Lithium is the mainstay treatment for bipolar disorder, improving brain white matter microstructure and regulating genes involved in immune response and cell signaling. In 116 patients affected by a major depressive episode in the course of bipolar disorder, we investigated the effect of long-term lithium treatment on gene expression in peripheral blood mononuclear cells and their association with white matter microstructure. Differential gene expression analysis identified three genes significantly upregulated in lithium-treated compared to nontreated patients: SEPTIN11, DGKK, and TPPP3; and two downregulated genes: LEF1-AS1 and PLXDC1. At tract-based spatial statistics, significant lithium-by-gene expression interactions were observed for SEPTIN11, LEF1-AS1, PLXDC1, and DGKK, indicating that the relationship between gene expression and white matter microstructure differed depending on lithium treatment status. Only in lithium-treated participants, LEF1-AS1 and PLXDC1 expression were associated with increased fractional anisotropy and decreased radial diffusivity and mean diffusivity, while SEPTIN11 expression was associated with increased axial diffusivity, mean diffusivity, and radial diffusivity. These genes are widely expressed in the brain, and their peripheral expression correlates with white matter microstructure measures associated with lithium treatment. This observation supports the potential usefulness of peripheral transcriptomic signatures to mark the individual biological impact of lithium treatment on the brain.

Long-acting injectable (LAI) antipsychotics are important for improving adherence and preventing relapse. Risperidone in-situ microparticles (ISM), a once monthly LAI using ISM technology, rapidly achieves therapeutic plasma levels without loading doses or oral supplementation. Real-world evidence on its use remains limited. This multicenter observational-naturalistic-retrospective study assessed prescribing patterns of risperidone-ISM across nine Public Mental Health Departments in Lombardy, Italy. Data from 218 inpatients and outpatients with psychotic disorders diagnosed according to diagnostic and statistical manual of mental disorders, fifth edition, text revision criteria were collected. Demographic, clinical, and pharmacological variables were analyzed. Patients were stratified by dose (75 vs. 100 mg), and group differences were assessed using χ2 and analysis of variance tests. Multivariable logistic regression identified independent correlates of prescription of the 100 mg dose. Sample's mean age was 41.8 years (69% male), with 71.1% receiving 100 mg. LAI initiation was primarily intended to improve adherence in 77.7% of cases. Among hospitalized patients, Brief Psychiatric Rating Scale scores decreased between admission and discharge (59.35 vs. 33.48); however, causality could not be inferred. The 100 mg group had significantly more male patients and showed higher rates of substance use and involuntary hospitalization, while the 75 mg group more often presented depressive symptoms and antidepressant use. In multivariable analysis, only involuntary hospitalization remained independently associated with receiving the 100 mg dose. This study provides real-world evidence on prescribing patterns of different risperidone-ISM doses and short-term clinical outcomes among treated patients.

Acute agitation often requires parenteral sedation in emergency care. Midazolam is widely used for its rapid onset, short duration of action, and availability for intramuscular and intravenous administration, but its efficacy and safety across emergency settings remain incompletely understood. Following Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines, we searched PubMed, Scopus, and Web of Science for original studies evaluating intramuscular or intravenous midazolam, as monotherapy or in combination regimens, for acute agitation in emergency department (ED), psychiatric emergency service (PES), and prehospital emergency medical service (EMS) settings. Twenty-three studies met the inclusion criteria. Intramuscular midazolam was generally associated with rapid early sedation in ED studies, although this advantage was sometimes offset by less sustained clinical effects and higher need for rescue or additional sedation. Intravenous midazolam monotherapy showed a greater need for active airway management in its main direct comparison with intravenous droperidol. Midazolam-droperidol combinations showed more consistent advantages for rapid early sedation in monitored ED settings. In PES and EMS, midazolam's role was more dependent on clinical context, operational constraints and postsedation monitoring. Midazolam appears a useful rapid-onset option, but should not be considered a consistently superior standalone strategy. Future multicenter studies should better elucidate its safest and most effective use.

Lithium remains a cornerstone of bipolar disorder treatment, yet it has a narrow-therapeutic index and depends on renal and volume status. Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide/GLP-1 agonists are now widely coprescribed in this population. Six bibliographically distinct reports published since 2025 describe lithium elevation or toxicity after initiation, switching, or escalation, and in June 2026 the European Medicines Agency's Pharmacovigilance Risk Assessment Committee opened a signal of a drug interaction leading to increased lithium levels. We separate three levels of evidence: (a) an uncontrolled pharmacovigilance signal; (b) plausible mechanistic pathways; and (c) a speculative temporal model. The candidate mechanisms are more constrained than previously appreciated: delayed gastric emptying alters absorption rate without demonstrably altering total exposure; GLP-1-mediated natriuresis acts in the opposite direction and does not persist; reduced lithium clearance after weight loss is sustained but quantitatively insufficient. The temporal framing is speculative and may partly reflect ascertainment bias. The reports describe two separable phenomena: acute toxicity events, largely explicable by intake and volume effects, and a sustained upward shift in concentration per unit dose, which is not. We set out falsifiable predictions and monitoring considerations, adopting rather than claiming the schedule proposed elsewhere.

Poor treatment adherence is a major challenge in the management of severe mental disorders, as it is associated with an increased risk of relapse, rehospitalization, symptom worsening, treatment resistance, and all-cause mortality. In 2023 a 2-month 960 mg formulation of aripiprazole 2 months ready-to-use (Ari 2MRTU) was introduced. Compared with monthly long-acting injectable (LAI) drugs, Ari 2MRTU may improve adherence and patient satisfaction by reducing the frequency of healthcare visits. The aim of this prospective longitudinal study was to provide preliminary real-world data on the effectiveness, safety, and acceptability of Ari 2MRTU. Fifty patients, most of whom had previously received aripiprazole, were assessed at baseline, 2 months, and 4 months. Data regarding effectiveness, safety, and acceptability outcomes were collected. Psychometric scores changes were analyzed employing linear mixed-effect regression models accounting for time, age, sex, and previous oral treatment with aripiprazole. Our preliminary findings suggest that Ari 2MRTU is associated with improvements in psychotic symptoms over time, while changes in affective symptoms were less consistent. The findings were also consistent with an overall favorable tolerability profile of Ari 2MRTU. Although adverse events were commonly reported, no unexpected safety signals emerged during the follow-up period, and patients' attitudes toward LAI treatment generally improved over time.

Levetiracetam (LEV) is a widely used antiepileptic but associated with psychiatric side effects. While mild reactions are common, manic and psychotic episodes are less frequent, though clinically significant. This review critically assesses published cases of (hypo)manic and psychotic episodes related to LEV. A systematic review was conducted using MEDLINE (PubMed), Cochrane Library, and Web of Science (up to 1 June 2025), restricted to studies with primary clinical data on (hypo)manic or psychotic episodes associated with LEV. The quality of each case was assessed using a critical appraisal checklist, and the Naranjo Adverse Drug Reaction Probability Scale was applied to evaluate causality. A total of 50 cases met the inclusion criteria: Eight (hypo)manic and 42 psychotic episodes. The most frequent psychiatric manifestations were delusions (48%), aggressiveness (44%), and manic symptoms (38%). Temporal lobe epilepsy was present in 26% of patients, and 66% had uncontrolled seizures. Although case reports describe an association between LEV and (hypo)manic and psychotic episodes, causality assessment based on the methodological approach applied indicated a low probability that LEV alone was responsible. Alternative explanations, including epilepsy-related factors and comorbid medical conditions, were frequently cited. In some cases, an alternative diagnosis might be manic episode with psychotic features .

Attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) frequently co-occur. However, evidence on the clinical effects of stimulant treatment in ADHD-BPD comorbidity remains limited. This prospective study aimed to investigate the longitudinal effects of methylphenidate (MPH) on borderline personality features in adults with ADHD-BPD. Thirty-six adults diagnosed with ADHD who also met the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for BPD were treated with MPH and followed for at least 16 weeks. Clinical ratings of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition BPD criteria and psychometric measures assessing symptom severity and personality functioning were obtained at baseline and follow-up. Twenty-four participants (66.7%) completed the follow-up. Follow-up duration ranged from 3.9 to 12.3 months, with a mean duration of 7.8 ± 2.48 months. The number of BPD criteria significantly decreased after treatment (r = 0.82, P < 0.001). Nineteen participants no longer met the diagnostic threshold for BPD, and 10 achieved remission (≤2 BPD criteria). Baseline anger dysregulation (P = 0.009) and mood stabilizer use (P = 0.029) were associated with continued MPH treatment. Our findings preliminarily suggest that MPH, especially combined with mood stabilizers, may be associated with clinical benefits and acceptable tolerability in patients with comorbid ADHD-BPD. While causal conclusions cannot be drawn, replication in randomized controlled trials is warranted.

Despite three decades of clinical trials, no pharmacological treatment has shown consistent efficacy for the core features of autism spectrum disorder (ASD), and regulatory approvals remain limited to risperidone and aripiprazole for severe irritability. This limited efficacy likely reflects a mismatch between underlying biology and broad trial designs. ASD is a clinically defined neurodevelopmental condition with marked etiologic heterogeneity, shaped by highly polygenic liability and a long tail of rare, often de novo , high-impact variants. Genomic studies implicate synaptic signaling, chromatin regulation, and excitatory-inhibitory processes, but this partial biological convergence does not support a single therapeutic target across the diagnostic spectrum. Debate over environmental risk factors, including prenatal acetaminophen exposure, also shows how weak causal inference can distort research priorities. We propose three priorities for ASD pharmacotherapy: genetically stratified mechanism-linked interventions, pharmacogenomics-informed symptomatic prescribing, and trials using validated or biomarker-informed endpoints that capture outcomes regarded as meaningful by autistic people.