Therapeutic Advances in Psychopharmacology最新文献

Background: Valproic acid (VPA)-induced hyperammonemia is a common condition whose clinical presentations can range from asymptomatic cases to severe hyperammonemic encephalopathy. This can happen at any stage of treatment and is difficult to predict, as it often occurs without any alteration in liver function tests.

Objectives: We aimed at exploring the association between hyperammonemia and clinical/biochemical characteristics among inpatients with mental disorders.

Design: This cross-sectional study was conducted on adults consecutively admitted to two acute psychiatric inpatient units in the Milan metropolitan area from October 2022 to October 2024. All participants were treated with oral VPA during hospitalization.

Methods: Sociodemographic, clinical, and biochemical data were retrieved from clinical interviews and electronic chart reviews. Univariate analyses and multiple logistic regressions were used to assess the association between hyperammonemia and candidate variables.

Results: We included 130 participants (mean age: 38.2 ± 15.3 years; males: 77.7%). Bipolar I (36.9%), personality (31.5%), and schizophrenia spectrum (20.8%) disorders were the most common diagnoses. Mean serum ammonium levels were 46.4 ± 17.5 μmol/L, with hyperammonemia observed in 52 (40.0%) participants. Univariate analyses estimated an association of hyperammonemia with male sex, the concomitant use of 2+ medications (besides VPA), treatment with antipsychotics, and a diagnosis of alcohol use disorder (AUD). No further clinical/biochemical features were associated with hyperammonemia, including serum VPA levels and daily dose of VPA. Regression models showed that the concomitant use of 2+ other medications (coeff. = 1.03, p = 0.018) and AUD (coeff. = 1.32, p = 0.018), but not male sex (p = 0.12) and the use of antipsychotics (p = 0.09), were associated with hyperammonemia.

Conclusion: Our findings highlight the potential influence of AUD and polypharmacy on the risk of hyperammonemia in subjects treated with oral VPA. Additional studies are needed to confirm these associations and to test their potential causal role in hyperammonemia. Clinical implications for limiting polypharmacy in people treated with oral VPA should be considered.

Background: Results from contemporary clinical trials of serotonergic psychedelic therapies have led to an increasing focus on their potential clinical use across mental disorders. However, studies examining mechanisms of clinical response to psychedelic therapy in psychiatric populations are limited. This review aimed to synthesize evidence from studies examining biomarkers of clinical response to psychedelic therapies.

Data sources and methods: A systematic search of four databases (MedLine, PsycInfo, EMBASE, and Web of Science) for studies investigating treatment response to psychedelic therapies in psychiatric populations that included both clinical outcomes and a related biomarker was conducted on January 10, 2024. Studies were included if they reported on prospective clinical trials involving the use of a psychedelic in participants diagnosed with any Diagnostic and Statistical Manual or International Classification of Diseases mental disorder, where a biological marker was measured and evaluated in association with treatment response.

Results: Nine studies investigating the effects of Ayahuasca and psilocybin in major depressive disorder and treatment-resistant depression were included in this review. Several potential biomarkers of response were explored through neuroimaging and blood samples, with significant associations found for serum brain-derived neurotrophic factor, serum C-reactive protein, cerebral activation of the amygdala, and functional connectivity between regions such as the ventromedial prefrontal cortex, anterior cingulate cortex, and posterior cingulate cortex.

Conclusion: Results of small studies suggest associations between several putative biomarkers and treatment response to psychedelic therapies. Future trials of psychedelic therapies should integrate biomarker assessment in longitudinal designs to advance the understanding of their mechanism of action in mental disorders.

Trial registration: This study protocol was registered to PROSPERO under the number CRD42021291171.

Background: Patients treated in early intervention for psychosis programs have better treatment outcomes and higher rates of long-acting injection (LAI) antipsychotic medication utilization (20%-50%) versus treatment as usual. These programs usually serve patients for 2-3 years, then most patients are discharged to other mental health services and studies of patients with longer-standing schizophrenia suggest switching to oral medications may be common. However, following patients post-discharge is complicated by the challenges of migrated patient records across clinical services and providers.

Objectives: To examine whether LAI use continues after discharge from an early intervention service for psychosis.

Design: This study was a retrospective cohort study examining the effects of continuation or discontinuation of LAI therapy in individuals who have completed treatment in an early intervention service (EIS) for psychosis.

Methods: A retrospective cohort was created from a group of individuals discharged from EIS for psychosis over a 3-year period from January 1, 2016 to December 31, 2018 and followed for mental health outcomes and antipsychotic medications prescribed for a subsequent 2-year period at discharge, 6, 12, 18, and 24 months post-discharge.

Results: Of 85 subjects discharged from three sites in three different provinces in Canada for whom full follow-up could be recorded, 60 subjects remained on LAI medications after 24 months (71%). The average age of the cohort was 22 years (SD 4.7) at admission to an EIS. At discharge, the most commonly used LAI was aripiprazole, and most subjects were maintained on the same formulation at 24 months, if still on LAI. Reasons for discontinuation were predominantly patient preference. Significant differences in clinical outcomes, measured through reduced rehospitalization were seen for those who remained on LAI as compared to those who did not.

Conclusion: LAI adherence is still strong 24 months after discharge from an EIS for psychosis.

Background: Job-related stress and its extreme form, burnout, continue to affect almost half of all frontline healthcare workers and first responders. Current treatments are inadequate.

Objectives: To evaluate a model of ketamine-assisted psychotherapy (KAP) delivered in a group format to address symptoms of anxiety, depression, trauma, and burnout via repeated measures of the Generalized Anxiety Disorder (GAD)-7, Patient Health Questionnaire (PHQ)-9, PTSD Checklist (PCL)-5, and Maslach Burnout Inventory (MBI).

Design: A retrospective cohort analysis of KAP's effect on GAD-7-item scale, PHQ-9-item scale, PTSD Checklist for DSM-5 (PCL-5), and MBI. GAD-7, PHQ-9, and PCL-5 were administered prior to the first group meeting, on the last group date, and 2 weeks after the completion of the final session. MBI was measured twice, as a pre- and post-intervention test. Mystical Experience Questionnaire (MEQ-30) was collected at each integration.

Methods: Participants were recruited via self-referrals and professional collaborations. Participants were screened into groups of six after completing a medical evaluation to rule out contraindications. The seven-week program included three ketamine sessions and four group psychotherapy sessions. Descriptive statistics of the cohort, pre- and post-KAP measurement comparisons, regression modeling, and visualizations were prepared.

Results: Median age was 41 years (24-60), 44% female, and 3% transgender. Participants were 97% White and 3% Hispanic. Many were receiving treatment for depression (59%), anxiety (50%), PTSD (34%), addictive disorders (37%), and other behavioral health conditions (37%). Median pre- versus post-KAP scores for GAD-7 (9.5 vs 6, p = 0.003), PHQ-9 (12 vs 5, p < 0.001), PCL-5 (27 vs 10, p < 0.001), and all three subcomponents of MBI were improved. The last value of MEQ-30 (75 vs 105, p < 0.001) was higher than the first.

Conclusion: KAP in group settings may offer a rapid reduction in depression, anxiety, and trauma-related symptoms. Adverse events were rare. This psychedelically oriented treatment model may represent a viable intervention for epidemic job-related stress in the healthcare workplace and larger controlled studies are warranted.

Background: Clozapine is the most effective drug for schizophrenia and is the only drug indicated for use in patients with treatment resistance. The therapeutic range of clozapine is narrow with extensive interindividual differences in serum levels at similar dosing, mainly due to variability in hepatic metabolism mediated by several cytochrome P450 (CYP) enzymes. Tobacco smoking is the most important environmental factor determining clozapine metabolism, while the effect of pharmacogenetic variability is unclear.

Objectives: To investigate the impact of CYP1A, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and NFIB alleles on clozapine levels stratified by smoking status in a large patient population.

Design: This is a retrospective naturalistic/observational study.

Methods: The study population was included from the therapeutic drug monitoring/pharmacogenetics service at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, during January 2005-November 2024. We assessed the influence of CYP1A rs247229 T, CYP1A2*1F, CYP2C19, CYP2D6, CYP3A4*22 and CYP3A5*3, and NFIB rs28379954 C genetic variants on clozapine dose-adjusted serum concentrations (CD) in both smokers and nonsmokers.

Results: The study comprised 663 participants (55% smokers). CYP1A T variant was significantly associated with reduced clozapine serum levels, compared to CYP1A CC genotype, both among smokers (-15%, p = 0.010) and nonsmokers (-16%; p = 0.011). Moreover, among smokers, participants with NFIB C variant had 40% reduced clozapine CD compared to participants with NFIB TT (p < 0.001), whereas carriers of the CYP3A5*1/*1 genotype exhibited a 37% lower clozapine CD compared to CYP3A5*3/*3 carriers (p = 0.024) among nonsmokers. CYP1A2*1F, CYP2C19, CYP2D6, and CYP3A4*22 variants did not have any significant impact on clozapine CD, regardless of smoking habits.

Conclusion: The CYP1A T, NFIB C, and CYP3A5*1 alleles have significant impact on clozapine serum levels. Incorporating genotype information for these variants, together with patient smoking status, would improve algorithms for precision dosing of clozapine.

Psychedelic-assisted therapy (PAT) has typically been evaluated using conventional randomised controlled trials (RCTs), which assess treatment efficacy under highly controlled conditions. However, PAT constitutes a complex intervention, integrating pharmacological, psychotherapeutic and contextual elements that interact dynamically with patient experiences and healthcare settings. Conventional RCTs, designed for simple interventions, may fail to capture these complexities. Pragmatic trials, by contrast, evaluate interventions under real-world conditions, assessing their effectiveness across diverse clinical environments and patient populations. This position paper advocates for the application of the UK Medical Research Council's (MRC) framework for complex interventions to the development and evaluation of PAT. This framework emphasises the necessity of articulating the underlying theory of therapeutic change, structuring intervention development into defined phases, accounting for contextual interactions and incorporating stakeholder perspectives throughout the research process. We argue that employing pragmatic trial designs, guided by the PRECIS-2 tool, will better align PAT research with the practicalities of healthcare delivery and facilitate the translation of research findings into clinical practice. Further, we address the philosophical divergence in the field between conceptualising PAT as primarily pharmacological versus psychotherapy-augmented, noting the implications of these positions for trial design and interpretation. We propose the integration of qualitative methodologies, adaptive trial designs and comparative effectiveness research to refine PAT interventions and address limitations inherent in conventional double-blind RCT approaches. Finally, we advocate for a pluralistic evidentiary model, combining academic and community-led research, to support the rigorous, equitable and sustainable development of psychedelic-assisted therapies and to avoid the historical setbacks that previously hindered progress in this field.

Background: Depressive disorders are a major global health challenge, with many individuals unresponsive to existing treatments. Novel psychedelic therapies show promise but require further research.

Objectives: This study aimed to evaluate the feasibility, safety and effectiveness of psilocybin with psychotherapeutic support for treatment-resistant depression (TRD), investigate predictors of treatment outcomes and deepen understanding of individual variability in response.

Design: Open-label, single-arm pilot trial with mixed-methods assessment.

Methods: Treatment consisted of two 25 mg psilocybin sessions, alongside three preparatory and six integration sessions. Depression severity was assessed using the self-rated Quick Inventory of Depressive Symptomatology at 3 weeks (primary endpoint) and at 20 weeks post-dose 2 (long-term follow-up). Potential predictors of clinical outcomes were evaluated using questionnaires, and qualitative interviews were used to capture individual experiences.

Results: At the aggregate level, a clinically meaningful reduction in depressive symptoms was observed at the primary endpoint (mean change = -7.14; p = 0.02; Hedges' g = -1.27; 95% CI [-2.40, -0.37]) and maintained long-term. Individual participant data revealed diverse response patterns. Two participants displayed a sustained treatment response, three relapsed, and two exhibited no substantial improvement. Exploratory analyses identified mindset prior to dosing, spiritual experiences and perceptual shifts during dosing as predictors of treatment trajectory, while treatment expectations were not a reliable predictor. Adverse events were largely consistent with previous studies, with no serious adverse events.

Conclusion: Findings add to the growing evidence base for psilocybin therapy and provide direction for further research on individual variability in response to better tailor treatments and enhance efficacy.

Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001097831).

Background: Postoperative delirium (POD) is associated with higher risks of postoperative complications ‌and‌ mortality (2- to 3-fold increase). Studies investigating the effect of intraoperative ketamine on POD risk have yielded conflicting results. This study aimed to assess the effects of intraoperative ketamine and its more potent version, esketamine, on POD.

Design: Systematic review and meta-analysis.

Objective: To evaluate the effect of intraoperative ketamine/esketamine on the incidence of POD.

Methods: We adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, and searched the PubMed, Embase, Medline (Ovid), Cochrane, Scopus, and Web of Science databases for the MeSH terms "ketamine" and "emergence delirium" from database inception to July 10, 2024. The primary outcome was POD incidence following general anesthesia. Data were analyzed using a common effects model, with between-study heterogeneity tested using the I ² statistic, and relative risk (RR) with 95% confidence intervals (CIs) for dichotomous data was used as the effect measure.

Results: A total of 18 studies with a total of 1571 participants met eligibility criteria. A meta-analysis of all studies suggests that the intraoperative use of ketamine/esketamine may reduce the incidence of POD (RR = 0.71, 95% CI: 0.56, 0.90, p < 0.01). In the drug subgroup, esketamine demonstrated enhanced efficacy in preventing POD compared to ketamine (RR = 0.59, 95% CI: 0.38, 0.90, p = 0.02). In addition, subanesthetic doses of ketamine/esketamine (⩽0.5 mg/kg) contributed to POD prevention (RR = 0.52, 95% CI: 0.34, 0.79, p < 0.01), whereas higher doses (>0.5 mg/kg) showed no statistically significant effect (RR = 0.89, 95% CI: 0.66, 1.21, p = 0.46). Further analysis revealed additional benefits of ketamine/esketamine in reducing POD incidence in cardiac surgery (RR = 0.46, 95% CI: 0.31, 0.68, p < 0.01), in the elderly (RR = 0.68, 95% CI: 0.52, 0.91, p < 0.01), and in the first 24 h post-surgery (RR = 0.52, 95% CI: 0.29, 0.94, p = 0.03).

Conclusion: Our findings suggest that perioperative administration of ketamine/esketamine had a protective effect against the incidence of POD, with esketamine demonstrating superior efficacy compared to ketamine. The treatment effect exhibited a dose-response relationship, with subanesthetic doses showing greater efficacy. Furthermore, ketamine/esketamine may offer additional benefits for patients with specific risk factors.

Background: Poor adherence to antipsychotic medications is the leading cause of relapses and hospitalizations in patients with schizophrenia, resulting in worse functional outcomes and quality of life. Long-acting injectable (LAI) antipsychotics are an effective therapeutic option to improve adherence, but they are often underutilized, particularly during inpatient care.

Objective: To investigate the predictive factors for LAI utilization among inpatients with schizophrenia and to assess whether initiating a LAI antipsychotic treatment during hospitalization reduces the risk of readmission.

Design: Observational prospective study.

Methods: Patients were evaluated at admission, discharge, and after 3 months. Two comparisons were performed: patients who initiated a LAI during the hospitalization versus those who continued with oral antipsychotics, and readmitted versus not-readmitted patients within 3 months. Factors statistically associated with LAI initiation or readmission were entered as independent variables in two backward logistic regression models, having "LAI initiation" and "rehospitalization at three months" as outcomes.

Results: One hundred two patients were included. Twelve were lost at follow-up. Forty-two (44%) initiated an LAI during the admission. Subjects who received LAI were significantly younger, more educated, and less adherent to treatment. Thirty (33%) patients were readmitted within 3 months after discharge. Re-hospitalized subjects had more psychiatric hospitalizations in the past and a lower rate of LAI antipsychotic treatment initiation during the studied hospitalization: 5/39 (13%) patients prescribed a LAI antipsychotic were readmitted within 3 months, compared with 25/51 (49%) prescribed an oral antipsychotic medication (OR = 0.19; p = 0.002).

Conclusion: Introducing LAI antipsychotic treatment during a psychiatric hospitalization may reduce the risk of early readmissions, thus facilitating the improvement of the course of the illness and the patient's quality of life.

Background: Suicidal ideation, attempts, and deaths present a major and tragic public health concern. Recent trials of psilocybin therapy (PT) have shown promise in treating treatment-resistant depression and have found a reduction in suicidal ideation. Given the growth of PT research, there is a need to further understand its effect on suicidal ideation, attempts, and deaths.

Objective: To assess and synthesize evidence on the effects of PT on suicidal ideation, attempts, and deaths in psychiatric patients.

Design: PRISMA-compliant systematic review and meta-analysis.

Data source: MEDLINE, EMBASE, Cochrane, and PsychINFO.

Method: Databases were searched for randomized controlled trials of PT in adults with psychiatric diagnoses that reported suicide outcomes (ideation, attempts, and deaths). Abstract and full-text screening were conducted, and suicide outcomes were extracted. Meta-analysis was performed with a random effects model to assess changes in suicide outcomes compared to control through the standardized mean difference (SMD). Assessment of heterogeneity, risk of bias, and subgroup analysis was completed.

Results: Nine studies were included (N = 593; 335 psilocybin & 258 control). Two studies were excluded from meta-analysis because suicide-related outcomes data were not available. Participants with PT experienced a small and significant decrease in suicidal ideation compared to control (k = 7, SMD = -0.24, 95% CI -0.42 to -0.06, p = 0.008, I ² = 0%). There was no publication bias found. Subgroup analysis found no significant differences between groups. No study reported suicide attempts or suicide deaths. Two studies had a high risk of bias.

Conclusion: Psilocybin therapy may reduce suicidal ideation in adults with psychiatric diagnoses. Current studies are limited by small sample size, lack of follow-up data, and assessment of blinding.

Trial registration: CRD42023445706.