Search Results (1,176)

Background: Schizophrenia in adolescence disrupts neurodevelopment and long-term functioning. While symptom reduction remains a primary treatment goal, quality of life (QoL) represents a critical, patient-centered outcome. Pharmacogenetic variability, particularly in CYP2D6 metabolism of second-generation antipsychotics, may influence tolerability and subjective well-being beyond symptom control. Materials and Methods: Forty-seven adolescents (aged 14–18 years) diagnosed with schizophrenia (DSM-5) were followed in routine clinical care. CYP2D6 genotyping classified patients as normal metabolizers (NM, n = 27) or reduced-function metabolizers (RFM, including intermediate/poor, n = 20). Symptom severity was assessed with PANSS, QoL was assessed with the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q), and adverse effects (hyperprolactinemia, extrapyramidal symptoms, sedation, metabolic changes) were monitored. Non-parametric tests and multiple linear regression were applied. Results: At 12 months, RFM patients showed significantly higher PANSS scores, markedly more adverse reactions (95% vs. 48.1%), and lower PQ-LES-Q total and domain scores (all p < 0.0001) compared to NM patients. A regression analysis identified the metabolizer status (β = −0.410, p = 0.001), extrapyramidal symptoms (β = −0.248, p = 0.003), sedation (β = −0.193, p = 0.029), and hyperprolactinemia (β = −0.190, p = 0.012) as independent predictors of a reduced QoL, explaining 84% of the variance. The residual symptom severity was not independently associated. Conclusions: In adolescent schizophrenia, the CYP2D6-reduced metabolizer status is the strongest independent predictor of long-term QoL impairment, associated primarily through a substantially higher burden of treatment-related adverse effects (metabolic, endocrine, neurological, and sedative) rather than through persistence of psychotic symptoms alone. These findings support early pharmacogenetic testing to guide individualized dosing and improve tolerability and patient-reported outcomes. Full article

In this study, Paliperidone Palmitate (PP), a second-generation antipsychotic, commonly used for the treatment of schizophrenia, was encapsulated in bio-based non-isocyanate polyurethane (NIPU) nanoemulsions. NIPU was synthesized via an isocyanate-free polyaddition route, addressing safety and environmental concerns associated with conventional polyurethanes. The drug-loaded nanoparticles were produced utilizing oil-in-water (O/W) emulsions followed by solvent evaporation and lyophilization. NIPU concentrations of 0.3% and 0.5% w/v, as well as 0.5% w/v PVA were employed, while PP was incorporated at 0.2%, 0.5% and 1% w/v. The formulations were characterized by FTIR, DSC and XRD analyses, and the mechanical strength of neat sponges was evaluated. The nanoparticle formation and size were assessed by DLS and SEM analyses. The water contact angle, porosity measurements and aquatic and enzymatic hydrolysis were additionally performed. The resulting nanocarriers exhibited controlled particle size, increased drug-loading values, structural stability and biodegradability. Lastly, the in vitro dissolution studies revealed a system-specific burst release behavior, and a controlled and sustained overall drug-release profile for majority of the formulations, thereby indicating the potential of NIPU nanocarriers for drug delivery applications, particularly where sustained therapeutic effects are required. Full article

Background: Biological sex contributes to variability in drug metabolism, receptor sensitivity, and susceptibility to adverse drug reactions (ADRs). Despite this, dosing recommendations for selective serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotics (SGAs) are still largely sex-neutral. This systematic review examines sex-related differences in pharmacokinetics (PK), pharmacodynamics (PD), and safety outcomes, with the aim of clarifying their potential implications for personalized psychopharmacology. Methods: A systematic search of PubMed was conducted for studies published between January 2010 and March 2026. The strategy combined MeSH terms and free-text keywords related to SSRIs, SGAs, sex differences, pharmacokinetics, pharmacodynamics, and ADRs. Two independent reviewers performed study selection and data extraction. Studies reporting sex-stratified PK, PD, or safety outcomes in humans were included. Owing to methodological heterogeneity, results were synthesized narratively. Results: Twenty-seven studies met the inclusion criteria. Overall, the evidence indicates clinically meaningful sex-related differences in psychotropic drug exposure and response. Women more frequently exhibited higher dose-adjusted serum concentrations, particularly for risperidone and some SSRIs, with age-related increases more evident in females. Pharmacodynamic findings suggest that women may reach comparable dopamine D2 receptor occupancy at lower olanzapine doses. Pharmacovigilance analyses revealed sex-specific adverse event patterns, including greater reporting of endocrine-related effects and QT prolongation in women. Conclusions: Sex influences psychotropic drug exposure, pharmacodynamic sensitivity, and safety profiles in ways that may be clinically relevant. Integrating sex-aware considerations into dosing strategies could improve therapeutic precision and reduce adverse outcomes, reinforcing the importance of sex as a key variable in personalized psychiatric care. Full article

Obsessive-compulsive disorder (OCD) is a chronic mental disorder characterized by distressing thoughts and repetitive behaviors that significantly impair daily functioning and quality of life. Many patients fail to achieve sufficient symptom relief with first-line treatments, such as cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs). Dopaminergic dysregulation has been implicated in the pathophysiology of OCD, providing a rationale for pharmacological augmentation strategies. This article presents a narrative review of the evidence regarding the efficacy, safety, and clinical applicability of antipsychotic agents and emerging pharmacological augmentation approaches, including extended-release methylphenidate (MPH-ER), in SSRI-resistant OCD. A literature search was conducted using PubMed, EBSCO, and Embase databases, with an additional search of Google Scholar, focusing on studies examining pharmacological augmentation in treatment-resistant OCD. Overall, the evidence base is limited by small sample sizes, short follow-up durations, heterogeneous response criteria, and a lack of head-to-head comparisons versus CBT augmentation, which constrains the generalizability of conclusions. Dopamine receptor antagonists, particularly risperidone, as well as the partial agonist aripiprazole, remain the most consistently supported augmentation strategies, while olanzapine and quetiapine may be considered in selected cases. Evidence for MPH-ER is currently limited—supported by one small RCT and two recent case series—and may be considered in carefully selected adults with comorbid ADHD or marked executive dysfunction, although larger controlled studies and long-term safety data are required before firm clinical recommendations can be made. Full article

Background/Objectives: Schizophrenia is a severe psychiatric disorder frequently characterised by sleep and circadian disturbances, which are closely linked to cognitive dysfunction, symptom exacerbation, and poor functional outcomes. A growing body of evidence implicates the orexin (hypocretin) system—an essential regulator of arousal, sleep–wake stability, metabolic processes, and motivated behaviour—in the pathophysiology and treatment response of psychotic disorders. We aimed to investigate the relationships between the orexinergic system and psychoses. Methods: On 3 March 2026, we searched the PubMed, Scopus, PsycInfo/Articles and Cinahl databases for studies dealing with the orexin system and psychotic disorders and treatment response. Results: We found 20 eligible studies reporting variable and inconsistent alterations in orexin signalling in patients with schizophrenia. Studies were mostly cross-sectional and heterogeneous in design. Antipsychotic medications interfere with orexin-dependent pathways, potentially contributing to both therapeutic effects and adverse outcomes such as sleep disruption and metabolic dysregulation. Conclusions: While evidence from preclinical studies could point to an influence of dopaminergic activity through orexinergic mechanisms, with possible attenuation of antipsychotic-induced motor side effects and improvement of attentional deficits associated with NMDA receptor hypofunction, the utility of dual orexin receptor antagonists (DORAs) in psychoses is unclear. Despite the high prevalence of insomnia in schizophrenia, its pharmacological management remains suboptimal, with current treatments often limited by reduced efficacy or tolerability concerns. DORAs, which are currently approved medications for the treatment of insomnia, represent a novel and mechanistically distinct therapeutic option that may improve sleep while modulating arousal- and cognition-related circuits relevant to psychosis. Full article

Background/Objectives: Metformin has been proposed as a potential treatment for hyperprolactinemia irrespective of etiology. Previous studies suggest that vitamin D deficiency attenuates the prolactin-lowering effect of metformin in women. This study examined whether vitamin D status modifies the effects of this agent on prolactin and other anterior pituitary hormones in men with iatrogenic hyperprolactinemia. Methods: Seventy-five adult men with antipsychotic-induced hyperprolactinemia and type 2 diabetes or prediabetes were enrolled. Participants were assigned to three equal groups based on vitamin D status and supplementation: vitamin D-naive men with sufficient levels (group 1), vitamin D-naive men with deficiency (group 2), and men with sufficient vitamin D levels receiving oral supplementation for at least six months (group 3). All participants received metformin (3 g/day) for six months. Plasma 25-hydroxyvitamin D, markers of glucose metabolism, total and monomeric prolactin, TSH, gonadotropins, ACTH, testosterone, and IGF-1 were measured at baseline and after treatment. Results: Baseline characteristics were comparable among groups except for 25-hydroxyvitamin D levels. Seventy participants completed the study. Metformin improved glycemic control and insulin sensitivity in all groups, with greater effects in men with sufficient vitamin D status. Reductions in total and monomeric prolactin were observed only in groups 1 and 3 and were associated with baseline prolactin concentrations and pretreatment 25-hydroxyvitamin D levels. These changes were accompanied by modest increases in LH and testosterone, and improvements in sexual functioning. Vitamin D levels and other hormonal parameters remained unchanged. The magnitude of the metformin effect did not differ between groups 1 and 3. Conclusions: Adequate vitamin D status is necessary for metformin to reduce prolactin levels in men with iatrogenic hyperprolactinemia. Full article

Objectives. The aim of our study was to track changes in ODQ scores in adolescents with depressive episodes taking sertraline, depending on CYP2C19 polymorphisms. Methods. This study included 88 adolescents (88% were female) aged 12–17 who were prescribed sertraline. Emotional blunting was assessed using the Oxford Depression Questionnaire (ODQ) scale when the antidepressant was prescribed, after one, three, and 8 weeks, taking into account other medications used. Part 3 of the ODQ scale assessed the changes that occurred after the prescription of an antidepressant. All patients were genotyped for CYP2C19*2, *3, and *17. Based on genotypes, the phenotypes of the CYP2C19 isoenzyme were determined. Results. The ODQ score at the time of enrollment was higher (65[50;79] points) compared with after 8 weeks (38.5[32.5;56.5] points). Part 3 of the ODQ-26 questionnaire remained approximately the same for 8 weeks. Patients with higher ODQ-26 values at enrollment (73[56;83] vs. 59[44;71] points) were more likely to be prescribed antipsychotics. Differences in ODQ scores remained significant up to 3 weeks after enrollment (50.5[41.5;68] vs. 45.5[36;54] points). The comparison of ODQ scores and their dynamics did not show significant differences depending on CYP2C19*2 or *17 polymorphisms, or the type of CYP2C19 metabolism. Conclusions. There was no increase in emotional blunting according to the ODQ score among adolescents with depression who took sertraline for eight weeks. No significant correlations were found between the carrier status of CYP2C19 gene variants and the development of apathy induced by antidepressants. Full article

Background: Elevated prolactin levels are associated with disturbances in female sexual function. While long-term therapy with dopamine agonists has been shown to improve these disturbances, the therapeutic benefits appear to be reduced in the presence of vitamin D deficiency or insufficiency. Therefore, the present study aimed to examine whether vitamin D status modulates the effects of metformin—a medication with less pronounced prolactin-lowering properties—on sexual function and depressive symptoms. Methods: The study cohort comprised three groups of reproductive-age women with drug-induced hyperprolactinemia and prediabetes, matched for age, glycated hemoglobin, and prolactin concentrations. Group I included 25 women with normal vitamin D status who were not receiving vitamin D supplementation. Group II consisted of 25 women with vitamin D deficiency or insufficiency that was adequately corrected through supplementation, while group III included 25 women with untreated vitamin D deficiency or insufficiency. All participants received metformin throughout the six-month study period. Female sexual function and depressive symptoms were assessed before and after metformin therapy using the Female Sexual Function Index (FSFI) and the Beck Depression Inventory-II (BDI-II), respectively. Additional outcome measures included plasma 25-hydroxyvitamin D, fasting plasma glucose, glycated hemoglobin (HbA_1c), the homeostatic model assessment of insulin resistance (HOMA-IR), prolactin, gonadotropins, and sex hormones. Results: Improvements in glucose homeostasis were observed across all groups; however, these changes were more pronounced in groups I and II than in group III. Reductions in prolactin concentrations (total and monomeric), accompanied by increases in gonadotropins, estradiol, and testosterone, were observed exclusively in women with normal vitamin D status. In groups I and II, metformin therapy resulted in significant improvements in total FSFI scores as well as in all individual domain scores. In contrast, in group III, the effects of metformin were limited to increases in the domain scores for lubrication and sexual satisfaction. Improvements in sexual function were positively associated with baseline 25-hydroxyvitamin D levels, reductions in prolactin concentrations, and, to a lesser extent, treatment-related changes in HbA_1c and increases in testosterone. A treatment-induced reduction in total BDI-II scores was observed only among women with normal vitamin D status. Conclusions: Low vitamin D status diminishes the beneficial effects of metformin on sexual function and depressive symptoms in reproductive-age women with iatrogenic hyperprolactinemia. Full article

Background: Schizophrenia is a heterogeneous disorder, and treatment-resistant schizophrenia (TRS) affects 20–30% of patients, yet objective biomarkers for its identification remain limited. Routine electroencephalography (EEG) offers a non-invasive window into cortical network dynamics, with previous studies reporting paroxysmal epileptiform activity and background slowing in a subset of patients. However, the biological significance of these findings—whether purely pathological or potentially compensatory—remains unclear. This study aimed to compare EEG abnormalities between TRS patients and those in clinical remission and to propose an integrative neurobiological interpretation. Methods: In a cross-sectional design, 89 patients with schizophrenia (39 TRS, 50 in remission) underwent routine EEG recordings using the international 10–20 system. TRS was defined according to TRRIP consensus criteria, requiring <20% symptom reduction after adequate antipsychotic trials. EEG analysis focused on the prevalence of interictal epileptiform discharges (IEDs) and the severity of background slowing, assessed on a 4-point ordinal scale. Results: IEDs were more than twice as prevalent in TRS patients compared to those in remission. Background slowing was significantly more severe in the TRS group, with the majority showing moderate-to-severe abnormalities versus predominantly normal-to-mild patterns in remission patients. Focal EEG abnormalities also followed this pattern. Multivariate analysis confirmed that both IEDs and background severity were independent predictors of TRS. Conclusions: EEG abnormalities, particularly IEDs and background slowing, are potential neurophysiological signatures associated with treatment resistance. We propose an integrative hypothesis suggesting that IEDs may originate as a failed compensatory mechanism—the brain’s attempt to restore network homeostasis. In chronic TRS these discharges become maladaptive, contributing to excitotoxicity and network dysfunction. This framework opens avenues for EEG-based stratification and novel therapeutic strategies targeting cortical excitability. Full article

Background: Psychosis is a common neuropsychiatric symptom associated with Parkinson’s disease (PD), with prevalence rates of up to 75% over the course of the disease. Parkinson’s disease psychosis (PDP) is associated with increased morbidity, caregiver burden, depression, poorer quality of life and progression of dementia. It has also been shown to be a strong predictive factor for long-term care placement, and results in up to 71% increase in risk of mortality compared with PD patients free from psychotic symptoms. Use of APs for PDP is common, with up to 35% of PD patients prescribed at least one AP within 7 years of PD diagnosis. Methods: Four electronic databases (Ovid MEDLINE, Embase, PsycINFO, PubMed) were systematically searched for double-blind, randomised, placebo-controlled clinical trials for the use of APs in the treatment of PDP and their effects on PD motor symptoms, according to PRISMA guidelines. Results: Eleven studies from ten publications were identified and included in this review. Four studies investigated quetiapine, three investigated olanzapine, two investigated clozapine and a further two investigated pimavanserin. Quetiapine showed no significant improvement for PDP over placebo in three of the four studies, with both olanzapine studies also showing no improvement. Olanzapine studies also showed significant motor worsening compared to placebo. Clozapine significantly improved psychosis compared with placebo in both studies, with large effect sizes in primary outcome measures; (−0.82, 95% CI −1.37 to −0.26), −0.89 (95% CI −1.42 to −0.36). Pimavanserin also showed significant improvement (−0.48, 95% CI −0.77 to −0.18). Quetiapine, clozapine and pimavanserin showed no significant worsening in motor scores compared with placebo groups. Conclusions: Data from the studies included in this review suggest that the use of quetiapine for the management of PDP may not be evidence based. Clozapine may improve PDP symptoms with low doses however significant side-effects may limit usability. The findings from this review support the use of clozapine as an alternative AP for the management of PDP when clinically appropriate. Full article

Background: Dual disorders (DDs) describe the coexistence of substance use disorder (SUD) and another mental health condition, commonly within psychotic and affective categories. These conditions represent a significant challenge in clinical management due to their bidirectional interactions and complexity. This study aims to evaluate the efficacy and safety of quetiapine, a second-generation antipsychotic, in patients with schizophrenia spectrum disorders and comorbid substance use disorders. Methods: A total of 28 participants with schizophrenia spectrum disorder and comorbid SUD underwent psychometric evaluations at baseline (T0), one month (T1) and three months post-initiation of quetiapine treatment (T2), administered at a mean dosage of 165 mg/day. Key outcome measures included psychopathological burden (PANSS), aggressivity (MOAS), substance craving (VAS Craving), and quality of life (Q-LES-Q-SF scales). Results: Quetiapine demonstrated significant reductions in psychopathological symptoms, with decreased PANSS total scores (p < 0.001). Positive symptoms (p < 0.001), negative symptoms (p = 0.002), substance craving (p = 0.001), and aggressivity (p = 0.006) also showed notable reductions. Quality of life significantly improved across Q-LES-Q-SF scores (p < 0.001). Quetiapine was well-tolerated, with no dropouts related to drug-induced side effects. Conclusions: This study provides preliminary evidence supporting the efficacy and safety of quetiapine in individuals with dual disorders. Improvements in psychopathology, substance craving, and quality of life underscore the importance of integrating tailored and comprehensive treatment strategies to address the multifaceted challenges of this challenging population. Full article

Background: Schizophrenia spectrum disorders (SSD) affect females differently than males, yet there is limited research on Physical Activity (PA) levels and sex differences in patients with SSD. This study aimed at comparing PA levels between female and male SSD patients and controls. Methods: Altogether, 132 SSD residents and outpatients (48 females and 84 males) and 113 controls (46 females and 67 males) were assessed using standardised clinical tools. PA was monitored for seven consecutive days using a tri-axial ActiGraph GT9X accelerometer and quantified using the Euclidean Norm Minus One (ENMO) as an index of overall movement intensity. Descriptive and regression analyses were conducted. Results: Most patients were unemployed and overweight; males were less educated, less often divorced, smoking more, and using more antipsychotics than females (p < 0.05). Patients were less likely to be married, educated, employed, and had higher BMI and smoking rates than controls. Among patients, there were no significant sex differences in daily PA levels. In the control group, males showed slightly higher PA levels than females, although this difference did not reach statistical significance. Objective PA levels were not significantly associated with clinical outcomes in either female or male patients with SSD. Conclusions: Patients with SSD exhibited similarly low levels of objectively measured PA regardless of sex, suggesting a “flattening” phenomenon of sex differences in PA. These findings highlight the need for interventions aimed at promoting PA in individuals with SSD and support further research to identify factors influencing PA engagement across sexes. Full article

Background/Objectives: Aggressive behaviour is commonly associated with neurodevelopmental disorders, such as autism spectrum disorder (ASD), and could be understood as a response to daily stress routines, which negatively impacts patients’ quality of life. Oxytocin (OT), a neuropeptide involved in social bonding and socio-affective regulation, has emerged as a promising candidate to enrich, rather than replace, current pharmacological approaches in managing ASD-associated aggressive behaviour. In this study, we examined the potential of OT to modulate aggressive behaviour frequency in a VPA-based animal model of ASD. Methods: Sixty adult zebrafish (1:1 sex ratio) were divided into six groups (n = 10/group) and received the following treatment for 7 consecutive days: CTR—control (no treatment); VPA (28.8 mg/L valproic acid); OT (33.2 ng/mL oxytocin); RIS (170 μg/L risperidone); VPA + OT (28.8 mg/L valproic acid and 33.2 ng/mL oxytocin); and VPA + RIS (28.8 mg/L valproic acid and 170 μg/L risperidone). The locomotor performance, and socio-affective and aggressive behaviours, were measured in the Novel Tank and Mirror Biting tests at the end of the treatments. Results: We observed that the VPA treatment led to locomotion and socio-affective impairments, as well as aggressive behaviour. Also, we found that OT and RIS had comparable potential to modulate the frequency of aggressive and anxiety-like behaviours. Conclusions: Our preliminary data showed that OT has the potential to modulate the frequency of anxiety-like and aggressive behaviours, similarly to the atypical antipsychotic, RIS, in our VPA zebrafish model. However, further studies are needed to investigate the mechanisms of action and their potential synergistic effects. Full article

Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group I mGluRs (mGluR1 and mGluR5) interact with PSD adaptor and scaffolding proteins, such as Homer, Shank, Norbin, and PICK1, as well as intracellular downstream effectors, creating a molecular network that resembles a Lego-like structure, where modular protein interactions fine-tune glutamatergic transmission. Evidence from preclinical research indicates that dysregulation of mGluR expression and function, along with disrupted PSD protein expression, may contribute to the pathophysiology of schizophrenia by altering glutamatergic neurotransmission and synaptic stability. Antipsychotic mechanisms of action may involve, at least in part, the modulation of mGluR activity mediated through PSD proteins. Notably, novel agents that enhance spinogenesis by acting at the level of PSD proteins, such as SPG302, may open promising avenues for therapeutics aimed at restoring synaptic integrity. While Group I mGluRs dominate postsynaptic regulation, Group II (mGluR2/3) and III (mGluR4/6/7/8) receptors -primarily presynaptic- inhibit neurotransmitter release and plasticity, offering complementary therapeutic avenues. Emerging strategies, such as allosteric modulators of mGluRs, aim to rebalance synaptic signaling in treatment-resistant schizophrenia. This review synthesizes how PSD proteins and mGluRs interact in schizophrenia, exploring their potential as druggable targets for novel therapies. Full article

Schizophrenia is a complex, chronic psychiatric disorder with significant global impact, characterized by persistent positive, negative, and cognitive symptoms that are not fully addressed by current treatments. This review aims to synthesize established theories and advancing mechanistic concepts and also critically compare the latest international treatment guidelines. Recent evidence expands beyond the traditional dopamine hypothesis to include glutamatergic, serotonergic, and cholinergic dysfunctions, as well as emerging mechanisms such as neuroinflammation, oxidative stress, iron dysregulation, and gut–brain interactions. A review of major international guidelines (APA, NICE, CINP, WFSBP, and others) confirms consensus on the use of second-generation antipsychotics as first-line therapy and the early introduction of clozapine for treatment-resistant cases. All guidelines emphasize the essential role of integrated psychosocial interventions, including cognitive behavioral therapy for psychosis, family psychoeducation, and supported employment. Differences remain regarding the prioritization of precision medicine, pharmacogenomics, and digital health innovations. Prognosis varies widely but improves with early intervention, sustained treatment adherence, and comprehensive physical health monitoring. Overall, schizophrenia care is evolving toward a precision-based, recovery-oriented model that integrates biological, psychological, and social strategies to improve long-term outcomes and quality of life. Full article