Journal of Psychopharmacology最新文献

Background: Clozapine (CLZ) stands out for its unique receptor profile, making it more effective than other antipsychotics, especially in treatment-resistant schizophrenia (TRS). There is growing evidence supporting its use in schizoaffective disorder (SZD), although diagnostic challenges and drug characteristics have complicated the implementation of specific clinical trials.

Aim: Compare efficacy and tolerability of CLZ in real-world patients with TRS and SZD.

Methods: Prospective, pragmatic, three-month, evaluator-blinded clinical trial with two randomised controlled arms (TRS groups) and a third fixed arm (SZD group). The clinical response was assessed by monthly visits during which the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale (MADRS), Calgary Depression Scale for Schizophrenia (CDSS), Clinical Global Impression (CGI) and Udvalg für Kliniske Undersogelser were administered. One hundred twenty-seven participants (74.8% men, 25.2% women; 84 TRS, 42 SZD; mean age of 38.53) completed the follow-up.

Results: Patients treated with CLZ showed a greater reduction in all the PANSS subscales, MADRS and CDSS. In cases of SZD, there was a significant decrease in positive (F: 3.72, p < 0.05) and negative (F: 6.58, p < 0.01) symptoms, the overall score of PANSS (F: 5.64, p < 0.01) and YMRS (F: 12.01, p < 0.01). Patients using CLZ had a better subjective perception of their treatment (χ²: 17.29, p < 0.01). CLZ prescription was the only predictor of better outcomes across all the scales and improved substance use (dual disorders).

Conclusions: CLZ was effective in reducing psychotic and affective symptoms in patients with dual psychosis, with better outcomes in SZD compared with TRS.EudraCT protocol trial:2021-001278-44 (Comparative analysis of the effectiveness of clozapine in resistant schizophrenia and schizoaffective disorder; clinicaltrialsregister.eu/ctr-search/trial/2021-001278-44/ES).

Background: Schizophrenia is a serious psychiatric disorder that affects over 24 million people worldwide. Current therapies treat positive symptoms but show little efficacy for negative and cognitive symptoms, which can impact quality of life. Development of effective medication for this unmet medical need is imperative. Phytocannabinoids, such as cannabidivarin (CBDV), show promising results for the treatment of neurological disorders and have demonstrated efficacy in preclinical models, including seizure, autism, Rett, and Fragile X syndromes.

Aim: To determine the effect of CBDV on cognitive and social deficits in a sub-chronic phencyclidine (scPCP) rat model of relevance to schizophrenia.

Methods: Female Lister Hooded rats received scPCP (2 mg/kg, intraperitoneally (i.p.)) or saline for 7 days, followed by a minimum 7-day drug-free washout. Rats were then treated with saline, CBDV (2, 10, and 20 mg/kg, i.p.), or risperidone (0.1 mg/kg, i.p.) 60 minutes before novel object recognition (NOR), social interaction (SI), and reversal learning (RL) testing.

Results: scPCP significantly impaired performance in all three behavioural tests. Deficits in the NOR and SI tests were significantly improved by CBDV (10 and 20 mg/kg), while 20 mg/kg was effective at reversing the deficits in RL. Risperidone also significantly reversed the scPCP-induced deficit in the NOR, RL, and SI paradigms.

Conclusion: Here, we are the first to demonstrate the ability of CBDV to ameliorate cognitive and social deficits in the scPCP rat model of relevance for schizophrenia, suggesting further research is justified into the potential therapeutic benefits of CBDV in patients.

Background: Lithium is an effective treatment for recurrent affective disorders, but it has a narrow therapeutic window and requires regular serum concentration monitoring, especially during periods of dose titration. Numerous attempts have been made to develop dose prediction methods to facilitate initiation and swift achievement of effective levels, but these typically lack sufficient accuracy and can be challenging to implement in practice.

Aims: Develop a pharmacokinetic model of lithium to enable accurate dose prediction which is adaptable for clinical practice.

Methods: The calculator was developed from a one-compartment model, which assumes that lithium distributes into total body water and requires only simple body measurements (age, sex, height and weight) as input variables. Its performance was compared to six commonly cited dose prediction methods in patients with bipolar disorder taking lithium, using two independent research samples from the United Kingdom (n = 40) and Germany (n = 18).

Results: Our one-compartment model performed better than the previous models, accurately predicting the required lithium dose within one 200 mg lithium carbonate tablet. The mean prediction error was 10 mg (SD = 148 mg) in this sample of euthymic subjects taking stable doses of lithium sampled at steady state.

Conclusions: This model sets a new benchmark for lithium dose prediction accuracy and requires only simple body measurements. Further validation work in larger, diverse samples and future developments, such as the ability of the model to back-calculate levels from samples taken outside the recommended 12-hour window, may support its translation and use in practice.

Background: While research on novel therapeutic applications of ketamine is expanding, particularly in controlled settings, there is limited exploration of its consumption related to self-treatment of psychiatric conditions. This study investigated the characteristics of people who use ketamine and psychedelics for self-treatment of psychiatric conditions, providing insight into patterns of use within this population.

Methods: Utilising the 2020 Global Drug Survey, the analysis incorporates data from 5831 respondents who reported self-treating with unregulated drugs to treat diagnosed psychiatric conditions. We compare three groups: those self-treating with only ketamine (n = 242), ketamine and other psychedelics (n = 1072), and non-ketamine psychedelic only substances (n = 4517). Negative binomial regression was conducted to assess the impact of self-treating psychiatric conditions with ketamine and other psychedelics on the volume of recreational ketamine use.

Results: A high proportion (>60%) had prior psychiatric diagnoses, with depression and anxiety being the most common. People who used both ketamine and other substances reported higher festival and clubbing attendance than the other two groups. People who used ketamine and combined it with other psychedelics used it more frequently (incidence rate ratio (IRR): 0.729, 95% confidence interval (CI): 0.336-1.581), while those using non-ketamine psychedelics only showed a significant reduction in ketamine usage volume (IRR: 0.160, 95% CI: 0.079-0.322) compared to other groups. Almost half of the respondents sought online advice before starting ketamine self-treatment.

Conclusion: This study extends knowledge about various populations using ketamine for self-treatment purposes, proposes areas for future research and suggests online platforms as the most effective place for harm reduction resources relating to ketamine use.

Psychedelic clinical research is expanding rapidly. This review analyses the state and trends in psychedelic clinical trial registrations. A systematic search of ClinicalTrials.Gov was conducted on 11 November 2024, to identify registered interventional trials investigating (therapeutic) effects of serotonergic psychedelics (e.g. lysergic acid diethylamide [LSD], psilocybin, [5-MeO-]DMT). Analyses included a negative binomial regression to assess time trends and descriptive summaries of study characteristics. Outcomes included registration trends, substance distribution, study phase progression, sample and trial characteristics, geographical distribution and psychotherapy reporting. A total of 241 trials were identified, with registrations rising exponentially after 2006 and an acceleration post-2019. Two-thirds of trials are ongoing or planned. Psilocybin remains the most frequently studied substance and is most advanced towards approval, but short-acting psychedelics ([5-MeO-]DMT) have recently been introduced with a more focused clinical scope. Industry involvement is increasing, though university-led research still dominates. Reports of psychotherapy components increased following 2023 FDA recommendations, though no major improvements in intervention descriptions were observed. The rapid expansion of registered psychedelic clinical trials with diverse indications and substances reflects growing clinical interest. While university-led studies initiated early investigations and established a broad knowledge base, later industry involvement increasingly prioritizes scalability and economic considerations by adopting a focused approach towards clinical approval. Inconsistent reporting of psychotherapeutic components limits cross-study comparability and complicates systematic investigations into which combinations of therapeutic elements (type, timing, intensity) may optimize clinical outcomes. Future efforts should focus on complete and standardized trial reporting at study registration to minimize bias, reduce interpretative ambiguity and facilitate cross-trial comparisons.

Background: The treatment of major depressive disorder (MDD) with available antidepressant drugs is characterized by considerable ineffectiveness. Classical psychedelics such as psilocybin and N,N-dimethyltryptamine (DMT), which act primarily as 5-hydroxytryptamine 2A (5-HT_2A) receptor agonists, have shown preliminary efficacy for inducing long-term remission in MDD after one or two doses. GM-2505 is a novel, 5-HT_2A receptor agonist, developed for treating MDD.

Methods: In this single-ascending dose, randomized, placebo-controlled, double-blind study, we characterized GM-2505's safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) profile in 48 healthy participants.

Results: Single intravenous (IV) doses up to 20 mg demonstrated an acceptable safety profile of mild transient adverse events, short-term, non-clinically significant increases in blood pressure and pulse, and no significant changes in electrocardiographs, consistent with other 5-HT_2A receptor agonists. In general, GM-2505 C_max and AUC_last increased dose proportionally, with t_1/2 of 40-50 minutes. Generally, dose-dependent effects were observed for neuroendocrine hormones, several neuropsychological and neurophysiological measures, and subjective drug effects. Dose-related effects were also observed in resting-state electroencephalography (rsEEG), with decreased power in the low frequency rsEEG bands (theta and alpha), and increased in the high frequency bands (slow and fast gamma).

Conclusions: These PD findings were similar in nature and magnitude to other 5-HT_2A receptor agonists that have been studied clinically. In line with the GM-2505 PK profile, the duration of cardiovascular and subjective effects was shorter than psilocybin but longer than DMT, demonstrating a potentially more practical temporal profile for use in a supervised clinical setting compared to longer-acting 5-HT_2A receptor agonists, with an optimal dose range of 10-15 mg IV. Clinical trial (ISRCTN64428072) registration: https://www.isrctn.com/ISRCTN64428072.

Psychedelic research is progressing at breakneck speed and is creating new challenges for drug developers, regulatory authorities, and legislators. Most "classic" psychedelics undergoing clinical investigation are C-I controlled drugs with perceived high potential for abuse and no medical use. These and next-generation psychedelic drug-candidates require scientific and clinical assessment of their abuse and dependence potential before transitioning into a controlled drug schedule assigned to clinically approved drugs (C-II to C-V). Food and Drug Administration is likely to undertake the first regulatory assessment of a "classic" psychedelic, and it has led in disseminating advice on how to address the clinical and regulatory challenges. We have built on this foundation by discussing areas of abuse and dependence evaluation procedures that remain unclear or have not previously been covered. Psychedelic drug-candidates can be classified into three categories, that is, "classic" (well-known compounds including psilocybin, N,N-dimethyltryptamine and lysergic acid diethylamide) and "novel" psychedelics (e.g., analogues of known psychedelics), and located between them is what we describe as "grey area" psychedelics (e.g., non-hallucinogenic 5-HT_2A agonists). In this review, we set out clear proposals for categorizing psychedelic drug-candidates, describe the development pathway and abuse/dependence testing procedures appropriate to each, and, finally, offer our perspective on how these drugs will be evaluated and scheduled under the auspices of the U.S. Controlled Substances Act. Although we used the United States as a test case, the principles and analyses we used and the screening framework for assessing the abuse potential of psychedelic drug-candidates are universally applicable and can be easily adapted to the regulatory requirements and procedures in other countries.

Background: Impaired inhibitory control has been observed in regular cannabis users. Theories suggest that regular cannabis use is maintained by reward-driven behaviour, which may be underpinned by adaptations in neural reward and inhibitory control systems, thus increasing vulnerability to dependency.

Aims: This study investigated neural correlates of cannabis cue-specific inhibitory control in regular cannabis users and non-users using functional near-infrared spectroscopy (fNIRS).

Methods: Thirty regular cannabis users and thirty non-user controls completed two inhibitory control tasks (Go/No/Go and Stop-Signal Task), and a measure of attentional bias (Cannabis Stroop task). fNIRS recorded prefrontal and orbitofrontal haemodynamic responses (oxygenated haemoglobin and deoxygenated haemoglobin). Group comparisons and exploratory regressions examined cannabis use characteristics as predictors of behavioural and neural outcomes.

Results: No significant group differences were found in behavioural performance or haemodynamic activity across tasks. Exploratory regressions showed no significant associations between cannabis use characteristics and behavioural or neural outcomes after adjusting for covariates.

Conclusions: No evidence of impaired inhibitory control, attentional bias, or differences in prefrontal function were found in non-dependent cannabis users. Future studies should investigate whether such deficits emerge with heavier or dependent use.

Introduction: Antenatal depression (AD) affects 7%-13% of pregnant women, with adverse implications for mother and child. Treatment often requires pharmacological intervention, typically with selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear whether SSRIs introduce developmental consequences in children distinct from those associated with AD alone. This systematic review aims to elucidate the behavioral and neurological consequences of AD and prenatal SSRI exposure on child development.

Methods: A systematic review of databases PubMed, PsycInfo, Web of Science, and Scopus was conducted using the PICO framework. Studies were eligible if they included at least two comparison groups: children with exposure to only AD (AD-only) and those exposed to both AD and in utero SSRIs (AD + SSRI). A total of 14 articles were included.

Results: Studies report effects of both AD + SSRI and AD-only exposure on several measures. When compared to controls (CON), both AD + SSRI and AD-only displayed alterations in the corticolimbic system, abnormal language development, and increases in internalizing and externalizing problems. Specific to AD + SSRI were alterations in the corticothalamic system and impairment of psychomotor functioning. Specific to AD-only were steeper white matter volume increases across childhood and lower arousal scores as infants. No significant differences between AD + SSRI, AD-only, and CON were reported on attention and interference suppression. Notably, inconsistencies were found on several measurements, for example, IQ, cortical, and subcortical volume.

Conclusion: We present an updated review of the potential implications of AD and SSRIs on child development. Ultimately, a preponderance of observational studies and numerous confounding factors make their effects difficult to disentangle, underscoring the need for further research.