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.
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.
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.
Akathisia is a common and often disabling adverse effect of antipsychotic treatment. Although previous studies have linked akathisia to dopamine D 2 ‑receptor blockade in the basal ganglia, there is limited evidence from [18F]fluorodeoxyglucose PET ([18F]FDG PET) acquired during clinically manifest akathisia. We report the case of a woman in her 50s with bipolar disorder and autoimmune diseases who developed marked akathisia after augmenting lithium with aripiprazole 10 mg/day. During the symptomatic period, a whole‑body [18F]FDG PET computed tomography was performed to investigate recurrent fevers and gastrointestinal symptoms. Brain images incidentally showed bilateral putaminal hypermetabolism relative to the cerebral cortex. Neurological and rheumatology consultations were negative. No other medications were modified during the same timeframe. Akathisia remitted completely after aripiprazole discontinuation and clonazepam up‑titration, and the Naranjo Adverse Drug Reaction Probability Scale score indicated a probable adverse drug reaction. Basal ganglia hypermetabolism relative to the cerebral cortex is reminiscent of PET findings in reversible hyperkinetic disorders. To our knowledge, this is the first case report showing an association between bilateral putaminal hypermetabolism on [18F]FDG PET and aripiprazole-induced akathisia. This hypothesis-generating observation warrants replication in prospective studies to elucidate how dopaminergic dysfunction in the basal ganglia may contribute to the emergence of akathisia.
Psychoses are often characterized by relapse and treatment resistance. Patients receiving electroconvulsive therapy (ECT) represent a high-risk subgroup. Although long-acting injectable (LAI) antipsychotics improve adherence compared with oral formulations, studies regarding their effectiveness when combined with ECT remain limited. Our study compared clinical outcomes between LAI and oral antipsychotics administered during ECT to patients with psychosis. We conducted a retrospective chart review of 65 patients, grouped according to antipsychotic formulation. Treatment response was defined by improvement on the Clinical Global Impression-Severity scale. Symptom changes were assessed using the Positive and Negative Syndrome Scale (PANSS). The LAI-ECT group showed a significantly higher response rate compared with the oral-ECT group (72.7 vs. 37.5%, P = 0.004). In multivariable analyses, LAI use remained significantly associated with treatment response ( P = 0.007). In the subgroup analysis of 48 patients, the LAI-ECT group exhibited greater reductions in total PANSS scores ( P = 0.014), which remained significant after adjustment for baseline severity ( P = 0.034). Greater symptom reductions were observed in the PANSS negative and general psychopathology subscales. These findings suggest an association between concurrent LAI antipsychotic administration during ECT and clinical outcomes, warranting further prospective validation.
Antipsychotic-induced hyperprolactinemia is a common and clinically relevant adverse effect of dopamine D 2 -blocking agents such as risperidone and paliperidone, yet evidence from Arab populations is scarce. This study explored demographic and pharmacological predictors of hyperprolactinemia in a large UAE cohort. A retrospective cross-sectional study was conducted at the Behavioral Science Institute, Al Ain Hospital, using electronic medical records from 2017 to 2023. Adults (≥18 years) with schizophrenia (Diagnostic and Statistical Manual, fifth edition) treated with risperidone or paliperidone (oral or long-acting injectable) for greater than or equal to 6 weeks before serum prolactin assessment were included. Among 835 patients, the mean age was 40.2 ± 14.0 years; 53.8% were male and 58.4% Emirati. The mean prolactin level was 1126 ± 1334 mIU/l; 61.9% had hyperprolactinemia. The paliperidone-oral group showed the highest mean prolactin (1369 mIU/l; P = 0.003). Sexual side effects occurred in 9.2%. Predictors included younger age, female gender, non-Emirati nationality, paliperidone use, and aripiprazole cotreatment. Hyperprolactinemia was common, particularly among younger females and patients receiving oral paliperidone, and was accompanied by marked under-recognition of sexual side effects. Our study underscores the need for routine endocrine monitoring, rational prescribing to minimize polypharmacy, and region-specific clinical guidelines in the UAE and Gulf region.
Olanzapine-samidorphan (Lybalvi) combines the antipsychotic olanzapine with the opioid receptor modulator samidorphan to mitigate olanzapine-associated weight gain. While clinical trials have supported comparable efficacy and improved metabolic outcomes relative to olanzapine alone, data on mood effects remain limited. We report the case of a 40-year-old man with no prior psychiatric history who was psychiatrically hospitalized, and developed clinically significant dysphoric and depressive symptoms shortly after transitioning from a new prescription of olanzapine monotherapy to olanzapine-samidorphan. His depressive symptoms, including anhedonia, amotivation, and fatigue, resolved rapidly upon resumption of olanzapine alone, with no recurrence over 6 months of follow-up. The temporal association and symptom resolution following discontinuation suggest a possible causal relationship. The pharmacologic profile of samidorphan, as a μ-opioid receptor antagonist and partial κ-agonist, may underlie this effect, as κ-receptor activation has been linked to dysphoria and anhedonia. Although large-scale studies of samidorphan have not demonstrated consistent prodepressive effects, individual susceptibility related to opioid receptor signaling may exist. This case highlights the need for clinical vigilance regarding emergent depressive symptoms in patients prescribed olanzapine-samidorphan, particularly those with prior mood vulnerability. Further investigation is warranted to clarify the neurobiological mechanisms and potential risk factors for mood disturbance associated with samidorphan-containing formulations.
Antipsychotic polypharmacy (APP), defined as the concurrent use of two or more antipsychotic agents, remains common in clinical practice despite antipsychotic monotherapy being the recommended standard for schizophrenia treatment. This nationwide cross-sectional survey examined the prevalence and determinants of APP among outpatients with schizophrenia in Japan. Data were collected from 3657 patients across 36 medical institutions between 21 and 25 October 2024. Patients were categorized into antipsychotic monotherapy and APP groups, and demographic and clinical characteristics, including age, sex, medication administration frequency, use of long-acting injectables, clozapine, and concomitant psychotropic medications, were compared. Antipsychotic doses were standardized to chlorpromazine equivalents and analyzed by sex and age group. APP was observed in 40.8% of patients. Multivariable analyses showed that APP was significantly associated with male sex, older age, long-acting injectable use, and concomitant use of antiparkinsonian agents, anxiolytics/hypnotics, and mood stabilizers, whereas clozapine use was inversely associated with APP. Chlorpromazine equivalent doses increased with the number of antipsychotics prescribed, peaking in patients aged 40-59 years and declining thereafter. Second-generation antipsychotics predominated overall, although first-generation antipsychotic use increased with polypharmacy. These findings underscore the importance of careful management of APP, taking sex- and age-related prescribing patterns into consideration.
Esmethadone is under development as an adjunctive treatment for major depressive disorder in patients with inadequate response to standard antidepressants. In the phase 3 study REL-1017-301, esmethadone did not meet the primary endpoint of mean change from baseline (CFB) in Montgomery-Åsberg Depression Rating Scale (MADRS) at day 28, although it showed statistically significant results on the key secondary endpoint of response rate. Post hoc exploratory analyses suggested efficacy in patients with baseline MADRS greater than or equal to 35 (severe depression) ( P = 0.006). The objective of this study was to enhance the reliability of these post hoc analyses through sensitivity analyses. (a) Sensitivity analyses for the primary endpoint using baseline MADRS cutoffs 31-37 showed larger treatment effects with higher baseline severity. Mixed model for repeated measures and per-protocol results were consistent. (b) CFB in MADRS was modeled for each treatment arm individually using all available data. The mean CFB in MADRS demonstrated separation between esmethadone and placebo arms for patients with a baseline score of 35 or higher. These exploratory, hypothesis-generating sensitivity analyses support the potential efficacy of esmethadone in patients with severe depression.
This multicenter, 6-month naturalistic observational study investigated the time from as-needed (PRN) administration of psychotropic medications to the onset of calming in patients with acute psychotic disorders. Newly admitted patients exhibiting moderate to marked agitation on the Agitation-Calmness Evaluation Scale (ACES) and requiring PRN treatment were included, and 170 first agitation episodes were analyzed. The primary outcome was time to onset of effect, defined as achieving ACES = 3. Medication refusal at baseline was far more frequent in patients with injectable formulations than those with oral or sublingual agents (65.5% vs. 4.3%). Kaplan-Meier estimates showed mean onset times (minutes) for oral/sublingual drugs as follows: asenapine sublingual, 30.0; olanzapine orally disintegrating tablet, 31.9; quetiapine, 46.6; and risperidone oral solution, 34.5. Using Cox proportional hazards models with asenapine as reference, quetiapine demonstrated a significantly lower hazard of achieving calming (hazard ratio 0.39), while risperidone showed a nonsignificant trend. For injectable antipsychotics, mean onset times were: olanzapine intramuscular, 36.3; haloperidol intramuscular, 47.5; and haloperidol intravenous, 45.0, with no significant differences among them. No serious adverse events were observed. The findings suggest that asenapine sublingual may offer faster calming in patients without refusal, and that future studies with shorter assessment intervals are warranted.
Major depressive disorder (MDD) is a severe and debilitating illness. Despite the available treatments, clinical outcomes remain suboptimal, and hence, it is crucial to identify predictive factors for response. This is a secondary analysis investigating the relationship between treatment preference and response to treatment in the antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) trial (NCT02977299) comparing three treatment arms [aripiprazole augmentation, repetitive transcranial magnetic stimulation (rTMS) augmentation, switching to venlafaxine XR or duloxetine] in MDD patients with treatment-resistant depression (TRD) who are currently on ongoing, stable, and adequate antidepressant therapy. Patient treatment preferences were recorded in the study entry. In total, 278 subjects were randomly assigned to one of three treatment groups: aripiprazole ( n = 92), rTMS ( n = 70), or venlafaxine/duloxetine ( n = 98). Of these 278 subjects, 256 (92.1%) had at least one postbaseline Montgomery-Asberg Depression Rating Scale (MADRS) score and a recorded treatment preference and were included in this secondary analysis. In the total population, participants' preferences did not affect their response to treatment, and the change in MADRS score was similar among patients who received their preferred treatment, had no preference, or received treatment against their preference ( P = 0.49). These results indicate that patient preference is not a significant factor that predisposes to optimal treatment outcomes.
Despite increasing attention to patient-centered care, the treatment of schizophrenia remains predominantly clinician-driven, with limited integration of patients' subjective needs. This paper critically examines the concept of unmet needs in schizophrenia. While structured tools exist, they are rarely used in routine care, and even less frequently from the patient's perspective. Drawing on international literature and Italian service data, this paper examines the systemic, clinical, and ethical implications of unmet needs, highlighting neglected domains including family support, physical health, and sexual well-being. Comparing mental health systems in Italy, Northern Europe, and the UK reveals systemic differences in the inclusion of patient voice in care planning. Finally, we address the issue of clinician training, proposing a reframing of professional competencies to include active listening, shared decision-making, and coproduction. Integrating patients' voices into need assessment is not optional; it is a prerequisite for meaningful, effective, and equitable care in schizophrenia.
