Therapeutic Advances in Psychopharmacology最新文献

Background: Individual responses to repetitive transcranial magnetic stimulation (rTMS) in schizophrenia vary, and predictive clinical tools are lacking.

Objectives: To develop and interpret machine learning models predicting individual rTMS treatment response using baseline clinical features.

Design: Exploratory, hypothesis-generating study using retrospective patient data with internal validation and interpretability analysis.

Methods: We analyzed 156 patients with schizophrenia, assessing baseline Positive and Negative Syndrome Scale (PANSS) and global assessment of functioning (GAF) scores. Machine learning models (Random Forest, XGBoost, support vector machine, logistic regression) were trained on demographic and clinical features. Performance was evaluated via cross-validation and a temporal hold-out test set. Shapley additive explanations (SHAP) were used for model interpretation.

Results: Baseline characteristics were comparable between groups (all p > 0.1). Although both groups improved clinically, between-group differences were not statistically significant. The Random Forest model achieved the highest performance: cross-validated area under the receiver operating characteristic curve (AUC) = 0.84, temporal hold-out AUC = 0.70. Learning curve analysis indicated performance plateaued around 100 cases. SHAP and decision tree analysis highlighted moderate baseline GAF and higher PANSS as key predictors for response.

Conclusion: Despite modest group-level efficacy, interpretable machine learning models identified baseline features associated with individual response to rTMS. These findings can inform personalized interventions, though future external validation is needed.

Trail registration: Not applicable.

Ketamine's development in psychiatry exemplifies the evolution of psychopharmacology over six decades. Originally introduced as a dissociative anesthetic and psychotomimetic probe, ketamine has been repositioned as a rapidly acting antidepressant, particularly for treatment-resistant depression (TRD). This narrative review draws on historical sources, clinical trials, regulatory documents, and conceptual analyses to examine ketamine's psychiatric trajectory, integrating historiographical and clinical perspectives to contextualize its shifting roles. Ketamine was initially valued in experimental psychopathology for modeling psychosis via N-methyl-D-aspartate receptor antagonism. By the early 2000s, clinical trials demonstrated rapid and robust antidepressant effects, challenging monoaminergic paradigms and stimulating new glutamatergic and neuroplasticity-based models of depression. Its dissociative effects, once interpreted as liabilities, became focal points of debate, though evidence suggests they are not essential for antidepressant efficacy. Intranasal esketamine received U.S. Food and Drug Administration approval in 2019 for TRD, while off-label intravenous racemic ketamine is widely used in practice. Ongoing challenges include safety, equity of access, regulatory oversight, and commercialization pressures. Ketamine's psychiatric history illustrates the fluidity of therapeutic meaning and the interplay of pharmacology, diagnosis, and culture. Its repositioning highlights new opportunities for rapid-acting treatments while underscoring the ethical and clinical responsibilities of integrating innovative agents into psychiatric care.

Novel interventions for post-traumatic stress disorder (PTSD) leverage the psychoactive properties of psychedelic compounds, such as ketamine, 3,4-methylenedioxymethamphetamine and psilocybin, which may overcome limitations of conventional treatments. Through the modulation of pathways involved in synaptic plasticity, psychedelic interventions are believed to enhance the mechanisms underlying memory processing and extinction. Multi-modal approaches to patient care can use existing treatments in combination with psychedelics to improve the efficacy of current psychotherapies, producing rapid and lasting improvement to chronic physiological and psychological symptoms. Modern methods for predicting treatment response will allow clinicians to personalise psychedelic interventions to the individual, capitalising on quantitative evidence to provide precision medical care. This review serves to identify limitations of the current treatment paradigm for PTSD, highlight how emerging psychedelic interventions may offer a solution to these considerations and explore the promise of precision medicine approaches for the future of PTSD treatment.

Background: Depressive disorders affect approximately 280 million globally, with many finding treatments ineffective or limited by side effects. Growing evidence suggests that psychedelic therapies may help alleviate depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing shows promise for major depressive disorder (MDD). However, research on LSD microdosing in clinical populations remains limited.

Objectives: This study aimed to understand the experiences of individuals participating in an open-label trial of LSD microdosing for MDD.

Design: Open-label pilot trial in target population (MDD; phase IIa).

Methods: Seventeen participants with MDD completed an 8-week LSD microdosing regimen, dosing twice weekly. Following the intervention, participants underwent semi-structured interviews regarding their experiences. Data were analysed using thematic analysis.

Results: Themes were grouped into five categories: enhanced self-determination, increased connectedness, improved cognitive processing, better emotional well-being, and negative effects.

Conclusion: Reported effects appeared to reinforce one another; that is, self-determination led to feeling more connected, which enhanced cognitive processing and ultimately improved emotional well-being and reduced depressive symptoms. However, this effect was not universal; some individuals reported negative effects or no significant improvement from microdosing LSD. This variability may be due to individual differences in response, insufficient dosage, or the treatment's lack of effectiveness for some individuals. The presence of side effects highlights the need for a careful titration protocol, while the lack of symptom improvement in some cases reinforces that microdosing is not a guaranteed solution, and expectations should remain realistic. The absence of a placebo control represents a key limitation as it precludes attribution of observed changes specifically to LSD.

Trial registration: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385758).

Background: Many antidepressant users experience the process of stopping as challenging because of withdrawal symptoms. Support factors, such as patients experiencing empathy from their healthcare providers, potentially contribute to successful discontinuation.

Objectives: To examine the relation between experienced empathy and successful antidepressant discontinuation.

Design: Part of a larger prospective cohort study in major depressive disorder patients using sertraline or citalopram recruited through university medical centres and connected general practitioners, pharmacies and mental health institutions. The larger study aimed to identify factors associated with remission and patients' experiences with discontinuing antidepressants.

Method: Patients were followed for 24 months. We measured objective and subjective discontinuation success. Subjective discontinuation was measured with the Discontinuation Success Scale, a scale with three subscales (subjective feeling of success, positive and negative effects of discontinuation). Empathy was measured with the Consultation and Relational Empathy (CARE) measure. To analyse the association between perceived empathy and discontinuation success, we used regression analyses.

Results: Of 918 participants in the larger study, 235 attempted discontinuation and 153 could be included in the analysis. About two-thirds of the participants were successful in discontinuing antidepressant medication. We did not find an association between perceived empathy and objective discontinuation success. Perceived empathy was positively associated with subjective success and negatively associated with the negative effects of discontinuation.

Conclusion: Although we could not demonstrate an association of perceived empathy and objective discontinuation, we consider the finding of a relation between subjective success as relevant because a successful experience regarding antidepressant discontinuation may positively influence the initiation of future attempts.

Background: Intravenous ketamine is effective in treatment-resistant bipolar depression (TRBD) with dosing typically based on actual body weight (ABW).

Objective: This study examined whether alternative normalization formulas are associated with treatment response.

Design: A retrospective exploratory analysis of a naturalistic registry for short-term ketamine use.

Methods: A total of 22 TRBD inpatients received short-term intravenous ketamine. Doses were recalculated using the Boer and Devine formulas for lean body mass (LBM) and ideal body weight (IBW), and the Mosteller formula for body surface area (BSA). Calculated doses were compared with ABW dosing in responders and nonresponders.

Results: Using the Mosteller formula, BSA-normalized doses ranged from 17.63-23.09 mg/m² in nonresponders and 15.73-23.89 mg/m² in responders. LBM- and IBW-based recalculations at 0.5 mg/kg yielded lower relative doses, particularly among nonresponders, suggesting potential underdosing.

Conclusion: These preliminary findings do not support alternative dosing formulas over ABW, but replication in larger controlled studies is warranted.

Background: Physical touch is often included as a supportive or therapeutic tool in psychedelic-assisted therapy (PAT), involving instrumental forms of physical contact, supportive touch and somatic techniques. However, participants under the influence of psychedelics have reduced capacity to provide consent, are more suggestible and may experience and interpret therapeutic touch in ways they did not expect prior to taking the drug. Yet little research has been conducted on the considerations and approaches to therapeutic touch in clinical trials of PAT.

Objectives: This study explored the experiences and perspectives of PAT researchers on the use and consent to therapeutic touch in clinical trials of PAT.

Design: A qualitative study using semi-structured interviews.

Methods: Sixteen PAT researchers involved in clinical trials of PAT were interviewed. Reflexive thematic analysis was used to analyse the data. The reporting of this study conforms to the Consolidated Criteria for Reporting Qualitative Research Checklist (COREQ).

Results: Three themes were uncovered through reflexive thematic analysis: (1) flexible frameworks, (2) therapeutic alliance and (3) boundary management. Researchers discussed consent challenges across the broad spectrum of physical contact existing in PAT protocols at the time. Researchers indicated that consent to therapeutic touch should be established prior to the dosing sessions and continually managed throughout the course of treatment. Flexibility in consent protocols enabled researchers to interpret and approach consent through the development of a strong therapeutic alliance; however, flexibility could also lead to challenges in boundary management. Researchers emphasised the need for greater ethical guidance in instances where trial participants change their established preferences during dosing sessions, and limits on expanding consent after drug administration.

Conclusion: Clear guidelines for obtaining consent, managing changing preferences and training on the management of boundary transgressions were viewed as essential for ethical research and practice of PAT.

Background: Depression affects approximately 5.7% of adults worldwide, and around one-third of these individuals develop treatment-resistant depression (TRD). Intravenous (IV) ketamine and esketamine (administered IV or intranasally (IN)) are novel treatment options for TRD; however, only IN esketamine currently holds FDA approval.

Objectives: Compare the acute effectiveness of IV ketamine with esketamine (IV or IN) in adults with TRD.

Design: Mantel-Haenszel random-effects meta-analysis of head-to-head studies. Response and remission at study end point were co-primary outcomes, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses explored the impact of diagnosis, study type, and publication format; heterogeneity was quantified with I ².

Data sources and methods: MEDLINE, Embase, Cochrane, APA Psycinfo, and Scopus were searched from inception through 19 March 2025. Eligible studies enrolled adults with unipolar or bipolar depression directly comparing IV ketamine with esketamine and reporting response or remission.

Results: Screening 1089 records identified eight studies (n = 978). Seven observational studies (n = 915) comparing IV ketamine with IN esketamine were included in the meta-analysis, while one randomized controlled trial (RCT) comparing IV formulations was summarized qualitatively. Pooled response from six studies gave OR = 1.26 (95% CI, 0.92-1.71; p = 0.15) and remission from seven studies gave OR = 1.31 (95% CI, 0.93-1.86; p = 0.12), both nonsignificantly favoring IV ketamine with negligible heterogeneity (I ² = 0%). Sensitivity analyses excluding bipolar depression or abstract-only reports yielded similar effect estimates, reinforcing the robustness of the findings. Evidence across three studies for faster onset with IV ketamine ranged from significant in one study to modest trends in two.

Conclusion: Based on the currently available comparative evidence, which is almost entirely observational, IV ketamine and IN esketamine show comparable acute response and remission rates, though IV ketamine may act faster. Large head-to-head RCTs are needed to confirm these findings.

Trial registration: The study protocol was prospectively registered on the Open Science Framework (OSF) at https://osf.io/5jzev.

[This corrects the article DOI: 10.1177/20451253251381074.].