Therapeutic Advances in Psychopharmacology最新文献

What is this summary about? The information summarized here relates to aripiprazole, a medicine that is used to treat conditions such as schizophrenia and bipolar I disorder. Researchers wanted to understand what levels of aripiprazole in the blood looked like following an injection of aripiprazole administered once every 2 months. They did this using a method known as population pharmacokinetics. Why was this research done? Researchers conduct clinical trials when developing new medicines to see how well they work and how safe they are. Clinical trials cannot cover every possible real-life scenario. Researchers can address this by performing population pharmacokinetic modeling and simulation, a process that involves computers and specialized software. Population pharmacokinetic modeling combines information from many people to show how a medicine is absorbed, distributed, broken down, and cleared from the body. It is also done to understand why these processes might vary between people. After the model is built, it can be used to simulate (estimate) the level of the medicine in the blood in situations not tested in clinical trials. What were the results? Simulations showed that an injection of aripiprazole given once every 2 months results in effective drug levels that last until the next dose is due. Drug levels with aripiprazole given once every 2 months are similar to those with injections of aripiprazole given once-monthly, but with fewer injections. What do the results mean? The results provide insight into aripiprazole levels in the blood in people newly starting or continuing treatment with aripiprazole once every 2 months. They add to information already collected in clinical trials. The findings supported the approval of aripiprazole once every 2 months in people living with schizophrenia or bipolar I disorder. They also helped inform the guidance that doctors follow when they prescribe the drug to their patients. The availability of aripiprazole once every 2 months may make treatment easier, and help people stick to their treatment over time.

Background: Anhedonia is a key symptom of bipolar depression and a target of ketamine's rapid antidepressant effects. However, many patients with treatment-resistant bipolar depression (TRBD) do not respond.

Objectives: This study aimed to identify clinical and sociodemographic characteristics that are associated with nonresponse of anhedonia following short-term ketamine treatment in TRBD.

Design: A retrospective analysis using data from two naturalistic, observational registries of 31 patients with TRBD and baseline anhedonia (Snaith-Hamilton Pleasure Scale (SHAPS) > 2). Patients received eight doses of ketamine (IV: 0.5 mg/kg; oral: 2.0-2.5 mg/kg) over a short-term treatment course.

Methods: Patients were classified as responders or nonresponders based on a ⩾50% reduction in SHAPS score by the seventh ketamine dose. Groups were compared on baseline sociodemographic and clinical features.

Results: Fourteen patients (45.2%) did not respond. Nonresponders had higher BMI, later illness onset, fewer hypomanic episodes, and lower employment rates.

Conclusion: Metabolic, illness-course, and psychosocial factors may predict reduced anti-anhedonic response to ketamine in TRBD.

Background: Despite their efficacy in improving positive symptoms, first- and second-generation antipsychotics (FGAs and SGAs) fail to provide benefit to a large portion of patients with schizophrenia. Evenamide, uniquely acting at the site of dysfunction, normalizes hippocampal glutamatergic aberrant activity and reduces downstream hyperdopaminergic state, potentially alleviating also negative and cognitive symptoms, and providing benefit to patients with treatment-resistant schizophrenia (TRS) or inadequate response to antipsychotics (APs).

Objectives: Evaluate the clinical benefits of glutamate modulation through evenamide as an add-on treatment to FGAs and SGAs in patients with TRS or inadequate response to APs.

Design: Post-hoc analyses of results from two phase II/III clinical trials with evenamide add-on to antipsychotic treatment.

Methods: Data from Study 014/015, an open-label, 1-year trial in patients with TRS, was analyzed to assess the proportion of patients no longer meeting the baseline severity criteria for TRS (modified Intent-to-Treat (mITT) population; Observed Cases (OC)) and the proportion of patients in the mITT population achieving remission. Data from Study 008A, a randomized, double-blind, placebo-controlled, 4-week trial in patients with schizophrenia not adequately benefiting from SGA (including clozapine), was analyzed to assess patients' response according to the number of previously failed AP attempts (ITT population; mixed model repeated measures (MMRM) linear regression model). The effect of evenamide on social functioning and life engagement was evaluated in both studies (mITT population) using an MMRM linear regression model for Study 008A and an OC analysis for Study 014/015.

Results: Patients with TRS receiving evenamide add-on for 1-year improved to such an extent that 55% of them no longer satisfied baseline TRS severity criteria, and approximately one-fourth achieved remission according to literature criteria (27.6% Lieberman et al., 1993; 25.0% Andreasen et al., 2005). In Study 008A, irrespective of the number of failed APs, a statistically significant drug-placebo difference was observed in patients with a single failed attempt (-4.9, p = 0.0122) and in those with 2 or more failed attempts (-2.36, p = 0.0311). Moreover, add-on treatment with evenamide in Study 014/015 was associated with a progressive improvement on the PANSS subdomains of social functioning and life engagement. In Study 008A as well, evenamide resulted in a greater effect, compared to placebo, on the same subdomains.

Conclusion: Add-on treatment with evenamide to APs (including clozapine) was associated with clinically meaningful and progressive long-term benefits across numerous post-hoc analyses including improvements on patient's daily life and functioning.

Background: Antipsychotic therapy can bring a great deal of benefit to individuals with schizophrenia and other psychiatric diagnoses, though this class of medications is also associated with intolerabilities due to possible adverse events. Notable adverse events commonly experienced include movement disorders and metabolic concerns that can occur even at low doses and minimal exposure.

Objectives: Describe the prescribing patterns of antipsychotics in the inpatient behavioral health setting, and report on characteristics that lead to populations having higher or lower dosing exposures to antipsychotic therapy that follows FDA guidelines.

Design: Multicentered, retrospective, cross-sectional chart review.

Methods: The study was conducted at two academic hospitals in the inpatient behavioral health setting. Information was collected on 785 cases of patients who were hospitalized during the study period with a psychiatric diagnosis that necessitated a prescription for an antipsychotic medication at the time of discharge. Differences in antipsychotic drug (dose, type, number, and duration of treatment) were characterized, and data were collected on clinician adherence to FDA guidance, as listed in the package insert of each antipsychotic drug. Primary outcomes were the amount of Total Chlorpromazine Equivalent Dosing doses and the clinician's adherence to FDA guidance.

Results: This study found that the male gender (p < 0.0001), no social support (p < 0.0025), more previous antipsychotic trials (p < 0.0001), and longer hospital stays (p < 0.0001) were statistically significant for patients receiving higher antipsychotic doses at discharge. Additionally, patients with comorbid diabetes (p < 0.0001), more antipsychotics at discharge (p = 0.001), and Medicare insurance (p = 0.005) were less likely to receive antipsychotic medication following FDA recommendations and current guidelines.

Conclusion: The results of this study can inform practice regarding antipsychotic prescribing patterns in different populations. Conducting prospective studies across a broader range of institutions, it is recommended to better understand the relationship between patient demographics and prescribing patterns during periods of acute illness.

Antidepressants are commonly prescribed for children and adolescents, but their discontinuation may result in withdrawal symptoms, though rarely described for this age group in the literature. Systematically examining the types and prevalence of withdrawal syndromes in children and adolescents in accordance with PRISMA guidelines is the aim of the present paper. A search of PubMed, Embase, Web of Science, and Cochrane Library was conducted from inception to December 2024. Inclusion criteria were: clinical populations; subjects aged 2-18; antidepressant discontinuation; assessment of withdrawal symptoms; randomized controlled trials (RCTs) or observational studies; rate/type of withdrawal symptoms. A total of 6227 citations were screened, leading to 12 studies, encompassing 690 participants aged 2-18 years, with eight RCTs and four observational studies. The analysis revealed common withdrawal symptoms across various antidepressant classes, predominantly affecting the central nervous and gastrointestinal systems. Symptoms such as nausea (14.6%-22.0%), headache (14.6%-15.0%), diarrhea (10.0%-22.0%), depression (10%), inner tension (44%), anxiety/worry (44%), and cough (33%) were frequently observed, especially after discontinuation of selective serotonin reuptake inhibitors. Such symptoms clustered in new withdrawal symptoms according to a diagnostic classification of withdrawal syndromes at discontinuation of antidepressants used in adults. Withdrawal symptoms and withdrawal syndromes following antidepressant discontinuation in children and adolescents are still neglected but pose significant clinical challenges, often resembling or exacerbating underlying conditions. Future research is needed, as well as a systematic assessment of these symptoms in the clinical realm (registered in OSF DOI: https://doi.org/10.17605/OSF.IO/GYQ9Z).

Extant literature pertaining to the administration of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for Alzheimer's disease, Parkinson's disease, major depressive disorder, bipolar disorder, substance-, alcohol- and nicotine-use disorders, suggests promising efficacy beyond the current FDA-approved indications (e.g., type 2 diabetes mellitus, obesity). The implicated brain regions of the aforementioned mental disorders contain glucagon-like peptide 1 (GLP-1) receptors associated with improving cognitive and behavioral functioning. Therefore, we aimed to systematically review the treatment effects of GLP-1RAs in various neurocognitive and psychiatric disorders. Online databases including PubMed, OVID, MEDLINE, Embase, PsycINFO and Google Scholar, were searched from inception until October 1, 2024. Additional studies were identified from the reference lists of the included articles. 22 studies were identified, with a total of 186,847 participants included. Results reported that GLP-1RAs meaningfully improved cognitive and affective functioning (e.g., memory), which in some cases was sustained beyond exposure to the agent. Separately, multiple epidemiological studies reported that GLP-1RAs have protective effects, with a suggestion of decrease in the incidence of mental disorders. These results provides the impetus for large, long-term, randomized controlled trials for GLP-1 RAs for the treatment of various mental disorders. This review is not registered in PROSPERO or any other registry.

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).