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The National Institute of Mental Health (NIMH) ‘fast-fail’ approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n  = 45) and placebo ( n  = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F (1,86) = 5.58, P  < 0.01; effect size = 0.58 (95% confidence interval, 0.13–0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the ‘fast-fail’ approach. A phase 2 proof-of-mechanism trial shows that a κ-opioid receptor antagonist improves reward-related functioning in the brain and a clinical measure of anhedonia in patients with mood and anxiety disorders, serving as a model for implementing the ‘fast-fail’ approach to psychiatric treatment development.

Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n =12) or placebo (placebo; n =12) in a double-blind randomized design 1 h and a half before the test. The same number of HC ( n =12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC.

Depression and anxiety disorders are common mental disorders worldwide. The MANAS trial aimed to test the effectiveness of an intervention led by lay health counsellors in primary care settings to improve outcomes of people with these disorders. In this cluster randomised trial, primary care facilities in Goa, India, were assigned (1:1) by computer-generated randomised sequence to intervention or control (enhanced usual care) groups. All adults who screened positive for common mental disorders were eligible. The collaborative stepped-care intervention offered case management and psychosocial interventions, provided by a trained lay health counsellor, supplemented by antidepressant drugs by the primary care physician and supervision by a mental health specialist. The research assessor was masked. The primary outcome was recovery from common mental disorders as defined by the International Statistical Classification of Diseases and Related Health Problems—10th revision (ICD-10) at 6 months. This study is registered with ClinicalTrials.gov, number NCT00446407. 24 study clusters, with an equal proportion of public and private facilities, were randomised equally between groups. 1160 of 1360 (85%) patients in the intervention group and 1269 of 1436 (88%) in the control group completed the outcome assessment. Patients with ICD-10-confirmed common mental disorders in the intervention group were more likely to have recovered at 6 months than were those in the control group (n=620 [65·0%] vs 553 [52·9%]; risk ratio 1·22, 95% CI 1·00–1·47; risk difference=12·1%, 95% CI 1·6%–22·5%). The intervention had strong evidence of an effect in public facility attenders (369 [65·9%] vs 267 [42·5%], risk ratio 1·55, 95% CI 1·02–2·35) but no evidence for an effect in private facility attenders (251 [64·1%] vs 286 [65·9%], risk ratio 0·95, 0·74–1·22). There were three deaths and four suicide attempts in the collaborative stepped-care group and six deaths and six suicide attempts in the enhanced usual care group. None of the deaths were from suicide. A trained lay counsellor-led collaborative care intervention can lead to an improvement in recovery from CMD among patients attending public primary care facilities. The Wellcome Trust.

This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5–45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated “much improved” (CGI-I = 2) or “very much improved” (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine’s safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Clinical trial registration information: Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders; https://clinicaltrials.gov; NCT01302964.

Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors. Recent functional neuroimaging studies suggest that these effects are mediated through OXT's effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT's effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HCs). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 μg) or placebo (PBO) before resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC), and in doing so, reversed (ie, 'normalized') the reduced amygdala-frontal connectivity observed relative to HCs evident on PBO. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on PBO and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.

Patients with generalized social anxiety disorder (GSAD) exhibit heightened activation of the amygdala in response to social cues conveying threat (eg, fearful/angry faces). The neuropeptide oxytocin (OXT) decreases anxiety and stress, facilitates social encounters, and attenuates amygdala reactivity to threatening faces in healthy subjects. The goal of this study was to examine the effects of OXT on fear-related amygdala reactivity in GSAD and matched healthy control (CON) subjects. In a functional magnetic resonance imaging study utilizing a double-blind placebo-controlled within-subjects design, we measured amygdala activation to an emotional face matching task of fearful, angry, and happy faces following acute intranasal administration of OXT (24 IU or 40.32 μg) and placebo in 18 GSAD and 18 CON subjects. Both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo, with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group. OXT had no effect on amygdala activity to emotional faces in the CON group, but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group, such that the hyperactivity observed during the placebo session was no longer evident following OXT (ie, normalization). These findings suggest that OXT has a specific effect on fear-related amygdala activity, particularly when the amygdala is hyperactive, such as in GSAD, thereby providing a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety.

Anxiety disorders are a major public health burden with limited treatment options. We investigated the long-term safety and efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with anxiety with or without life-threatening illness. This study was an -planned long-term follow-up of an investigator-initiated, two-centre trial that used a double-blind, placebo-controlled, two-period, random-order, crossover design with two sessions with either oral LSD (200 μg) or placebo per period. Participants ( = 39) were followed up 1 year after the end-of-study visit to assess symptoms of anxiety, depression and long-term effects of psychedelics using Spielberger's State-Trait Anxiety Inventory-Global (STAI-G), the Beck Depression Inventory (BDI), the Persisting Effects Questionnaire and measures of personality traits using the NEO Five-Factor Inventory. Participants reported a sustained reduction of STAI-G scores compared with baseline (least square means (95% CI) = -21.6 (-32.7, -10.4), = 1.04, < 0.001, for those who received LSD in the first period (94 weeks after the last LSD treatment) and -16.5 (-26.2, -6.8), = 1.02, < 0.05, for those who received LSD in the second period (68 weeks after the last LSD treatment)). Similar effects were observed for comorbid depression with change from baseline BDI scores of -8.1 (-13.2, -3.1), = 0.71, < 0.01, and -8.9 (-12.9, -4.9), = 1.21, < 0.01, for the LSD-first and placebo-first groups, respectively. Personality trait neuroticism decreased ( < 0.0001) and trait extraversion increased ( < 0.01) compared with study inclusion. Individuals attributed positive long-term effects to the psychedelic experience. Patients reported sustained long-term effects of LSD-assisted therapy for anxiety.

Individuals with generalized anxiety disorder (GAD) often face challenges with self-regulation and limited access to traditional therapy. Although acceptance and commitment therapy (ACT) has demonstrated both efficacy and effectiveness in promoting psychological flexibility, scalable solutions are necessary to address these barriers. This study introduces Anzeilax, an ACT-based digital therapeutic (DTx) that incorporates self-talk as a novel mechanism of action (MoA) to enhance psychological flexibility in the treatment of GAD. This study aimed to evaluate the efficacy of Anzeilax in reducing anxiety symptoms in individuals with GAD. A 10-week, parallel-group, superiority randomized controlled trial (RCT) was conducted with 96 participants diagnosed with GAD (Generalized Anxiety Disorder 7-item scale [GAD-7] scores≥10, age≥19 years). The participants were randomly assigned (1:1) to receive either Anzeilax alongside treatment as usual (TAU, treatment group; n=48, 50%) or TAU alone (control group; n=48). Only the outcome evaluators were blinded to the group assignment. The primary outcome was the change in the GAD-7 score from baseline to week 10. The secondary outcomes included the Beck Anxiety Inventory (BAI) for anxiety symptoms, the Penn State Worry Questionnaire (PSWQ) for pathological worry, and the Hospital Anxiety and Depression Scale (HADS) for anxiety (HADS-A) and depression (HADS-D) symptoms. All self-report outcomes were assessed at baseline and at weeks 5 (midintervention), 10 (postintervention), and 15 (follow-up). During the trial, 34 (71%) and 31 (65%) participants in the treatment group maintained at least 80% of the prescribed usage frequency at weeks 5 and 10, respectively. Based on the full analysis set (FAS), participants using Anzeilax demonstrated significant improvement in anxiety symptoms compared to the control group. Analysis of the primary outcome at 10 weeks postintervention compared to baseline exhibited a significant reduction in GAD-7 scores (adjusted mean difference -2.26, 95% CI -3.78 to -0.74, P=.002). Secondary outcomes at the same time point indicated consistent improvements, with significant group-by-time interactions observed in the GAD-7 (Cohen d=0.60, P=.008), BAI (Cohen d=0.50, P=.008), PSWQ (Cohen d=0.62, P=.002), and HADS-A (Cohen d=0.50, P=.01) scores. These improvements were sustained at the follow-up assessment (week 15). Although the differences in depressive symptoms between the two groups did not present statistical significance, notable improvements were observed in the treatment group. Anzeilax demonstrated clinically meaningful efficacy in reducing anxiety symptoms when combined with TAU. The results showed consistent improvements across multiple anxiety measures, with effects sustained through follow-up. The incorporation of context-sensitive self-talk within an ACT-based DTx framework offers a promising and accessible solution for treating individuals with GAD. ClinicalTrials.gov NCT06010654; https://clinicaltrials.gov/study/NCT06010654.

Anxiety disorders are the most common mental disorders in adolescents. However, only 50% of pediatric patients with anxiety disorders respond to the first-line pharmacologic treatments—selective serotonin reuptake inhibitors (SSRIs). Thus, identifying the neurofunctional targets of SSRIs and finding pretreatment or early-treatment neurofunctional markers of SSRI treatment response in this population is clinically important. We acquired pretreatment and early-treatment (2 weeks into treatment) functional magnetic resonance imaging during a continuous processing task with emotional and neutral distractors in adolescents with generalized anxiety disorder (GAD, N = 36) randomized to 8 weeks of double-blind escitalopram or placebo. Generalized psychophysiological interaction analysis was conducted to examine the functional connectivity of the amygdala while patients viewed emotional pictures. Full-factorial analysis was used to investigate the treatment effect of escitalopram on amygdala connectivity. Correlation analyses were performed to explore whether pretreatment and early (week 2) treatment-related connectivity were associated with treatment response (improvement in anxiety) at week 8. Compared to placebo, escitalopram enhanced emotional processing speed and enhanced negative right amygdala-bilateral ventromedial prefrontal cortex (vmPFC) and positive left amygdala-right angular gyrus connectivity during emotion processing. Baseline amygdala-vmPFC connectivity and escitalopram-induced increased amygdala-angular gyrus connectivity at week 2 predicted the magnitude of subsequent improvement in anxiety symptoms. These findings suggest that amygdala connectivity to hubs of the default mode network represents a target of acute SSRI treatment. Furthermore, pretreatment and early-treatment amygdala connectivity could serve as biomarkers of SSRI treatment response in adolescents with GAD. The trial registration for the study is ClinicalTrials.gov Identifier: NCT02818751.

This study examined the relationship between caregivers’ and youths’ treatment expectations and characteristics of exposure tasks (quantity, mastery, compliance) in cognitive-behavioral therapy (CBT) for childhood anxiety. Additionally, compliance with exposure tasks was tested as a mediator of the relationship between treatment expectations and symptom improvement. Data were from youth (N = 279; 7–17 years old) enrolled in the Child/Adolescent Anxiety Multimodal Study (CAMS) and randomized to cognitive-behavioral therapy (CBT) or the combination of CBT and sertraline for the treatment of separation anxiety disorder, generalized anxiety disorder, and social phobia. Caregivers and youth independently reported treatment expectations prior to randomization, anxiety was assessed pre- and post-treatment by independent evaluators blind to treatment condition, and exposure characteristics were recorded by the cognitive-behavioral therapists following each session. For both caregivers and youths, more positive expectations that anxiety would improve with treatment were associated with greater compliance with exposure tasks, and compliance mediated the relationship between treatment expectations and change in anxiety symptoms following treatment. Additionally, more positive parent treatment expectations were related to a greater number and percentage of sessions with exposure. More positive youth treatment expectations were associated with greater mastery during sessions focused on exposure. Findings underscore the importance of addressing parents’ and youths’ treatment expectations at the outset of therapy to facilitate engagement in exposure and maximize therapeutic gains.