Journal of Psychopharmacology最新文献

Background: Treatment acceptability impacts patient preference, adherence and clinical outcomes and is recognised as important in developing new treatments.

Aims: To evaluate factors associated with the acceptability of home-based transcranial direct current stimulation as a potential treatment for major depressive disorder (MDD).

Methods: We conducted exploratory factor analysis using principal component analysis with varimax rotation and parallel analysis to identify underlying factors and calculated Cronbach's alpha for both questionnaires. One questionnaire was investigated in a general population sample and another in a double-blind, randomised, sham-controlled clinical trial in MDD.

Results: The general population cohort consisted of 879 participants (628 women), and the clinical trial cohort included 151 MDD participants (104 women). The clinical trial questionnaire was assessed at baseline and after the 10-week randomised treatment. In the general population, two factors emerged: expected benefits and safety, and potential burdens (eigenvalues 4.27 and 1.22). In the clinical trial, one factor was evident at each time point. At baseline, all items were highly correlated and loaded onto a single factor (eigenvalue 1.52, explaining 30.45% of variance). At week 10, all components except side effects loaded onto a single factor (eigenvalue 1.84, explaining 36.71%). No differences were found between active and sham treatment arms. Acceptability components were well-related: two distinct factors (expected benefits and burdens) were found in the general population, while a single factor of general acceptability was observed in the MDD cohort.

Conclusions: These findings highlight the dynamic nature of acceptability and the importance of assessing it in treatment development.

Introduction: Schizophrenia is a severe mental disorder that impacts thoughts, emotions, and behavior, affecting 0.32% of the global population. While antipsychotic medications are crucial for managing symptoms, nearly half of individuals with schizophrenia experience weight gain, leading to treatment non-compliance and further health complications. Our systematic review and network meta-analysis aim to provide comprehensive evidence on the safety and efficacy of pharmacological and non-pharmacological interventions for antipsychotic-induced weight gain.

Methods: We conducted this study in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, following our protocol (CRD42024599597). We searched PubMed, Scopus, Web of Science, and Cochrane Library until July 2025. Only randomized placebo-controlled trials were included. We focused on anthropometric measurements and safety profiles. The primary outcome was weight change, while the secondary outcomes included waist-hip ratio, waist circumference, and hip circumference.

Result: Fifty-five studies were included in the meta-analysis, with a total of 2977 individuals. Regarding the weight change, the highest three interventions hold the highest probability of being the most effective therapy in weight loss compared to the Usual care group were Semagultide (MD: -13.5 [-17.3, -9.57], followed by Metformin + NutriEx (MD: -6.34, [-9.85, -2.9]), then Nizatidine (MD: -5.46 [-7.77, -2.76]). According to non-pharmacological interventions, all interventions showed significant reductions in weight (p-value < 0.05).

Conclusion: We found that Semaglutide has the highest probability of being the most effective therapy in the reduction of weight gain and BMI. Liraglutide was associated with mild adverse effects. Additional trials focusing on non-pharmacological approaches are essential.

Background: Psychedelic-assisted therapy (PAT) has demonstrated substantial efficacy across a range of mental disorders. However, heterogeneity between patients confers differential responsiveness. This systematic review aims to explore factors which may predict therapeutic responses to PAT.

Methods: A systematic search was performed from inception through to March 2024 and studies that assessed predictors of response related to the use of classic psychedelics for mental disorders were included.

Results: A total of 54 studies investigating potential predictors of treatment response to psychedelic-assisted therapy were included in the review. These studies encompassed adult populations diagnosed with substance-use disorders, major depressive disorder, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder and existential distress related to life-threatening illness as well as naturalistic samples reporting psychopathological symptoms without a formally confirmed diagnosis. The most frequently reported predictor of therapeutic response was the intensity of the acute psychedelic experience, particularly mystical-type experiences (MTEs), though this was not consistent across all disorders or time points. Factors related to set, setting and dose were frequently associated with the likelihood and intensity of MTEs.

Conclusions: The acute psychedelic experience, especially MTEs, was the most frequently reported predictor of therapeutic response. Future trials should explore a broader range of predictors, include longer-term follow-up and improve methodological consistency to strengthen the evidence base for reliable predictors of therapeutic response.

Background: Ketamine and esketamine ("es/ketamine") treatment protocols have been investigated in patients' samples with treatment-refractory anxiety disorders. We systematically reviewed publications in which es/ketamine was used to treat anxiety symptoms in the context of either Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) anxiety disorders or treatment-resistant depression (TRD).

Method: The literature search of English-language studies combining each of the keywords "ketamine" or "esketamine" with various psychopathological terms produced 4086 results. Through the use of specific inclusion/exclusion criteria, a total of 78 studies were eligible for inclusion.

Results: Eleven studies investigated ketamine pharmacotherapy (no esketamine study was found) of patients suffering primarily from a DSM-5 anxiety disorder. Additionally, we found 67 studies which: (a) reported es/ketamine pharmacotherapy for treating primarily unipolar/bipolar depression and secondarily assessed changes in anxiety symptoms (N = 55); or (b) compared the outcome (depression/suicidality severity) of es/ketamine between "anxious" versus "non-anxious" TRD (N = 12). These studies were notably heterogeneous, and included randomized controlled trials, crossover trials, open-label studies, and case reports. Methods of administration of ketamine varied, including subcutaneous, intravenous, intramuscular, and oral; outcome measures also varied. Study findings suggest that es/ketamine is associated with a reduction of anxiety in the context either of anxiety disorders or of unipolar/bipolar TRD. These effects are sustained, especially with repeated doses and maintenance treatment: however, after terminating maintenance treatment anxiety symptoms may soon re-emerge. The tablet formulation reduces anxiety more slowly, but with fewer side effects.

Conclusion: There are indications that es/ketamine pharmacotherapy may reduce pathological anxiety, although relapse may follow its termination. More studies are needed to confirm these preliminary findings.

Background: Psychedelics induce profound changes in perception and thinking; however, little is known about the neural mechanisms and prediction of these effects.

Aims: Investigating ayahuasca-induced experiences, mind-wandering, and electroencephalogram (EEG) oscillations, beyond the prediction of subjective experiences by baseline EEG.

Methods: In a randomised, double-blind, placebo-controlled, parallel-arm design, 50 healthy volunteers received 1 mL/kg of ayahuasca or placebo. We measured subjective psychedelic experiences (Hallucinogen Rating Scale (HRS), Mystical Experience Questionnaire (MEQ)) and mind-wandering (Amsterdam Resting-State Questionnaire (ARSQ)). EEG signals were assessed before administration (+0h), and 2 hours (+2h) and 4 hours (+4h) post-administration. Relationships between subjective and EEG effects were examined.

Results: Ayahuasca, compared to placebo, induced subjective experiences, including changed perception, cognition, emotion (HRS), mystical experiences (MEQ), and visual, discontinuous, and content-laden thinking (ARSQ). Ayahuasca, compared to placebo, changed EEG oscillations, including decreased global alpha as well as increased frontomedial delta and right posterior theta and beta. Under ayahuasca, lower theta correlated with higher mystical experiences (MEQ) and higher alpha correlated with lower Thoughts about Nothing (ARSQ). Baseline global EEG oscillations predicted ayahuasca-induced experiences, with lower theta linked to higher interoception (HRS Heart Beat, HRS Rush, ARSQ Somatic Awareness) and lower beta linked to higher positive emotionality (HRS Happy).

Conclusion: Ayahuasca induced consciousness alterations, visual, bodily, emotional, and mystical experiences, chaotic and meaningful mind-wandering, and decreased especially alpha. While acute theta seems inversely related to mystical experiences, baseline theta and beta seem to inversely predict interoception and emotionality.

This systematic review explores the role of the endocannabinoid system (ECS) in prodromal psychosis and its potential as a therapeutic target. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 22 studies published between 2000 and 2025 were analyzed, comprising preclinical research, genetic studies, neuroimaging investigations, and clinical trials. Converging evidence suggests that ECS alterations precede and potentially contribute to the development of psychotic symptoms, with CB1 receptor modifications and endocannabinoid levels correlating with symptom severity and transition risk to full-blown psychosis. Neuroimaging studies revealed reduced CB1 receptor availability in key brain regions in high-risk subjects, and intervention studies, particularly with cannabidiol-though its therapeutic mechanisms likely extend beyond ECS modulation to include dopaminergic and other neurotransmitter pathways-have shown promising results. Proposed mechanisms of action include stress response attenuation, neuroinflammatory modulation, neurodevelopmental stabilization, and normalization of the dopamine-glutamate interface. Despite limitations of existing studies, primarily small size and short duration, this review provides a solid foundation for developing ECS-targeted interventions as a promising approach to modify disease trajectory during the prodromal phase, potentially offering safer and more effective therapeutic options for individuals at clinical high risk for psychosis.

Background: Whether starting antidepressants (ADs) precipitates treatment-emergent mania (TEM) in young people with major depressive disorder (MDD) is still debated. A recent nationwide cohort study found no short-term risk, but its transferability to more diverse settings is unknown.

Methods: Using the TriNetX global electronic-health-record network, we emulated a target trial in children and adolescents aged 6-17 years with a first MDD diagnosis (2016-2024). Patients who initiated an AD within 3 months formed the exposed cohort, and those who did not served as controls. After 1:1 propensity-score matching, 105,728 participants (52,864 per group) were followed for 3 months. The primary outcome was a composite of new mania/bipolar diagnosis or lithium initiation.

Results: The exposed group had a significantly higher risk of the primary composite outcome compared to the unexposed group (45 vs. 27 events; Hazard ratio = 1.64, 95% confidence interval, 1.01-2.63, p = 0.041). However, it lost statistical significance when disaggregating the composite outcome, in landmark time-split analyses, and when restricting the cohort to patients with a prior history of healthcare encounters.

Conclusion: In a large, multinational real-world cohort, AD initiation was associated with a non-robust increase in short-term TEM risk. The observed association appeared susceptible to unmeasured confounding factors. These results underscore the importance of careful assessment and monitoring rather than indiscriminate AD use or avoidance in this population.

Objective: (-)-OSU6162 is an antagonist at dopaminergic D₂ receptors which - like other D₂ antagonists - dampens spontaneous activity in animals exploring a novel environment. However, unlike other D₂ antagonists, (-)-OSU6162 has unexpectedly been found to stimulate locomotor activity in inactive, habituated rodents. To what extent the compound may increase activity also in other situations characterised by reduced locomotion is unknown, and it has also not been clarified whether two other receptors also targeted by (-)-OSU6162 - serotonergic 5-HT_2A receptors and sigma-1 receptors - are involved in its unusual behavioural profile. The objective of the present study was to investigate the possible impact of (-)-OSU6162 on the pronounced inactivity in the form of freezing displayed by rats exposed to context-conditioned fear. For comparison, the effect of amphetamine - another dopamine-augmenting and activating compound - was also explored in the same paradigm.

Methods: The impact of (-)-OSU6162 and amphetamine on the expression of freezing was assessed in rats exposed to contextual fear conditioning using electrical foot shocks. It was also assessed whether the increase in activity observed in animals treated with (-)-OSU6162 could be countered by pretreatment with a D₂/D₃ antagonist (raclopride), a 5-HT_2A inverse agonist (MDL100907), or a sigma-1 receptor antagonist (BD1063).

Results: While (-)-OSU6162 markedly reduced freezing behaviour, amphetamine abolished it completely. The effect of (-)-OSU6162 was countered by raclopride but neither by MDL100907 nor by BD1063.

Conclusion: (-)-OSU6162 reduces the expression of context-conditioned fear displayed as freezing by a mechanism involving D₂ but not 5-HT_2A or sigma-1 receptors.

"Psychedelic research - Going global" is a Special Issue of the Journal of Psychopharmacology that has been compiled and published as a tribute to Dr. Roland R Griffiths in recognition of his pioneering and pivotal contribution to the field of psychedelic research. Dr. Griffiths was Professor in the Departments of Psychiatry and Neurosciences at Johns Hopkins University School of Medicine, and latterly, the founding director of the Center for Psychedelic and Consciousness Research. It is not an exaggeration to state that his discoveries, indefatigable support and advocacy laid the foundations of the global revival of psychedelic research. The issue commences with a tribute written by many of Dr. Griffiths' scientific colleagues and friends. This homage summarises the fundamental contribution Dr. Griffiths made to research in many areas of neuropharmacology and psychiatry, in addition to his more recent published work on the neurobehavioural and therapeutic effects of the psychedelics. Other articles in this edition comprise a mix of commentaries, reviews, and original research and are divided under the headings of non-clinical, clinical, and strategic/regulatory. This Special Issue attracted contributions by experts from around the world, and as a compendium of knowledge, it is an invaluable resource that provides a clear perspective on the current status of research in the field. Dr. Griffiths was a scientist who maintained an open mind to ideas and knowledge from every source, and we are certain he would fully endorse the concept of Psychedelic research - Going global.