Journal of Psychopharmacology最新文献

Intranasal administration of oxytocin is emerging as a potential pharmacological option for mitigating social difficulties and regulating stress in autism spectrum disorder. However, initial single-dose and multiple-dose trials showed mixed results, with some demonstrating improvements in social and repetitive behavior and others showing no benefit over placebo. This perspective aims to elucidate factors contributing to this variability and to highlight pitfalls and opportunities in the field. We identified two major factors: design-related elements and individual participant characteristics. Pertaining to design-related elements, optimal dosing regimens have yet to be established, but appear to favor moderate intervention durations (i.e., 4-6 weeks) with intermittent and intermediate dosing (i.e., 24-32 IU every other day). Also, the context of the intervention seems crucial, as enhanced outcomes are mainly observed when oxytocin administration is paired with a socially stimulating and supporting environment. In addition, more adequate outcome measures have to be established to effectively assess oxytocin's impact, including behavioral scales and objective biophysiological markers tapping into stress and neurophysiological regulation. Future research should also account for individual participant differences in biological sex, developmental stage and cognitive and adaptive functioning, and incorporate (epi)genetic screening to identify responders. Overall, refining study designs and personalizing intervention protocols are essential for optimizing oxytocin's prosocial and anxiolytic effect in autism.

Background: Recent clinical trials suggest promising antidepressant effects of psilocybin, despite methodological challenges. While various studies have investigated distinct mechanisms and proposed theoretical opinions, a comprehensive understanding of psilocybin's neurobiological and psychological antidepressant mechanisms is lacking.

Aims: Systematically review potential antidepressant neurobiological and psychological mechanisms of psilocybin.

Methods: Search terms were generated based on existing evidence of psilocybin's effects related to antidepressant mechanisms. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, 15 studies were systematically reviewed, exploring various therapeutic change principles such as brain dynamics, emotion regulation, cognition, self-referential processing, connectedness, and interpersonal functioning.

Results: Within a supportive setting, psilocybin promoted openness, cognitive and neural flexibility, and greater ability and acceptance of emotional experiences. A renewed sense of connectedness to the self, others, and the world emerged as a key experience. Imaging studies consistently found altered brain dynamics, characterized by reduced global and within default mode network connectivity, alongside increased between-network connectivity.

Conclusions: Together, these changes may create a fertile yet vulnerable window for change, emphasizing the importance of a supportive set, setting, and therapeutic guidance. The results suggest that psilocybin, within a supportive context, may induce antidepressant effects by leveraging the interplay between neurobiological mechanisms and common psychotherapeutic factors. This complements the view of purely pharmacological effects, supporting a multileveled approach that reflects various relevant dimensions of therapeutic change, including neurobiological, psychological, and environmental factors.

Background: Options for 'treatment-resistant bipolar depression' (TRBD) are limited. Two small, short-term, trials of pramipexole suggest it might be an option.

Aims: To evaluate the clinical effectiveness and safety of pramipexole in the management of TRBD.

Methods: A multi-centre randomised, double-blind controlled trial including participants ⩾18 years old with TRBD (failure to respond, tolerate or clinical contraindication/patient refusal of ⩾2 of quetiapine, olanzapine, lamotrigine or lurasidone) randomised 1:1 to pramipexole (max 2.5 mg/day salt weight) or placebo added to ongoing mood stabiliser (n = 39). Primary outcome: Quick Inventory of Depressive Symptoms, Self-rated (QIDS-SR) at 12 weeks. Up to 48 weeks follow-up.

Results: Pramipexole (n = 18) was associated with a greater reduction in QIDS-SR score at 12 weeks versus placebo (n = 21, 4.4 (4.8) vs 2.1 (5.1)): a medium sized (d = -0.72) but not statistically significant difference (95% CI: -0.4 to 6.3, p = 0.087). Similarly, there was a non-significant approximate 2-point (d = -0.76) improvement in pleasure at 6 weeks (95% CI: -0.11 to 4.20). Significant advantages of pramipexole on QIDS-SR score (6.28 points: 95% CI: 1.85-10.71) and psychosocial function (5.36 points: 95% CI: 0.38-10.35) were seen at 36 weeks post-randomisation, and on the response (46% vs 6%; p = 0.026) and remission (31% vs 0%; p = 0.030) rates at trial exit (48 weeks or last available data after 16 weeks for those affected by the early study closure). Hypomania ratings were significantly higher at 12 weeks. Otherwise, pramipexole was well tolerated.

Conclusions: Clinically large, but statistically non-significant, effects of pramipexole on depression at 12 weeks, with significant longer-term benefits on mood and function were observed. Pramipexole use was complicated by dose titration and increased hypomanic symptoms. The small sample size limits interpretation. Furthermore, larger randomised placebo-controlled trials are warranted.

Objective: Therapeutic drug monitoring (TDM) indicators have been suggested to predict overall outcome responses to olanzapine (OLZ) treatments in terms of efficacy and metabolic syndrome. This study aimed to investigate whether paraoxonase-1 (PON-1) activity can be used to predict schizophrenia patient outcomes.

Methods: Schizophrenic patients (N = 50) aged between 20 and 65 years who received OLZ treatment were recruited, and their Positive and Negative Syndrome Scale scores, PON-1 activity, and olanzapine drug levels normalized by dose (OLZ/D) and its metabolite N-desmethyl-olanzapine (DMO), together with biochemical parameters, were determined.

Results: PON-1 activity and OLZ/D were significantly correlated in 50 patients (correlation coefficient, r = 0.355; p = 0.0115). There was also a statistically significant correlation between the ratio of PON-1 activity normalized by homocysteine (Hcy) and OLZ/D (correlation coefficient r = 0.361; p = 0.01) and a significant negative correlation between the ratio of PON-1 activity normalized by Hcy and triglyceride/high-density lipoprotein (TG/HDL; correlation coefficient r = -0.328; p = 0.02).

Conclusions: PON-1 activity can be used as an alternative tool for monitoring TDM through the measurement of OLZ together with its metabolite, DMO, to identify patients who have higher activity. Those who show an optimal response or who have lower activity might have greater cardiometabolic risk under long-term olanzapine treatment. Longitudinal monitoring is warranted to confirm such observations.

Background: Delirium is a severe neuropsychiatric disorder associated with increased morbidity and mortality. Numerous precipitating factors and etiologies merge into the pathophysiology of this condition which can be marked by agitation and psychosis. Judicious use of antipsychotic medications such as intravenous haloperidol reduces these symptoms and distress in critically ill individuals.

Aims: This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model for the antipsychotic medication haloperidol; estimate plasma and unbound interstitial brain concentrations for repetitive haloperidol administrations used in hyperactive delirium treatment; determine dopamine receptor occupancy and antagonism under these conditions; and correlate these results with Richmond Agitation-Sedation Scale (RASS) scores and the risk of developing extrapyramidal symptoms (EPSs).

Methods: The PBPK model for single and repetitive administrations of peroral and intravenous haloperidol was developed with PK-Sim software. The pharmacodynamic (PD) model for RASS scores with haloperidol unbound interstitial brain concentration passed as the regressor was developed with the MonolixSuite 2021R platform.

Results: Peak haloperidol plasma and unbound interstitial brain concentrations following a single 2 mg intravenous dose are 32 ± 5 nM and 2.4 ± 0.4 nM. With repetitive administrations, dopamine receptor occupancy is 70%-83% and D2_LR antagonism is 1%-10%. Variations in dopamine receptor occupancy correlate with changes in RASS scores in individuals with hyperactive delirium. There is a linear association between the odds ratio of developing EPS and peak D2_LR antagonism as functions of dopamine receptor occupancy.

Conclusions: Haloperidol dopamine receptor occupancy time course and D2_LR antagonism parallel RASS score changes and EPS risk, respectively.

Background: Hypnotics have been linked to suicidal behaviors. While existing evidence has established findings of associations, more knowledge is needed regarding benzodiazepine (BZD) and non-benzodiazepine (n-BZD) hypnotics.

Aim: To examine whether individuals in treatment with hypnotics had higher rates of suicide and suicide attempts than those not in treatment.

Methods: A longitudinal nationwide cohort design was applied to individual-level register data, including all individuals aged 15+ years who lived in Denmark from 1995 to 2021. Incidence rate ratios (IRR) for suicide and suicide attempts were estimated using Poisson regression models. Using the National Prescription Registry, individuals who redeemed prescriptions for hypnotics at pharmacies were identified. Death by suicide was identified in the Cause of Death Register.

Results: A total of 7,311,630 individuals were observed over 122,681,369 person-years. In all, 678 males and 553 females died by suicide while in treatment with BZD, resulting in respective adjusted IRRs of 2.1 (95% CI: 1.9-2.4) and 2.6 (95% CI: 2.3-3.0), when compared to those not in treatment. A total of 1774 males and 1212 females died by suicide while in treatment with n-BZD and the adjusted IRRs were 3.4 (95% CI: 3.1-3.7) and 3.6 (95% CI: 3.4-3.9), respectively.

Conclusions: While confounding by indication is likely to be a major contributor, the fact that individuals in treatment with BZD or n-BZDs had higher rates of suicide and suicide attempts when compared to those not in treatment emphasizes the need to carefully monitor their mental state.

Introduction: Eating disorders are characterized by maladaptive eating behaviors and preoccupations around body shape, weight, and eating. The serotonin system has been among the most widely studied neurobiological factors in relation to eating disorders. Recent research also highlighted the role of oxytocin.

Aims and methods: This article aims to review animal and human studies on the involvement of central serotonin and oxytocin, and their interplay in eating disorders in particular. We synthesize results from studies using animal models of eating disorders and from research conducted in healthy individuals and clinical populations.

Results/outcomes: Altered serotonin neurotransmission and oxytocin levels in the brain-particularly in the hypothalamus, brainstem, and limbic regions-were associated with disturbances in eating behaviors and related maladaptive cognitions and emotions. These brain regions were found to constitute a typical neural network through which both central serotonin and oxytocin might operate in a bidirectional manner.

Conclusions/interpretation: Based on the preceding findings, we describe a developmental biopsychosocial model relevant to eating disorders, including the role of serotonin-oxytocin interactions in the brain. While it is clear that eating disorders are multifactorial in which many biopsychosocial pathways are involved, the current review highlights the importance of well-designed translational research when studying mechanisms of serotonin-oxytocin interactions in the brain. Such research would help to better understand the effects of joint central oxytocin and serotonin administration as a possible preventive or therapeutic intervention for eating disorders.

Ketamine has recently been shown to be non-inferior to electroconvulsive therapy (ECT), one of psychiatry's most effective treatments for depression. Given the novelty of ketamine as well as its interventional nature, ketamine is currently viewed as an alternative to ECT and as such, considered a third-line agent for treatment-refractory depression. However, available data suggest that ketamine carries a low side-effect burden and is better tolerated than many second-line augmentation strategies for depression. With this combination of higher efficacy and lower side-effect burden in conjunction with what is known about treatment outcomes in relation to the duration of untreated illness, it is in the best interest of patients for the field of psychiatry to evaluate ketamine as a second-line augmentation strategy for refractory depression.

Background: Ketamine has received attention owing to its rapid and long-lasting antidepressant effects; however, its clinical application is restricted by its addictiveness and adverse effects. S-ketamine, which is the S-enantiomer of ketamine, is considered safer and better tolerated by patients than ketamine.

Aims: This study aimed to identify the key gene targets and potential signalling pathways associated with the mechanism of S-ketamine in major depressive disorder (MDD) treatment.

Methods: The GSE98793 dataset was extracted from the Gene Expression Omnibus database, and differentially expressed genes were identified in blood samples from patients with MDD and healthy individuals. The hub genes among the differentially expressed genes were identified and enrichment analysis was performed. The therapeutic targets and related signalling pathways of S-ketamine in MDD treatment were analysed. The 3D structures of the target proteins were predicted using AlphaFold2, and molecular docking was performed to verify whether S-ketamine could be successfully docked to the predicted targets. A quantitative polymerase chain reaction was performed to determine the effect of ketamine on the screened targets. Among 228 target genes annotated using pharmacophore target gene analysis, 3 genes were identified and 2 therapeutic signalling pathways were discovered.

Results: S-ketamine exerts downregulatory effects on TGM2 and HSP90AB1 expression but exerts an up-regulatory effect on ADORA3 expression. The protein structures of the therapeutic targets were successfully predicted using AlphaFold2.

Conclusions: S-ketamine may alleviate depression by targeting specific genes, including TGM2, HSP90AB1 and ADORA3, as well as signalling pathways, including the gonadotropin-releasing hormone and relaxin signalling pathways.