Journal of Psychopharmacology最新文献

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.

Background: Chronic stress is prevalent in most societies, impairing cognition, mood, and social functioning. Research suggests that supplements containing extracts from Scutellaria baicalensis root and Crataegus laevigata fruits may offer support in this regard.

Aims: To investigate the acute and chronic effects of a S. baicalensis, C. laevigata, and magnesium/chromium containing herbal supplement on psychological well-being, cognition, and sleep in subjectively stressed but principally healthy adults.

Methods: Forty-three participants (35 analysed) aged 18-75 years received the herbal supplement and a placebo for 15 days. Psychological well-being, and sleep were measured after 7 and 15 days of treatment. Cognitive performance was evaluated following a bolus dose of two tablets and after 15 days, with and without an observed multitasking stressor.

Results: The herbal supplement significantly improved performance on a task of attention and working memory (as evidenced by a reduction in serial 3's subtraction errors) following an acute dose and improved working memory performance (an increase in the number of correct serial 7's subtraction) during the stressor, irrespective of dose. Cognitive effects were less consistent in the absence of the stressor. Chronic supplementation improved mood and anxiety, reducing total mood disturbance, anger/hostility, and Trait anxiety scores. A higher proportion of subjects experienced ⩾30% gains in social satisfaction scores after 7 days. No serious adverse effects were reported.

Conclusions: The herbal supplement is safe and enhances mood, reduces subjective anxiety, and improves cognition under stress, though cognitive effects are variable without stress exposure.The study was registered on clinicaltrials.gov (identifier: NCT05757050).

Background: Controlled laboratory studies demonstrate that caffeine acutely impairs sleep quality. However, the impact of daily caffeine intake, which is common in society, on community-derived physiological sleep measures is unknown.

Aims: Because good quality sleep is important for general health and well-being, we explored causal effects of habitual caffeine consumption on objective and subjective sleep variables collected at home.

Methods: We used dedicated, two-sample Mendelian Randomization (MR) and causal matching methods, including MR-Egger, inverse variance weighting, and weighted median, to analyze large community-based datasets taken from the UK Biobank (n = 485,511) and the HypnoLaus (n = 1702) cohorts.

Results: While self-rated sleep quality and morningness-eveningness did not differ, all statistical models revealed that four or more caffeinated beverages per day shorten total sleep time when compared to fewer caffeine containing drinks per day. The estimated reductions in sleep length varied from 11 to 229 minutes. Intriguingly, consistent with the homeostatic facet of sleep-wake regulation, the shorter sleep in high habitual caffeine consumers was characterized by increased non-rapid-eye movement sleep depth as measured by all-night electrical brain activity.

Conclusions: The data show that high habitual caffeine intake alters the characteristics of sleep in the general population, while sparing the major physiological principles of sleep-wake regulation possibly due to adaptation.

Background: Anxiety is a normal emotion representing a reaction to potential danger, whereas fear can be defined as a reaction to real, explicit danger. Anxiety-like behavior in animal models has been associated with differences in the serotonergic system.

Aims: To understand the roles of the 5-HT1A receptor in zebrafish anxiety-like behavior and sociality.

Methods: Adult zebrafish were treated with 8-OH-DPAT and subjected to the phototaxis (light-dark preference) assay, the novel tank test (NTT), or the social preference test. Separate cohorts were treated with increasing doses of 8-OH-DPAT, while 5-HT1A receptors were blocked with a silent dose of WAY 100635.

Results: 8-OH-DPAT (0.3 mg/kg) decreased anxiety-like behavior in the NTT, but increased it in the phototaxis (light-dark preference) assay, both considered assays for anxiety-like behavior for this species. The same dose decreased social approach in both the social investigation and social novelty phases of the social preference test. Blocking the 5-HT1A receptor with WAY 100635 (0.01 mg/kg) shifted the dose-response curve (0.03-3 mg/kg) for the NTT rightward.

Conclusions: These effects suggest a participation of the 5-HT1A heteroreceptors in zebrafish anxiety and social preference, modulating anxiety in a test-dependent way and decreasing sociality. Thus, the study of this receptor is important for a better understanding of anxiety-like behavior in zebrafish and its relationship with similar phenomena in vertebrates.

Background: This study intended to examine network homogeneity (NH) alterations in drug-naive patients with panic disorder (PD) before and after treatment and whether NH could serve as a potential biomarker.

Methods: Fifty-eight patients and 85 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. Patients were rescanned following a 4-week course of paroxetine monotherapy. NH was computed to evaluate intra-network functional integration across the Yeo 7-Network. Machine learning (ML) was employed to assess the diagnostic and prognostic potential of NH metrics. Transcriptome-neuroimaging association analyses were conducted to explore the molecular correlates of NH alterations.

Results: Compared with HCs, patients showed disrupted intra-network integration in the frontoparietal, default mode, sensorimotor, limbic, and ventral attention networks, with prominent NH alterations in the superior frontal gyrus (SFG), middle temporal gyrus (MTG), superior temporal gyrus (STG), somatosensory cortex, insular, and anterior cingulate cortex. Importantly, the SFG, MTG, and STG demonstrated cross-network abnormalities. After treatment, clinical improvement correlated with normalized NH in the SFG and additional changes in the inferior occipital gyrus and calcarine sulcus within the visual network. ML demonstrated the utility of NH for PD classification and treatment outcome prediction. Transcriptome-neuroimaging analysis identified specific gene profiles related to NH alterations.

Conclusions: NH reflects both pathological features and treatment-related changes in PD, providing a measure of network dysfunction and therapeutic response. Cross-network NH disruptions in hub regions and visual processing may reflect core neuropharmacological mechanisms underlying PD. ML findings support the potential of NH as a neuroimaging biomarker for diagnosis and treatment monitoring in PD.

Background: A brief inhalation of 35% CO₂ triggers subjective fear and physiological responses occurring during naturally occurring panic attacks (PAs). This CO₂ model enables to study effects of pharmacological interventions on experimental panic provocation and examine the biological mechanisms involved in PAs.

Aims: To provide a quantification of the effects of pharmacological interventions on the response to CO₂ inhalation, which was still lacking despite decades of research and numerous studies having addressed these effects.

Methods: A systematic search was performed to identify peer-reviewed papers reporting effects of pharmacological interventions to the 35% CO₂ inhalation. Multilevel meta-analyses were performed to quantify the effects of such interventions on self-reported anxiety and PA symptoms.

Results: Thirty-six studies, containing data of 980 participants (both panic disorder patients and healthy individuals), were included. Several studies reported effects of multiple pharmacological interventions, resulting in 48 effect sizes for the meta-analysis of the effects on anxiety and 34 for the effects on PA symptoms. Significant decreases in induced anxiety (-.55 (95% confidence interval (CI): -.81 to -.29), p < 0.0001) and PA symptoms (-0.31 (95%CI: -.51 to -.11), p = 0.0026) were seen after pharmacological interventions aimed at symptom reduction. Induced anxiety was significantly decreased (-.81 (95%CI: -1.13 to -.48), p < 0.0001) after pharmacological interventions that enhanced the serotonergic system.

Conclusions: This meta-analysis supports the notion that specific drugs can reduce the sensitivity to 35% CO₂ challenge, supporting a role for this procedure as experimental model to investigate panic pharmacology.