Human reward processing varies along cue-centric and outcome-centric axes, but the mechanistic basis of individual variation in incentive salience attribution remains incompletely characterized. Here we show, using fMRI across five cohorts (N-total = 1251; N1 = 890; N2 = 245; N3 = 34; N4 = 48; N5 = 34), two reproducible imaging phenotypes mirroring sign- and goal-tracking (ST-like, GT-like). ST-like individuals showed dominant ventral striatal responses to reward-anticipation cues and sustained incentive salience attribution; GT-like individuals showed heightened responses to reward outcomes. This distinction was replicable across sites and independent samples. Single-dose and repeated-dose D2/D3 antagonism (risperidone, haloperidol, amisulpride) selectively reduced anticipatory ventral striatal activity in ST, with single-dose antagonism additionally producing a parallel drop in self-reported energy. Instead, D2/D3 partial agonism (aripiprazole) increased anticipatory and reduced outcome-phase responses in GT. In a psychosis cohort, antipsychotic D2 affinity was associated with blunted anticipatory signals and higher negative symptom burden, offering a neuroimaging-driven basis for stratifying patients and predicting response to dopaminergic agents.

Hypothermia is a rare, potentially life-threatening adverse effect of antipsychotics, including risperidone. Defined as a core temperature<35°C (95°F), it can occur even at therapeutic doses and may be underrecognized, particularly in older adults or medically complex patients.

Current literature lacks detailed characterization of polymeric nanocarriers against the various dosage form conditions. Design-of-experiment-based approaches lead to a specific aim with a specific active substance, carrier system, drug-delivery route, and clinical purpose. However, the same core formulation could be used for multiple purposes across varying environmental conditions. Nasal drug delivery gained a lot of attention in recent years due to its beneficial properties in increasing the bioavailability of various drugs. Current research aims to describe the effect and relationships between a thermosensitive polymeric micelle formulation base, encapsulating risperidone as a model active substance, and the main physicochemical parameters of nasal drug delivery (pH, viscosity, ionic strength etc.). Evaluation of intranasally suitable thermal changes revealed that the different conditions caused the colloidal properties of the polymeric micelles to change or, in some cases, remain unchanged despite the changes. The study also highlighted the importance of storage of nanoparticles, as solid-state storage conditions provided a 1-month stable formulation of polymeric micelles, with a size of approximately 25 nm, in monodisperse size distribution. The low critical solution temperature was also monitored, and under simulated nasal conditions, the nanocarriers exhibited increased, rapid, burst-like drug release and permeation profiles.

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.

Schizophrenia is still a large psychiatric problem worldwide, therefore much study into the structural, electronics and pharmacokinetic properties of therapeutic drugs used in its treatment are needed. The present study has been performed by employing Density Functional Theory (DFT) calculations, molecular electrostatic potential (MEP) mapping, analytical Fukui function evaluation, ADMET profiling and molecular docking in an effort to comprehensively evaluate eight important antipsychotic drugs. DFT studies highlighted important electronic features. Global reactivity descriptors indicated a higher oxidative stability in aripiprazole, opposite to the marked reactivity sensitivity of haloperidol. FMO analysis and Fukui condensation maps suggested that nucleophilic localisation was mainly on the nitrogen lone-pairs, while electrophilic areas were on the phenyl ring motifs. Structural divergence was observed in Olanzapine and Haloperidol. Comprehensive ADMET and multi-endpoint toxicity profiling for understanding physiological disposition revealed that gastrointestinal absorption is a common limitation, but all tested drugs possess excellent blood-brain barrier (BBB) permeability needed for central nervous system target engagement, along with generation-dependent acute toxicity profiles. Toxicity screening showed that aripiprazole had the highest LD50 (800 mg/kg) and minimum risks at the endpoints. Finally, target-directed molecular docking against human glycine transporter 1 (PDB ID: 8WFK) quantified binding architectures in the range of -7.3 to -10.0 kcal/mol. Risperidone showed the highest affinity (-10.0 kcal/mol) due to strong electrostatic interactions with the primary anchoring residue Asp474 and hydrophobic stabilisation through Tyr142, Trp322 and Pro383. The redocking validated the results with RMSD 1.24Å. The MEP maps confirmed that the binding affinity to GlyT1 is the large negative potential localisation around the hydrogen-bond accepting heteroatoms, as well as the large electrochemically neutral hydrophobic regions. These insights provide a crucial integrated framework for optimising the next generation antipsychotic drug design.

Objectives. To identify associations between CYP3A4*22 and CYP3A5*3 genotypes, CYP2D6 phenotype, and the effectiveness and safety of antipsychotics in neurotypically developed boys with conduct disorders. Methods: The study included neurotypically developed boys aged 7-12 years who were hospitalized for conduct disorders. All patients were prescribed an antipsychotic. Patient follow-up lasted 14 days. Treatment effectiveness was assessed using a clinical aggression assessment (checklist) and the CGI-S, CGI-I, and CGAS scales. Safety was assessed using the UKU SERS and SAS scales. Patients were examined upon enrollment in the study, on day 5, and on day 14. All patients were genotyped for the CYP3A4*22 (rs35599367, C>T), CYP3A5*3 (rs776746, 6986T>C) CYP2D6*3 (rs35742686), CYP2D6*4 (G1846A, rs3892097), CYP2D6*6 (rs5030655), CYP2D6*10 (C100T, rs1065852), CYP2D6*41 (rs28371725) loci. CYP2D6 metabolism type was determined based on genotyping results, and patients were divided into two subgroups: those with normal metabolism (NM) and those with intermediate or poor metabolism (IM + PM). Results: Patients taking carbamazepine (n = 11) were excluded from the analysis of associations between treatment outcomes and the CYP3A4*22 and CYP3A5*3 polymorphisms. The analysis of associations between treatment outcomes and CYP2D6 metabolism type was conducted in two stages: the overall sample and a subsample of patients who were prescribed risperidone (n = 80). No significant associations were found between carrier status of the CYP3A4*22 and CYP3A5*3 polymorphisms and treatment effectiveness parameters. Analysis of the overall sample did not reveal any significant associations between CYP2D6 metabolism subtypes and the effectiveness parameters of drug therapy. Analysis of patients receiving risperidone revealed one statistically significant association: patients with CYP2D6 IM + PM reported headaches more frequently (16.1% vs. 2%; p = 0.03). Carrier status of the CYP3A4*22 polymorphism was significantly associated with asthenia and lethargy on day 5 (50% vs. 9.4%; p = 0.008). Conclusions: Our study identified only a few significant associations between the CYP3A4*22 polymorphism, CYP2D6 slow metabolism, and patients' reports of early adverse reactions in a 14-day observation period. Further research is needed to identify pharmacogenetic predictors of the efficacy and safety of antipsychotics in neurotypical children with conduct disorders.

Poor adherence to pharmacotherapy remains a major challenge in the long-term management of severe psychiatric disorders. Although long-acting injectable (LAI) antipsychotics can provide effective and sustained drug exposure while supporting treatment continuity, their pharmaceutical and clinical characteristics vary considerably according to the active pharmaceutical ingredient and formulation technology. Specific formulations may be associated with limitations such as complex release kinetics, injection-site reactions, or the need for oral supplementation during treatment initiation. Hydrogel-based delivery systems have emerged as a versatile class of biomaterials that may address these limitations through their tunable physicochemical properties, high water content, biocompatibility, and capacity for controlled, sustained drug release. Their adaptable architecture further enables diverse drug-loading strategies and multiple routes of administration, expanding the design space for next-generation long-acting formulations. In this narrative review, we provide a comprehensive overview of hydrogel-based depot systems for psychiatric pharmacotherapy, focusing on hydrogel composition (natural, synthetic, and hybrid polymers), crosslinking mechanisms, stimuli-responsive and injectable formulations, drug loading and release strategies, and their translational potential. Current research has primarily focused on antipsychotic delivery, where hydrogel formulations of risperidone, paliperidone, aripiprazole, olanzapine, quetiapine and the investigational peptide PAOPA show possible sustained drug release and prolonged therapeutic activity in preclinical models. Compared with conventional depot technologies, hydrogel systems may offer greater formulation flexibility and the potential for more controlled pharmacokinetic profiles and prolonged drug exposure. These characteristics could ultimately support reduced dosing frequency and treatment continuity. We also discuss the key challenges limiting clinical translation, including optimization of release kinetics, scalable manufacturing, sterilization, long-term stability, and regulatory considerations. Collectively, current evidence supports the technological potential of hydrogel-based systems to provide tunable drug loading, depot formation, and sustained release. However, their development as clinically meaningful next-generation LAI therapies will require long-term in vivo evaluation, robust pharmacokinetic-pharmacodynamic characterization, injection-site safety assessment, reproducible and scalable manufacturing, and well-designed clinical trials.