Hyperprolactinaemia is a common adverse effect of antipsychotic medication, primarily resulting from dopamine D2 receptor blockade. It is characterised by menstrual irregularities, gynaecomastia, galactorrhoea and, with prolonged exposure, an increased risk of osteoporosis and breast cancer. When switching towards a prolactin-sparing antipsychotic is not feasible, adjunctive use of aripiprazole - a dopamine D2 partial agonist - has emerged as a validated strategy to mitigate hyperprolactinaemia without compromising antipsychotic efficacy. However, alternative options are needed for patients who cannot tolerate aripiprazole. Here we report the use of brexpiprazole, a dopamine D2 partial agonist structurally related to aripiprazole, to counteract paliperidone-induced hyperprolactinaemia effectively in a patient who developed a cutaneous reaction to aripiprazole. During the follow-up period with adjunctive brexpiprazole in combination with paliperidone, neither a recurrence of psychotic symptoms nor a reappearance of the skin reaction previously experienced with aripiprazole was observed.

The discovery and development of new active pharmaceutical ingredients (APIs) is a complex and resource-intensive process characterized by high attrition rates and significant translational uncertainty. While advances in computational chemistry and AI have accelerated early-stage candidate identification, successful clinical translation depends not only on pharmacological activity but also on appropriate pharmaceutical formulation. This review examines the critical role of formulation development in bridging molecular discovery with clinical evaluation, emphasizing physicochemical characterization, enabling formulation strategies for poorly soluble compounds, and integration of mechanistic tools such as physiologically based pharmacokinetic (PBPK) and physiologically based biopharmaceutics modeling (PBBM). Particular attention is given to modified-release systems, amorphous solid dispersions, and long-acting injectable formulations, highlighting how formulation design directly influences systemic exposure, variability, and clinical reliability. Case studies of posaconazole and long-acting injectable aripiprazole demonstrate how rational reformulation and process optimization can significantly improve pharmacokinetic consistency and therapeutic performance while introducing technological and regulatory complexity. Emerging trends indicate a paradigm shift toward formulation-informed and model-integrated drug development, where AI, mechanistic modeling, and Quality by Design (QbD) principles are increasingly used to predict formulation performance and support clinical and regulatory decision-making. Integration of formulation science with predictive modeling and data-driven approaches enables earlier identification of translational risks, improves development efficiency, and enhances the probability of clinical success. Overall, formulation development should be regarded as a central determinant of clinical outcomes and regulatory success, rather than a downstream technical activity, supporting more predictive and efficient pharmaceutical development.

Objective: This post hoc analysis assessed the benefit-risk of aripiprazole once-monthly 400 mg (AOM 400) as acute and long-term maintenance treatment for patients diagnosed with schizophrenia, based on number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).

Post-traumatic confusional state (PTCS) is a disabling sequel of pediatric traumatic brain injury (TBI), with little guidance on pharmacologic management when aggression and poor impulse control dominate and adherence is poor. We describe a 9-year-old boy with severe TBI who evolved from coma to a prolonged PTCS characterized by agitation, externalizing behaviors, and dysexecutive symptoms. Multiple oral agents-risperidone, methylphenidate, olanzapine, and aripiprazole-were trialed over several years with minimal benefit and poor adherence. Following an acute agitation episode in 2022, long-acting injectable (LAI) paliperidone palmitate was initiated (100 mg then 150 mg monthly) with adjunct nightly risperidone 2 mg. Over two years, aggression markedly decreased and functional status improved from Rancho Los Amigos Level IV ("confused-agitated") to Level VIII ("purposeful-appropriate"). Cognitive testing at age 19 showed average intellectual ability but persistent executive dysfunction. Adverse effects were limited to weight gain and asymptomatic hyperprolactinemia; no extrapyramidal or cardiac events occurred. While spontaneous recovery and developmental maturation cannot be excluded, this case suggests LAI paliperidone can be a practical option to stabilize severe PTCS-related behavioral dysregulation when oral adherence fails. Larger, controlled studies are needed to clarify efficacy, safety, and long-term neurocognitive impact of LAI antipsychotics in pediatric TBI.

Hypersensitivity reactions to second-generation antipsychotics and mood stabilizers are uncommon and can lead to serious complications. These medicines are generally well tolerated, but there have been reports of unusual allergic reactions, such as hives or itching, associated with these drugs. The patient is a 45-year-old woman who presented with a recurrence of a manic episode of bipolar I disorder and developed skin complications and itching after receiving valproate and levetiracetam. She subsequently experienced severe skin allergic reactions, including hives and itching, after taking various second-generation antipsychotics, including risperidone, aripiprazole, and quetiapine. These allergic reactions occurred shortly after starting the medication and resolved after discontinuing the drug. The purpose of this case report is to highlight the importance of being aware of the possibility of concomitant hypersensitivity with various antipsychotic and anticonvulsant medications, which can affect the diagnosis and treatment of the disease.

Schizophrenia is a chronic mental health condition that most commonly develops in the third decade of life, but may emerge during adolescence, although in rare cases it can also present in childhood. Pre-adult onset is associated with substantial morbidity, functional impairment, and long-term disability. Accurately diagnosing schizophrenia in youth is particularly challenging, as its symptoms frequently overlap with or are misattributed to other psychiatric or developmental conditions. Conversely, misdiagnosis can also occur when psychotic symptoms are present in patients suffering from other conditions. Establishing an accurate and timely diagnosis is therefore critical to prevent errors in treatment and to optimize prognosis and functional outcomes. Antipsychotic medications are first-line interventions for schizophrenia in youth, with second-generation antipsychotics (SGAs) having the strongest evidence base in this population. Randomized controlled trials and open-label studies support the efficacy of risperidone, aripiprazole, olanzapine, quetiapine, paliperidone, lurasidone, and brexpiprazole in reducing psychotic symptoms in adolescents. In contrast, ziprasidone and asenapine have not demonstrated clear benefit in treatment of schizophrenia in youth. Similar to studies in adults, evidence from pediatric clinical trials suggests that clozapine remains the most effective option for treatment-resistant adolescent schizophrenia, although its use requires close monitoring for hematologic and other adverse effects. While SGAs are generally favored over first-generation antipsychotics (FGAs) in youth because of their reduced propensity for causing extrapyramidal side effects as well as a stronger evidence base to support their use, their safety profiles require careful consideration. Weight gain, metabolic syndrome, sedation, extrapyramidal symptoms, and endocrine effects have been reported in youth with schizophrenia. Such side effects can significantly impact adherence and long-term physical health, necessitating the need for ongoing monitoring and thoughtful agent selection tailored to each patient's individual clinical profile and risk factors. Overall, current evidence supports SGAs as the foundation of psychopharmacologic treatment for schizophrenia in pediatric-aged patients, with clozapine reserved for refractory cases. However, the relative paucity of pediatric-specific data compared with adult populations underscores the importance of continued research to guide clinical practice. In the meantime, accurate diagnosis, early intervention, and vigilant monitoring of both therapeutic response and side effects remain essential to optimizing outcomes for youth with schizophrenia.

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.

Bipolar-spectrum illness emerging after traumatic brain injury (TBI) can be difficult to treat and may present with mixed or agitated depressive features that appear sensitive to glutamatergic modulation. In post-TBI cases, diagnostic certainty is often limited because irritability, impulsivity, sleep disturbance, affective lability, and cognitive change may overlap with frontal-limbic injury syndromes. This case is, therefore, framed as probable bipolar-spectrum disorder secondary to TBI rather than definitive idiopathic bipolar disorder. The Cheung Glutamatergic Regimen (CGR)--low-dose dextromethorphan with CYP2D6 inhibition plus piracetam--is used here only as a shorthand for an open-source, free-to-use, non-proprietary combination of off-patent components, not as a branded product. This report describes a woman in her mid-thirties with right frontal atrophy after a 2009 subdural hematoma who later developed probable bipolar-spectrum illness. On 21 October 2025, she presented with severe depressive relapse, insomnia, persistent rumination, irritability, and hypnagogic phenomena, with a Patient Health Questionnaire-9 (PHQ-9) score of 22. After partial improvement on valproate, risperidone, and Deanxit, dextromethorphan 30 mg nightly and piracetam 600 mg nightly were added on 5 November 2025. Within weeks, rumination decreased and mental flexibility improved, but transient mild hypomanic or frontal-disinhibition-like symptoms emerged, especially inappropriate laughter with a moria-like quality. She self-reduced dextromethorphan to 22.5 mg, piracetam was increased, and euthymia returned. Over the next six months, PHQ-9 scores improved to 10-12 and Generalized Anxiety Disorder-7 (GAD-7) scores to 8-13, with functional gains including exercise and motorcycle riding lessons. Later medications included aripiprazole, paroxetine-controlled release, pregabalin, and low-dose quetiapine. By April 2026, dextromethorphan and piracetam were used as needed during stress-related or premenstrual dips. No further psychotic symptoms were reported, and later mild dissociative or cognitive complaints became manageable after dose adjustment. This single-patient course suggests a three-phase pattern: induction with a narrow therapeutic window and brief activation/overshoot, stabilization after titration, and later PRN maintenance. Dextromethorphan appeared temporally most linked to both clinical benefit and transient activation, while piracetam may have acted as a modulator. However, causal inference is limited by the uncontrolled design, early PHQ-9 improvement before CGR initiation, later polypharmacy, unmeasured pharmacokinetics, absence of standardized mania/cognitive measures, and incomplete PRN-frequency documentation. The case is also only hypothesis-generating in relation to transcriptomic findings implicating bipolar-specific plasticity-related biology. Low-dose oral glutamatergic augmentation may warrant study as a closely monitored induction and consolidation strategy in post-TBI bipolar-spectrum illness, but prospective controlled trials are needed before broader recommendations can be made.