Therapeutic Advances in Psychopharmacology最新文献

Background: Oral contraceptives (OC) offer a range of ethinyl estradiol (EE) doses and progestin types, with evidence indicating marked differences in cognitive and emotional abilities in OC users. However, it remains unclear whether dose variations in EE (low vs high) and progestin androgenicity (androgenic vs anti-androgenic) are associated with variations in cognitive and emotional abilities.

Objectives: Our study aimed to investigate the cognitive and emotional effects of various OC formulations.

Design: Online between-subjects experimental design.

Methods: Based on regular monophasic OC formulation use, 96 participants (26 ± 7 years) were recruited and categorised into one of four groups: low EE androgenic (n = 26), high EE androgenic (n = 24), low EE anti-androgenic (n = 21) and high EE anti-androgenic (n = 25). The Repeatable Battery for the Assessment of Neuropsychological Status, emotion recognition task, and the Positive and Negative Affect Schedule were administered. Visual analogue scales were also administered to assess rejection sensitivity before and after a social exclusion task (Cyberball task). Analysis of variance (2 × 2) models were used to compare cognitive and socio-emotional abilities between groups.

Results: Anti-androgenic users demonstrated higher intensity ratings for emotional faces, and heightened feelings of insecurity after a social stressor. Overall positive and negative affect, as well as performance on objective cognitive tests, were similar across OC formulations.

Conclusion: In OC users, OC formulations containing an anti-androgenic progestin were associated with greater perceived intensity of emotional faces as well as heightened rejection sensitivity. However, these subtle differences in task performance did not translate to differences in overall affect or cognitive performance.

Formal guidelines recommend that opioids should be stopped when risks outweigh benefits. These guidelines generally recommend gradual dose tapering at a rate tolerable to the patient. However, there is considerable variation regarding the pattern of dose tapering recommended, with some suggesting linear tapers (with a fixed reduction of dose at each step), while others recommend increasingly small dose reductions as the total dose gets lower. No biological rationale has been put forward for these recommendations. We examined the pharmacodynamic properties of opioids to derive pharmacologically rational principles for tapering. As dictated by the law of mass action, the relationship between dose of opioid and effect on its principal target, the mu-opioid receptor, is hyperbolic, with diminishing incremental effects for increasing doses. This suggests that in order to mitigate withdrawal symptoms, opioid doses should be tapered according to a corresponding hyperbolic pattern, with dose reductions becoming increasingly small as total dose reduces. This can be approximated by proportional decreases (e.g. 1%-10% reduction of the most recent dose every 1-2 weeks). Dose reductions should be titrated to withdrawal symptoms throughout the process, and final doses before complete cessation will need to be very small (such as 0.1 mg of buprenorphine or 1 mg of methadone, or less). The duration required for this strategy of tolerable tapering after long-term use may require many months or years for some patients. The theoretical proposals in this paper offer a pharmacologically rational strategy that should prompt review of clinical practice and guidelines. Gradual, hyperbolic tapering should be evaluated in randomised controlled trials.

Background: Psychotropic medications are often inappropriately prescribed for behavioural and psychological symptoms of dementia (BPSD), posing significant risks such as falls, stroke and death. Although non-pharmacological interventions (NPIs) are the first-line treatment for BPSD, their use in practice remains limited.

Objectives: This study explored general practitioners' (GPs') and physicians' perspectives on using psychotropic medications compared to NPIs for managing BPSD in Australian residential aged care homes (RACHs).

Design: Semi-structured online in-depth interviews were conducted with GPs and physicians managing BPSD in Australian RACHs.

Methods: The interviews were audio-recorded, transcribed and analysed using inductive thematic analysis, with transcripts coded using NVivo 14 to generate themes.

Results: Four GPs and eleven physicians were interviewed, and four major themes emerged: (1) knowledge of best practices of BPSD management, (2) awareness of current challenges in BPSD management, (3) non-involvement, blame shifting and rationalisation: perceived reasons for the current challenges and (4) suggested solutions. GPs and physicians were aware of best practices in managing BPSD, highlighting the importance of NPIs as more effective first-line strategies, with psychotropic medications reserved as a last resort. They also admitted that psychotropic over-prescription and inadequate NPI implementation persisted in BPSD management in Australian RACHs. Physician participants often distanced themselves from and blamed the GPs, staff and relatives of residents with dementia for the current problems. Systemic barriers, including insufficient resources, limited care continuity and organisational structures, were also reported to hinder psychotropic deprescribing. Implementing NPIs was deemed to be impeded by inadequate training and low confidence in their effectiveness. The participants suggested strengthening workforce capacity, incentivising NPIs and encouraging interdisciplinary collaboration.

Conclusion: The results highlighted the gap between GPs' and physicians' knowledge of best practices and actual prescribing practices for BPSD in Australian RACHs. Improved workforce and support for NPIs could reduce reliance on psychotropics and align BPSD management with best practices.

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).