Japanese Society of Anxiety and Related Disorders/Japanese Society of Neuropsychopharmacology: Clinical practice guideline for social anxiety disorder (2021).

The development of clinical practice guidelines for social anxiety disorder began in March 2018 when the Joint Clinical Practice Guideline Development Committee for Anxiety and Obsessive-Compulsive Disorders was formed by the Japanese Society of Anxiety and Related Disorders and Japanese Society of Neuropsychopharmacology to jointly develop guidelines for anxiety and obsessive-compulsive disorders. Based on the universal concept of evidence-based medicine, three clinical questions (CQs) about pharmacotherapy and psychotherapy were developed for clinical guidelines for social anxiety disorder, panic disorders, and obsessive-compulsive disorder in accordance with the Minds "Manual for Guidelines Development 2017 by the Japan Council for Quality Health Care: CQ1-"What is the recommended pharmacotherapy for social anxiety disorder in adults?"; CQ2-"What is the recommended psychotherapy (psychological intervention) for social anxiety disorder in adults?"; and CQ3-"What are the recommendations regarding monotherapy and combination therapy for social anxiety disorder in adults in terms of pharmacotherapy and psychotherapy (psychological interventions)?" Summarized recommendations for social anxiety disorder in adults are selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitor for CQ1, cognitive behavioral therapy for CQ2, and there are no recommendations regarding monotherapy and combination therapy for CQ3. These were answered by considering the balance between benefits and harms based on systematic reviews of each. The aim of this brief guideline for the standard-of-care (i.e., medical treatment) for social anxiety disorder in adults (18 years and older) was to help "shared decision making," in which medical professionals, including physicians, and patients share scientific evidence to decide on a course of treatment.

Attention Bias Modification Treatment Versus a Selective Serotonin Reuptake Inhibitor Or Waiting List Control for Social Anxiety Disorder: A Randomized Clinical Trial.

OBJECTIVE: Social anxiety disorder is common and impairing. The efficacy of pharmacotherapy is moderate, highlighting the need for alternative therapies. This study compared the efficacy of gaze-contingent music reward therapy (GC-MRT), an eye-tracking-based attention bias modification treatment, with a selective serotonin reuptake inhibitor (SSRI) treatment or a waiting list control condition in reducing social anxiety disorder symptoms. Superior clinical effects of similar magnitude were expected for the active treatments relative to the control condition. METHODS: Participants were 105 treatment-seeking adults with social anxiety disorder, randomly allocated to 12 weeks of GC-MRT, SSRI, or waiting list control. Mean changes in clinician-rated and self-reported social anxiety symptoms from baseline to mid- and posttreatment assessments were compared between groups using generalized estimating equations. Changes in attentional dwell time on threat were also examined. RESULTS: Analysis indicated a significant differential reduction in symptoms between groups. Patients in the GC-MRT and SSRI groups had lower social anxiety scores at the mid- and posttreatment assessments compared with patients in the waiting list group. The efficacy of the active treatments did not differ. Only patients in the GC-MRT group showed reduction in dwell time on threat from baseline to posttreatment assessment. CONCLUSIONS: Eye-tracking-based attention bias modification is an acceptable and effective treatment option for social anxiety disorder.

New frontiers in the pharmacological treatment of social anxiety disorder in adults: an up-to-date comprehensive overview.

INTRODUCTION: Social anxiety disorder (SAD) is associated with scarce functioning and poor quality of life. Although selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are currently first-line treatments, side effects are common and affect treatment compliance in approximately 50% of patients. This review aimed to summarize data on the efficacy of unlabeled molecules for SAD treatment. AREAS COVERED: Research in the main psychiatric databases was conducted (PubMed, PsychINFO, and EMBASE-Ovid) to select studies investigating the efficacy of marketed molecules not labeled for SAD treatment. EXPERT OPINION: Pregabalin at high doses (450-600 mg/day) appears to be a reliable alternative strategy for SAD treatment. Among the SSRIs not labeled for SAD, citalopram showed the most promising results. Quetiapine, levetiracetam, and other antidepressants/serotonergic agents, such as fluoxetine, duloxetine, monoamine oxidase inhibitors, tricyclics, mirtazapine, atomoxetine, nefazodone, vilazodone, and buspirone, presented negative, limited, or contrasting results. Data on anticonvulsants, olanzapine, tiagabine, and ketamine were positive, but preliminary. The risk/benefit ratio must be considered in the prescription of unlabeled compounds; treatment with pregabalin may be associated with somnolence and dizziness. Future research may contribute to the identification of targeted molecules for the treatment of this disorder.

Serotonin and dopamine transporter availability in social anxiety disorder after combined treatment with escitalopram and cognitive-behavioral therapy.

Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

Antidepressants for social anxiety disorder: A systematic review and meta-analysis.

AIM: This systematic review is aimed to update and reintegrate the pharmacotherapy of social anxiety disorder (SAD), including the Japanese medical database. METHODS: We conducted a systematic review and meta-analysis of pharmacotherapy of SAD according to the Medical Information Distribution Service. We used data from a most recent systematic review, and updated search were conducted using MEDLINE, PubMed, CENTRAL, ICTRP, and ICHUSHI from August 1st, 2017 to January 31st, 2022. The outcome were response rates assessed by Clinical Global Impressions Improvement, efficacy assessed by the Liebowitz Social Anxiety Scale (LSAS), and dropout rates. We performed a random effect of meta-analysis to obtain the differences in each outcome between active medication and placebo. We used RevMan version 5.3 for analyses. RESULTS: We identified 5 studies through update search and performed meta-analysis for 33 studies on selective serotonin reuptake inhibitor (SSRI) and 6 studies on serotonin noradrenalin reuptake inhibitor (SNRI). The response rate (RR = 1.62) and the LSAS score reduction (mean difference = -9.65) of SSRI, and the response rate (RR = 1.57) and the LSAS score reduction (mean difference = -11.72) of SNRI were significantly different from placebo. The dropout rates of SSRI or SNRI were not significant. The response rates of SSRIs in both Japanese studies (RR = 1.44) and countries other than Japan (RR = 1.67) were significant. Most findings were based on low quality of evidence. CONCLUSION: SSRIs are valid option for pharmacotherapy of SAD including Japanese patients. SNRIs are another effective option. However, the results should be interpreted cautiously due to several risk of bias.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial.

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (ß = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (ß = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens.

Effects of ayahuasca on the endocannabinoid system of healthy volunteers and in volunteers with social anxiety disorder: Results from two pilot, proof-of-concept, randomized, placebo-controlled trials.

OBJECTIVE: To assess endocannabinoid (anandamide, AEA; 2-arachidonoylglycerol, 2-AG) plasma levels in healthy volunteers and in volunteers with social anxiety disorder (SAD) after a single oral dose of ayahuasca or placebo. METHODS: Post hoc analysis of endocannabinoid plasma levels (baseline, 90 and 240 min after drug intake) from two parallel-group, randomized, placebo-controlled trials. In Study 1, 20 healthy volunteers ingested ayahuasca (average 1.58 mg/ml dimethyltryptamine (DMT)) or placebo, and in Study 2, 17 volunteers with SAD received ayahuasca (average 0.680 mg/ml DMT) or placebo. RESULTS: A significant difference was observed in AEA concentrations in Study 2 after ayahuasca intake (Χ2 (2) = 6.5, p = 0.03, Friedman test), and near significant differences (increases) were observed between baseline and 90 (Z = 0, p = 0.06, Wilcoxon test) and 240 (Z = 10, p = 0.06) minutes after ayahuasca intake. CONCLUSIONS: Although our findings suggest that ayahuasca could modulate AEA levels in SAD patients, the high interindividual variability in both trials and the small samples preclude definitive conclusions. More research with larger samples is needed to better understand the effects of ayahuasca and other hallucinogens in the endocannabinoid system.

Potential processes of change in MDMA-Assisted therapy for social anxiety disorder: Enhanced memory reconsolidation, self-transcendence, and therapeutic relationships.

OBJECTIVE: Researchers have suggested that psychotherapy may be enhanced by the addition of 3,4-methylenedioxymethamphetamine (MDMA), particularly in the treatment of disorders wherein interpersonal dysfunction is central, such as social anxiety disorder. We review literature pertaining to three potential processes of change that may be instigated during sessions involving MDMA administration in the treatment of social anxiety disorder. DESIGN: This is a narrative review that integrates research on the etiology and maintenance of social anxiety disorder and mechanisms of action of MDMA to examine how MDMA may enhance psychotherapy outcomes. RESULTS: We first outline how MDMA may enhance memory reconsolidation in social anxiety disorder. We then discuss how MDMA may induce experiences of self-transcendence and self-transcendent emotions such as compassion, love, and awe; and how these experiences may be therapeutic in the context of social anxiety disorder. We subsequently discuss the possibility that MDMA may enhance the strength and effectiveness of the therapeutic relationship which is a robust predictor of outcomes across many disorders as well as a potential key ingredient in treating disorders where shame and social disconnection are central factors. CONCLUSION: We discuss how processes of change may extend beyond the MDMA dosing sessions themselves.

The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics.

Social anxiety disorder (SAD) is a highly prevalent psychiatric disorder that presents with an early age of onset, chronic disease course, and increased risk of psychiatric comorbidity. Current treatment options for SAD are associated with low response rates, suboptimal efficacy, and possible risk of adverse effects. Investigation of new neurobiological mechanisms may aid in the identification of more specific therapeutic targets for the treatment of this disorder. Emerging evidence suggests that the endogenous cannabinoid system, also referred to as the endocannabinoid system (ECS), could play a potential role in the pathophysiology of SAD. This review discusses the known pathophysiological mechanisms of SAD, the potential role of the ECS in this disorder, current drugs targeting the ECS, and the potential of these novel compounds to enhance the therapeutic armamentarium for SAD. Further investigational efforts, specifically in human populations, are warranted to improve our knowledge of the ECS in SAD.

Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial.

It has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [11C]DASB and [11C]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

The enhancing effects of testosterone in exposure treatment for social anxiety disorder: a randomized proof-of-concept trial.

Individuals with a social anxiety disorder (SAD) show hypofunctioning of the hypothalamus-pituitary-gonadal (HPG) axis, which is linked to social fear and avoidance behavior. As testosterone administration has been shown to facilitate social-approach behavior in this population, it may enhance the effectiveness of exposure treatment. In this proof-of-concept study, we performed a randomized clinical assay in which 55 women diagnosed with SAD received two exposure therapy sessions. Session 1 was supplemented with either testosterone (0.50 mg) or placebo. Next, transfer effects of testosterone augmentation on within-session subjective fear responses and SAD symptom severity were assessed during a second, unenhanced exposure session (session 2) and at a 1-month follow-up, respectively. The participants having received testosterone showed a more reactive fear pattern, with higher peaks and steeper reductions in fear levels in session 2. Post-hoc exploration of moderating effects of endogenous testosterone levels, revealed that this pattern was specific for women with high basal testosterone, both in the augmented and in the transfer session. In contrast, the participants with low endogenous testosterone showed reduced peak fear levels throughout session 1, again with transfer to the unenhanced session. Testosterone did not significantly affect self-reported anxiety. The effects of testosterone supplementation on fear levels show transfer to non-enhanced exposure, with effects being modulated by endogenous testosterone. These first preliminary results indicate that testosterone may act on important fear mechanisms during exposure, providing the empirical groundwork for further exploration of multi-session testosterone-enhanced exposure treatment for SAD.

The effect of intranasally administered oxytocin on observed social behavior in social anxiety disorder.

Research has shown that patients with a social anxiety disorder (SAD) show social performance deficits. These deficits are a maintaining factor in SAD, as mending social behavior improves interpersonal judgments and reduces social anxiety. Thus finding ways to enhance social behavior is evidently of importance in the treatment of SAD. This double-blind, placebo-controlled study investigated the effect of an intranasal administration of the hormone oxytocin (24 IU) on social behavior and anxious appearance in SAD patients (N = 40) and healthy controls (N = 39). Forty minutes after oxytocin administration participants were submitted to two live social situations (i.e., a waiting room situation and a getting acquainted task). The participants ('self-rated') and observers ('observer-rated') scored participants' social behavior and anxious appearance. Participants also rated their positive and negative affect. Confirming the social performance deficits in SAD, observers regarded SAD patients as more anxious and less socially skilled than healthy controls. Results indicated oxytocin-induced improvement of observer-rated social behavior in SAD patients compared to placebo but only in the getting acquainted task. This effect was not perceived as such by patients themselves and did not improve their affect ratings. In conclusion, this study found support for the idea that oxytocin helps SAD patients to perform better in social interactions, although this improvement seemed context-dependent (i.e., only present in the getting-acquainted task) and 'not perceived by the patient.

Monoamine Oxidase Inhibitors (MAOIs) in Psychiatric Practice: How to Use them Safely and Effectively.

Monoamine oxidase inhibitors (MAOIs) were among the first licensed pharmacological treatments for patients with depression but over time have fallen out of mainstream clinical use. This has led to a loss of clinician training opportunities and reduced availability of MAOIs for prescribing. This article provides a concise and practical overview of how to use MAOIs safely and effectively in psychiatric practice. We consider the history of MAOIs, why they are not used more frequently, their mechanisms of action, availability, indications and efficacy, general tolerability, withdrawal symptoms, and safety considerations (including hypertensive reactions and serotonin syndrome). Practical advice is given in terms of dietary restrictions, interactions with other medications (both prescribed and non-prescribed), and how prescribers can stop and switch MAOIs, both within the drug class and outside of it. We also provide advice on choice of MAOI and treatment sequencing. Lastly, we consider emerging directions and potential additional indications.

Ayahuasca Improves Self-perception of Speech Performance in Subjects With Social Anxiety Disorder: A Pilot, Proof-of-Concept, Randomized, Placebo-Controlled Trial.

BACKGROUND: Ayahuasca is a classic hallucinogen with anxiolytic and antidepressive properties. Anecdotal evidence also suggests that it improves performance (eg, singing, speech). This controlled trial assessed the effects of ayahuasca on speech performance and anxiety in individuals with social anxiety disorder. METHODS: Seventeen volunteers with social anxiety disorder participated in a pilot, proof-of-concept, randomized, parallel-group trial. Self-perception of performance during a public-speaking test was assessed with the Self-statements During Public Speaking Scale primary outcome). Secondary outcomes included anxiety/subjective effects (Visual Analog Mood Scale; Bodily Symptoms Scale), recognition of emotions in facial expressions (REFE), tolerability measures (cardiovascular measures, self-reports), and brain-derived neurotrophic factor plasma levels. Effects on anxiety and REFE were assessed again 7, 14, and 21 days postdrug. FINDINGS: Compared with placebo, ayahuasca significantly improved self-perception of speech performance (Self-statements During Public Speaking Scale) and increased somatic symptoms (Bodily Symptoms Scale). There was also a significant time × group interaction in the cognitive deterioration Visual Analog Mood Scale factor and a significant effect of time in the REFE task, especially in reaction time. Other measures were not significantly modified. Ayahuasca was well tolerated, producing mainly nausea, gastrointestinal discomfort, and vomiting. CONCLUSIONS: Ayahuasca improved self-perception of speech performance in socially anxious individuals. These effects occurred independent of task-related anxiety and REFE, suggesting that ayahuasca could specifically improve the cognitive aspect of speech performance. Further studies should try to unveil the mechanisms involved in the effects of ayahuasca and to better understand its effects on anxiety.

Sleep quality and outcome of exposure therapy in adults with social anxiety disorder.

INTRODUCTION: Poor sleep is prevalent among individuals with social anxiety disorder (SAD) and may negatively affect exposure therapy outcomes. Poor sleep may impair memory and learning, and thus compromise fear extinction learning thought to take place in exposure therapy. We examined poor sleep as a predictor of exposure therapy outcomes for SAD and the moderating role of d-cycloserine (DCS) on this relationship. METHODS: Participants were 152 individuals with a primary diagnosis of SAD. As part of a randomized clinical trial evaluating the efficacy of DCS for enhancing the effects of exposure therapy, they completed self-report baseline measure of sleep quality, and self-report sleep diaries assessing sleep duration (total sleep time [TST]) and sleep quality the nights before and after treatment sessions. RESULTS: Poorer baseline sleep quality was significantly associated with slower improvement over time and worse symptom outcomes at the end of treatment and follow-up after controlling for baseline symptoms of depression and social anxiety. Greater TST the night before treatment predicted lower SAD symptoms at the next session, after controlling for symptoms at the previous session. There was no relation between prior or subsequent night sleep quality on symptoms at the next session. No associations were moderated by DCS. CONCLUSIONS: We replicated and extended findings indicating that poor sleep quality is associated with poorer exposure therapy outcomes for SAD. Assessing for sleep difficulties before treatment initiation and incorporating sleep interventions into treatment may enhance exposure therapy outcomes for SAD.

Distress, quality of life and disability in treatment-seeking young adults with social anxiety disorder.

AIM: This study aimed to: (a) examine whether treatment-seeking young adults with social anxiety disorder (SAD) demonstrate similar degrees of distress, quality of life (QoL) and disability to those with other mental disorders; and (b) investigate the impact of comorbidity, specific comorbid conditions and antidepressants use on distress, QoL and disability in treatment-seeking young adults with SAD. METHODS: A cohort of treatment-seeking young adults (aged 16-45) diagnosed with SAD (N = 298) or other mental health disorders (N = 842; including depression, N = 349; bipolar, N = 141; psychosis, N = 173) completed self-report assessments of distress, QoL and disability. RESULTS: Young adults with SAD showed distress and disability of similar degree to those with most other mental disorders. Specifically, young adults with SAD reported significantly lower QoL than those with major depressive disorder or obsessive-compulsive disorder. Furthermore, young adults with SAD had the most difficulties in getting along with others and the second highest level of distress in comparison to other psychiatric groups. In comparison to antidepressants use, the presence of comorbidity showed a substantial negative influence on these health outcomes, particularly when presenting with comorbid depression or obsessive-compulsive disorder. CONCLUSIONS: Findings highlight significant impairments in young adults seeking treatment for SAD and the important moderating influence of comorbidity. This emphasizes the urgent need for effective management and treatment for its presentation and comorbidities in mental health services targeting young adults.

Emotional and interpersonal mechanisms in community SSRI treatment of social anxiety disorder.

BACKGROUND: Affective and interpersonal behavioural patterns characteristic of social anxiety disorder show improvement during treatment with serotonin agonists (e.g., selective serotonin reuptake inhibitors), commonly used in the treatment of social anxiety disorder. The present study sought to establish whether, during community psychopharmacological treatment of social anxiety disorder, changes in positive or negative affect and agreeable or quarrelsome behaviour mediate improvement in social anxiety symptom severity or follow from it. METHODS: Adults diagnosed with social anxiety disorder (n = 48) recorded their interpersonal behaviour and affect naturalistically in an event-contingent recording procedure for 1-week periods before and during the first 4 months of treatment with paroxetine. Participants and treating psychiatrists assessed the severity of social anxiety symptoms monthly. A multivariate latent change score framework examined temporally lagged associations of change in affect and interpersonal behaviour with change in social anxiety symptom severity. RESULTS: Elevated agreeable behaviour and positive affect predicted greater subsequent reduction in social anxiety symptom severity over the following month of treatment. Elevated negative affect, but not quarrelsome behaviour, predicted less subsequent reduction in symptom severity. LIMITATIONS: Limitations included limited assessment of extreme behaviour (e.g., violence) that may have precluded examining the efficacy of paroxetine because of the lack of a placebo control group. CONCLUSION: The present study suggests that interpersonal behaviour and affect may be putative mechanisms of action for serotonergic treatment of social anxiety disorder. Prosocial behaviour and positive affect increase during serotonergic treatment of social anxiety disorder. Specifically, modulating agreeable behaviour, positive affect and negative affect in individuals' daily lives may partially explain and refine clinical intervention.

Anxiolytic effects of acute and maintenance ketamine, as assessed by the Fear Questionnaire subscales and the Spielberger State Anxiety Rating Scale.

BACKGROUND: Ketamine has rapid anxiolytic effects in treatment-resistant obsessive compulsive, post-traumatic stress, generalised anxiety and social anxiety disorders. OBJECTIVES: This study aimed to assess changes following acute and maintenance ketamine therapy on the Fear Questionnaire (FQ) subscales and the Spielberger State Anxiety Inventory (SSAI). METHODS: This secondary analysis used data from a mixed open-label and double-blinded placebo-controlled study. A total of 24 patients received short-term ascending subcutaneous doses of ketamine and were then eligible to enter a 3-month maintenance phase of 1 mg/kg ketamine dosed once or twice weekly. FQ and SSAI data were analysed using mixed models to identify between-dose differences and to describe trends during maintenance. RESULTS: Acute ketamine dosing showed a rapid dose-related reduction in all three FQ subscales (agoraphobia, social phobia and blood-injury phobia) and in the SSAI. A progressive decrease in pre-dose rating-scale scores was evident during the 3 months of maintenance therapy. CONCLUSIONS: Ketamine demonstrated dose-related improvements in all FQ subscales and in the SSAI. Both scales appear to be suitable tools to assess the anxiolytic effects of ketamine in patients with treatment-resistant anxiety. Furthermore, ketamine appears to have broad, dose-related anti-phobic effects. These findings raise the possibility that ketamine may have therapeutic potential in the treatment of other phobic states, such as specific phobia.

Neuropeptide Y as Alternative Pharmacotherapy for Antidepressant-Resistant Social Fear.

In many social anxiety disorder (SAD) patients, the efficacy of antidepressant therapy is unsatisfactory. Here, we investigated whether mice deficient for the lysosomal glycoprotein acid sphingomyelinase (ASM-/-) represent an appropriate tool to study antidepressant-resistant social fear. We also investigated whether neuropeptide Y (NPY) reduces this antidepressant-resistant social fear in ASM-/- mice, given that NPY reduced social fear in a mouse model of SAD, namely social fear conditioning (SFC). We show that neither chronic paroxetine nor chronic amitriptyline administration via drinking water were successful in reducing SFC-induced social fear in ASM-/- mice, while the same treatment reduced social fear in ASM+/- mice and completely reversed social fear in ASM+/+ mice. This indicates that the antidepressants paroxetine and amitriptyline reduce social fear via the ASM-ceramide system and that ASM-/- mice represent an appropriate tool to study antidepressant-resistant social fear. The intracerebroventricular administration of NPY, on the other hand, reduced social fear in ASM-/- mice, suggesting that NPY might represent an alternative pharmacotherapy for antidepressant-resistant social fear. These results suggest that medication strategies aimed at increasing brain NPY concentrations might improve symptoms of social fear in SAD patients who fail to respond to antidepressant treatments.