Journal of Psychopharmacology最新文献

Background: Risky decision-making is a cardinal feature of bipolar disorder (BD), yet no targeted pharmacotherapies exist for this behavioral deficit. Dopamine transporter knockdown (DAT KD) mice reproduce the DAT hypoexpression profile of BD and demonstrate pharmacologically sensitive, BD-relevant patterns of risky decision-making and hyperexploration in the cross-species translatable Iowa Gambling Task (IGT) and Behavioral Pattern Monitor (BPM), respectively. Agonists of the trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor that presynaptically modulates dopamine transmission, may normalize these deficits and thereby represent a novel therapeutic avenue for the management of BD.

Aims: Assessment of the impact of TAAR1 activation on BD-relevant behaviors in a mouse model of mania.

Methods: The effects of the TAAR1 agonist R05256390 (0, 0.3, and 1.0 mg/kg, i.p.; within-subjects) were first determined on unconditioned exploration in male and female DAT KD and wildtype (WT) littermate mice in the BPM and then on risky decision-making in the IGT (1.0 mg/kg).

Results: Consistent with people with BD, DAT KD mice exhibited hyperlocomotion, elevated specific exploration, and more linear movement in the BPM, plus elevated risk preference in the IGT. R05256390 (0.3 and 1 mg/kg) reduced locomotion in DAT KD males and WT females, respectively, as well as specific and diversive exploration across genotypes. TAAR1 activation also reduced risky choice in DAT KD mice while elevating this behavior in WTs.

Conclusions: These findings support the potential for TAAR1 agonists as novel treatments for hyperactivity and risky decision-making in BD, and suggest an inverted U-shaped relationship between dopamine tone and decision-making optimization.

Background: Major depressive disorder (MDD) is a globally prevalent condition associated with significant morbidity and cognitive dysfunction. Vortioxetine, a novel antidepressant with multimodal serotonergic activity, has shown potential advantages over conventional antidepressants in both efficacy and tolerability. This meta-analysis evaluates the efficacy, cognitive improvement, and safety profile of vortioxetine in MDD.

Methods: A comprehensive search of multiple search engines yielded 16 randomized controlled trials that studied the efficacy of vortioxetine and other antidepressants. About 3127 MDD patients in the vortioxetine group and 3102 in the control group were analyzed. Primary efficacy outcomes were changes in Montgomery-Åsberg Depression Rating Scale, Clinical Global Impression-Improvement, and Clinical Global Impression-Severity scores, and the secondary outcome measure was cognition using the digit symbol substitution test scores. Safety was assessed via reported adverse effects (AEs), including the treatment-induced sexual dysfunction. The sensitivity analysis was done excluding the study with a high impact.

Results: Vortioxetine demonstrated a small but significant reduction in depressive symptoms compared to placebo, but showed similar efficacy to duloxetine and venlafaxine. Excluding the high-impact study did not cause much variation in the findings. There was a small but statistically insignificant improvement in cognition with vortioxetine compared to the control group. Vortioxetine had a favorable safety profile with only mild symptoms reported. The most commonly reported symptom was nausea. Vortioxetine also showed a non-significant trend toward fewer sexual AEs.

Conclusion: Vortioxetine is an effective and well-tolerated antidepressant for the management of MDD. Though the tolerability was comparable to other antidepressants, there was a potentially lower incidence of sexual side effects. A further elaborate exploration in terms of dose-specific efficacy and cognitive improvement will be promising for optimizing individualized treatment strategies.

This perspectives piece reflects on some of the major scientific contributions in psychopharmacology, cognitive neuroscience, and public policy of Professor Barbara J. Sahakian, Commander of the Most Excellent Order of the British Empire (CBE). Her pioneering research has advanced the understanding of brain mechanisms, including neurotransmitter modulation, and psychological processes involved in cognition, emotion, and motivation, leading to novel treatments for disorders such as Alzheimer's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. She has also contributed to a better understanding of brain mechanisms underlying and psychological processes involved in these disorders. She has championed early detection of Alzheimer's disease through neuropsychological tools, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) test and contributed to identifying cognitive and neural changes in Huntington's disease gene carriers. Beyond clinical research, Sahakian has influenced public health policy through initiatives such as the UK Government Foresight Project on Mental Capital and Wellbeing and the National Institute for Health and Care Excellence guidelines on gambling-related harms. She has also led efforts in neuroethics and public engagement, co-authoring accessible science books and participating in global forums. Recent research emphasises preventative psychiatry, including lifestyle interventions, such as diet, sleep, social connection, and lifelong learning as preventive strategies for cognitive decline and mental health problems. Through interdisciplinary collaborations and mentorship, Sahakian continues to inspire the next generation of scientists to pursue innovative research for societal benefit in neuropsychopharmacology and cognitive neuroscience.

Background: Emerging evidence suggests that the cholinergic system, through its modulation of dopamine via muscarinic and nicotinic receptors, holds therapeutic promise in schizophrenia. Xanomeline (M1/M4 muscarinic agonist) with trospium (muscarinic antagonist) was approved by the US-FDA, alongside emerging M4 and nicotinic modulators. To date, no network meta-analysis (NMA) has evaluated these agents for schizophrenia. Hence, the present NMA was conducted to evaluate and compare the efficacy and safety of cholinergic modulators in schizophrenia.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses - NMA guidelines, we conducted a Bayesian NMA of randomized controlled trials (RCTs) from MEDLINE/PubMed, Embase, Web of Science, Cochrane, and International Clinical Trials Registry Platform (ICTRP). Eligible RCTs assessed cholinergic modulators versus placebo in adults with schizophrenia. The primary outcome was a change in positive and negative syndrome scale (PANSS) total scores; secondary outcomes included PANSS subscales, scale for the assessment of negative symptoms, clinical global impression-severity (CGI-S), and adverse events. Data were extracted independently, and the risk of bias (ROB) was assessed using the Cochrane ROB 2 tool. A Bayesian NMA was conducted using the "gemtc" package in R, with Surface under the Cumulative Ranking (SUCRA) scores used to rank efficacy.

Results: The present NMA included 30 RCTs (3128 participants) assessing 14 interventions across 4 groups versus placebo. Muscarinic agonists (Standardized mean difference (SMD): -0.61; 95%credible interval (CrI): -0.97, -0.26) and nicotinic agonists (SMD: -0.26; 95%CrI: -0.51, -0.01) significantly reduced PANSS total scores, with muscarinic agonists ranking highest (SUCRA: 95.41%). Tropisetron 5 mg and xanomeline 125 mg showed significant efficacy. Muscarinic agonists improved PANSS positive, negative, and CGI-S scores. No significant difference in adverse events was observed.

Conclusions: Tropisetron and xanomeline demonstrated better efficacy in reducing schizophrenia symptoms, offering a promising alternative to traditional antipsychotics with comparable safety. Further RCTs and NMAs are needed to confirm these findings and guide clinical practice.

Background: Despite multiple treatment options available for obsessive-compulsive disorder (OCD), the response still remains unsatisfactory due to various factors. Hence, there is a continuous need to explore newer treatment modalities for OCD. Neuroinflammation might be one such contributing factor.

Aim: We aimed to study the clinical outcome of early Celecoxib (Selective Cyclooxygenase-2 Inhibitor) add-on therapy to fluoxetine treatment in OCD over 8 weeks and explored the association of the outcomes with biochemical parameters, serum interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF).

Methods: Forty-four drug-naive patients diagnosed with OCD (as per International Classification of Diseases-10) were recruited and randomized into 2 groups of 22 participants each. The study participants received fluoxetine and celecoxib (800 mg/day), and the control group received fluoxetine and a placebo. The clinical variables were measured at 0, 2, 4 and 8 weeks using the standard Yale-Brown Obsessive Compulsive Scale (YBOCS) for severity of symptoms. Serum IL-6 and BDNF were assessed at 0 and 8 weeks.

Results: The study group showed a greater mean change (6.56 ± 1.04) of YBOCS scores over 8 weeks (p ⩽ 0.001, Hedge's g = 1.918). Response rate was higher in the study group (33%) than in controls (11.1%; Number Needed to Treat = 4.2). Reduction in YBOCS scores was positively correlated with the decrease in inflammatory marker (IL-6) in the study group (r = 0.478, p = 0.033). No significant side effects were observed.

Conclusion: Celecoxib holds promise as a potentially safe early add-on treatment in OCD for rapid improvement in psychopathology, with further research warranted in this area.

Clinical trial registration: The study was registered with the Clinical Trial Registry of India (Reference no. CTRI/2022/01/039407). https://ctri.nic.in/Clinicaltrials/rmaindet.php?trialid=64361&EncHid=59518.51563&modid=1&compid=19.

Introduction: Vascular dementia (VaD) is the second leading cause of major neurocognitive disorder and is frequently associated with behavioral and psychological symptoms of dementia (BPSD), which worsen clinical outcomes and increase caregiver burden. Despite their relevance, effective pharmacological treatments for BPSD in VaD are limited. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits anxiolytic, antipsychotic, and neuroprotective properties.

Objective: To evaluate the efficacy, tolerability, and safety of CBD in reducing BPSD in older adults with VaD.

Methods: This randomized, double-blind, placebo-controlled trial included 30 participants with VaD and clinically significant BPSD, who received either CBD (300 mg/day) or placebo for 4 weeks. Primary outcomes were changes in the Neuropsychiatric Inventory (NPI) and the Brief Psychiatric Rating Scale (BPRS) scores. Secondary outcomes included cognitive (Mini-Mental State Examination, Informant Questionnaire on Cognitive Decline in the Elderly) and functional (Katz Index, Lawton Scale) measures, along with adverse effects (Udvalg for Kliniske Undersøgelser scale). A mixed-design repeated measures analysis of variance with post hoc Sidak tests was used.

Results: CBD significantly reduced NPI scores (interaction: F(1.58, 44.31) = 3.61, p = 0.05, partial eta squared (ηp²) = 0.11) and BPRS scores (interaction: F(2.12, 59.43) = 4.02, p < 0.05, ηp² = 0.13) compared to placebo. No significant differences were observed in cognitive or functional outcomes. Adverse events were mild and similar between groups.

Conclusion: CBD was well tolerated and effectively reduced BPSD in VaD without cognitive or functional impairment. These findings warrant further trials with larger samples, extended durations, and dose-optimization strategies to confirm its therapeutic potential. This study was registered at the Brazilian Clinical Trials Registry (ReBEC; ID: RBR-686kmpz, available at https://ensaiosclinicos.gov.br/rg/RBR-686kmpz).

Little is known about whether 3,4-methylenedioxy-N-methamphetamine (MDMA) neurocognitive side effects improve with sustained abstinence. This study aimed to systematically review and synthesise the existing literature on the long-term neurocognitive side effects of recreational MDMA use after a minimum of 6 months of abstinence. We searched relevant databases utilising terms related to (1) MDMA and (2) neurocognition. A qualitative synthesis of study findings was organised with reference to the neurocognitive domains defined in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM5). Fourteen articles met the inclusion criteria, assessing learning and memory (n = 8), executive function (n = 10), complex attention (n = 5), language (n = 2) and perceptual motor function (n = 1). Meta-analysis and assessment of bias were undertaken only for the domain of 'learning and memory' and included five studies. People with current and previous MDMA use had poorer learning and memory performance compared to people who were MDMA-naïve (Hedges' g = -1.06 and -1.37, respectively); there was no significant difference between current and abstinent MDMA users (Hedges' g = 0.03). A longer period of abstinence did not demonstrate greater improvements or recovery in learning and memory. There was limited evidence to conclude that MDMA use is associated with neurocognitive impairments in other domains. Overall, these conclusions are based on low-quality findings.