Maintenance of Wellness in Patients With Obsessive-Compulsive Disorder Who Discontinue Medication After Exposure/Response Prevention Augmentation: A Randomized Clinical Trial.

IMPORTANCE: Serotonin reuptake inhibitors (SRIs) are the only medications approved for obsessive-compulsive disorder (OCD), yet most patients taking SRIs exhibit significant symptoms. Adding exposure/response prevention (EX/RP) therapy improves symptoms, but it is unknown whether patients maintain wellness after discontinuing SRIs. OBJECTIVE: To assess whether patients with OCD who are taking SRIs and have attained wellness after EX/RP augmentation can discontinue their SRI with noninferior outcomes compared with those who continue their SRI therapy. DESIGN, SETTING, AND PARTICIPANTS: A 24-week, double-blind, randomized clinical trial was performed from May 3, 2013, to June 25, 2018. The trial took place at US academic medical centers. Participants included 137 adults with a principal diagnosis of OCD (≥1 year) who were taking an SRI (≥12 weeks), had at least moderate symptoms (defined as Yale-Brown Obsessive-Compulsive Scale [Y-BOCS] score ≥18 points), and received as many as 25 sessions of EX/RP therapy. Those who attained wellness (Y-BOCS score ≤14 points; 103 patients [75.2%]) were study eligible. Data were analyzed from June 29, 2019, to October 2, 2021. INTERVENTION: Participants were randomly assigned either to receive taper to placebo (taper group) or to continue their SRI (continuation group) and monitored for 24 weeks. MAIN OUTCOME AND MEASURES: The Y-BOCS score (range, 0-40 points) was the primary outcome; the Hamilton Depression Rating Scale (HDRS; range, 0-52 points) and the Quality-of-Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF; range, 0%-100%) scores were secondary outcomes. Outcomes were assessed at 8 time points by independent evaluators who were blinded to randomization. The taper regimen was hypothesized to be noninferior to continuation at 24 weeks using a 1-sided α value of .05. RESULTS: A total of 101 patients (mean [SD] age, 31.0 [11.2] years; 55 women [54.5%]) participated in the trial: 51 patients (50.5%) in the taper group and 50 patients (49.5%) in the continuation group. At 24 weeks, patients in the taper group had noninferior results compared with patients in the continuation group (mean [SD] Y-BOCS score: taper group, 11.47 [6.56] points; continuation group: 11.51 [5.97] points; difference, -0.04 points; 1-sided 95% CI, -∞ to 2.09 points [below the noninferiority margin of 3.0 points]; mean [SD] HDRS score: taper group, 5.69 [3.84] points; continuation group, 4.61 [3.46] points; difference, 1.08 points; 1-sided 95% CI, -∞ to 2.28 points [below the noninferiority margin of 2.5 points]; mean [SD] Q-LES-Q-SF score: taper group, 68.01% [15.28%]; continuation group, 70.01% [15.59%]; difference, 2.00%; 1-sided 95% CI, -∞ to 6.83 [below the noninferiority margin of 7.75]). However, the taper group had higher rates of clinical worsening (23 of 51 [45%] vs 12 of 50 [24%]; P = .04). CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial show that patients with OCD who achieve wellness after EX/RP therapy could, on average, discontinue their SRI with noninferior outcomes compared with those who continued their SRI. Those who tapered the SRI had higher clinical worsening rates. Future research should evaluate if SRI half-life alters these rates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01686087.

Maximizing remission from cognitive-behavioral therapy in medicated adults with obsessive-compulsive disorder.

Practice guidelines for adults with obsessive-compulsive disorder (OCD) recommend augmenting serotonin reuptake inhibitors (SRIs) with exposure and ritual prevention (EX/RP). However, fewer than half of patients remit after a standard 17-session EX/RP course. We studied whether extending the course increased overall remission rates and which patient factors predicted remission. Participants were 137 adults with clinically significant OCD (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score ≥18) despite an adequate SRI trial (≥12 weeks). Continuing their SRI, patients received 17 sessions of twice-weekly EX/RP (standard course). Patients who did not remit (Y-BOCS ≤12) received up to 8 additional sessions (extended course). Of 137 entrants, 123 completed treatment: 49 (35.8%) remitted with the standard course and another 46 (33.6%) with the extended course. Poorer patient homework adherence, more Obsessive-Compulsive Personality Disorder (OCPD) traits, and the Brain-Derived Neurotrophic Factor (BDNF) Val66MET genotype were associated with lower odds of standard course remission. Only homework adherence differentiated non-remitters from extended course remitters. Extending the EX/RP course from 17 to 25 sessions enabled many (69.3%) OCD patients on SRIs to achieve remission. Although behavioral (patient homework adherence), psychological (OCPD traits), and biological (BDNF genotype) factors influenced odds of EX/RP remission, homework adherence was the most potent patient factor overall.

Comparison of the Association Between Goal-Directed Planning and Self-reported Compulsivity vs Obsessive-Compulsive Disorder Diagnosis.

Importance: Dimensional definitions of transdiagnostic mental health problems have been suggested as an alternative to categorical diagnoses, having the advantage of capturing heterogeneity within diagnostic categories and similarity across them and bridging more naturally psychological and neural substrates. Objective: To examine whether a self-reported compulsivity dimension has a stronger association with goal-directed and related higher-order cognitive deficits compared with a diagnosis of obsessive-compulsive disorder (OCD). Design, Setting, and Participants: In this cross-sectional study, patients with OCD and/or generalized anxiety disorder (GAD) from across the United States completed a telephone-based diagnostic interview by a trained rater, internet-based cognitive testing, and self-reported clinical assessments from October 8, 2015, to October 1, 2017. Follow-up data were collected to test for replicability. Main Outcomes and Measures: Performance was measured on a test of goal-directed planning and cognitive flexibility (Wisconsin Card Sorting Test [WCST]) and a test of abstract reasoning. Clinical variables included DSM-5 diagnosis of OCD and GAD and 3 psychiatric symptom dimensions (general distress, compulsivity, and obsessionality) derived from a factor analysis. Results: Of 285 individuals in the analysis (mean [SD] age, 32 [12] years; age range, 18-77 years; 219 [76.8%] female), 111 had OCD; 82, GAD; and 92, OCD and GAD. A diagnosis of OCD was not associated with goal-directed performance compared with GAD at baseline (ß [SE], -0.02 [0.02]; P = .18). In contrast, a compulsivity dimension was negatively associated with goal-directed performance (ß [SE], -0.05 [0.02]; P = .003). Results for abstract reasoning task and WCST mirrored this pattern; the compulsivity dimension was associated with abstract reasoning (ß [SE], 2.99 [0.63]; P < .001) and several indicators of WCST performance (eg, categories completed: ß [SE], -0.57 [0.09]; P < .001), whereas OCD diagnosis was not (abstract reasoning: ß [SE], 0.39 [0.66]; P = .56; categories completed: ß [SE], -0.09 [0.10]; P = .38). Other symptom dimensions relevant to OCD, obsessionality, and general distress had no reliable association with goal-directed performance, WCST, or abstract reasoning. Obsessionality had a positive association with requiring more trials to reach the first category on the WCST at baseline (ß [SE], 2.92 [1.39]; P = .04), and general distress was associated with impaired goal-directed performance at baseline (ß [SE],-0.04 [0.02]; P = .01). However, unlike the key results of this study, neither survived correction for multiple comparisons or was replicated at follow-up testing. Conclusions and Relevance: Deficits in goal-directed planning in OCD may be more strongly associated with a compulsivity dimension than with OCD diagnosis. This result may have implications for research assessing the association between brain mechanisms and clinical manifestations and for understanding the structure of mental illness.

Task-based fMRI predicts response and remission to exposure therapy in obsessive-compulsive disorder.

Exposure and ritual prevention (EX/RP) is an effective first-line treatment for obsessive-compulsive disorder (OCD), but only some patients achieve minimal symptoms following EX/RP. Herein, we investigate whether task-based neural activity can predict who responds best to EX/RP. Unmedicated adult patients with OCD (n = 36) and healthy participants (n = 33) completed the Simon Spatial Incompatibility Task during high-resolution, multiband functional MRI (fMRI); patients were then offered twice-weekly EX/RP (17 sessions). Linear mixed-effects models were used to identify brain regions where conflict-related activity moderated the slope of change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores across treatment. Conflict-related activity in the left pallidum and 35 cortical parcels/regions significantly predicted symptom improvement with EX/RP for patients with OCD (false discovery rate-corrected P < 0.05). Significant parcels/regions included cingulo-opercular and default mode network regions, specifically the anterior insula and anterior and posterior cingulate. Summarizing across these parcels/regions, greater conflict-related activity predicted greater EX/RP response and which patients achieved remission (Y-BOCS score ≤ 12; Cohen's d = 1.68) with >80% sensitivity and specificity. The association between brain activity and treatment response was partially mediated by patient EX/RP adherence (b = -2.99; 43.61% of total effect; P = 0.02). Brain activity and adherence together were highly predictive of remission. Together, these findings suggest that cingulo-opercular and default mode regions typically implicated in task control and introspective processes, respectively, may be targets for novel treatments that augment the ability of persons with OCD to resolve cognitive conflict and thereby facilitate adherence to EX/RP, increasing the likelihood of remission.

A randomized controlled pilot trial of vilazodone for adult separation anxiety disorder.

BACKGROUND: Separation anxiety disorder was recently recognized by fifth edition of the Diagnostic and Statistical Manual of Mental Disorders as a diagnosis in adults, but no publications to date have characterized a sample of patients seeking treatment for adult separation anxiety disorder (ASAD) or assessed treatment efficacy. We hypothesized that vilazodone, a selective serotonin reuptake inhibitor (SSRI) and serotonin 1a (5HT1a ) receptor partial agonist, would have efficacy in ASAD, because SSRIs have appeared efficacious in children with mixed diagnoses including separation anxiety disorder and in animal models of separation anxiety. METHODS: In this pilot study, 24 adults (ages 18-60) with a principal diagnosis of ASAD were randomized to 12 weeks of double-blind treatment with vilazodone (n = 13) or placebo (n = 11). Outcome was assessed by an independent evaluator and self-ratings, and analyzed with mixed effect models. RESULTS: This sample was predominantly female (67%), with comorbid psychiatric disorders (58%), and adult onset of separation anxiety disorder (62%). Response rates at week 12 did not differ significantly between groups. Across all time points, the vilazodone group evidenced greater improvement on the Structured Clinical Interview for Separation Anxiety Symptoms (P = .026) and the Quality of Life Enjoyment and Satisfaction Questionnaire (P = .011), and trends toward greater improvement on the Adult Separation Anxiety Questionnaire (P = .054) and the Clinical Global Impression-Change Scale (P = .086), all with large between-group effect sizes. CONCLUSIONS: Findings demonstrate feasibility of a clinical trial in ASAD, and they suggest that vilazodone may have efficacy in the treatment of ASAD and warrants further study.

COMBINED MIRTAZAPINE AND SSRI TREATMENT OF PTSD: A PLACEBO-CONTROLLED TRIAL.

BACKGROUND: Combined treatment with a selective serotonin reuptake inhibitor (SSRI) plus mirtazapine has shown superior efficacy in some studies of depression, but has not been studied in posttraumatic stress disorder (PTSD). This study aimed to assess acceptability of combined sertraline plus mirtazapine treatment for PTSD and to estimate its effect size relative to sertraline plus placebo. METHODS: Thirty-six adults with PTSD were randomized to 24 weeks of double-blind treatment with sertraline plus mirtazapine or sertraline plus placebo. Outcomes were analyzed with mixed effects models. RESULTS: The combined treatment group showed a significantly greater remission rate (P = .042) and improvement in depressive symptoms (P = .023) than the sertraline plus placebo group. There were no significant group differences in the two primary outcomes of treatment retention and PTSD severity, or in other secondary outcomes (sleep impairment, sexual functioning, quality of life, and physical and mental functioning), but the combined treatment group showed numerical advantages on all of these outcomes, and effect sizes relative to sertraline plus placebo ranged from small to moderate (d = .26-.63). Both treatments were well-tolerated, with significantly increased appetite but not weight gain in the combined treatment group. CONCLUSION: Findings suggest that combined treatment of PTSD with sertraline plus mirtazapine may have clinically meaningful advantages in symptomatic improvement, relative to SSRI treatment alone, and acceptable tolerability. Combined treatment with an SSRI plus mirtazapine in PTSD deserves additional study as initial treatment or as an augmentation strategy for nonresponders to an SSRI.

Six-month outcomes from a randomized trial augmenting serotonin reuptake inhibitors with exposure and response prevention or risperidone in adults with obsessive-compulsive disorder.

OBJECTIVE: To compare outcomes after 6-month maintenance treatment of adults diagnosed with obsessive-compulsive disorder (OCD) based on DSM-IV criteria who responded to acute treatment with serotonin reuptake inhibitors (SRIs) augmented by exposure and response prevention (EX/RP) or risperidone. METHOD: A randomized trial was conducted at 2 academic sites from January 2007 through December 2012. In the acute phase, 100 patients on therapeutic SRI dose with at least moderate OCD severity were randomized to 8 weeks of EX/RP, risperidone, or pill placebo. Responders entered the 6-month maintenance phase, continuing the augmentation strategy they received acutely (n = 30 EX/RP, n = 8 risperidone). Independent evaluations were conducted every month. The main outcome was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). RESULTS: Intent-to-treat analyses indicated that, after 6-month maintenance treatment, EX/RP yielded OCD outcomes that were superior to risperidone (Y-BOCS = 10.95 vs 18.70; t40 = 2.76, P = .009); more patients randomized to EX/RP met response criteria (Y-BOCS decrease ≥ 25%: 70% vs 20%; P < .001) and achieved minimal symptoms (Y-BOCS ≤ 12: 50% vs 5%; P < .001). During maintenance, OCD severity decreased slightly in both conditions (Y-BOCS decrease = 2.2 points, P = .020). Lower Y-BOCS at entry to maintenance was associated with more improvement in both conditions (r38 = 0.57, P < .001). CONCLUSIONS: OCD patients taking SRIs who responded to acute EX/RP or risperidone maintained their gains over 6-month maintenance. Because EX/RP patients improved more during acute treatment than risperidone-treated patients, and both maintained their gains during maintenance, EX/RP yielded superior outcomes 6 months later. The findings that 50% of patients randomized to EX/RP had minimal symptoms at 6-month maintenance, a rate double that of prior studies, suggests that EX/RP maintenance helps maximize long-term outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00389493.

Cognitive-behavioral therapy vs risperidone for augmenting serotonin reuptake inhibitors in obsessive-compulsive disorder: a randomized clinical trial.

IMPORTANCE: Obsessive-compulsive disorder (OCD) is one of the world's most disabling illnesses according to the World Health Organization. Serotonin reuptake inhibitors (SRIs) are the only medications approved by the Food and Drug Administration to treat OCD, but few patients achieve minimal symptoms from an SRI alone. In such cases, practice guidelines recommend adding antipsychotics or cognitive-behavioral therapy consisting of exposure and ritual prevention (EX/RP). OBJECTIVE: To compare the effects of these 2 SRI augmentation strategies vs pill placebo for the first time, to our knowledge, in adults with OCD. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial (conducted January 2007-August 2012) at 2 academic outpatient research clinics that specialize in OCD and anxiety disorders. Patients (aged 18-70 years) were eligible if they had OCD of at least moderate severity despite a therapeutic SRI dose for at least 12 weeks prior to entry. Of 163 who were eligible, 100 were randomized (risperidone, n = 40; EX/RP, n = 40; and placebo, n = 20), and 86 completed the trial. INTERVENTIONS: While continuing their SRI at the same dose, patients were randomized to the addition of 8 weeks of risperidone (up to 4 mg/d), EX/RP (17 sessions delivered twice weekly), or pill placebo. Independent assessments were conducted every 4 weeks. MAIN OUTCOME AND MEASURE: The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) to measure OCD severity. RESULTS: Patients randomized to EX/RP had significantly greater reduction in week 8 Y-BOCS scores based on mixed-effects models (vs risperidone: mean [SE], -9.72 [1.38]; P < .001 vs placebo: mean [SE], -10.10 [1.68]; P < .001). Patients receiving risperidone did not significantly differ from those receiving placebo (mean [SE], -0.38 [1.72]; P = .83). More patients receiving EX/RP responded (Y-BOCS score decrease ≥25%: 80% for EX/RP, 23% for risperidone, and 15% for placebo; P < .001). More patients receiving EX/RP achieved minimal symptoms (Y-BOCS score ≤12: 43% for EX/RP, 13% for risperidone, and 5% for placebo; P = .001). Adding EX/RP was also superior to risperidone and placebo in improving insight, functioning, and quality of life. CONCLUSIONS AND RELEVANCE: Adding EX/RP to SRIs was superior to both risperidone and pill placebo. Patients with OCD receiving SRIs who continue to have clinically significant symptoms should be offered EX/RP before antipsychotics given its superior efficacy and less negative adverse effect profile. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00389493.

Six-month follow-up of a randomized controlled trial augmenting serotonin reuptake inhibitor treatment with exposure and ritual prevention for obsessive-compulsive disorder.

OBJECTIVE: This article describes the long-term effects of augmenting serotonin reuptake inhibitors (SRIs) with exposure and ritual prevention or stress management training in patients with DSM-IV obsessive-compulsive disorder (OCD). METHOD: Between November 2000 and November 2006, 111 OCD patients from 2 academic outpatient centers with partial SRI response were randomized to the addition of exposure and ritual prevention or stress management training, delivered twice weekly for 8 weeks (acute phase); 108 began treatment. Responders (38 of 52 in the exposure and ritual prevention condition, 11 of 52 in the stress management training condition) entered a 24-week maintenance phase. The Yale-Brown Obsessive Compulsive Scale (YBOCS) was the primary outcome measure. RESULTS: After 24 weeks, patients randomized to and receiving exposure and ritual prevention versus stress management training had significantly better outcomes (mean YBOCS scores of 14.69 and 21.37, respectively; t = 2.88, P = .005), higher response rates (decrease in YBOCS scores ≥ 25%: 40.7% vs 9.3%, Fisher exact test P < .001), and higher rates of excellent response (YBOCS score ≤ 12: 24.1% vs 5.6%, Fisher exact test P = .01). During the maintenance phase, the slope of change in YBOCS scores was not significant in either condition (all P values ≥ .55), with no difference between exposure and ritual prevention and stress management training (P > .74). Better outcome was associated with baseline variables: lower YBOCS scores, higher quality of life, fewer comorbid Axis I diagnoses, and male sex. CONCLUSIONS: Augmenting SRIs with exposure and ritual prevention versus stress management training leads to better outcome after acute treatment and 24 weeks later. Maintenance outcome, however, was primarily a function of OCD severity at entrance. Greater improvement during the acute phase influences how well patients maintain their gains, regardless of treatment condition.

A placebo-controlled trial of phenelzine, cognitive behavioral group therapy, and their combination for social anxiety disorder.

CONTEXT: Medication and cognitive behavioral treatment are the best-established treatments for social anxiety disorder, yet many individuals remain symptomatic after treatment. OBJECTIVE: To determine whether combined medication and cognitive behavioral treatment is superior to either monotherapy or pill placebo. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Research clinics at Columbia University and Temple University. PARTICIPANTS: One hundred twenty-eight individuals with a primary DSM-IV diagnosis of social anxiety disorder. INTERVENTIONS: Cognitive behavioral group therapy (CBGT), phenelzine sulfate, pill placebo, and combined CBGT plus phenelzine. MAIN OUTCOME MEASURES: Liebowitz Social Anxiety Scale and Clinical Global Impression (CGI) scale scores at weeks 12 and 24. RESULTS: Linear mixed-effects models showed a specific order of effects, with steepest reductions in Liebowitz Social Anxiety Scale scores for the combined group, followed by the monotherapies, and the least reduction in the placebo group (Williams test = 4.97, P < .01). The CGI response rates in the intention-to-treat sample at week 12 were 9 of 27 (33.3%) (placebo), 16 of 34 (47.1%) (CBGT), 19 of 35 (54.3%) (phenelzine), and 23 of 32 (71.9%) (combined treatment) (chi(2)(1) = 8.76, P < .01). Corresponding remission rates (CGI = 1) were 2 of 27 (7.4%), 3 of 34 (8.8%), 8 of 35 (22.9%), and 15 of 32 (46.9%) (chi(2)(1) = 15.92, P < .01). At week 24, response rates were 9 of 27 (33.3%), 18 of 34 (52.9%), 17 of 35 (48.6%), and 25 of 32 (78.1%) (chi(2)(1) = 12.02, P = .001). Remission rates were 4 of 27 (14.8%), 8 of 34 (23.5%), 9 of 35 (25.7%), and 17 of 32 (53.1%) (chi(2)(1) = 10.72, P = .001). CONCLUSION: Combined phenelzine and CBGT treatment is superior to either treatment alone and to placebo on dimensional measures and on rates of response and remission.

A randomized, controlled trial of cognitive-behavioral therapy for augmenting pharmacotherapy in obsessive-compulsive disorder.

OBJECTIVE: Although serotonin reuptake inhibitors (SRIs) are approved for the treatment of obsessive-compulsive disorder (OCD), most OCD patients who have received an adequate SRI trial continue to have clinically significant OCD symptoms. The purpose of this study was to examine the effects of augmenting SRIs with exposure and ritual prevention, an established cognitive-behavioral therapy (CBT) for OCD. METHOD: A randomized, controlled trial was conducted at two academic outpatient clinics to compare the effects of augmenting SRIs with exposure and ritual prevention versus stress management training, another form of CBT. Participants were adult outpatients (N=108) with primary OCD and a Yale-Brown Obsessive Compulsive Scale total score > or = 16 despite a therapeutic SRI dose for at least 12 weeks prior to entry. Participants received 17 sessions of CBT (either exposure and ritual prevention or stress management training) twice a week while continuing SRI pharmacotherapy. RESULTS: Exposure and ritual prevention was superior to stress management training in reducing OCD symptoms. At week 8, significantly more patients receiving exposure and ritual prevention than patients receiving stress management training had a decrease in symptom severity of at least 25% (based on Yale-Brown Obsessive Compulsive Scale scores) and achieved minimal symptoms (defined as a Yale-Brown Obsessive Compulsive Scale score < or = 12). CONCLUSIONS: Augmentation of SRI pharmacotherapy with exposure and ritual prevention is an effective strategy for reducing OCD symptoms. However, 17 sessions were not sufficient to help most of these patients achieve minimal symptoms.

Post-treatment effects of exposure therapy and clomipramine in obsessive-compulsive disorder.

We sought to determine whether adults with obsessive-compulsive disorder (OCD) who respond to intensive exposure and response (ritual) prevention (EX/RP) with or without clomipramine (CMI) fare better 12 weeks after treatment discontinuation than responders receiving CMI alone. After receiving 12 weeks of treatment (EX/RP, CMI, EX/RP+CMI, or pill placebo [PBO] in a randomized clinical trial conducted at three outpatient research centers), 46 adults with OCD who responded to treatment (18 EX/RP, 11 CMI, 15 EX/RP+CMI, 2 PBO) were followed after treatment discontinuation for 12 weeks. Patients were assessed every 4 weeks with the Yale-Brown Obsessive-Compulsive Scale, the National Institutes of Health Global Obsessive-Compulsive Scale, and the Clinical Global Impressions scale by an evaluator who was blind to original treatment assignment. The primary hypothesis was that EX/RP and EX/RP+CMI responders would be less likely to relapse 12 weeks after treatment discontinuation than responders to CMI alone. Twelve weeks after treatment discontinuation, EX/RP and EX/RP+CMI responders, compared to CMI responders, had a significantly lower relapse rate (4/33 = 12% versus 5/11 = 45%) and a significantly longer time to relapse. The CMI relapse rate was lower than previously reported. Nonetheless, responders receiving intensive EX/RP with or without CMI fared significantly better 12 weeks after treatment discontinuation than responders receiving CMI alone.

Citalopram treatment of social anxiety disorder with comorbid major depression.

Treatment of patients with both social anxiety disorder and major depression has been little studied although social anxiety disorder and depression frequently co-occur. Each disorder has been shown to respond to serotonin reuptake inhibitor treatment. Objectives of this study were to characterize a sample of these comorbid patients and to assess response to treatment with citalopram. Patients with primary DSM-IV generalized subtype of social anxiety disorder and comorbid major depression (N = 21) were assessed for symptoms of each disorder, including atypical depressive features, and functional impairment. Patients were treated with a flexible dose of open label citalopram for 12 weeks. Response rates for the intention-to-treat sample at week 12 were 14/21 (66.7%) for social anxiety disorder and 16/21 (76.2%) for depression. All continuous measures of social anxiety, depression, and functional impairment improved significantly with treatment, but depression symptoms responded more rapidly and more completely than social anxiety symptoms. Mean dose of citalopram at study endpoint was 37.6 mg/day. Only three patients (14.3%) fulfilled DSM-IV criteria for atypical features of depression, although 18 (85.7%) fulfilled the criterion for interpersonal rejection sensitivity. Citalopram treatment may benefit patients with primary social anxiety disorder and comorbid major depression, and it should be further studied in controlled trials. Improvement in social anxiety disorder symptoms lagged behind improvement in depression, and greater than 12 weeks of treatment may be required to assess full social anxiety response in patients with comorbid depression. The overlap of social anxiety disorder with atypical features of depression may primarily be due to the shared feature of rejection sensitivity.