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.

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.

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.

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.

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.

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.

Childhood maltreatment and social anxiety disorder: implications for symptom severity and response to pharmacotherapy.

BACKGROUND: Childhood maltreatment has been associated with symptom severity, reduced quality of life, and impaired functioning in adults with social anxiety disorder (SAD). No study has investigated how childhood maltreatment impacts pharmacotherapy outcomes in this population, despite evidence for such a link in depression. The current study replicates previous work on childhood maltreatment within SAD and examines its impact on response to pharmacotherapy. METHODS: One hundred and fifty six individuals seeking treatment for SAD completed the Childhood Trauma Questionnaire, which measures various types of abuse and neglect, along with the measures of symptom severity, quality of life, and disability. Data from a subset of patients enrolled in a paroxetine trial (N = 127) were analyzed to gauge the impact of childhood maltreatment on attrition and treatment response. RESULTS: All types of maltreatment except for sexual abuse and physical abuse were related to greater symptom severity. Emotional abuse and neglect were related to greater disability, and emotional abuse, emotional neglect, and physical abuse were related to decreased quality of life. Emotional abuse significantly predicted attrition. A time by emotional abuse interaction suggests that for those who stayed the course, the impact of emotional abuse on severity of social anxiety weakened significantly over time. CONCLUSIONS: Emotional maltreatment was most strongly linked to dysfunction in SAD, despite a tendency in the anxiety literature to focus on the effects of sexual and physical abuse. Additionally, individuals reporting emotional abuse were more likely to dropout from pharmacotherapy, but those who stayed the course displayed similar outcomes to those without such a history.

Personality disorders in hypochondriasis: prevalence and comparison with two anxiety disorders.

OBJECTIVE: Symptoms of hypochondriasis are sometimes attributed to personality psychopathology by health care providers. The goals of this study were to assess the prevalence of personality disorder (PD) comorbidity in hypochondriasis (HYP) and to compare the PD comorbidity profile of patients with HYP with that found among patients with other disorders characterized by intrusive thoughts and fears. METHODS: Structured Clinical Interview for DSM-IV Axis I and Axis II Disorders (SCID-I and SCID-II) were administered to 179 individuals: 62 with HYP, 46 with obsessive-compulsive disorder (OCD), and 71 with social anxiety disorder (SAD). For group contrasts, the samples were "purified" of the comparison comorbid disorders. General linear models were used to test the combined effect of group (HYP, OCD, SAD), age, and gender on the PD outcome variables. RESULTS: 59.7% of HYP subjects had no Axis II comorbidity. The most common PDs in HYP were paranoid (19.4%), avoidant (17.7%), and obsessive-compulsive (14.5%). HYP significantly differed from SAD in the likelihood of a cluster C disorder, whereas no significant difference was noted for HYP vs. OCD. The proportion of subjects having at least two PDs was not significantly different for HYP vs. OCD or for HYP vs. SAD. CONCLUSION: Although 40% of patients with hypochondriasis have PD comorbidity as assessed by the SCID-II, the amount of PD comorbidity is not significantly different than found among individuals with two comparison anxiety disorders. Therefore, health providers should be aware that PD may complicate the clinical profile of HYP, but they should avoid assuming that PD psychopathology is the primary source of hypochondriacal distress.

Social anxiety and functional impairment in patients seeking surgical evaluation for hyperhidrosis.

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.

Fear and avoidance of eye contact in social anxiety disorder.

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.

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.

Quality of life and functional impairment in obsessive-compulsive disorder: a comparison of patients with and without comorbidity, patients in remission, and healthy controls.

BACKGROUND: Several studies have demonstrated that obsessive-compulsive disorder (OCD) is associated with interference in quality of life (QOL) and functional impairment. However, these studies did not compare individuals in remission to individuals who continue to have the disorder, predominantly used comparisons with norms and not with a matched normal sample, and did not always consider the impact of comorbidity. METHODS: We administered multiple measures that assess QOL and functional impairment to 66 OCD patients who had previously consented for a clinical trial and to 36 age and sex matched individuals who denied any psychiatric history. RESULTS: Results confirm that OCD was associated with significantly lower QOL and functional impairment compared to healthy controls (HCs) in areas of work, social life, and family life. Individuals with OCD and other comorbid psychiatric diagnoses showed the poorest QOL and functioning, with comorbid depression accounting for much of the variance. The levels of QOL and functioning in individuals in remission tended to lie in between HCs and individuals with current OCD: their QOL or functioning did not differ significantly from HCs nor did they consistently differ significantly from those who had current OCD. CONCLUSION: These results suggest that individuals who are in remission have improved levels of QOL and functioning, whereas individuals with OCD are significantly impaired, and individuals with OCD and comorbid disorders are the most impaired. Treatment strategies should be focused on achieving remission of all symptoms to have the greatest impact on functioning and QOL.

Dopamine transporters, D2 receptors, and dopamine release in generalized social anxiety disorder.

BACKGROUND: Dopamine D2 receptor and dopamine transporter (DAT) availability in the striatum (STR) have each been reported abnormal in generalized social anxiety disorder (GSAD) in studies using single photon emission computerized tomography (SPECT). D2 receptors and DAT have not previously been studied within the same GSAD subjects, however, and prior GSAD studies have not assessed dopamine release or subdivided the STR into functional subregions. METHODS: Unmedicated adults with GSAD (N=17) and matched healthy comparison (HC) subjects (N=13) participated in this study. Of these, 15 GSAD and 13 HC subjects completed baseline assessment of D2 receptor availability using positron emission tomography (PET) with the radiotracer [11C]raclopride. Twelve GSAD and 13 HC subjects completed a repeat scan after intravenous administration of d-amphetamine to study dopamine release. Twelve of the GSAD subjects and 10 of the HC subjects also completed SPECT with the radiotracer [123I] methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate ([123I]beta-CIT) to assess DAT availability. RESULTS: GSAD and HC groups did not differ significantly in striatal DAT availability, the overall striatal or striatal subregion D2 receptor availability at baseline, or change in D(2) receptor availability after d-amphetamine. Receptor availability and change after d-amphetamine were not significantly associated with severity of social anxiety or trait detachment. CONCLUSIONS: These findings do not replicate previous findings of altered striatal DAT and D2 receptor availability in GSAD subjects assessed with SPECT. The differences from results of prior studies may be due to differences in imaging methods or characteristics of samples.

Screening for social anxiety disorder with the self-report version of the Liebowitz Social Anxiety Scale.

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.

A double-masked, placebo-controlled study of fluoxetine for hypochondriasis.

This study assessed the efficacy, durability, and tolerability of fluoxetine for hypochondriasis, a disorder for which controlled pharmacological trials are scarce. Fifty-seven patients with hypochondriasis were enrolled: 12 discontinued during the placebo run-in, and 45 were randomized to either fluoxetine or placebo for 12 weeks (acute treatment). Responder status was defined as a Clinical Global Impression rating for hypochondriasis of much or very much improved. Secondary outcome measures included severity of hypochondriasis, somatization, anxiety, and depression. Responders to acute treatment entered a 12-week maintenance phase to week 24. Sustained responders at week 24 entered a 12-week double-masked discontinuation phase. Primary analysis used the intent-to-treat sample. More patients responded with improvement in hypochondriasis when given fluoxetine compared with placebo, starting at week 8 (50.0% vs 19.0%, P = 0.03) and continuing to week 12 (62.5% vs 33.3%, P = 0.05). Mean dose at week 12 dose was 51.4 mg (SD, +/-23 mg). The acute treatment response was maintained to week 24 with more responders in the fluoxetine compared with the placebo group (54.2% vs 23.8%, P = 0.04). Significant improvement was not noted on the continuous secondary outcomes measures of hypochondriasis, with the exception of the Clinical Global Impression hypochondriasis severity scale at week 24. Likelihood of response was not associated with severity of psychiatric comorbidity. Durability of response after controlled drug discontinuation could not be reasonably assessed, given the small sample size of patients who entered the discontinuation phase (n = 10). Fluoxetine was well tolerated, with no significant differences in discontinuation due to side effects between treatment groups. Fluoxetine is a moderately effective and well-tolerated treatment for hypochondriasis.

Statistical choices can affect inferences about treatment efficacy: a case study from obsessive-compulsive disorder research.

Longitudinal clinical trials in psychiatry have used various statistical methods to examine treatment effects. The validity of the inferences depends upon the different method's assumptions and whether a given study violates those assumptions. The objective of this paper was to elucidate these complex issues by comparing various methods for handling missing data (e.g., last observation carried forward [LOCF], completer analysis, propensity-adjusted multiple imputation) and for analyzing outcome (e.g., end-point analysis, repeated-measures analysis of variance [RM-ANOVA], mixed-effects models [MEMs]) using data from a multi-site randomized controlled trial in obsessive-compulsive disorder (OCD). The trial compared the effects of 12 weeks of exposure and ritual prevention (EX/RP), clomipramine (CMI), their combination (EX/RP&CMI) or pill placebo in 122 adults with OCD. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale. For most comparisons, inferences about the relative efficacy of the different treatments were impervious to different methods for handling missing data and analyzing outcome. However, when EX/RP was compared to CMI and when CMI was compared to placebo, traditional methods (e.g., LOCF, RM-ANOVA) led to different inferences than currently recommended alternatives (e.g., multiple imputation based on estimation-maximization algorithm, MEMs). Thus, inferences about treatment efficacy can be affected by statistical choices. This is most likely when there are small but potentially clinically meaningful treatment differences and when sample sizes are modest. The use of appropriate statistical methods in psychiatric trials can advance public health by ensuring that valid inferences are made about treatment efficacy.

A randomized trial of interpersonal therapy versus supportive therapy for social anxiety disorder.

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.

Long-term follow-up study of patients with refractory obsessive-compulsive disorder.

The authors prospectively followed patients with treatment-resistant obsessive-compulsive disorder (OCD). Between 1988 and 1995, 56 patients with a history of inadequate response to oral clomipramine received 14 infusions of intravenous clomipramine. The follow-up period ranged from 4 to 11 years after treatment. Of the 44 subjects interviewed at follow-up, 70.5% had current OCD and 29.5% had sub-threshold OCD. Almost half reported feeling much improved or very much improved compared to their state prior to treatment with intravenous clomipramine.