Journal of Psychopharmacology最新文献

Background: Research suggests that a greater perception of hostility in social cues increases aggression, and alcohol influences perception of social cues. Taken together, this could explain some instances of alcohol-related aggression. This study investigated whether social drinkers interpret faces as more hostile following acute alcohol compared to placebo, and whether alcohol influences the tendency to approach or avoid emotional facial expressions.

Methods: Regular non-dependent drinkers (N = 84) participated in a double-blind placebo-controlled experiment. Participants completed two sessions and were tested following an alcoholic drink (0.4 g/kg), and matched placebo. In each session, they completed tasks measuring hostile attribution bias (HAB) towards emotional faces (happy, sad, angry, disgust, surprise, and fear), and approach/avoidance tendencies towards emotional faces (angry, happy, sad and disgust).

Results: Alcohol did not affect global hostility ratings of emotional facial expression (p = 0.342). However, it did increase global hostility ratings of ambiguous emotional faces after alcohol (drink by intensity interaction; p = 0.002). At an emotion-specific level, happy faces were seen as more hostile after alcohol when compared to placebo (p = 0.009; irrespective of emotional intensity). Alcohol did not affect approach/avoidance tendencies when seeing emotional faces following alcohol.

Conclusions: These findings suggest that alcohol increases hostile judgements of ambiguous emotional faces. They also suggest that happy faces are perceived to be more hostile following alcohol. As an increased HAB when processing socially relevant information increases aggressive responding, this increased hostile perception of happy faces following alcohol may increase the likelihood of aggressive behaviour.

Psychedelic drugs are increasingly under investigation as potential therapeutic agents for mental health conditions and are being increasingly used recreationally. Psychedelic use may result in an episode of intense psychological distress, commonly referred to as a "bad trip." Bad trips represent a potentially volatile, erratic, and dangerous situation, which may, in extreme cases, require presentation to accident and emergency departments and psychiatric hospital admission. Managing such cases requires careful consideration, with priority given to non-pharmacological strategies. When these measures prove insufficient, an alternative approach may be necessary, one that can effectively attenuate or terminate the psychedelic state and restore psychological stability. Despite clinical relevance, there is no systematic evaluation of pharmacological interventions to terminate such experiences. This review identifies and critically appraises candidate medications with potential utility as abortive agents, including serotonin antagonists, drugs for psychosis, and select drugs for anxiety and depression. We review these agents, their mechanisms of action, pharmacokinetics, safety profiles, and applicability in acute care settings. Binding strength at the molecular level, potency to functionally block receptor-mediated effects, and lack of side effects are key considerations. We conclude by proposing a provisional framework for the pharmacologic management of adverse psychedelic experiences and highlight key priorities for future research.

Background: The trajectory and predictors of response under routine clinical care of esketamine nasal spray (ESK NS) over treatment-resistant depression (TRD) require elucidation.

Methods: This retrospective, longitudinal cohort study was conducted across three Spanish centers. Adults diagnosed with TRD who initiated ESK NS and completed at least the induction phase were included. Assessments occurred at baseline, weeks 2, 4, 8, 12, 16, and at discharge. Primary outcomes included depressive severity assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), functioning assessed with the Sheehan Disability Scale (SDS), and suicidal risk assessed with the Columbia-Suicide Severity Rating Scale (C-SSRS). Multivariable logistic regression examined several response predictors.

Results: The study included 50 patients (52% women). Significant improvements were observed in MADRS and SDS scores at every time point (all p < 0.001), with notable increases during weeks 8-16, coinciding with optimization phase. The median time to response was 8 weeks, and to remission was 16 weeks. The last observation across the entire cohort indicated response and remission rates of 70% and 68%, respectively. C-SSRS risk categories shifted early toward lower risk with no suicide attempts during monitored treatment. Higher Maudsley Staging Model scores, indicating greater refractoriness, independently predicted lower odds of response (OR: 0.50, 95% CI: 0.29-0.86) and remission (OR: 0.59, 95% CI: 0.36-0.97). Among those discharged, 86% remained clinically stable over approximately 10 months.

Conclusions: In real-world clinical setting, ESK NS produces progressive improvements in depressive symptoms and functioning that often consolidating beyond the induction phase, especially during optimization phase.

Rationale: The nature and role of the psychological support provided in psychedelic-assisted treatments for psychiatric disorders are currently the object of debate. How this support is conceptualized-as a vector for therapeutic change or framework for risk minimization-has far-reaching consequences in terms of how these treatments should be regulated, delivered, and studied.

Objectives: To determine whether psychological interventions in psychedelic trials meet accepted definitions of psychotherapy using a common factors framework. We assess whether self-described psychedelic-assisted psychotherapies align with psychotherapy criteria and whether trials where support is not defined as psychotherapy nonetheless embed psychotherapeutic elements.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched PubMed and PsycINFO in January 2024 for all available clinical trials of psilocybin, MDMA, or lysergic acid diethylamide reporting any psychological support. Articles were assessed against a 4-item common factors framework.

Results: We screened 224 records, reviewed 52 full-text documents, and included 29 clinical trials (449 patients). Of the 29 trials, 69% met all 4 factors. Of the 19 psychotherapy-labeled trials, 84% met all 4 factors. Of the 10 non-psychotherapy-labeled studies, 40% met 4 factors.

Conclusions: Findings indicate that the psychological interventions in most therapeutic psychedelic trials qualify as psychotherapy. We highlight the clinical implications in terms of clinician training and treatment timeframe. We emphasize the ethical imperative to measure and address the intervention complexity inherent to psychedelic trials, to optimize clinical outcomes and safeguard patients.

Introduction: This review provides an overview of Roland R. Griffiths' history of research, and his mentoring and collaborating approach to science that contributed to his impact in behavioral and neuropsychopharmacology and psychedelic medicines development.

Approach: The approach was to summarize studies in his major domains of research, including preclinical and clinical abuse liability assessment science, alcohol, benzodiazepines, caffeine, tobacco, and psychedelics. All the authors of this review were mentored by and collaborated with Griffiths-some over several decades-and were able to provide personal perspectives and insights into Griffiths' approach to science and scientific collaborations, including insights into how major research initiatives were conceived and evolved with personal anecdotes and quotes.

Overview: Roland Griffiths is widely described as a "scientist's scientist," driven by his powerful curiosity to explore new frontiers in behavioral biology and neuropharmacology, with a passion to pursue humanity-serving science. His methodical approach to research development and then systematic extension and assessment of the generalizability of findings contributed to the evolution of thinking and scientific methods for abuse liability assessment, policy, and regulation of alcohol and other sedatives, tobacco and nicotine, caffeinated products and other stimulants, and in his last 2 decades, psychedelics. His inclusive and collegial approach to science, mentoring, and collaborating fueled his creativity and productivity and a fountain of innovation and research that will go on in perpetuity. Nowhere is this more evident than at the Johns Hopkins Center for Psychedelic and Consciousness Research established in the last few years of his life, in part because of his remarkable scientific life.

Background: Current treatments for obsessive-compulsive disorder (OCD), including serotonin reuptake inhibitors and cognitive-behavioral therapy, are often insufficient. Psilocybin, a 5HT2a agonist psychedelic, has shown promise for treating OCD, but rigorous evidence is still needed.

Aims: This randomized clinical trial evaluated safety, tolerability, and benefit of multiple psilocybin doses in OCD patients.

Methods: Fifteen participants were randomized to receive 4 weekly sessions of high-dose (300 µg/kg), low-dose (100 µg/kg) psilocybin, or active placebo (lorazepam) in a double-blind Phase 1 (n = 5 per condition), followed by four additional high-dose sessions (single-blind Phase 2). OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS) following each session, and prospectively for 6 months. Safety was evaluated via adverse event systematic assessment, suicide severity rating, and psychosis screening.

Results: Psilocybin was generally well-tolerated, with no serious adverse events, or psychotic symptoms, and no significant changes in suicide severity scores. Psilocybin but not placebo significantly reduced YBOCS scores. At the end of 8-week treatment, after participants had received at least four high doses of psilocybin, 73.3% were responders (⩾35% reduction in YBOCS scores), with 40% in remission. These effects diminished but remained substantial at 6 months. Post hoc analysis of cumulative dosing correlated with YBOCS score reductions at the end of treatment.

Conclusions: Administration of up to eight doses of psilocybin in a clinical research setting appears to be safe and potentially effective for patients with OCD. Larger trials are needed to further support efficacy and refine treatment protocols.

Clinical trial registration: ClinicalTrials.gov ID NCT03300947.

Background: The continual emergence of novel synthetic cathinones poses significant public health concerns due to their unpredictable pharmacological profiles and potential for abuse. Among these, 4-F-3-Me-α-PVP-a newly identified analogue of α-PVP-has recently surfaced on the illicit drug market, yet its biological effects remain uncharacterized.

Aim: To provide the first comprehensive pharmacological evaluation of 4-F-3-Me-α-PVP.

Methods: In vitro transporter inhibition was assessed using HEK293 cells expressing human dopamine (DA), norepinephrine, and serotonin transporter (DAT, NET, or SERT). In male rodents, locomotor activity was measured after i.p. (mice) or s.c. (rats) administration. In vivo microdialysis in rats quantified extracellular DA in the nucleus accumbens. Rewarding and reinforcing effects were evaluated using conditioned place preference (CPP) in mice and intravenous self-administration (IVSA) in rats under fixed-ratio and progressive-ratio schedules.

Results: In vitro assays revealed that 4-F-3-Me-α-PVP acts as a potent DAT and NET inhibitor, with additional, though weaker, activity at SERT. In vivo, 4-F-3-Me-α-PVP significantly increased locomotor activity in male rodents (10 and 30 mg/kg in mice; 3 mg/kg in rats). Importantly, 4-F-3-Me-α-PVP also increased extracellular DA levels in the rat nucleus accumbens (3 mg/kg, s.c.), pointing to its potential for abuse. Behavioral assays further demonstrated rewarding and reinforcing effects in rodents, with significant CPP in mice at all doses tested and dose-dependent IVSA in rats observed under both fixed-ratio and progressive-ratio schedules.

Conclusions: Collectively, these findings indicate that 4-F-3-Me-α-PVP possesses substantial psychostimulant and abuse-related effects in rodents, underscoring the need for regulatory vigilance and continued investigation into emerging synthetic cathinones.

Background: Anxiety is characterized by hypervigilance, distractibility and selective processing of negative information. There is growing evidence that prefrontal function underlies biases in threat processing and attention control in anxiety. We examined the effect of 20 min of 2 mA dorsolateral prefrontal cortex transcranial direct current stimulation (tDCS) (bipolar-balanced montage) on subjective anxiety, autonomic arousal and threat processing in the 7.5% CO₂ experimental medicine model of anxiety.

Methods: A between-subjects healthy volunteer double-blind randomized design compared 2 mA tDCS stimulation of the PFC versus sham tDCS on subjective anxiety, autonomic arousal and antisaccade performance during 7.5% CO₂ challenge.

Results: tDCS did not moderate subjective and autonomic response to CO₂ challenge. tDCS reduced erroneous eye movements toward threat images relative to neutral images.

Conclusion: Twenty minutes of active 2 mA tDCS over the left dorsolateral prefrontal cortex may reduce threat processing biases during experimentally induced anxiety and could help target early positive changes in emotion processing.

Background: Cognitive impairments are prevalent in schizophrenia and are associated with functional outcomes, yet there are currently no approved treatments to address these deficits. Roflumilast, a phosphodiesterase 4 inhibitor, has previously been shown to improve verbal memory in healthy and schizophrenia populations.

Aims: This study aimed to investigate the neural changes which occur with roflumilast administration and which may underpin these cognitive effects.

Methods: Ten participants with schizophrenia were administered 8 days of placebo, 100 and 250 µg of roflumilast in a 3-way crossover design. We present analyses of seed-based functional connectivity (FC) with bilateral hippocampus (HC) and regional cerebral blood flow measured with arterial spin labelling.

Results: Results indicated that 250 µg roflumilast was associated with significantly greater FC between HC and prefrontal cortex (PFC) compared to placebo. There was also a significant increase in cerebral blood flow with 250 µg roflumilast relative to placebo in the dorsolateral PFC and HC.

Conclusions: These changes provide preliminary support for a cerebral mechanism of action of roflumilast, which includes modulation of brain regions involved in memory known to be impaired in patients with schizophrenia. This data supports existing findings suggesting roflumilast has the potential to be an effective treatment for cognitive impairments in schizophrenia.

Background: The efficacy of clozapine in treatment-resistant schizophrenia is limited by significant pharmacokinetic variability due to genetic polymorphisms, drug interactions, and environmental factors, necessitating personalized dosing strategies.

Aims: This study aimed at developing a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model integrating genetics and clinical factors to guide precision dosing of clozapine.

Methods: A simulation study was conducted to develop a PBPK/PD model using R (mrgsolve) to simulate clozapine plasma and brain concentrations, multireceptor occupancies, clinical efficacy, and safety risks (agranulocytosis, seizures, cardiotoxicity). The model incorporated multiple genetic profiles (CYP1A2, CYP2D6, and ABCB1), drug interactions (with fluvoxamine and carbamazepine), smoking effects, and ethnic-specific adjustments. Simulations evaluated steady-state outcomes, therapeutic drug monitoring (TDM) protocols, and optimal dosing. Validation used literature datasets, with sensitivity analyses assessing enzyme activity impacts.

Results: The model demonstrated high predictive accuracy, with simulations revealing substantial variability in clozapine concentrations, primarily driven by CYP1A2 polymorphisms. Model-informed genotype-guided dosing achieved therapeutic levels, markedly improving clinical response and significantly reducing adverse events. Fluvoxamine posed high-risk interactions, particularly in poor metabolizers, while smoking reduced concentrations, requiring dose adjustments. Ethnic-specific dosing addressed population variability, with tailored recommendations for special populations (elderly, pediatric). Sensitivity analyses identified glutathione status as a key determinant in agranulocytosis risk, underscoring the importance of genetic polymorphisms in glutathione S-transferases (GSTT1 and GSTM1) in safety outcomes.

Conclusions: This PBPK/PD model provides a robust framework for precision clozapine therapy, supporting genotype-guided dosing and TDM to optimize efficacy and safety. The implementation of pharmacogenetic testing could transform clinical practice, offering a framework for optimized resource utilization and risk minimization.