Efficacy, safety, and tolerability of nivasorexant in adults with binge-eating disorder: A randomized, Phase II proof of concept trial.

OBJECTIVE: This Phase II, placebo-controlled, double-blind study investigated the efficacy, safety, and tolerability of nivasorexant in the treatment of adults with moderate to severe binge-eating disorder (BED). METHODS: Adults meeting the DSM-5 BED criteria were randomized 1:1 to placebo or nivasorexant (100 mg b.i.d.). The primary endpoint was the change from baseline to Week 12 in the number of binge eating (BE) days per week. Exploratory efficacy endpoints included cessation of BE in the last 4 weeks of treatment; and change from baseline to Week 12 in the number of BE episodes/week, the clinician global impression (CGI) of change, the Yale-Brown Obsessive-Compulsive Scale modified for BE, and the Hamilton rating scale for depression (HAMD-17). Key safety outcomes included treatment-emergent adverse events (TEAEs) and adverse events of special interest (i.e., somnolence and fatigue). RESULTS: Sixty-eight participants were randomized to each treatment arm. The change from baseline to Week 12 in the number of BE days/week was the same for placebo (least squares mean [LSM]: -2.93) and nivasorexant (LSM: -2.93), with no difference between the treatment groups (LSM difference = .000 [95% confidence interval (CI): -.69, .69], p = .9992). Furthermore, no differences between treatment groups were observed in the exploratory efficacy endpoints. Nivasorexant was well tolerated; the overall incidence of TEAEs was balanced between treatment groups, and the frequency of somnolence and fatigue in the nivasorexant group were similar to placebo. DISCUSSION: In this proof-of-concept study, 100 mg b.i.d. nivasorexant did not improve BE in adults with moderate to severe BED. PUBLIC SIGNIFICANCE: The results of this Phase II study indicate that nivasorexant was well tolerated in adults with BED, but did not improve binge eating behavior over placebo. Further research is needed to improve our understanding of the role of the orexin-1 receptor in BED.

Neural circuits of anxiolytic and antidepressant pherine molecules.

In this review, we describe proposed circuits mediating the mechanism of action of pherines, a new class of synthetic neuroactive steroids with demonstrated antianxiety and antidepressant properties, that engage nasal chemosensory receptors. We hypothesize that afferent signals triggered by activation of these peripheral receptors could reach subgroups of olfactory bulb neurons broadcasting information to gamma-aminobutyric acid (GABAergic) and corticotropin-releasing hormone (CRH) neurons in the limbic amygdala. We propose that chemosensory inputs triggered by pherines project to centrolateral (CeL) and centromedial (CeM) amygdala neurons, with downstream effects mediating behavioral actions. Anxiolytic pherines could activate the forward inhibitory GABAergic neurons that facilitate the release of neuropeptide S (NPS) in the locus coeruleus (LC) and GABA in the bed nucleus of the stria terminalis (BNST) and inhibit catecholamine release in the LC and ventral tegmental area (VTA) leading to rapid anxiolytic effect. Alternatively, antidepressant pherines could facilitate the CRH and GABAergic neurons that inhibit the release of NPS from the LC, increase glutamate release from the BNST, and increase norepinephrine (NE), dopamine (DA), and serotonin release from the LC, VTA, and raphe nucleus, respectively. Activation of these neural circuits leads to rapid antidepressant effect. The information provided is consistent with this model, but it should be noted that some steps on these pathways have not been demonstrated conclusively in the human brain.

Managing dissociative symptoms following the use of esketamine nasal spray: a case report.

Patients with treatment-resistant depression (TRD) treated with esketamine nasal spray commonly experience transient symptoms of dissociation. Manifestations of dissociation, such as feelings of detachment from the environment, can cause considerable anxiety for patients. Nonpharmacologic interventions may help clinicians to manage associated anxiety and confusion due to dissociation following administration of esketamine nasal spray. We present the case of a 64-year-old woman with major depressive disorder who participated in a clinical trial evaluating the efficacy and safety of esketamine nasal spray in conjunction with an oral antidepressant for TRD. The patient received flexible doses of esketamine nasal spray (56 or 84 mg) twice weekly for 4 weeks. On treatment day 1, the patient was administered 56 mg of esketamine nasal spray using two nasal spray devices (28 mg per device). Twenty minutes after the first esketamine nasal spray device was administered, the patient experienced a dissociative episode lasting 40 minutes that caused anxiety and confusion. The patient was encouraged to listen to music during treatment sessions, which resulted in notable improvement of her symptoms. Listening to music of choice immediately following esketamine nasal spray administration along with reassurance from staff may help manage confusion and anxiety associated with dissociation.

The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study.

JNJ-42165279 is a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of fatty acid amides (FAA) including anandamide (AEA), palmitoylethanolamide (PEA), and N-oleoylethanolamide (OEA). We assessed the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with JNJ-42165279 in subjects with social anxiety disorder (SAD). This was a multicenter, double-blind, placebo-controlled study randomizing subjects to 12 weeks of treatment with either JNJ-42165279 (25 mg daily) or placebo (PBO). The primary endpoint was the change in the Liebowitz Social Anxiety Scale (LSAS) total score from baseline to end of study. Secondary endpoints included the Hamilton Anxiety Scale (HAM-A), Hamilton Depression Rating Scale (HDRS17), and the Clinical Global Impression-Improvement (CGI-I). Samples were collected for plasma concentration of AEA, PEA, OEA, and JNJ-42165279. A total of 149 subjects were enrolled with a mean baseline LSAS total score of 102.6 (SD 16.84). The mean change from baseline (SD) in LSAS total score at week 12 was numerically greater for JNJ-42165279: -29.4 (27.47) compared to PBO: -22.4 (23.57) but not significant. The percentage of subjects with ≥30% improvement from baseline in the LSAS total score was significantly higher for JNJ-42165279 (42.4%) compared to PBO (23.6%) (p value = 0.04). The percentage of subjects with a CGI-I score of much or very much improved was also significantly higher for JNJ-42165279 (44.1%) than for PBO (23.6%) (p value = 0.02). The drug was well tolerated. JNJ-42165279 appears to elicit an anxiolytic effect in subjects with SAD although trough concentrations with 25 mg once daily appeared to be insufficient to completely inhibit FAAH activity which may have led to suboptimal efficacy. ClinicalTrials.gov Identifier: NCT02432703.

Pharmacotherapy for social anxiety disorder: Interpersonal predictors of outcome and the mediating role of the working alliance.

Social anxiety disorder (SAD) is highly prevalent and associated with high levels of impairment and distress. Therapies for SAD leave many patients symptomatic at the end of treatment, and little is known about predictors or mechanisms of treatment outcome. Given the interpersonal dysfunction fundamental to SAD, this study investigated whether prominent interpersonal features of SAD (submissive behavior, childhood maltreatment, suppression of anger, and depression) predicted attrition and response to pharmacotherapy and whether the working alliance mediated these relationships. This is the first study to examine the role of the working alliance in pharmacotherapy for SAD. One hundred thirty-eight treatment-seeking individuals with a primary diagnosis of SAD received 12 weeks of open treatment with paroxetine. Higher levels of depression predicted greater severity of SAD at the end of treatment, and higher levels of submissive behavior and childhood emotional maltreatment predicted a greater probability of attrition from treatment. The psychiatrist-assessed working alliance mediated response to pharmacotherapy for individuals who reported a history of emotional maltreatment. These results identify variables that predict pharmacotherapy outcome and emphasize the importance of the working alliance as a mechanism of treatment response for those with a history of emotional maltreatment. Implications for person-specific treatment selection are discussed.

Vortioxetine versus placebo in major depressive disorder comorbid with social anxiety disorder.

BACKGROUND: Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD) are highly comorbid, yet the combined condition has not been subject to any placebo-controlled treatment trials. This study reports a trial of vortioxetine, an antidepressant that has also shown benefit in Generalized Anxiety Disorder (GAD), in patients meeting DSM-5 criteria for both MDD and SAD. METHODS: The study was a 12-week double-blind, placebo-controlled comparison of vortioxetine 10-20 mg/day or placebo administered on a 1:1 ratio. The study was designed to include 40 male or female outpatients aged 18-70 years. The primary endpoint was the "composite" Clinical Global Impression of Improvement (CGI-I) responder rate, factoring in improvement in both MDD and SAD features. Major secondary outcome measures were changes on the Montgomery Asberg Depression Rating Scale (MADRS) and Liebowitz Social Anxiety Scale (LSAS). RESULTS: On the composite CGI-I, 10 of 20 (50%) vortioxetine and six of 20 (30%) placebo-treated patients were rated as responders, a non-significant difference. However, vortioxetine-treated patients did show significantly greater improvement than those on placebo on both the MADRS (effect size 0.672) and LSAS (effect size 0.714). Efficacy in depression was seen before improvement in SAD. Adverse effects were similar to those previously reported. CONCLUSIONS: In this preliminary trial vortioxetine appears safe and effective for patients with MDD comorbid with SAD, with robust effect sizes on dimensional measures of both depression and social anxiety, but failure to separate from placebo on the primary outcome measure of composite responder rate. More studies of patients with comorbid conditions are needed, as this mirrors what is often seen in clinical practice.

The structure of vulnerabilities for social anxiety disorder.

Social anxiety disorder symptoms are generally proposed to be related to broad temperamental vulnerabilities (e.g., a low level of approach and high level of avoidance temperament), specific psychological vulnerabilities (e.g., fears of negative and positive evaluation), and additional disorders (e.g., major depressive disorder). However, existing tests of such a model have either not considered depressive symptoms or relied on samples of undergraduates. We examined these and related questions via a latent variable model in a large dataset (N=2253) that combined participants across a variety of studies. The model had adequate fit in the whole sample, and good fit in a subsample in which more participants completed the depression measure. The model indicated that low level of approach and high level of avoidance temperament contributed to fears of evaluation and social anxiety symptoms, and that fears of evaluation additionally contributed independently to social anxiety symptoms. The relationship between social anxiety and depressive symptoms was entirely accounted for by these vulnerabilities: Depressive symptoms were only predicted by avoidance temperament.

Effect of as-needed use of intranasal PH94B on social and performance anxiety in individuals with social anxiety disorder.

BACKGROUND: There are no medications approved for as-needed use for feared situations for individuals with social anxiety disorder (SAD). In the present study, intranasal PH94B was provided for use as needed during stressful events. METHODS: Twenty-two subjects were randomized (double-blind) to 2 weeks of treatment with intranasal PH94B or placebo. Following self-administration of medication prior to a feared event, peak levels of anxiety were recorded using the Subjective Units of Distress Scale (SUDS). After 2 weeks, subjects were crossed over to the opposite treatment for 2 weeks. Average peak SUDS during treatment with PH94B and placebo were compared using a paired t-test. RESULTS: Significant differences in favor of PH94B were found on the primary outcome measure: mean peak SUDS change from baseline for all subjects receiving PH94B was 15.6 points versus 8.3 points for placebo (paired t = 3.09, P = .006, effect size of .658). PH94B showed less superiority over placebo when placebo was given second rather than first, likely due to a carryover effect. Looking between groups at just the first 2 weeks of treatment, PH94B also showed trend superiority to placebo on the Liebowitz Social Anxiety Scale (LSAS) (P = .07) and a significant difference on the Patient Global Impression of Change (P = .024) and the LSAS Avoidance subtotal (P = .02). CONCLUSIONS: While further study is needed, these results, combined with earlier findings, suggest that PH94B could represent a useful as-needed treatment for SAD, and continue to validate the nasal chemosensory system as a novel mechanism for medication delivery.

Clinical presentation and pharmacotherapy response in social anxiety disorder: The effect of etiological beliefs.

Therapies for social anxiety disorder (SAD) leave many patients symptomatic at the end of treatment and little is known about predictors of treatment response. This study investigated the predictive relationship of patients' etiological attributions to initial clinical features and response to pharmacotherapy. One hundred thirty-seven individuals seeking treatment for SAD received 12 weeks of open treatment with paroxetine. Participants completed the Attributions for the Etiology of Social Anxiety Scale at baseline in addition to measures of social anxiety and depression at baseline and over the course of treatment. A latent class analysis suggested four profiles of etiological beliefs about one's SAD that may be characterized as: Familial Factors, Need to be Liked, Bad Social Experiences, and Diffuse Beliefs. Patients in the more psychosocially-driven classes, Need to be Liked and Bad Social Experiences, had the most severe social anxiety and depression at baseline. Patients in the Familial Factors class, who attributed their SAD to genetic, biological, and early life experiences, had the most rapid response to paroxetine.These results highlight the effect of biological and genetically-oriented etiological beliefs on pharmacological intervention, have implications for person-specific treatment selection, and identify potential points of intervention to augment treatment response.

The Social Interaction Phobia Scale: Continued support for the psychometric validity of the SIPS using clinical and non-clinical samples.

The present study sought to extend findings supporting the psychometric validity of a promising measure of social anxiety (SA) symptoms, the Social Interaction Phobia Scale (SIPS; Carleton et al., 2009). Analyses were conducted using three samples: social anxiety disorder (SAD) patients, generalized anxiety disorder (GAD) patients, and healthy controls. SIPS scores of SAD patients demonstrated internal consistency and construct validity, and the previously demonstrated three-factor structure of the SIPS was replicated. Further, the SIPS total score uniquely predicted SA symptoms, and SIPS scores were significantly higher for SAD patients than GAD patients or controls. Two cut-off scores that discriminated SAD patients from GAD patients and from healthy controls were identified. The current study is the first to replicate the SIPS three-factor model in a large, treatment-seeking sample of SAD patients and establish a cut-off score discriminating SAD from GAD patients. Findings support the SIPS as a valid, SAD-specific assessment instrument.

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.

Perception matters for clinical perfectionism and social anxiety.

Despite research documenting a relationship between social anxiety and perfectionism, very little research has examined the relationship between social anxiety and clinical perfectionism, defined as the combination of high personal standards and high maladaptive perfectionistic evaluative concern. In the current studies we examined whether clinical perfectionism predicted social anxiety in a large sample of undergraduates (N=602), in a clinical sample of participants diagnosed with social anxiety disorder (SAD; N=180), and by using a variance decomposition model of self- and informant-report of perfectionism (N=134). Using self-report, we found that an interaction of personal standards and evaluative concern predicted both social interaction anxiety and fear of scrutiny, but not in the theorized direction. Specifically, we found that self-report of low standards and high evaluative concern was associated with the highest levels of social anxiety, suggesting that when individuals with SAD hold low expectations for themselves combined with high concerns about evaluation, social anxiety symptoms may increase. Alternatively, when an informants' perspective was considered, and more consistent with the original theory, we found that the interaction of informant-only report of personal standards and shared-report (between both primary participant and informant) of concern over mistakes was associated with self-reported social anxiety, such that high concern over mistakes and high personal standards predicted the highest levels of social anxiety. Theoretical, clinical, and measurement implications for clinical perfectionism are discussed.

A 12-Week Double-Blind, Placebo-Controlled, Flexible-Dose Trial of Vilazodone in Generalized Social Anxiety Disorder.

OBJECTIVE: To examine the efficacy, safety, and tolerability of vilazodone for subjects (aged 18-75 years) with generalized social anxiety disorder. METHOD: Forty-four subjects with generalized social anxiety disorder (DSM-IV-TR criteria) were randomized to vilazodone or placebo in a 12-week double-blind, flexible-dose trial. Change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) was the primary outcome measure. Secondary outcome measures included response and remission rates and changes in depression and anxiety. Data were collected between November 2012 and April 2014. The study was conducted at a private clinical trials facility in New York, New York. RESULTS: The mean baseline LSAS score was 91.9 (SD = 17.5) and the mean Clinical Global Impressions-Severity scale score was 5.3 (SD = 0.56), indicating marked to severe illness. There were no significant baseline differences in severity of social anxiety between the treatment groups. At the end of treatment, in the intent-to-treat sample (n = 39), the vilazodone group had improved significantly more than the placebo group by 14.3 points on the LSAS (t = 1.80, P = .04, one-tail test) (Cohen d = 0.58). CONCLUSIONS: The findings suggest that vilazodone may be a promising treatment for social anxiety disorder. Further study is needed given the limited sample size. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01712321.

Effect of an acute intranasal aerosol dose of PH94B on social and performance anxiety in women with social anxiety disorder.

OBJECTIVE: Although social anxiety disorder is a common and sometimes disabling condition, there are no approved treatments that can be used on an as-needed basis. The authors examined the acute use of PH94B, an intranasally administered neurosteroidal aerosol, for the acute management of the symptoms of social anxiety disorder. METHOD: The authors conducted a phase 2, multicenter, randomized, double-blind, placebo-controlled, single-dose study of PH94B. Ninety-one women 19-60 years of age with generalized social anxiety disorder received placebo intranasal spray (single-blind) 15 minutes before laboratory-simulated public speaking and social interaction challenges. Patients who experienced significant distress during at least one challenge returned 1 week later to receive either intranasal PH94B or placebo aerosol spray (double-blind) before repeat challenges. RESULTS: Patients who received PH94B during the second set of challenges had a significantly greater decrease in mean Subjective Units of Distress scores during the public speaking and social interaction challenges compared with the first set of challenges, than did patients who received placebo for both sets of challenges. A significantly greater proportion of the PH94B group were much or very much improved from the first to the second sets of challenges compared with the placebo group (75% and 37%, respectively). The side effects of PH94B were benign. CONCLUSIONS: PH94B may be a novel, effective, and well-tolerated acute treatment for performance and social anxiety in women with social anxiety disorder.

Evaluation of the psychometric properties of two short forms of the social interaction anxiety scale and the social phobia scale.

The Social Interaction Anxiety Scale and Social Phobia Scale are widely used measures of social anxiety. Using data from individuals with social anxiety disorder (n = 435) and nonanxious controls (n = 86), we assessed the psychometric properties of two independently developed short forms of these scales. Indices of convergent and discriminant validity, diagnostic specificity, sensitivity to treatment, and readability were examined. Comparisons of the two sets of short forms to each other and the original long forms were conducted. Both sets of scales demonstrated adequate internal consistency in the patient sample, showed expected patterns of correlation with measures of related and unrelated constructs, adequately discriminated individuals with social anxiety disorder from those without, and showed decreases in scores over the course of cognitive-behavioral therapy and/or pharmacotherapy. However, some significant differences in scale performance were noted. Implications for the clinical assessment of social anxiety are discussed.

Social anxiety disorder in DSM-5.

With the publication of DSM-5, the diagnostic criteria for social anxiety disorder (SAD, also known as social phobia) have undergone several changes, which have important conceptual and clinical implications. In this paper, we first provide a brief history of the diagnosis. We then review a number of these changes, including (1) the primary name of the disorder, (2) the increased emphasis on fear of negative evaluation, (3) the importance of sociocultural context in determining whether an anxious response to a social situation is out of proportion to the actual threat, (4) the diagnosis of SAD in the context of a medical condition, and (5) the way in which we think about variations in the presentation of SAD (the specifier issue). We then consider the clinical implications of changes in DSM-5 related to these issues.

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 double-blind, randomized, placebo-controlled study assessing the efficacy and tolerability of desvenlafaxine 10 and 50 mg/day in adult outpatients with major depressive disorder.

BACKGROUND: In an effort to establish the lowest effective dose of desvenlafaxine (administered as desvenlafaxine succinate), we assessed the efficacy, safety, and tolerability of 10- and 50-mg/day desvenlafaxine vs placebo for the treatment of major depressive disorder. METHODS: Adult outpatients with DSM-IV-defined major depressive disorder and a 17-item Hamilton Rating Scale for Depression (HAM-D(17)) total score ≥20 were randomly assigned to receive placebo or desvenlafaxine (10 or 50 mg/day) after a 6- to 14-day single-blind placebo lead-in period in an 8-week, phase 3, fixed-dose trial. The primary efficacy measure was change from baseline in the HAM-D(17) score analyzed using analysis of covariance. Efficacy analyses were conducted with the intent-to-treat population, using the last observation carried forward. RESULTS: The intent-to-treat population included 673 patients. Change from baseline to final evaluation in adjusted HAM-D(17) total scores was not significantly different comparing desvenlafaxine 10 mg/day (-9.28) and desvenlafaxine 50 mg/day (-8.92) with placebo (-8.42). There were no differences among treatment groups in the rates of treatment response or remission. Discontinuations due to adverse events occurred in 1.8%, 0.9%, and 1.8% of patients in the placebo and desvenlafaxine 10- and 50-mg/day groups, respectively. Overall rates of treatment-emergent adverse events with both doses were similar to placebo. CONCLUSIONS: Both doses of desvenlafaxine failed to separate from placebo. However, in a companion study reported separately, desvenlafaxine 50 mg, but not 25 mg, separated from placebo. Taken together, these studies suggest that 50 mg is the minimum effective dose of desvenlafaxine for the treatment of major depressive disorder. CLINICALTRIALS.GOV IDENTIFIER: NCT00863798 http://clinicaltrials.gov/ct2/show/NCT00863798?term=00863798&rank=1.

The evidence-based pharmacotherapy of social anxiety disorder.

Social anxiety disorder (SAD) is a highly prevalent and often disabling disorder. This paper reviews the pharmacological treatment of SAD based on published placebo-controlled studies and published meta-analyses. It addresses three specific questions: What is the first-line pharmacological treatment of SAD? How long should treatment last? What should be the management of treatment-resistant cases? Based on their efficacy for SAD and common co-morbid disorders, tolerability and safety, selective serotonin reuptake inhibitors (SSRIs) and venlafaxine should be considered the first-line treatment for most patients. Less information is available regarding the optimal length of treatment, although individuals who discontinue treatment after 12-20 wk appear more likely to relapse than those who continue on medication. Even less empirical evidence is available to support strategies for treatment-resistant cases. Clinical experience suggests that SSRI non-responders may benefit from augmentation with benzodiazepines or gabapentin or from switching to monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase A, benzodiazepines or gabapentin. Cognitive-behavioural is a well-established alternative first line therapy that may also be a helpful adjunct in non-responders to pharmacological treatment of SAD.