ObjectiveDescribe concurrent use of two long-acting injectable (LAI) antipsychotics in selected patients with treatment-resistant schizophrenia and persistent aggression at a forensic health facility. Evidence remains limited for this off-licence strategy.MethodsRetrospective case series conducted at a specialist forensic psychiatric hospital in Melbourne, Australia. All inpatients using concurrent LAI antipsychotics between March 2022 and March 2023 were included (N = 26). De-identified clinical data, including information for behavioral outcomes (Dynamic Appraisal of Situational Aggression [DASA]), institutional incidents, adverse effects and Defined Daily Dose (DDD) were extracted. Analyses were descriptive with exploratory unadjusted odds ratios.ResultsConcurrent LAI antipsychotics were predominantly prescribed to males (24/26, 92.3%) with chronic schizophrenia. Persistent aggression (22/26, 84.6%) was the commonest indication. Most frequent combination was olanzapine pamoate and zuclopenthixol decanoate and DDD median was 2.17 (range 0.48-10.13). Although the study design precluded identifying causal relationships, improvements were observed in DASA scores (21/26, 80.8%), incident frequency (22/26, 84.6%), and as-required-medication use (19/26, 73.1%). Adverse effects were common.ConclusionsSelected forensic patients with high-risk behaviors may benefit from concurrent LAI antipsychotics. Enhanced side-effect monitoring and multidisciplinary oversight are required when used. Data interpretation was limited by observational design, concomitant medications, and absence of standardized symptom measures.

Converging findings point to brain- and body-wide energetic dysregulation in psychotic disorders, implicating metabolic abnormalities across different levels of investigation, including genetic, cellular, postmortem, and in vivo neuroimaging studies. The present review synthesizes this literature documenting aberrant energy production and use, specifically related to mitochondrial and redox dysregulation, in psychotic disorders. Mitochondrial DNA, copy number variants, polygenic risk, and candidate genes involved in metabolic pathways converge on glycolytic, mitochondrial, redox, and oxidative stress mechanisms. Consistent with these findings, cell studies, primarily from ex vivo brain tissue samples and induced pluripotent stem cells (iPSC), show misdistribution and structural fragmentation of mitochondrial networks and dysregulation in the expression of proteins involved in several metabolic processes. Inherent dysregulations, at the genetic and cellular level, may affect both neuronal and glial health, as observed at the tissue level. Neuroimaging studies demonstrate metabolic dysregulations in vivo, including central insulin resistance and redox and bioenergetic aberrations that are associated with cognitive impairment and altered brain networks. We also consider the effects of antipsychotic medications on energy metabolism. Finally, we propose a framework for future work and treatment approaches to target energetic dysregulations, including existing metabolic treatments. The metabolic mechanisms that interact to produce and perpetuate aberrant neuronal health and functioning in psychotic disorders are complex. Nevertheless, the findings highlight pathways that might be targeted for the development of novel treatments, providing an opportunity to develop more efficacious and better-tolerated interventions.

STAGES trial was a triple-blind noninferiority trial that investigated intensive psychosocial treatment with or without low-dose antipsychotics in young people with first-episode psychosis with a short duration of untreated psychosis, who were low-risk and had stable family support. Participants received cognitive behavioural case management combined with either low-dose risperidone/paliperidone or placebo. Only 7% of the screened individuals were included (N = 90), with just 30% completing the protocol, reflecting trial challenges. Both groups showed significant improvements in social and occupational functioning (primary outcome) and symptoms at 6 months, with placebo demonstrating noninferior outcomes. At 24 months, the groups did not significantly differ, though noninferiority could not be confirmed. Neuroimaging findings revealed that placebo recipients showed reduced basal ganglia volume and widespread cortical thinning relative to healthy controls, while antipsychotics increased basal ganglia volume and attenuated cortical thinning. This demonstrates that antipsychotics do not cause tissue loss early in treatment, and delaying medication may hasten illness-related brain volume loss. Metabolic analyses showed that antipsychotics contributed to greater weight gain and metabolic changes, though some risk existed without medication. Cognitive analyses revealed baseline illness-associated cognitive impairment, with verbal learning/memory decline over 6 months in the medication group only, suggesting early cognitive side effects. STAGES trial findings demonstrate that carefully selected low-risk first-episode psychosis patients can achieve clinical improvement through psychosocial interventions alone while minimising potential negative metabolic and cognitive effects. However, delaying medication may result in adverse structural brain changes. The results support integrated treatment and shared decision-making approaches that balance symptom management, functional recovery and preservation of physical, cognitive and brain health.