Past Studies

Since its founding in 1977 the Depression Evaluation Service has conducted over a hundred studies and has been awarded dozens of private and federally funded grants. Our team has published hundreds of papers, many in collaboration with other research groups.

(2017) Do social functioning and symptoms improve with continuation antidepressant treatment of persistent depressive disorder? An observational study.

J Affect Disord; 210:258-264. doi: 10.1016

Hellerstein DJ, Hunnicutt-Ferguson K, Stewart JW, McGrath PJ, Keller S, Peterson BS, Chen Y.


To determine efficacy of continued treatment with the serotonin norepinephrine reuptake inhibitor duloxetine on symptom reduction and functional improvement in outpatients with dysthymia.


Fifty outpatients with DSM-IV-TR diagnosed dysthymia who had participated in a 10 week double-blind, placebo-controlled study of duloxetine received open treatment for three months. Nineteen duloxetine responders continued duloxetine, 24 patients initially treated with placebo started open duloxetine treatment, and 7 duloxetine non-responders were treated with desvenlafaxine or bupropion, selected by clinician choice.


Patients continuing duloxetine maintained symptom improvement, 84% meeting response and 63% remission criteria at week 22. Patients initially treated with placebo showed similarly high levels of response (83%) and remission (62%) at week 22, and most duloxetine non-responders subsequently responded to other antidepressants. Duloxetine-continuation patients improved modestly between weeks 10 and 22 on measures of social and cognitive functioning and temperament. Despite this improvement concurrently across several functional domains, 66.7% of patients continuing duloxetine remained in the impaired range of functioning according to the Social Adjustment Scale (SAS).


Continued duloxetine treatment appears to be effective in maintaining symptom response in dysthymic disorder, and has positive effects on social functioning. However, the majority of patients do not show normalization of functioning, even when controlling for remission status. Additional treatments should be considered to target residual impairments in social functioning in mood remitted patients with persistent depressive disorder.

TRIAL REGISTRATION: Identifier: NCT00360724.

(2015) Vilazodone for the treatment of major depressive disorder: an evidence-based review of its place in therapy.

Hellerstein DJ, Flaxer J.

Core Evid; 10:49-62. doi: 10.2147


It has clearly been demonstrated that depressive disorders constitute a major worldwide public health problem, with massive economic and quality-of-life consequences. Existing pharmacological treatments have limited efficacy, with only about a third of patients achieving remission on any one medication. Delayed onset of action and variable tolerability contribute to this limited efficacy. Vilazodone, introduced in the US in 2011, has been described as the first member of the serotonin partial agonist-reuptake inhibitor (SPARI) class of medications, combining serotonin-reuptake inhibition with 5-HT1A partial agonism. This agent could potentially have benefits for subgroups of depressed patients, including depressed patients with comorbid anxiety and patients with anxiety disorders, and might have fewer sexual side effects than selective serotonin-reuptake inhibitors (SSRIs).


We reviewed existing clinical trials that assess the benefits of vilazodone for treatment of major depression.


In clinical trials, including two Phase III studies and two Phase IV studies, vilazodone has been shown to have efficacy greater than placebo on the Montgomery-Åsberg Depression Rating Scale, comparable efficacy to citalopram, and continued benefit after 52 weeks of treatment. The safety profile for vilazodone is comparable to other SSRI medications, and tolerability also appears generally comparable to other SSRI medications.


Vilazodone, which has been described as the first-of-class SPARI medication, may potentially have benefits for subgroups of patients, particularly those depressed individuals with coexisting anxiety symptoms or anxiety disorders. However, convincing evidence for these benefits has as yet not been published.

(2015) Treatment of maternal depression in a medication clinical trial and its effect on children.

Am J Psychiatry; 172(5):450-9.

Weissman MM, Wickramaratne P, Pilowsky DJ, Poh E, Batten LA, Hernandez M, Flament MF, Stewart JA, McGrath P, Blier P, Stewart JW.


Observational studies show that when a depressed mother's symptoms remit, her children's psychiatric symptoms decrease. Using randomized treatment assignment, the authors sought to determine the differential effects of a depressed mother's treatment on her child.


The study was a randomized double-blind 12-week trial of escitalopram, bupropion, or the combination of the two in depressed mothers (N=76), with independent assessment of their children (N=135; ages 7-17 years).


There were no significant treatment differences in mothers' depressive symptoms or remission. Children's depressive symptoms and functioning improved significantly among those whose mothers were in the escitalopram group (compared with those whose mothers were in the bupropion and combination treatment groups). Only in the escitalopram group was significant improvement of mother's depression associated with improvement in the child's symptoms. Exploratory analyses suggested that this may be due to changes in parental functioning: Mothers in the escitalopram group reported significantly greater improvement, compared with the other groups, in their ability to listen and talk to their children, who as a group reported that their mothers were more caring over the 12 weeks. Maternal baseline negative affectivity appeared to moderate the effect of maternal treatment on children, although the effect was not statistically significant. Children of mothers with low negative affectivity improved in all treatment groups. Children of mothers with high negative affectivity improved significantly only for those whose mothers were in the escitalopram group.


The effects of the depressed mother's improvement on her children may depend on her type of treatment. Depressed mothers with high anxious distress and irritability may require medications that reduce these symptoms in order to show the effect of her remission on her children. Identifier: NCT00519428.

(2014) Combination antidepressant therapy for major depressive disorder: speed and probability of remission.

Stewart JW, McGrath PJ, Blondeau C, Deliyannides DA, Hellerstein D, Norris S, Amat J, Pilowsky DJ, Tessier P, Laberge L, O'Shea D, Chen Y, Withers A, Bergeron R, Blier P.

J Psychiatr Res. 52:7-14. doi: 10.1016


Only about a third of patients with an episode of major depressive disorder remit with a given treatment and few remissions occur within the first weeks of treatment. This study tested whether combining escitalopram and bupropion as initial treatment would result in quicker remission and a higher remission rate than monotherapy with either drug.


Two hundred forty-five outpatients aged 18-65 having non-psychotic, non-bipolar major depression were randomly assigned to double-blind treatment with bupropion or escitalopram or the combination dosed to a maximum of bupropion 450 mg/d and/or escitalopram 40 mg/d for 12 weeks. A Montgomery-Asberg Depression Rating Scale score of 22 was required for randomization, while a Hamilton Rating Scale for Depression score ≤ 7 defined remission. We hypothesized that bupropion plus escitalopram would outperform both monotherapies in both earlier onset of remission and higher rate of remission.


Primary analyses did not demonstrate that dual therapy outperformed both monotherapies in either timing of remission or remission rate. All three treatments were well tolerated.


These results do not support initial use of bupropion plus escitalopram to speed or enhance antidepressant response.

(2010) Escitalopram versus placebo in the treatment of dysthymic disorder.

Hellerstein DJ, Batchelder ST, Hyler S, Arnaout B, Toba C, Benga I, Gangure D.

Int Clin Psychopharmacol; 25(3):143-8. doi: 10.1097

Numerous studies have assessed the acute efficacy of antidepressants, including selective serotonin reuptake inhibitors, in treating dysthymic disorder; however, escitalopram, the S-enantiomer of citalopram, has not been studied. Thirty-six outpatients with Structured Clinical Interview for DSM-III-R-diagnosed dysthymic disorder, aged 23-65 years (mean±SD=44.7±11 years), were randomly assigned to double-blind escitalopram (maximum dose 20 mg/day) versus placebo for 12 weeks. Inclusion criteria included age 18-65 years and Hamilton Depression Rating Scale (HDRS) score≥12. We hypothesized that escitalopram would be superior to placebo in the HDRS-24 item total score at week 12. We also hypothesized the superiority of escitalopram over placebo for secondary measures, including the percentage of participants classified as responders and remitters, as well as social functioning (Social Adjustment Scale), clinical global impression-improvement, Global Assessment of Functioning Scale. Participants' baseline HDRS-24 averaged 23.4±5.9. Final HDRS-24 scores at last observation carried forward did not differ significantly between escitalopram-treated (mean±SD=10.88±5.83) and placebo-treated individuals (mean±SD=16.4±6.34) (F=2.82, degrees of freedom=1,32, P=0.10). Significant differences favoring active medication were found on the Social Adjustment Scale and the Clinical Global Impression Severity and Global Assessment of Functioning Scale, but not in the percentages of responders or remitters. A larger study sample or higher escitalopram dose may show more significant placebo-medication differences.

(2009) Does dual antidepressant therapy as initial treatment hasten and increase remission from depression?

Stewart JW, McGrath PJ, Deliyannides RA, Quitkin FM.

Journal of Psychiatric Practice; 15(5):337-45. doi: 10.1097


Only 30%-40% of depressed patients remit after 8 weeks of treatment with an antidepressant. We hypothesized that beginning treatment with two antidepressants would improve remission rates.


Relatively treatment-naive depressed outpatients (with DSM-IV diagnoses of major depressive disorder, dysthymic disorder, or depression not otherwise specified) were initially treated with a combination of escitalopram (ESC) plus bupropion (BUP), using rapid dose escalation to ESC 40 mg/day plus BUP 400 to 450 mg/day by study day 15 in an open-label, 8-week study. Remission was defined as a score < or =7 on the 17-item Hamilton Rating Scale for Depression (HAM-D17) at the end of the study. Recruitment occurred between July, 2003, and June, 2006, and the final patient completed the protocol in July, 2006.


Fifty-five patients signed informed consent, 49 of whom received at least one dose of study medication. Of the 49 patients, 28 (57%) were women and 30 (61%) had a current diagnosis of major depressive disorder; the mean age was 38+/-12 years, and the mean pre-treatment HAM-D17 score was 16+/-4. Sixteen (33%) of the patients remitted by study week 2, and 31 (63%) by week 8. Nine patients (18%) dropped out prior to their week 8 visit, 5 of them because of side effects.


The lack of a comparison group and the use of non-blind raters are drawbacks of this study.


This open-label study suggests that increased numbers of patients may benefit from dual therapy with ESC plus BUP and that the benefit may perhaps include an increased likelihood of early response. Identifier: NCT00296712

(2008) Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report.

J Clin Psychiatry; 69(12):1847-55.

McGrath PJ, Khan AY, Trivedi MH, Stewart JW, Morris DW, Wisniewski SR, Miyahara S, Nierenberg AA, Fava M, Rush AJ.


This study examined demographic and clinical correlates of DSM-IV major depressive disorder with melancholic features and assessed whether melancholic features were predictive of response to a selective serotonin reuptake inhibitor antidepressant.


Participants with major depressive disorder (N = 2875) at primary and specialty care sites who received the first step treatment with citalopram in the Sequenced Treatment Alternatives to Relieve Depression study were included. Patients were enrolled between July 2001 and April 2004. Melancholic features were ascribed by previously developed algorithms of telephone interview ratings prior to treatment. Demographics, clinical features, and treatment response were compared between those with and without melancholic features.


The 23.5% of participants with melancholic features were characterized by higher severity scores, greater rates of previous suicide attempts and ratings of current suicidal risk, and more concurrent psychiatric comorbidity. Unadjusted remission rates for those with melancholic features were statistically significantly reduced in absolute terms by up to 8.4% compared to those without melancholic features, which is a 24.1% decrease in relative chance of remission (p < .0001). Following adjustments for between-group baseline differences, remission rates were no longer different.


Melancholic features are associated with a significantly reduced remission rate with an SSRI. This effect appears to be accounted for by demographic and clinical features associated with melancholic features. Identifier: NCT0021528.

(2005) Remission rates with 3 consecutive antidepressant trials: effectiveness for depressed outpatients.

Quitkin FM, McGrath PJ, Stewart JW, Deliyannides D, Taylor BP, Davies CA, Klein DF.

J Clin Psychiatry; 66(6):670-6.


This effectiveness study assessed remission rates in patients who had the opportunity to receive up to 3 antidepressant trials if unresponsive.


One hundred seventy-one consecutive outpatients entered 1 of 3 studies for the treatment of major depressive disorder (DSM-IV criteria) from January 1999 through December 2001. This group primarily received fluoxetine as a first treatment in trials lasting 6 to 12 weeks (a small number received gepirone). If unimproved, patients received a second or third trial (primarily clinician's choice). A standard criterion to determine remission-a score of 7 or less on the 17-item Hamilton Rating Scale for Depression-was used. In order to contrast remission rates with first-generation antidepressants, patients' outcomes in a previously published study that compared placebo, phenelzine, and imipramine were also examined (N = 420).


In an intent-to-treat analysis, 66% (113/171) of patients who were treated with second-generation antidepressants and 65% (275/420) of patients who were treated with first-generation antidepressants eventually achieved remission.


Remission rates in the effectiveness study are approximately 20% higher than the rates usually cited, a result of our choice to examine outcome following 3 treatment trials. This choice is dictated by good clinical practice. The usual procedure when comparing treatment modalities is to assess outcome after a single anti-depressant trial. The cumulative high remission rates suggest antidepressants are effective and should encourage more patients to seek treatment and physicians to develop techniques to improve patient adherence.

(2004) Citalopram in the treatment of dysthymic disorder.

Hellerstein DJ, Batchelder S, Miozzo R, Kreditor D, Hyler S, Gangure D, Clark J.

Int Clin Psychopharmacol; 19(3):143-8.

This study aimed to provide preliminary data on the tolerability and effectiveness of citalopram for patients with dysthymic disorder. Twenty-one adult subjects meeting DSM-IV criteria for dysthymic disorder were enrolled in this 12-week open-label study, of whom 15 had pure dysthymia (e.g. no major depression in the past 2 years). Citalopram was initiated at 20 mg/day, and increased to a maximum of 60 mg/day. Response was defined as 50% or greater drop in score on the Hamilton Depression Rating Scale (HDRS) and a Clinical Global Impressions-I score of 1 ('very much improved') or 2 ('much improved'). Of these 15 pure dysthymic disorder subjects, all completed the trial, and 11 (73.3%) were treatment responders. All paired sample t-tests were highly significant, demonstrating significant average improvement on all measures of symptomatology and functioning. Scores on the 24-item HDRS decreased from 22.3+/-4.3 at baseline to 9.1+/-7.8 at week 12 [t(14)=6.1, P<0.001]. In addition, improvement was noted in self-reported measures of temperament and social functioning. The average final dose of citalopram was 39 mg/day. Side-effects were reported by nine of 15 subjects (60%), most frequently gastrointestinal symptoms (n=5), dry mouth (n=5) and sexual side-effects (n=3). These findings suggest the effectiveness and tolerability of citalopram in treating dysthymic disorder. Double-blind prospective studies are needed comparing citalopram both to placebo and to other medications, assessing both initial and sustained response to treatment.

(2000) Double-blind comparison of sertraline, imipramine, and placebo in the treatment of dysthymia: effects on personality.

Hellerstein DJ, Kocsis JH, Chapman D, Stewart JW, Harrison W.

Am J Psychiatry; 157(9):1436-44.


Although previous studies have shown that dysthymia, or chronic depression, commonly responds to antidepressant medications (with improvements in depressive symptoms and psychosocial functioning), there have been no systematic studies of the impact of antidepressant treatment on personality variables in patients with this disorder.


In a multicenter study, 410 patients with early-onset primary dysthymia were treated in a randomized prospective fashion with sertraline, imipramine, or placebo. The data were analyzed in terms of the subjects' scores on the Tridimensional Personality Questionnaire, a 100-item self-report instrument that measures four temperamental dimensions: harm avoidance, reward dependence, novelty seeking, and persistence.


At baseline, the harm avoidance scores of the dysthymic subjects were approximately 1.5 standard deviations higher than those of a previously reported community sample. After treatment, there was a significant decrease in harm avoidance scores, with no significant between-group differences. Remission of dysthymia was associated with significantly greater improvement in harm avoidance, with the greatest numerical change found in the patients treated with sertraline. Subjects' Tridimensional Personality Questionnaire scores were correlated at a 0.50 level with the Social Adjustment Scale both pre- and posttreatment, suggesting that a high degree of harm avoidance may be associated with poor social functioning.


Before treatment, chronically depressed patients demonstrate an abnormality in temperament, as measured by elevated degrees of harm avoidance. Remission of dysthymia is associated with improvement in this aspect of temperament.

(2000) A method to quantify rater bias in antidepressant trials.

Petkova E, Quitkin FM, McGrath PJ, Stewart JW, Klein DF.

Neuropsychopharmacology; 22(6):559-65.

Some studies indicate that the blind in clinical trials of the efficacy of antidepressant drugs is less than perfect. It has been suggested that, as a consequence of this incomplete blind, biased raters inflate efficacy and that, in fact, these drugs are relatively ineffective. However, in the literature, we could find no prior attempt to quantify rater bias and, thus, measure its contribution to claims of antidepressant efficacy. We used the distribution of SCL-90 (Symptom Check List) depression scale scores to derive a patient-based effect size, and contrasted this with the clinician-based effect size. We propose the difference between these two effect sizes (patient self-rating and clinician-derived) to be an indirect measure of bias. If patients had a prodrug bias, this method would be invalid. However the response rate from studies with active placebo suggest a patient prodrug bias is unlikely. The effect sizes derived from patient self-ratings are smaller than those derived from clinician ratings. This allows for the possibility that some clinician ratings were biased. However, quantifying the effect of bias suggests that it was insufficient to invalidate the original study conclusions based on clinician ratings, because the proportion of responders, based on patient self-ratings, differed significantly between the two drugs and placebo. Their 95% confidence intervals (CI) did not overlap. This analysis allows that some clinician ratings may be biased. However, the extent of bias appears insufficient to alter conclusions based on clinician ratings regarding efficacy of antidepressant drugs in this trial. Application of our approach in other trials is necessary to establish generalizability.

(1994) Duration of antidepressant trials: clinical and research implications.

J Clin Psychopharmacology; 14(1):64-6.

Donovan SJ, Quitkin FM, Stewart JW, Ocepek-Welikson K, Harrison W, McGrath PJ, Nunes EV, Wager S, Tricamo E.

The objective of our study was to demonstrate that additional antidepressant benefit occurs between weeks 4 and 6 in adult outpatients, even when dose is not increased. Response between weeks 4 and 6 was studied among depressed outpatients randomly assigned to imipramine, phenelzine, or placebo under double-blind conditions. Patients were selected for analysis only if they did not have a dose increase after the start of the fourth week of treatment (day 22). Eighty-eight patients met this condition. Conditional probability analysis was performed. Nonresponders to 4 weeks (28 days) of treatment had a significantly greater likelihood of responding by week 6 if they were on phenelzine rather than placebo. The same is probably true for patients on imipramine. In research and clinical care, 4 weeks is too short a trial of phenelzine to conclude a lack of efficacy. Four weeks is probably also too short a trial of imipramine.


(1993) Atypical depression. A valid clinical entity?

Stewart JW, McGrath PJ, Rabkin JG, Quitkin FM.

Psychiatr Clin North Am.; 16(3):479-95.

The history of atypical depression is summarized, and the results of several treatment outcome studies are reviewed. A number of clinical course, family, and biologic variables in patients with atypical depression are investigated, and these patients are compared with patients with other depressive conditions. The Atypical Depression Diagnostic Scale Question Book also is presented.

(1988) Social functioning in chronic depression: effect of 6 weeks of antidepressant treatment.

Stewart JW, Quitkin FM, McGrath PJ, Rabkin JG, Markowitz JS, Tricamo E, Klein DF.

Psychiatry Res.; 25(2):213-22.

Social functioning was assessed in 189 nonmelancholically depressed outpatients. Patients were then treated for 6 weeks in a double-blind trial of phenelzine, imipramine, or placebo and functioning was reassessed. Before treatment, younger, more severely depressed, more chronically depressed patients and those with a DSM-III diagnosis of major depression plus dysthymic disorder were more functionally impaired than patients without these characteristics. Chronically depressed patients who responded to treatment reported significantly improved functioning while nonresponders did not. These results suggest that for some chronically depressed patients, impaired functioning results at least partly from the Axis I mood disorder instead of being entirely attributable to Axis II character pathology.

(2013) Is depression with atypical features associated with trauma history?

Withers AC, Tarasoff JM, Stewart JW.

J Clin Psychiatry; 74(5):500-6.


Although studies have linked childhood trauma to depression resembling the atypical subtype, a majority of these studies did not use DSM-IV criteria for atypical features nor assess trauma both before and after depression onset. This study examined the relationship between atypical depression and lifetime trauma with the hypothesis that atypically depressed patients would report a higher number of trauma exposures than nonatypically depressed patients.


Raters blind to depressive subtype investigated trauma history by reviewing the Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition (SCID-I/P) posttraumatic stress disorder modules and social history sections in charts of depressed outpatients who had participated in treatment studies between 1985 and 2010. Rates of trauma both before and after depression onset were compared for 292 depressed patients with and without DSM-IV-defined atypical features using χ2 tests and binary logistic regressions. This chart review was conducted from 2009 to 2011.


Lifetime trauma was reported significantly more often by depressed patients with atypical features than by those without (P < .001). Patients with atypical features reported significantly more traumatic experiences both prior to (P = .012) and following (P = .015) depression onset. When sex and age at onset or duration of depression were used as covariates, depressive subtype was a significant predictor of reported trauma both prior to (P = .028) and following (P = .011) depression onset.


These results suggest that a relationship exists between atypical depression and lifetime trauma that may be more complex than the etiologic pathways outlined in prior research. Rather, trauma and atypical depression may be interrelated throughout life.