabilizers, benzodiazepines, barbiturates, other sedative-hypnotics, chronic opiates, or additional antidepressants, psychotherapy, electroconvulsive therapy, vagal nerve stimulations therapy, transcranial magnetic stimulation therapy, or phototherapy.

Arms: arm 1: sertraline 100 mg po daily and riluzole 50 mg po bid arm 2: sertraline 100 mg po daily and placebo
Interventions: intervention 1: Riluzole intervention 2: Sertraline intervention 3: placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
Version Date: 05.01.18 
 
Riluzole Augmentation Pilot in Depression (RAPID) Trial 
 
I. 
Background and Significance 
 
Affecting an estimated 151.2 million people worldwide, depression remains the 
leading cause of years lived in disability.i  Unfortunately, first-line treatments for 
major depression, primarily agents that inhibit reuptake of monoamines 
(serotonin, dopamine, and nor epinephrine) achieve symptomatic remission in 
only one to two thirds of patients, depending on the number of medication trials.ii 
Standard antidepressant medications, primarily selective serotonin reuptake 
inhibitors (SSRIs) also take four to eight weeks to work, iii and with the majority 
of patients requiring multiple trials of medications, patients can remain 
symptomatic for several months. iv During this time, depressed individuals not 
only experience the disability associated with social withdrawal, low energy, 
decreased concentration, sleep problems, and appetite disturbance, but also 
potentially acute risks arising from suicidal thoughts and behaviors.v As a 
consequence, there is a great need for novel antidepressant agents that are 
more effective and rapidly acting. 
 
Recent attention has focused on the glutamatergic system as a new, distinct 
target for depression treatment. vi,vii Dysregulation of glutamate, the primary 
excitatory neurotransmitter in the central nervous system, has been the primary 
excitatory neurotransmitter in the central nervous system, has been associated 
with depression in humans as well as animal models. viii These observations have 
been further heightened by preliminary clinical experience with ketamine, a 
glutamatergic NMDA receptor antagonist and AMPA receptor modulator with 
anesthetic properties. 
 
In small placebo-controlled crossover studies, single-dose intravenous ketamine 
has demonstrated a significant antidepressant effect within hours among 
individuals with treatment-resistant major depression ix and bipolar depression. x  
While the response from ketamine can be striking, the effect typically wanes over 
the course of days. While the response from ketamine can be striking, the effect 
typically wanes over the course of days. For treatment-resistant patients, one 
open-label study with repeated, scheduled dosing was similarly effective and well 
tolerated for up to two weeks,xi though the longer-term safety and efficacy of 
ketamine treatment remains unknown. In addition, sedation, dissociation, and 
psychotic symptoms represent potential side effects. Nonetheless, in light of the 
dramatic results seen with ketamine, the relevance of glutamate 
neurotransmission in psychiatric illness continues to grow, with some authors 
arguing that “glutamate-based depression” represents a distinct, though 
common, phenotype of the disorder. xii 
 


 
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Riluzole (Rilutek, Sanofi), an oral modulator of glutamate activity with 
neuroprotective and anticonvulsant properties, is currently approved by the 
United States Food and Drug Administration for treatment of amyotrophic lateral 
sclerosis (ALS). In patients with ALS, riluzole has been shown to modestly slow 
progression of the disease and prolong time until death. xiii In vitro, riluzole has 
the capacity to reduce excess glutamate activity though several mechanisms, 
most uniquely by enhancing astrocytic glutamate uptake. xiv Importantly, while 
riluzole modulates glutamate transmission, it does not share the 
psychotomimetic or anesthetic effects of ketamine at physiologic concentrations. 
The net effect of riluzole on glutamate activity includes a relatively rapid increase 
in brain-derived neurotrophic factor (BDNF) expression and promotion of 
hippocampal neurogenesis xv, one proposed final mechanism for antidepressant 
efficacy. xvi 
 
Recent animal studies of riluzole have supported its antidepressant properties. In 
a rodent model of depression (chronic unpredictable stress), riluzole not only 
improved behavioral measures, but also reversed the stress-induced glial 
pathology typically seen in the prefrontal cortex. xvii In the olfactory bulbectomy 
model of depression, rats given riluzole showed significant, dose-dependent 
improvement in hyper emotionality scores after one administration as well as 
with repeated, sub-chronic dosing. xviii In chronic (22-day) administration of 
riluzole, rats showed improvements in immobility time during the forced swim 
test, indicative of a sustainable antidepressant effect. xix  
 
Preliminary studies using riluzole to treat depression in humans are also 
promising, though larger, double-blinded controlled trials are needed. An open-
label trial of riluzole in ten patients with severe treatment-resistant depression 
led to a 9.6-point (36%) reduction in Hamilton Depression Rating Scale (HDRS) 
score in six weeks. xx  A similar 8-week trial augmenting lithium treatment in 
acutely depressed bipolar patients yielded a significant reduction in Montgomery-
Asberg Depression Rating Scale (MADRS) scores, without eliciting any hypomania 
or mania. xxii  Positive results with riluzole have also been seen in small open 
trials of patients with generalized anxiety disorder and obsessive-compulsive 
disorder, xxiii suggesting anxiolytic as well as antidepressant effects. 
 
This proposed study sets out to examine the antidepressant effects of riluzole in 
two novel ways. The first is by using a double-blinded design, addressing the 
significant issue of placebo response seen in antidepressant trials. xiv To our 
knowledge, this methodology has not yet been used in any published riluzole 
trials among patients with unipolar depression. Second, unlike previous studies 
that have specifically examined patients with treatment-resistant depression, 
already subject to current and past medication trials, we propose using Riluzole 
alongside standard serotonin reuptake inhibitor therapy in currently untreated 
major depression. By doing so, we seek to examine the potential role of riluzole 
as a first-line augmentation agent, with the hypothesis that it will improve the 


 
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problematic efficacy and response time inherent in standard antidepressant 
therapy. 
 
II. 
SPECIFIC AIMS  
 
This study will determine if riluzole augmentation of standard sertraline 
monotherapy leads to a more rapid and complete antidepressant response 
among individuals with untreated major depressive disorder.  
 
The specific objectives are:  
 
1) To examine the additive effect of riluzole on absolute HDRS scores, remission 
rate, response rate, and time to antidepressant response 
  
2) To evaluate the tolerability of initiating riluzole and standard SSRI therapy 
simultaneously in treatment-naïve individuals, and  
 
3) To assess any beneficial changes in co-morbid anxiety symptoms as measured 
by the HARS.  
 
It is hypothesized that compared to SSRI treatment alone, dual therapy with 
SSRIs and riluzole will be equally well tolerated and lead to a greater reduction in 
HDRS and HARS scores, greater response and remission rates as well as shorter 
time to response. 
 
III. SUBJECT SELECTION 
 
Overall study population:   
Adult outpatients with a current, untreated major depressive episode. 
 
Inclusion Criteria: 
● Adults (ages 18-75) who meet DSM-IV criteria for a major depressive episode,  
● Hamilton Depression Rating Scale (HDRS) >22, and  
● No antidepressant treatment for at least three weeks. 
 
Exclusion Criteria: 
● Active drug or alcohol disorder in the past 3 months 
● History of psychosis, history of mania or hypomania 
● Epilepsy or history of seizures 
● Hypothyroidism  
● Congenital QTc prolongation 
● Liver disease 
● Lung disease 
● Acute suicide or homicide risk 
● Pregnant women, breastfeeding women, women of childbearing age not using  


 
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   contraception 
● Unstable medical illness 
● Elevated thyroid-stimulating hormone (TSH>5.0mlU/L), or  
● Abnormal liver function tests (ALT>50 U/L or AST>50 U/L) 
● ADD / ADHD (Attention deficit hyperactivity disorder) 
 
Disallowed therapies include: other psychotropic medications, including 
antipsychotics, mood stabilizers, benzodiazepines, barbiturates, other sedative-
hypnotics, chronic opiates, or additional antidepressants, psychotherapy, 
electroconvulsive therapy, vagal nerve stimulations therapy, transcranial 
magnetic stimulation therapy, or phototherapy. 
 
Source of subjects and recruitment methods:  
Adult subjects will be recruited from primary care and psychiatry clinics at 
Brigham and Women’s Hospital by physician referral, a brochure, and a poster. 
Patients presenting to the Brigham Psychiatric Specialties clinic with a chief 
complaint of depression will be informed of the study during their first 
appointment. Patients will be under no obligation to enroll in the study; they will 
have the choice to continue usual care in the clinic or to seek further screening to 
participate in the study. Subjects will not be recruited from among the 
investigators’ own patients. While some subjects will come from BWH clinics 
(Psychiatry and Medicine), they will not come from the investigators' panels. 
Contact information for the study coordinator will be listed on the poster. When 
subjects contact the coordinator, they will first be asked a series of screening 
questions as outlined in the screening phone script. These questions will confirm 
that the patient has a depressed mood, that they are not currently taking 
antidepressant medication, and that they do not meet one of the basic exclusion 
criteria. 
We will enroll a maximum of 120 patients in order to randomize 42 eligible 
subjects. Assuming a non-completion rate of approximately 20%, customary in 
clinical trials of antidepressants, we anticipate 36 completers. With a total of 36 
subjects completing the protocol, randomized 1:1 to each arm, the study will be 
powered to detect a clinically-significant difference of 3.5 units on the HDRS 
between the groups, assuming =.05 and =.8. 
 
IV. SUBJECT ENROLLMENT 
 
Subjects will be adults with major depression seeking treatment, recruited from 
primary care and psychiatry clinics at Brigham and Women’s Hospital by 
physician referral, a brochure, and a poster. Patients presenting to the Brigham 
Psychiatric Specialties clinic with a chief complaint of depression will be informed 
of the study during their first appointment. Demographics will reflect the referral 
patterns of the participating centers.  Subjects may also be recruited through 
newspaper advertisement, flyers, internet announcements. Contact information 
for the study coordinator will be listed on the poster. When subjects contact the 


 
5 
coordinator, they will first be asked a series of screening questions as outlined in 
the screening phone script. These questions will confirm that the patient has a 
depressed mood, that they are not currently taking antidepressant medication, 
and that they do not meet one of the basic exclusion criteria.  
 
Given the gender distribution in the prevalence of depression, it is expected that 
approximately 2/3 of the sample size will be female and 1/3 will be male. 
 
Eligible subjects will be randomized to one of two treatment conditions: sertraline 
+ riluzole or sertraline + placebo. Study staff will instruct the subjects to abstain 
from alcohol and to report any changes in their medical condition during the 
study period. Subjects will be reminded to avoid any additional psychiatric care 
during the study, and to contact staff with any concerns or questions.  
The randomization and assignment of the subjects will be done by the Brigham 
and Women’s Hospital Investigation Drug Service (IDS). The pharmacy will 
assign each subject to sertraline + riluzole or sertraline + placebo.  
 
Details about the study, including objectives, procedures, and potential risks and 
discomforts will be given in both oral and written form to the subject by the 
principal investigator ( Dr. David J. Wolfe) or a physician co-investigators Dr. 
Jane L. Erb and Dr. Arthur Joseph III Barsky. Subjects will be given the 
opportunity to ask any questions and will be given ample time to consider 
whether they wish to participate. They will be informed that refusal to participate 
will not interfere with their subsequent medical care. 
 
 
V. STUDY PROCEDURES 
 
The study design represents a two-arm, randomized, placebo-controlled trial.  
The primary study interventions are summarized in the schematic and table, 
below. 
 
Study Visit 1 and 2 
At the first study visit, the principle investigator or study physician will obtain 
informed consent and answer any questions from the subject. Clinical study staff 
will then administer the Structured Clinical Interview for DSM Disorders to 
confirm a diagnosis of major depressive episode, and to rule out diagnoses of 
exclusion. If there are no exclusions at that point, the study staff will administer 
the HDRS, the Hamilton Anxiety Rating Scale (HARS), the Clinical Global 
Impressions (CGI) scale. These measures are all customary for clinical trials of 
antidepressant medication. Subjects with active suicidal ideation, represented by 
a score of >2 on HDRS item 3, will be ineligible for the study and referred for 
urgent or emergent clinical assessment as indicated in the safety plan, to rule 
out potential safety risks and medical causes of depression. All subjects will then 
have blood tests to assess liver and thyroid function, as well as a urine toxicology 


 
6 
screen. Women of childbearing age will also receive a qualitative urine pregnancy 
test. All laboratory testing will occur at the Brigham and Women’s Center for 
Clinical Investigation.  
 
Eligible subjects will be randomized to one of two treatment conditions: sertraline 
+ riluzole or sertraline + placebo. Study staff will instruct the subjects to abstain 
from alcohol and to report any changes in their medical condition during the 
study period. Subjects will be reminded to avoid any additional psychiatric care 
during the study, and to contact staff with any concerns or questions. give you a 
study diary to fill out at home each day.  Subjects will be given a study diary to 
take home with them, where they will write down the time they take the study 
drug, how much of the study drug they take and whether they have any side 
effects.    
 
Subjects will be randomized to one of the treatment groups based on a 
randomization schedule provided by the Brigham & Women’s Hospital 
Investigational Drug Service (IDS) pharmacist assigned to the study. The 
pharmacy will assign each subject to sertraline + riluzole or sertraline + placebo. 
All subjects will begin at a 50 mg daily oral dose of sertraline, and for the 
experimental subjects, riluzole 50 mg twice per day (oral). Consistent with 
established clinical practice, as well as antidepressant trials employing variable 
dosing strategies, the sertraline will be increased to 100 mg daily if the subject 
tolerates the 50 mg daily dose. In event of adverse reactions attributable to the 
sertraline, the dose will be reduced to 50 mg.  
 
Study visits 3 - 6 
In the subsequent four study visits, conducted at two-week intervals, the subject 
will receive repeat screening with the HDRS, HARS, CGI and SAFTEE. 
Following currently-recommended clinical guidelines for riluzole, on week 4 
following treatment initiation, subjects will have a repeat serum test for liver 
function. Using a more conservative safety limit than that recommended in 
clinical practice, any subjects at that point with an ALT >2 times the upper limit 
of normal will be instructed to discontinue the riluzole and receive placebo 
instead. The subject will be informed of the change as the protocol requires an 
additional check of liver function at the end of the study. In that case, the liver 
function tests will be repeated at week 8 to ensure that the values have 
normalized.  
 
At each study visit, the study staff will enter the data into case report forms on 
RedCap. All laboratory values will be reviewed by the Principle Investigator or 
another physician co-investigator. All study data will be stored securely on 
RedCap and de-identified prior to data analysis and only group data will be 
reported. Paper files for each subject, including the consent form, screening 
materials, subject medication diaries, and any additional correspondence will be 


 
7 
stored in a locked filing cabinet in the office of the Principle Investigator at 
Brigham and Women's Hospital. 
 
VI. BIOSTATISTICAL ANALYSIS 
 
The baseline data to be collected and analyzed are: subject age at enrollment, 
age of onset of first depressive episode, gender, number of previous 
antidepressant medication trials, and number of past depressive episodes, CGI, 
HARS, and HDRS. Subsequent, repeated measures for analysis will be CGI, 
HARS, and HDRS. The planned study end-point is at eight weeks after 
randomization, and is not based on any pre-determined treatment response. All 
analyses will compare values between the two treatment arms.  
 
Baseline measurements for continuous variables (e.g., age of onset, lifetime 
number of depressive episodes, current age) will be assessed by t-test. 
Categorical measurements, such as gender, will be compared with Fisher’s exact 
test or chi-square as appropriate. For the study outcomes, the absolute change 
in HDRS, HARS, and CGI will be individually evaluated with analysis of variance 
(ANOVA), while the proportion of subjects achieving remission (HDRS < 7) and 
response (HDRS >50% reduced from baseline) of their depression will be 
compared using Fisher’s exact or chi-square as appropriate. All applicable tests 
will be two-tailed with an alpha set at 0.05.  
 
Assuming a non-completion rate of approximately 20%, customary in clinical 
trials of antidepressants, we will enroll 42 subjects. With a total of 36 subjects, 
randomized 1:1 to each arm, the study will be powered to detect a clinically-
significant difference of 3.5 units on the HDRS between the groups, assuming 
α=.05 and β=.8. For subjects who discontinue the trial prematurely, the HDRS, 
HARS, and CGI values will be treated using the last observation carried forward 
method. 
 
VII. RISKS AND DISCOMFORTS  
 
Riluzole is an FDA-approved drug. The most common (=5%) adverse events that 
occurred in the ALS marketing trials in patients treated with riluzole vs placebo 
were: asthenia (19.2% vs 12.2%, respectively), nausea (16.3% vs 10.6%), lung 
function decrease (not associated with decreased vital capacity; 10.2% vs 
9.4%), headache (7.3% vs 6.6%), rhinitis (6.4% vs 6.3%), hypertonia (6.1% vs 
5.9%), abdominal pain (5.1% vs 3.8%), and hypertension (5.1% vs 4.1%). Less 
common side effects are include: vomiting, abdominal pain, dizziness, 
depression, pruritis, rhinitis, hypertension, and weight loss. While not strictly 
contraindicated in the prescribing information, for the purposes of this study, 
patients with baseline liver disease or interstitial lung disease will be excluded 
from participating. 
 


 
8 
Sertraline is an FDA-approved drug. The most commonly reported side effects of 
this drug are: Constipation (3% to 8% ), Diarrhea (13% to 24% ), Indigestion 
(6% to 13% ), Nausea (13% to 30%), Nausea and vomiting (2% to 30% ), 
Dizziness (6% to 17% ), Headache (25%), Insomnia (12% to 28% ), 
Somnolence (2% to 15% ), Tremor (5% to 11% ), Abnormal ejaculation (7% to 
19% ), Reduced libido (up to 11% ), Fatigue (10% to 16% ). In rare instances, 
individuals undergoing treatment with antidepressants can experience an 
increase in suicidal thoughts.  
 
With the blood draws, there are risks of pain and bruising at the phlebotomy site, 
as well as lightheadedness. 
 
The effect of riluzole and sertraline on an embryo or fetus (developing baby still 
in the womb), or on a breastfeeding infant, is unknown and may be harmful. 
Because of these unknown risks, women cannot take part in this study if they are 
pregnant or are trying to become pregnant.  
 
The assessment of psychiatric history, including depression and substance abuse, 
can make some people feel uncomfortable. Some may also be especially 
concerned about the confidentiality of mental health information. The study staffs 
are individuals trained in mental health assessment, and will make every effort to 
make the subjects comfortable. All subjects will be assured that their history and 
responses will be kept confidential within the study, except as required by law, in 
the case of acute safety concerns, and in the instances detailed in the research 
consent form. 
 
 
VIII. POTENTIAL BENEFITS 
 
No benefits can be guaranteed to the study participant. 
 
Since all subjects will be receiving standard antidepressant medication in addition 
to the experimental drug, it is expected that the majority of subjects who 
complete the study will achieve a decrease or resolution of their depression 
symptoms. For subjects assigned to riluzole augmentation, it is hypothesized 
that this response will be more robust and occur more quickly. The results of this 
study have the potential to improve the effectiveness and speed of depression 
treatment, as well as better inform our knowledge in the role of glutamate in the 
pathophysiology of the illness. 
 
IX. MONITORING AND QUALITY ASSURANCE 
 
Since riluzole and sertraline are both approved by the FDA, a Data and Safety 
Monitoring Board is not required for this study. The principal investigator, Dr. 
David Wolfe, will be responsible for monitoring the safety of all subjects. In the 


 
9 
event that Dr. Wolfe is unavailable, co-investigators Dr. Jane L. Erb and Dr.  
Arthur Joseph III Barsky will be available to monitor the safety of all subjects.  
 
Study safety meetings, including the principal investigator, study coordinators, 
and study physicians will meet every other week to review the current subjects 
and any reported side effects. 
 
In general terms, a subject will be discontinued from the study for the following 
reasons:  
(1) The subject has experienced an adverse event that, in the opinion of the 
principal investigator requires early termination,  
(2) The subject becomes a safety risk at any time during the trial,  
(3) The subject withdraws consent. 
 
Specific to this study, subjects will be closely monitored for adverse events and 
suicidal thoughts at every visit, and for changes in liver function at 4 weeks. 
Safety labs (i.e. liver function tests) will be repeated at week 8 for subjects 
whose tests at week 4 exceeded the pre-determined safety limit of an ALT >2 
times the upper limit of normal. In line with usual clinical practice, repeat labs 
are not indicated for all subjects at week 8 (the study endpoint) as any increased 
values would have been seen before this time. 
 
Subjects who develop active suicidal ideation, represented by a score of >2 on 
HDRS item 3, will be referred for urgent or emergent clinical assessment. A 
patient who develops active suicidal thoughts will be urgently evaluated by a 
study physician (all of whom are psychiatrists). In any case where there are 
acute safety concerns arising from suicidality (such as a plan or actual intent), 
the patient will be sent to the BWH Emergency Department for further evaluation 
under Section 12a. If there are no acute safety concerns based on the urgent 
evaluation, the patient will be monitored according to protocol and instructed to 
contact study staff immediately with any worsening in their mood or thinking.  
The study doctor will review the urgent or emergent safety assessment and 
determine if the subject can continue in the study. Any subject who requires a 
level of care exceeding customary outpatient services (i.e., psychiatric 
hospitalization or participation in a partial hospital program) will be removed 
from the study. If a subject must be transferred from the study into clinical care, 
the study physicians will continue to follow the subjects until they are accepted 
into appropriate, longer-term care, if clinically indicated. If the subject chooses to 
discontinue the sertraline at the end of the study, the study physician will 
prescribe a safe taper of the medication, and arrange for appropriate psychiatric 
follow up, as clinically indicated. 
 
 
 


 
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During all portions of this research study, the privacy and confidentiality of all 
participants will be maintained at all times.  
At each study visit, the study staff will enter the data into case report forms on 
RedCap. All laboratory values will be reviewed by the Principle Investigator or 
another physician co-investigator. All study data will be stored securely on 
RedCap and de-identified prior to data analysis and only group data will be 
reported. Paper files for each subject, including the consent form, screening 
materials, subject medication diaries, and any additional correspondence will be 
stored in a locked filing cabinet in the office of the Principle Investigator at 
Brigham and Women's Hospital. 
If an adverse event occurs, or there is an abnormal finding during laboratory 
testing, that information will be released to the subjects primary physician with 
the subject’s permission and written release. 
 
X. REFERENCE 
 
i. World Health Organization The global burden of disease: 2004 update. Geneva. 
2008. 
 
ii. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, 
Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, 
Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in 
depressed outpatients requiring one or several treatment steps: a STAR*D 
report. Am J Psychiatry. 2006 Nov;163(11):1905-17. 
 
iii. Uher R, Mors O, Rietschel M, Rajewska-Rager A, Petrovic A, Zobel A, 
Henigsberg N, Mendlewicz J, Aitchison KJ, Farmer A, McGuffin P. Early and 
delayed onset of response to antidepressants in individual trajectories of change 
during treatment of major depression: a secondary analysis of data from the 
Genome-Based Therapeutic Drugs for Depression (GENDEP) study. J Clin 
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iv.  Gaynes BN, Dusetzina SB, Ellis AR, Hansen RA, Farley JF, Miller WC, Stürmer 
T. Treating depression after initial treatment failure: directly comparing switch 
and augmenting strategies in STAR*D. J Clin Psychopharmacol. 2012 
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v.  Zisook S, Lesser IM, Lebowitz B, Rush AJ, Kallenberg G, Wisniewski SR, 
Nierenberg AA, Fava M, Luther JF, Morris DW, Trivedi MH. Effect of 
antidepressant medication treatment on suicidal ideation and behavior in a 
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Enhance Depression Outcomes Study. J Clin Psychiatry. 2011 Oct;72(10):1322-
32. 
  


 
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vi.  Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G, 
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