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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.

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.

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.

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.

Background: More rapidly acting antidepressants are needed for individuals with major depressive disorder (MDD). A new class of neuroactive steroids called pherines have shown rapid and potent effects when administered intranasally. A study of pherine PH10 was conducted in subjects with MDD. Methods: Thirty subjects with MDD were randomized to 8 weeks of self‐administered intranasal PH10 low dose (3.2mg), PH10 high dose (6.4mg), or placebo. Changes on the Hamilton 17‐item depression rating scale (HAM‐D‐17) were compared. Results: Overall comparison of HAM‐D‐17 endpoint scores for the three treatment groups showed a trend for difference (p = 0.07). Pairwise comparisons showed a greater reduction in HAM‐D‐17 scores for high dose PH10 (p = 0.022) and a trend for low dose PH10 (p = 0.101) compared to treatment with placebo. There were strong effect sizes for both active treatment groups versus placebo at study endpoint, as well as after one week of treatment. Treatments were well tolerated and there were no Serious Adverse Events. Conclusions: Results from this small trial must be considered tentative. Findings suggest that PH10 could represent a useful treatment for MDD with a rapid onset of efficacy, and continue to validate the nasal chemosensory neural circuits as a novel mechanism of action of pherines. &nbsp

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.

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.

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.

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.

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.

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.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).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).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.ClinicalTrials.gov identifier: NCT00389493.

The Brief Fear of Negative Evaluation Scale (BFNE; Leary Personality and Social Psychology Bulletin, 9, 371–375, 1983) assesses fear and worry about receiving negative evaluation from others. Rodebaugh et al. Psychological Assessment, 16, 169–181, (2004) found that the BFNE is composed of a reverse-worded factor (BFNE-R) and straightforwardly-worded factor (BFNE-S). Further, they found the BFNE-S to have better psychometric properties and provide more information than the BFNE-R. Currently there is a lack of research regarding the measurement invariance of the BFNE-S across gender and ethnicity with respect to item thresholds. The present study uses item response theory (IRT) to test the BFNE-S for differential item functioning (DIF) related to gender and ethnicity (White, Asian, and Black). Six data sets consisting of clinical, community, and undergraduate participants were utilized (N=2,109). The factor structure of the BFNE-S was confirmed using categorical confirmatory factor analysis, IRT model assumptions were tested, and the BFNE-S was evaluated for DIF. Item nine demonstrated significant non-uniform DIF between White and Black participants. No other items showed significant uniform or non-uniform DIF across gender or ethnicity. Results suggest the BFNE-S can be used reliably with men and women and Asian and White participants. More research is needed to understand the implications of using the BFNE-S with Black participants.

Obsessive-compulsive disorder (OCD) is a severe condition with varied symptom presentations. The behavioral treatment with the most empirical support is exposure and ritual prevention (EX/RP). This study examined the impact of symptom dimensions on EX/RP outcomes in OCD patients.The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was used to determine primary symptoms for each participant. An exploratory factor analysis (EFA) of 238 patients identified five dimensions: contamination/cleaning, doubts about harm/checking, hoarding, symmetry/ordering, and unacceptable/taboo thoughts (including religious/moral and somatic obsessions among others). A linear regression was conducted on those who had received EX/RP (n=87) to examine whether scores on the five symptom dimensions predicted post-treatment Y-BOCS scores, accounting for pre-treatment Y-BOCS scores.The average reduction in Y-BOCS score was 43.0%, however the regression indicated that unacceptable/taboo thoughts (β=.27, p=.02) and hoarding dimensions (β=.23, p=.04) were associated with significantly poorer EX/RP treatment outcomes. Specifically, patients endorsing religious/moral obsessions, somatic concerns, and hoarding obsessions showed significantly smaller reductions in Y-BOCS severity scores.EX/RP was effective for all symptom dimensions, however it was less effective for unacceptable/taboo thoughts and hoarding than for other dimensions. Clinical implications and directions for research are discussed.

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.

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).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.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.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.

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.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.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).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.

Primary hyperhidrosis is characterized by excessive sweating and often accompanied by social avoidance. Social anxiety disorder (SAD) is characterized by fear and avoidance of social situations, often partly related to fears of showing signs of excessive autonomic nervous system activation, such as sweating. To clarify the relationship of hyperhidrosis and SAD, this study assessed severity of sweating, overall social anxiety and social anxiety due to sweating, and disability in 2 groups: patients seeking surgical treatment for hyperhidrosis (n = 40) and patients seeking treatment for SAD (n = 64). Hyperhidrosis and SAD patients overlapped in severity of overall social anxiety and social anxiety related to sweating. Hyperhidrosis patients reported elevated levels of social anxiety, with mean severity near the threshold for the generalized subtype of SAD, but significantly lower social anxiety than in the SAD patients. Significantly more hyperhidrosis patients than SAD patients attributed most of their social anxiety to sweating (76% vs 20%). Among hyperhidrosis patients, the pattern of correlations of sweating, social anxiety, and disability was consistent with a model of social anxiety as a mediator of sweating-related disability. The overlap of symptoms in patients presenting for treatment of SAD or hyperhidrosis suggests that both social anxiety and sweating should be assessed in these patients and considered as potential targets of treatment.

Despite elevated rates of obsessive compulsive personality disorder (OCPD) in patients with obsessive compulsive disorder (OCD), no study has specifically examined comorbid OCPD as a predictor of exposure and ritual prevention (EX/RP) outcome. Participants were adult outpatients (n = 49) with primary OCD and a Yale-Brown Obsessive Compulsive Scale (YBOCS) total score ≥ 16 despite a therapeutic serotonin reuptake inhibitor dose for at least 12 weeks prior to entry. Participants received 17 sessions of EX/RP over 8 weeks. OCD severity was assessed with the YBOCS pre- and post-treatment by independent evaluators. At baseline, 34.7% of the OCD sample met criteria for comorbid DSM-IV OCPD, assessed by structured interview. OCPD was tested as a predictor of outcome both as a diagnostic category and as a dimensional score (severity) based on the total number of OCPD symptoms coded as present and clinically significant at baseline. Both OCPD diagnosis and greater OCPD severity predicted worse EX/RP outcome, controlling for baseline OCD severity, Axis I and II comorbidity, prior treatment, quality of life, and gender. When the individual OCPD criteria were tested separately, only perfectionism predicted worse treatment outcome, over and above the previously mentioned covariates. These findings highlight the importance of assessing OCPD and suggest a need to directly address OCPD-related traits, especially perfectionism, in the context of EX/RP to minimize their interference in outcome.

The validity of both the Social Interaction Anxiety Scale and Brief Fear of Negative Evaluation scale has been well-supported, yet the scales have a small number of reverse-scored items that may detract from the validity of their total scores. The current study investigates two characteristics of participants that may be associated with compromised validity of these items: higher age and lower levels of education. In community and clinical samples, the validity of each scale's reverse-scored items was moderated by age, years of education, or both. The straightforward items did not show this pattern. To encourage the use of the straightforward items of these scales, we provide normative data from the same samples as well as two large student samples. We contend that although response bias can be a substantial problem, the reverse-scored questions of these scales do not solve that problem and instead decrease overall validity.

Background Excessive fear of scrutiny is a defining feature of social anxiety disorder. Eye contact may trigger feelings of being scrutinized, and although eye contact is commonly feared in persons with social anxiety disorder, it has been studied little. The purpose of this study was to characterize fear and avoidance of eye contact in patients with social anxiety disorder and in nonpatient samples. Methods Gaze fears and avoidance, social anxiety, and depression were assessed in 44 patients with generalized social anxiety disorder, 17 matched healthy comparison subjects, and 79 undergraduates. Patients were reassessed after 8 to 12 weeks of treatment with paroxetine. A new self-report instrument, the Gaze Anxiety Rating Scale (GARS), was used to assess fear and avoidance of eye contact, and its psychometric properties were analyzed. Results Patients with generalized social anxiety disorder, in comparison with healthy control participants, reported significantly increased levels of fear and avoidance of eye contact, which decreased significantly after 8 to 12 weeks of treatment with paroxetine. Fear and avoidance of eye contact were significantly associated with severity of social anxiety in all 3 samples. The GARS demonstrated excellent internal consistency within each sample. Conclusions Self-reported fear and avoidance of eye contact are associated with social anxiety in both nonpatient and social anxiety disorder samples. Preliminary psychometric analyses suggest that the GARS has utility in the assessment of gaze anxiety.

This multicenter, double-blind, placebo-controlled, 2-arm, parallel-group study was carried out to determine the effectiveness and safety of the novel anticonvulsant levetiracetam for the treatment of generalized social anxiety disorder (GSAD).After a 1-week, single-blind, placebo run-in period, 217 adult outpatients meeting DSM-IV criteria for social anxiety disorder, generalized type, were randomly assigned (1:1) to 12 weeks of double-blind treatment with either levetiracetam (n = 111) or placebo (n = 106). Participants were required to have scores ofor= 60 on the Liebowitz Social Anxiety Scale (LSAS) and a total score ofor= 17 on the 17-item Hamilton Depression Rating Scale (HDRS). The primary outcome measure was mean change from baseline on LSAS total score. Levetiracetam was initiated at 250 mg/d and flexibly titrated up to a maximum dose of 3,000 mg/d (1,500 mg bid). Dosage was held stable for the last 6 weeks of treatment. The study was conducted from September 2003 to June 2004.No statistically significant difference was found between the adjusted mean changes in LSAS score for levetiracetam (-24.4) and placebo (-28.7) using an efficacy intent-to-treat, last- observation-carried-forward analysis. Rates of response (or= 30% reduction in LSAS score) were similar with 41.3% (levetiracetam) and 46.6% (placebo). No significant between-group differences were found on secondary outcome measures, which included changes in Sheehan Disability Scale, Clinical Global Impression of Change, and HDRS scores.Although well-tolerated, levetiracetam failed to separate from placebo in this trial for the treatment of moderate to severe GSAD.

Objective: This study examined whether the self-report version of the Liebowitz Social Anxiety Scale (LSAS-SR) could accurately identify individuals with social anxiety disorder and individuals with the generalized subtype of social anxiety disorder. Furthermore, the study sought to determine the optimal cutoffs for the LSAS-SR for identifying patients with social anxiety disorder and its generalized subtype. Methods: Two hundred and ninety-one patients with clinician-assessed social anxiety disorder (240 with generalized social anxiety disorder) and 53 control participants who were free from current Axis-1 disorders completed the LSAS-SR. Results: Receiver Operating Characteristic analyses revealed that the LSAS-SR performed well in identifying participants with social anxiety disorder and generalized social anxiety disorder. Consistent with Mennin et al.’s [2002: J Anxiety Disord 16:661–673] research on the clinician-administered version of the LSAS, cutoffs of 30 and 60 on the LSAS-SR provided the best balance of sensitivity and specificity for classifying participants with social anxiety and generalized social anxiety disorder, respectively. Conclusions: The LSAS-SR may be an accurate and cost-effective way to identify and subtype patients with social anxiety disorder, which could help increase the percentage of people who receive appropriate treatment for this debilitating disorder. Depression and Anxiety 26:34–38, 2009. & 2008 Wiley-Liss, Inc.

Objective: Although emerging data indicate that sample composition may influence the effectiveness of mental health interventions, the extent to which subjects in clinical trials represent affected community samples remains unknown. The goal of this study was to assess the proportion of community-dwelling adults with major depressive episode (MDE) who would meet eligibility criteria for a traditional efficacy trial in patients with MDE. Method: We applied a standard set of exclusion criteria used in clinical trials in patients with MDE to the 2001-2002 National Epidemiologic Survey for Alcohol and Related Conditions (NESARC), the largest psychiatric epidemiologic study in the United States to date (N = 43,093). Because individuals who seek treatment for a disorder may systematically differ from those who do not, we applied the criteria first to all individuals with a current diagnosis of MDE (N = 3119) (diagnosed according to DSM-IV) and then to the subsample of individuals who sought treatment (N = 1359). Results: Among the full sample of individuals with MDE, 75.8% were excluded by one or more study eligibility criteria. Approximately two thirds (66.9%) of the subsample of those who sought treatment were excluded. The percentage of subjects excluded by individual study criteria ranged from 2.4% to 47.4% in the overall sample and 0% to 38.4% in the treatment-seeking sample. For both groups, the presence of comorbid, nondepressive, non-substance use Axis I disorders and the duration of the depressive episode excluded the largest percentage of individuals. Conclusion: The design of traditional clinical trials tends to exclude a majority of individuals with MDE. Selection of exclusion criteria may have a powerful influence on the generalizability of study results. Clinical trials should explain the rationale for their exclusion criteria and estimate the impact of eligibility criteria on the generalizability of trial results.

Seventy patients seeking treatment for social anxiety disorder (SAD) were randomly assigned to 14 weekly individual sessions of interpersonal therapy (IPT) or supportive therapy (ST). We hypothesized that IPT, a psychotherapy with established efficacy for depression and other psychiatric disorders, would lead to greater improvement than ST. Patients in both groups experienced significant improvement from pretreatment to posttreatment. However, improvement with IPT was not superior to improvement with ST. Mean scores on the Liebowitz Social Anxiety Scale decreased from 67.7 to 46.9 in the IPT group and 64.5 to 49.8 in the ST group. There were also no differences in proportion of responders between IPT and ST. Only for a scale measuring concern about negative evaluation (Brief Fear of Negative Evaluation Scale) was IPT superior. Limitations of this initial controlled trial of IPT include a nonsequential recruitment strategy and overlap in the administration of the two therapies. It is recommended that future studies of IPT for SAD include a more carefully defined control therapy condition, different therapists administering each therapy, a larger sample, and a more rigorous strategy for long-term follow-up assessments.

Dopamine D(2) receptor availability in the striatum has been reported to be low in generalized social anxiety disorder (GSAD) and obsessive-compulsive disorder (OCD), but it has not been studied in persons with comorbid OCD and GSAD (OCD+GSAD). D(2) receptor availability was assessed in 7 subjects with OCD+GSAD, 8 with OCD, and 7 matched healthy comparison (HC) subjects, all unmedicated adults. D(2) receptor availability was assessed with single-photon emission computerized tomography (SPECT) to measure binding potential (BP) of the D(2) receptor radiotracer [(123)I] iodobenzamide ([(123)I]IBZM). Mean striatal [(123)I]IBZM BP was significantly lower in the OCD+GSAD group (72.58 mL/g, SD=18.17) than in the HC group (118.41 mL/g, SD=45.40; P=.025). Mean BP in the OCD group (93.08 mL/g, SD=36.90) did not differ significantly from the HC group (P=.247). Trait detachment, as measured by the Detachment subscale of the Karolinska Scales of Personality, was negatively correlated with D(2) availability across all subjects (r(s)= -.55, P=.013). Comorbid GSAD and OCD may be associated with decreased availability of D(2) receptors in the striatum, consistent with prior findings in GSAD. Prior findings of decreased D(2) receptor availability in noncomorbid OCD were not confirmed. Decreased D(2) receptor availability was also associated with trait detachment, supporting prior findings in samples of healthy subjects.

In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo- or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

Taijin-Kyofu-Sho (TKS), an East Asian syndrome of interpersonal fear and avoidance, that has been considered culture-bound, overlaps with social anxiety disorder to an unknown extent. The offensive subtype of TKS is characterized by two features considered atypical of social anxiety disorder: the belief that one displays physical defects and/or socially inappropriate behaviors (offensive TKS symptoms) and fear of offending others (allocentric focus), but no studies have systematically evaluated these two features in patients with social anxiety disorder. The purpose of this study was to assess offensive TKS symptoms and allocentric focus of fear in US (n = 181) and Korean (n = 64) patients with DSM-IV social anxiety disorder, using the newly developed TKS Questionnaire. Seventy-five percent of patients with social anxiety disorder in the US and Korea endorsed at least one of the five offensive TKS symptoms surveyed. The severity of features of offensive TKS was significantly associated with severity of social anxiety symptoms, depressive symptoms, and disability in both samples. These results suggest that features of the offensive subtype of TKS are not uncommon among US patients with social anxiety disorder and may not be as culturally specific as previously believed. They also suggest that Western clinicians should assess patients with social anxiety for features of offensive TKS, and they support further consideration of integrating TKS features into conceptualizations of social anxiety disorder.

This study evaluated the efficacy and tolerability of desvenlafaxine succinate (desvenlafaxine) in the treatment of major depressive disorder (MDD).In this 8-week, multicenter, randomized, double-blind, placebo-controlled trial, adult outpatients (aged 18-75 years) with a primary diagnosis of MDD (DSM-IV criteria) were randomly assigned to treatment with desvenlafaxine (100-200 mg/day) or placebo. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) score at final on-therapy evaluation. The Clinical Global Impressions-Improvement scale (CGI-I) was the key secondary measure. Other secondary measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity of Illness scale, Visual Analog Scale-Pain Intensity (VAS-PI) overall and subcomponent scores, and HAM-D(17) response and remission rates. The study was conducted from June 2003 to May 2004.Of the 247 patients randomly assigned to treatment, 234 comprised the intent-to-treat population. Following titration, mean daily desvenlafaxine doses ranged from 179 to 195 mg/day. At endpoint, there were no significant differences in scores between the desvenlafaxine (N = 120) and placebo (N = 114) groups on the HAM-D(17) or CGI-I. However, the desvenlafaxine group had significantly greater improvement in MADRS scores (p = .047) and in VAS-PI overall pain (p = .008), back pain (p = .006), and arm, leg, or joint pain (p.001) scores than the placebo group. The most common treatment-emergent adverse events (at least 10% and twice the rate of placebo) were nausea, dry mouth, constipation, anorexia, somnolence, and nervousness.Desvenlafaxine was generally safe and well tolerated. In this study, it did not show significantly greater efficacy than placebo on the primary or key secondary efficacy endpoints, but it did demonstrate efficacy on an alternate depression scale and pain measure associated with MDD.ClinicalTrials.gov identifier NCT00063206.

Objective: To compare trends in office-based treatment of mental disorders between Hispanics and non-Hispanics. Design, Setting, and Participants: Analysis of a nationally representative sample of visits to office-based physicians conducted between 1993 and 2002 (N = 251,905). Visits were grouped into 3 discrete time periods, 1993-1996, 1997-1999 and 2000-2002. Main Outcome Measures: Rate of diagnosis, type of mental health visit, type of treatment received (medication or psychotherapy), rate of psychotropic medications prescription, and specialty of the treating physician. Results: From 1993-1996 to 2000-2002, the proportion of office visits in which mental health care was provided decreased for Hispanics from 12.2% to 11.7% while it increased from 13.1% to 15.7% for non-Hispanics (P < 0.05). Visits with a diagnosis of mental disorder decreased from 5.2% to 5.1% in Hispanics but increased from 6.0% to 8.8% in non-Hispanics (P < 0.05). Visits resulting in prescription of a psychotropic medication decreased from 10.2% to 9.3% in Hispanics, while they increased from 10.2% to 12.5% in non-Hispanics (P < 0.05). Psychotherapy visits decreased from 2.4% to 1.3% in Hispanics (P < 0.05), whereas they remained constant (2.5%) in non-Hispanics. Visits to a psychiatrist decreased from 2.5% to 1.3% in Hispanics (P < 0.05), while they increased (nonsignificantly) from 3.1% to 3.5% for non-Hispanics. Most differences persisted after adjusting for age and insurance status. Conclusions: From 1993 to 2002, there was an increase in mental health care disparities between Hispanics and non-Hispanics treated by office-based physicians. Improvement of the mental health care for Hispanics continues to be an important public health priority, with clear opportunities and challenges for health care policy-makers and practitioners.

This study examined the efficacy and tolerability of duloxetine 60-120 mg/day for the treatment of patients with generalized anxiety disorder. This was a multicenter, randomized, double-blind, flexible-dose, placebo and active-controlled (venlafaxine extended-release 75-225 mg/day) trial designed to assess duloxetine 60-120 mg/day during 10 weeks of treatment in adults with Diagnostic and statistical manual of mental disorders-IV-defined generalized anxiety disorder. The primary efficacy outcome measure was mean change from baseline to endpoint in the Hamilton Anxiety Rating Scale total score assessed using analysis of covariance. A total of 487 patients were randomly assigned to duloxetine (n=162), venlafaxine XR (n=164), or placebo (n=161). Significantly greater improvement on the Hamilton Anxiety Rating Scale total score occurred in the duloxetine (P=0.007) and venlafaxine XR (P

This study evaluated the efficacy of paroxetine for symptoms and associated features of chronic posttraumatic stress disorder (PTSD), interpersonal problems, and dissociative symptoms in an urban population of mostly minority adults. Adult outpatients with a primary DSM-IV diagnosis of chronic PTSD received 1 week of single-blind placebo (N = 70). Those not rated as significantly improved were then randomly assigned to placebo (N = 27) or paroxetine (N = 25) for 10 weeks, with a flexible dosage design (maximum 60 mg by week 7). Significantly more patients treated with paroxetine were rated as responders (14/21, 66.7%) on the Clinical Global Impression-Improvement Scale (CGI-I) compared to patients treated with placebo (6/22, 27.3%). Mixed effects models showed greater reductions on the Clinician-Administered PTSD Scale (CAPS) total score (primary plus associated features of PTSD) in the paroxetine versus placebo groups. Paroxetine was also superior to placebo on reduction of dissociative symptoms [Dissociative Experiences Scale (DES) score] and reduction in self-reported interpersonal problems [Inventory of Interpersonal Problems (IIP) score]. In a 12-week maintenance phase, paroxetine response continued to improve, but placebo response did not. Paroxetine was well tolerated and superior to placebo in ameliorating the symptoms of chronic PTSD, associated features of PTSD, dissociative symptoms, and interpersonal problems in the first trial conducted primarily in minority adults.

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.

Objective: The purpose of the study was to asses the efficacy of desvenlafaxine in patients with the generalized form of Social Anxiety Disorder (GSAD). Methods: 63 patients with GSAD were randomized to desvenlafaxine or placebo in a 12 week double blind trial. Change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) was the primary outcome measure. Secondary outcome measures included response, defined as much improved or very much improved on the Clinical Global Impression of Change (CGI-I) and remission rates (defined as the proportion of patients with an endpoint LSAS total score of 30 or less. Changes in depression and anxiety, measured by the Hamilton Depression (Ham-D 17) and Anxiety Scales (Ham-A), were also assessed. Outcome analyses were performed in the intent to treat (ITT) and completer samples. Results: The mean baseline LSAS was 92.8 and mean Clinical Global Impression of Severity (CGI-S) was 5.4, indicating severe illness, with no baseline differences between treatment groups. At the end of treatment, in the ITT sample (N=58), the drug group had improved more than the placebo group by 9.7 points on the LSAS, a trend difference (p=0.085, 1 tailed). Cohen’s d was 0.36, indicative of a moderate effect size. There were also trend differences in response (69% versus 48.3%, p=0.09, 1 tailed) and remission rates (20.7% versus 3.4%, p=0.051, t tailed), and significant differences on the Hamilton Depression scale (2.5 versus 0.3, p=0.02, 1 tailed) in favor of desvenlafaxine. Findings in the completer sample were similar to those in the ITT sample. Conclusions: These findings must be considered preliminary because the limited sample size reduced statistical power and renders interpretation of the findings less precise.. Nevertheless these initial results suggest that desvenlafaxine has efficacy for social anxiety disorder similar to that seen with more extensively studied medications that have received FDA approval for this condition. Therefore, pending further study, desvenlafaxine may prove to be a useful treatment for Social Anxiety Disorder.

The aim of this study was to confirm in a large clinical sample that subjects with obsessive–compulsive disorder (OCD) have deficits on certain tasks of executive functioning, non-verbal memory, and/or motor speed. Our ultimate goal was to evaluate whether these deficits contribute to functional impairment and could be the target of a novel treatment intervention. Therefore, in a sample of convenience, the clinical characteristics and neuropsychological performance of adults with OCD and matched healthy controls were evaluated; neuropsychological tasks of executive functioning, non-verbal memory, and motor speed that have shown strong effects in prior studies were used. Primary analyses compared subjects with current OCD only (current-OCD, n = 30), subjects with current OCD plus a comorbid disorder (comorbid-OCD, n = 15), subjects with a history of OCD ( n = 15), and matched healthy controls ( n = 35). Secondary analyses examined whether clinical characteristics (e.g., OCD severity or medication status) were associated with neuropsychological performance. We found no significant overall differences in neuropsychological performance among the four groups. In pairwise comparisons, current-OCD subjects differed significantly from healthy controls only on the Benton Visual Retention Test. OCD severity had little effect and medication status had no effect on neuropsychological performance. In sum, contrary to our expectations, we found few differences in neuropsychological performance between OCD subjects and healthy controls. Whether there are reliable neuropsychological deficits in OCD that can be easily identified in a clinical sample and that contribute to functional impairment remains unclear and requires further study.

The Brief Fear of Negative Evaluation Scale (BFNE; M. R. Leary, 1983a) is often used to assess fear of negative evaluation, the core feature of social anxiety disorder. However, few studies have examined its psychometric properties in large samples of socially anxious patients. Although the BFNE yields a single total score, confirmatory factor analysis indicated a 2-factor solution to be more appropriate, with the 1st factor consisting of all straightforwardly worded items (BFNE-S) and the 2nd of all reverse-scored items (BFNE-R). Support was obtained for the convergent and discriminant validity of the BFNE and BFNE-S, but not the BFNE-R. These results suggest that standard scoring of the BFNE may not be optimal for patients with social anxiety disorder.

The purpose of the study was to test the relative and combined efficacy of clomipramine and exposure and ritual prevention in the treatment of obsessive-compulsive disorder (OCD) in adults. Serotonin reuptake inhibitors (SRIs) and cognitive behavior therapy by exposure and ritual prevention are both established treatments for OCD, yet their relative and combined efficacy have not been demonstrated conclusively.A double-blind, randomized, placebo-controlled trial comparing exposure and ritual prevention, clomipramine, their combination (exposure and ritual prevention plus clomipramine), and pill placebo was conducted at one center expert in pharmacotherapy, another with expertise in exposure and ritual prevention, and a third with expertise in both modalities. Participants were adult outpatients (N=122 entrants) with OCD. Interventions included intensive exposure and ritual prevention for 4 weeks, followed by eight weekly maintenance sessions, and/or clomipramine administered for 12 weeks, with a maximum dose of 250 mg/day. The main outcome measures were the Yale-Brown Obsessive Compulsive Scale total score and response rates determined by the Clinical Global Impression improvement scale.At week 12, the effects of all active treatments were superior to placebo. The effect of exposure and ritual prevention did not differ from that of exposure and ritual prevention plus clomipramine, and both were superior to clomipramine only. Treated and completer response rates were, respectively, 62% and 86% for exposure and ritual prevention, 42% and 48% for clomipramine, 70% and 79% for exposure and ritual prevention plus clomipramine, and 8% and 10% for placebo.Clomipramine, exposure and ritual prevention, and their combination are all efficacious treatments for OCD. Intensive exposure and ritual prevention may be superior to clomipramine and, by implication, to monotherapy with the other SRIs.

Social phobia is characterized by a fear of negative evaluation in social or performance situations and a strong tendency for sufferers to avoid feared social interactions or situations (see also pages 51-5). Over the last few years, several studies have documented the high prevalence and clinical significance of social phobia. At same time, a substantial body of literature has developed that shows that social phobia is quite responsive to psychopharmacological treatment yet approaches in this area are still under-utilized. This contribution reviews medications currently used in the treatment of social phobia (with a particular focus on those studied in placebo-controlled trials) (see Figure 1), and gives guidelines for future directions in research.

Background Serotonergic abnormalities have been hypothesized to contribute to obsessive–compulsive disorder (OCD). This study examined whether brain serotonin transporter (SERT) availability is altered in OCD using positron emission tomography (PET) and the SERT PET radiotracer [ 11 C]McN 5652. Methods Eleven OCD subjects, free of psychiatric medications and comorbid depression, and 11 matched healthy control subjects underwent PET scans following injection of [ 11 C]McN 5652 and magnetic resonance imaging (MRI) scans. Total distribution volumes (V T ) were derived by kinetic analysis (one tissue compartment model) using the arterial input function. Two measures of SERT availability were computed: binding potential (BP) and specific to nonspecific partition coefficient (V 3 ″). Groups were compared using region of interest (ROI) analysis and voxelwise analysis of spatially normalized parametric maps; ROIs were selected based on their relatively high SERT density and included subcortical (dorsal caudate, dorsal putamen, ventral striatum, midbrain, thalamus) and limbic (hippocampus, amygdala, anterior cingulate cortex) regions. Results No significant group differences were observed in [ 11 C]McN 5652 BP or V 3 ″ in the ROIs. No significant group differences were detected in the voxelwise analysis of BP or V 3 ″ maps. Conclusions OCD without comorbid depression, may not be associated with major changes in SERT availability in subcortical and limbic regions.

Placebo-controlled trials have evaluated the efficacy of several medications in the treatment of social anxiety disorder but information regarding their relative efficacy is lacking. We compared the efficacy of medications systematically studied for the treatment of social anxiety disorder using meta-analytic techniques. The methodology included a database search of articles published between January 1980 and June 2001 and manual searches of bibliographies in published manuscripts. Trials were included if they reported outcome data on the Liebowitz Social Anxiety Scale (LSAS) or a categorical measure of responder status. Data were extracted independently by two authors. The Q statistic was used to assess homogeneity across trials. All analyses were conducted using intent-to-treat data. There was substantial heterogeneity across trials. The medications with largest effect sizes were phenelzine [effect size, 1.02; 95% Confidence Interval (CI), 0.52–1.52], clonazepam (effect size, .97; 95% CI, 0.49–1.45), gabapentin (effect size, .78; 95% CI, 0.29–1.27), brofaromine (effect size, .66; 95% CI, 0.38–0.94), and the selective serotonin reuptake inhibitors (SSRIs; effect size, .65; 95% CI, 0.50–0.81). There were no statistically significant differences between medications or medication groups. However, formal methods of interim monitoring adapted for meta-analyses suggested strongest evidence of efficacy for SSRIs and brofaromine. Several medications are efficacious for the treatment of social anxiety disorder. The stability of the SSRI effect size estimate in conjunction with other evidence for safety and tolerability and their ability to treat comorbid conditions supports the use of SSRIs as the first-line treatment. Direct comparisons of SSRIs vs. other promising medications deserve consideration. Depression and Anxiety 18:29–40, 2003. © 2003 Wiley-Liss, Inc.

To date, all clinical trials using a single therapeutic modality (psychotherapy or pharmacotherapy) have found that even the best validated treatments for adults with chronic Posttraumatic Stress Disorder (PTSD) leave a substantial proportion of patients with disabling residual symptoms.We reviewed the treatment course of three research patients with PTSD who received trauma-focused psychotherapy after experiencing a partial response to medication. Structured diagnostic interviews, validated symptom measures, and standardized treatment approaches were used to assess treatment response.All patients partially benefited from medication treatment, and the degree of benefit varied substantially. Also, all patients experienced an additional reduction in PTSD symptoms after a time-limited course of prolonged exposure therapy (PE). This finding differs from anecdotal observations among U.S. War veterans and has never been documented systematically among civilian adults with chronic PTSD.Maximizing treatment outcome in adults with chronic PTSD may require additional psychotherapy after a partial medication response, and further study is warranted.

The present study examined social anxiety, anger, and depression among 234 persons with social anxiety disorder and 36 nonanxious controls. In addition to greater social anxiety, persons with social anxiety disorder exhibited more severe depression, greater anger, and poorer anger expression skills than did nonanxious control participants. Analyses investigating attrition and response to cognitive-behavioral group treatment (CBGT) among a subset of 68 persons treated for social anxiety disorder indicated that patients who experienced anger frequently, perceived unfair treatment, and were quick-tempered were less likely to complete a 12-session course of CBGT. Among treatment completers, significant reductions in the frequent experience of anger to perceived negative evaluation and in anger suppression were noted. However, those who suppressed anger responded less favorably to CBGT. Future directions and clinical implications are discussed.

Social anxiety disorder is well suited to the spectrum concept because it has trait-like qualities of early onset, chronicity, and no empirically derived threshold that demarcates normal from clinically significant trait social anxiety. Social anxiety disorder has been shown to respond to relatively specific pharmacologic and cognitive-behavioral therapies, which makes identification of other conditions that may lie on the social anxiety disorder spectrum important because of possible treatment implications. Biologic markers associated with social anxiety disorder also may be shared by similar but nonidentical traits, such as behavioral inhibition and detachment. Clarification of the trait spectrums associated with specific biologic systems offers an opportunity for improving the understanding of the origin of these conditions. Strong evidence exists that at least some forms of shyness, avoidant personality disorder, and selective mutism lie on a social anxiety disorder spectrum. For several other disorders that share a prominent focus on social comparison, significant subgroups of patients seem to have features of social anxiety disorder. These disorders include major depression (especially the atypical subtype), body dysmorphic disorder, and eating disorders. Several other disorders marked by social dysfunction or inhibition, including substance use disorders (especially alcoholism), paranoid disorder, bipolar disorder, autism, and Asperger's disorder, also may show some overlap with social anxiety disorder features (e.g., social anxiety as a cause or complication of substance abuse, social avoidance in paranoid disorder, social disinhibiton in bipolar disorder, and social communication deficits in autism and Asperger's disorder). Social anxiety disorder also is associated with other anxiety disorders in general and other phobias in particular. In respect to traits, a growing body of evidence links behavioral inhibition to the unfamiliar to a social anxiety disorder spectrum with some specificity. Biologic measures of dopamine system hypoactivity have been linked to social anxiety disorder, trait detachment, and general deficits in reward and incentive function. It remains to be clarified, however, whether this brain system function is best characterized by a social anxiety disorder spectrum or some variant that incorporates social reward deficits or social avoidance behavior. Social anxiety disorder, shyness, and behavioral inhibition all seem to have a genetic component, but more research is needed to attempt to identify a more specifically heritable temperament associated with these conditions. Finally, the emergent concept of a social anxiety spectrum needs maturation. Although the notion of a single social anxiety disorder spectrum currently has some clinical use, the authors believe that exclusive focus on the notion of a single continuum with two extremes--from social disinhibition in mania to the most severe form of social anxiety, avoidant personality disorder--is premature and limiting in respect to etiologic research. An alternative approach is to conceptualize multiple, probably overlapping spectra in this area of social psychopathology. Individual dimensions might be based on various core phenomenologic, cognitive, or biologic characteristics. A bottom-up biologic approach holds promise for identifying spectra with a common etiology that might respond to specific treatments. Taking a pluralistic view of the concept of spectrum at this stage may help accelerate our understanding of social anxiety and related disorders.

To examine the safety and efficacy of fluoxetine in child and adolescent obsessive-compulsive disorder (OCD).Between 1991 and 1998, 43 patients were randomly assigned to fluoxetine or placebo for 8 weeks. Dosing was fixed for the first 6 weeks (up to 60 mg/day) and then could be increased to 80 mg/day. Responders entered an 8-week maintenance phase. The primary outcome measures were the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinical Global Impression-Improvement (CGI-I) scale. Analyses were done on the intent-to-treat sample.Fluoxetine patients (n = 21) had significantly lower CY-BOCS scores than placebo patients (n = 22) after 16 (but not 8) weeks. Fluoxetine responders (n = 11) had significantly lower CY-BOCS scores than placebo responders (n = 7) after an additional 8 weeks of treatment. After 16 weeks, 57% of fluoxetine (versus 27% of placebo) patients were much or very much improved on the CGI-I scale (p.05). No patient terminated the study because of adverse medication effects.Fluoxetine was well tolerated and effective for the treatment of child and adolescent OCD, but fluoxetine's full effect took more than 8 weeks to develop.

The Interpersonal Sensitivity Measure (IPSM) was developed to assess hypersensitivity to interpersonal rejection, a suggested trait of depression-prone personality (Aust NZ J Psychiatry 23 (1989) 341). Although studies of the IPSM and interpersonal rejection sensitivity have primarily been conducted in depressed populations, it is important to investigate interpersonal rejection sensitivity as a relevant construct in the assessment of social anxiety. This study examined the psychometric properties of the IPSM in treatment-seeking individuals with social anxiety disorder. The results of this investigation support the convergent and divergent validity and internal consistency of the IPSM in socially anxious individuals. An exploratory factor analysis of the scale was also conducted after the original factor and subscale structure was shown to be a poor fit for the present data. Three factors emerged (Interpersonal Worry and Dependency, Low Self-Esteem, and Unassertive Interpersonal Behavior), and 29 items were retained. Because they demonstrated negative factor loadings on Factor 2, it is suggested that the scoring for four items of the original IPSM be reversed. In summary, the revised IPSM assesses three aspects of interpersonal rejection sensitivity and appears to be a valid and reliable instrument for its assessment in social anxiety disorder.

This article examines a clinical sample of 66 Dominican and Puerto Rican subjects who reported ataques de nervios and also psychiatric disorder, and disentangles the phenomenological experiences of ataque de nervios, panic attacks, and panic disorder. In-depth cultural interviews assessed the symptomatic phenomenology of ataque episodes from the local perspective as well as in terms of key panic features, such as recurrence, rapid peaking of symptoms, and lack of provocation. Independent diagnostic assessments of panic attacks and disorder were also used to establish the phenomenological overlap between ataque and panic. Our findings indicate that 36 percent of ataques de nervios fulfill criteria for panic attacks and between 17 percent and 33 percent for panic disorder, depending on the overlap method used. The main features distinguishing ataques that fulfill panic criteria from ataques that do not include whether the episodes were provoked by an upsetting event in the person's life and the rapidity of crescendo of the actual attack. A key finding is that ataques often share individual phenomenological features with panic episodes, but that these features usually do not "run together" during the ataque experience. This confirms previous findings that ataque is a more inclusive construct than panic disorder. The importance of these findings for the clinical diagnosis and treatment of persons with ataques is discussed.

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.

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.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.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.PH94B may be a novel, effective, and well-tolerated acute treatment for performance and social anxiety in women with social anxiety disorder.