Search Results (23)

Background: Olanzapine (Ola) is a second-generation antipsychotic with clinical utility limited by poor brain bioavailability due to blood–brain barrier restriction, hepatic first-pass metabolism, and systemic side effects. This study aimed to develop and optimize a novel intranasal polymersome-based nanocarrier (Poly_Ola) to enhance brain targeting, therapeutic efficacy, and safety of Ola. Methods: Poly_Ola was prepared using poloxamer 401 and optimized through a Box–Behnken Design to minimize particle size and maximize entrapment (EE%) and loading efficiency (LE%). The formulation was characterized by size, morphology, drug release, and serum stability. In vivo studies in adult male Sprague-Dawley rats assessed pharmacokinetics (plasma and brain concentrations), pharmacodynamic efficacy in a ketamine-induced schizophrenia model, and systemic safety markers including metabolic, hepatic, and testicular oxidative stress indicators. Results: Optimized Poly_Ola exhibited a particle size of 78.3 ± 4.5 nm, high EE% (91.36 ± 3.55%), and sustained in vitro drug release. It remained stable in serum for 24 h. Intranasal administration significantly improved brain delivery of Ola, achieving a 2.7-fold increase in C_max and a 5.7-fold increase in AUC compared to oral dosing. The brain T_max was 15 min, with high drug-targeting efficiency (DTE% = 365.38%), confirming efficient nose-to-brain transport. Poly_Ola-treated rats showed superior antipsychotic performance, reduced extrapyramidal symptoms, and improved systemic safety evidenced by mitigated weight gain, glycemic control, normalized liver enzymes, and reduced oxidative stress. Conclusions: Poly_Ola offers a safe and effective intranasal delivery platform for Ola, enabling targeted brain delivery and improved management of schizophrenia with reduced peripheral toxicity. Full article

Background and Objectives: Recent studies suggest that the binary categorization of first-generation antipsychotics (FGAs) as being primarily responsible for extrapyramidal symptoms (EPSs) and second-generation antipsychotics (SGAs) for cardiometabolic abnormalities is an oversimplification. SGAs also demonstrate antagonistic affinity for D2 receptors, indicating their potential to induce EPSs. This study utilized the Korea Adverse Event Reporting System (KAERS) database to explore adverse drug event (ADE) signals related to both FGAs and SGAs. Materials and Methods: Relevant ADE reports from January 2013 to December 2022 were extracted from the KAERS database and analyzed using disproportionality analysis, employing the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) with its 95% lower confidence interval (LCI) indices. Results: Of the initial dataset of 2,890,702 ADE reports, those with insufficient data and duplicates were removed, resulting in a final dataset of 5249 reports for analysis. Aripiprazole, an SGA, showed signals for movement disorders, including EPSs (PRR 4.7, ROR 4.8, IC 2.2), tremors (PRR 5.3, ROR 5.4, IC 2.4), and akathisia (PRR 18.6, ROR 19.3, IC 3.5). Notably, for quetiapine, cardiovascular signals were detected, including increased blood pressure (PRR 2.1, ROR 2.3, IC 0.5), and tachyarrhythmia (PRR 13.9, ROR 14.1, IC 1.8), along with peripheral edema (PRR 2.5, ROR 2.5, IC 0.2). Metabolic abnormalities, such as weight gain and increased appetite, were identified for four SGAs: aripiprazole, olanzapine, quetiapine, and risperidone. Safety signals related to movement disorders were not detectable for FGAs, likely due to the limited number of ADE reports available for analysis. Conclusions: Our study findings support that the distribution of ADEs between FGAs and SGAs is not strictly binary. Aripiprazole, despite being an SGA, showed signals for extrapyramidal movement disorders. Four SGAs (aripiprazole, olanzapine, quetiapine, and risperidone) were linked to metabolic side effects, while quetiapine was associated with cardiovascular safety signals. Full article

Prolonged use of atypical antipsychotics (AAPs) is commonly associated with increased cardiovascular disease risk. While weight gain and related health issues are generally considered the primary contributors to this risk, direct interference with mitochondrial bioenergetics, particularly in the liver where these drugs are metabolized, is emerging as an additional contributing factor. Here, we compared the effects of two AAPs with disparate metabolic profiles on the response of Fao hepatoma cells to oxidative stress: olanzapine (OLA), which is obesogenic, and aripiprazole (ARI), which is not. Results showed that cells treated with ARI exhibited resistance to H₂O₂-induced oxidative stress, while OLA treatment had the opposite effect. Despite enhanced survival, ARI-treated cells exhibited higher apoptotic rates than OLA-treated cells when exposed to H₂O₂. Gene expression analysis of pro- and anti-apoptotic factors revealed that ARI-treated cells had a generally blunted response to H₂O₂, contrasting with a heightened response in OLA-treated cells. This was further supported by the reduced activation of MAPKs and STAT3 in ARI-treated cells in response to H₂O₂, whereas OLA pre-treatment enhanced their activation. The loss of stress response in ARI-treated cells was consistent with the observed increase in the mitochondrial production of O₂^•-, a known desensitizing factor. The physiological relevance of O₂^•- in ARI-treated cells was demonstrated by the increase in mitophagy flux, likely related to mitochondrial damage. Notably, OLA treatment protected proteasome activity in Fao cells exposed to H₂O₂, possibly due to the better preservation of stress signaling and mitochondrial function. In conclusion, this study highlights the underlying changes in cell physiology and mitochondrial function by AAPs. ARI de-sensitizes Fao cells to stress signaling, while OLA has the opposite effect. These findings contribute to our understanding of the metabolic risks associated with prolonged AAP use and may inform future therapeutic strategies. Full article

Metabolic syndrome (MetS) is the most common adverse drug reaction from psychiatric pharmacotherapy. Neuroreceptor blockade by the antipsychotic drug clozapine induces MetS in about 30% of patients. Similar to insulin resistance, clozapine impedes Akt kinase activation, leading to intracellular glucose and glutathione depletion. Additional cystine shortage triggers tryptophan degradation to kynurenine, which is a well-known AhR ligand. Ligand-bound AhR downregulates the intracellular iron pool, thereby increasing the risk of mitochondrial dysfunction. Scavenging iron stabilizes the transcription factor HIF-1, which shifts the metabolism toward transient glycolysis. Furthermore, the AhR inhibits AMPK activation, leading to obesity and liver steatosis. Increasing glucose uptake by AMPK activation prevents dyslipidemia and liver damage and, therefore, reduces the risk of MetS. In line with the in vitro results, feeding experiments with rats revealed a disturbed glucose-/lipid-/iron-metabolism from clozapine treatment with hyperglycemia and hepatic iron deposits in female rats and steatosis and anemia in male animals. Decreased energy expenditure from clozapine treatment seems to be the cause of the fast weight gain in the first weeks of treatment. In patients, this weight gain due to neuroleptic treatment correlates with an improvement in psychotic syndromes and can even be used to anticipate the therapeutic effect of the treatment. Full article

Antipsychotic medications are essential for managing severe mental illnesses like schizophrenia, which impacts about 1% of the global population. Despite efficacy, in some cases, they can induce hyperprolactinemia, affecting roughly half of the patients. The prevalence of this condition varies with the specific medication used. Although prolactinomas are rare among schizophrenia patients, treating them with dopamine agonists poses conflicts with antipsychotic medication, necessitating careful monitoring and adjustments. The aim of this study was to explore the presence of brain tumors, prolactinomas, and other structural brain changes in schizophrenia patients treated with second-generation antipsychotics using cerebral computed tomography (CT) scans. We conducted a cross-sectional study involving 152 hospitalized patients diagnosed between 1 January 2020 and 31 March 2024. Evaluations included cerebral CT scans, prolactin level assessments, and the monitoring of side effects. Patients, with an average age of 42.79 years and an illness duration of 17.89 years, predominantly received olanzapine (46.05%) and risperidone (36.84%). Side effects, reported by 61.78% of patients, included tremors, dizziness, and weight gain. Abnormal prolactin levels were observed in 53.95% of patients, more prevalent in females on risperidone and in both genders on olanzapine. No prolactinomas were detected on CT scans. Managing hyperprolactinemia in schizophrenia patients undergoing antipsychotic therapy is essential to prevent long-term complications and to ensure treatment compliance. Full article

This review aimed to investigate the metabolic alterations associated with psychopharmacological treatment of neuropsychiatric disorders, which can significantly impact patients’ physical health and overall quality of life. The study utilized the PRISMA methodology and included cross-sectional, retrospective studies, and randomized clinical trials from reputable databases like SCOPUS, CLARIVATE, SCIENCE DIRECT, and PUBMED. Out of the 64 selected studies, various psychotropic drug classes were analyzed, including antidepressants, anticonvulsants, and antipsychotics. Among the antidepressants, such as amitriptyline, Imipramine, and clomipramine, weight gain, constipation, and cardiovascular effects were the most commonly reported metabolic adverse effects. SSRI antidepressants like Fluoxetine, Sertraline, Citalopram, Escitalopram, and Paroxetine exhibited a high prevalence of gastrointestinal and cardiac alterations. Regarding anticonvulsants, valproic acid and Fosphenytoin were associated with adverse reactions such as weight gain and disturbances in appetite and sleep patterns. As for antipsychotics, drugs like Clozapine, Olanzapine, and Risperidone were linked to weight gain, diabetes, and deterioration of the lipid profile. The findings of this review emphasize the importance of continuous monitoring for adverse effects, particularly considering that the metabolic changes caused by psychopharmacological medications may vary depending on the age of the patients. Future research should focus on conducting field studies to further expand knowledge on the metabolic effects of other commonly prescribed psychotropic drugs. Overall, the study highlights the significance of understanding and managing metabolic alterations induced by psychopharmacological treatment to enhance patient care and well-being. Full article

Lurasidone and quetiapine are effective atypical mood-stabilizing antipsychotics, but lurasidone and quetiapine are listed as lower-risk and high-risk for weight gain/metabolic complications, respectively. The pathophysiology of the discrepancy of metabolic adverse reactions between these antipsychotics remains to be clarified. The GABA isomer, β-aminoisobutyric acid (BAIBA) enantiomer, was recently re-discovered as myokine via an AMP-activated protein kinase activator (AMPK) enhancer and inhibitory gliotransmitter. Notably, activation of AMPK in peripheral organs improves, but in the hypothalamus, it aggravates metabolic disturbances. Therefore, we determined effects of chronic administration of lurasidone and quetiapine on intracellular and extracellular levels of the BAIBA enantiomer. L-BAIBA is a major BAIBA enantiomer in the hypothalamus and astrocytes, whereas L-BAIBA only accounted for about 5% of total plasma BAIBA enantiomers. Chronic lurasidone administration did not affect body weight but decreased the L-BAIBA level in hypothalamus and cultured astrocytes, whereas chronic quetiapine administration increased body weight and the L-BAIBA level in hypothalamus and astrocytes. Contrary, neither lurasidone nor quetiapine affected total plasma levels of the BAIBA enantiomer since D-BAIBA levels were not affected by these antipsychotics. These results suggest that activation of intracellular L-BAIBA signaling is, at least partially, involved in the pathophysiology of metabolic adverse reaction of quetiapine. Furthermore, this study also demonstrated that lurasidone and quetiapine suppressed and enhanced astroglial L-BAIBA release induced by ripple-burst stimulation (which physiologically contributes to cognitive memory integration during sleep), respectively. Therefore, L-BAIBA probably contributes to the pathophysiology of not only metabolic adverse reactions, but also a part of clinical action of lurasidone or quetiapine. Full article

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010–2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice. Full article

It is estimated that in patients taking antipsychotic drugs (APDs), metabolic syndrome occurs 2–3 times more often than in the general population. It manifests itself in abdominal obesity, elevated glucose concentration, and dyslipidemia. Despite the high prevalence of this disorder, only a small percentage of patients receive appropriate and effective treatment, and none of the available methods for preventing or treating APD-induced metabolic side effects is satisfactory. A promising supplement to antipsychotic therapy appears to be ligands of the serotonin 6 (5-HT₆) receptor. The present study aimed to examine the chronic effects of the selected APDs (haloperidol, risperidone, olanzapine), administered alone and in combination with a selective 5-HT₆ agonist (WAY-181187) or antagonist (SB-742457), on weight gain, food intake, serum lipid profile, glucose level, and a spectrum of hormones derived from adipose (leptin, adiponectin) and gastrointestinal (insulin, ghrelin) tissue in rats. SB-742457 inhibited increased weight gain and alleviated hyperglycemia induced by APDs more strongly than did WAY-181187, but also intensified dyslipidemia. WAY-181187 tended to improve the lipid profile, but increased the glucose level. The greatest benefits were obtained when WAY-181187 or SB-742457 were co-administered with haloperidol. It is difficult to assess whether the modification of the serum levels of insulin, leptin, ghrelin, and adiponectin depended on the treatment applied or other drug-independent factors; therefore, further research is needed. Full article

Although a number of mood-stabilising atypical antipsychotics and antidepressants modulate serotonin type 7 receptor (5-HT7), the detailed contributions of 5-HT7 function to clinical efficacy and pathophysiology have not been fully understood. The mood-stabilising antipsychotic agent, lurasidone, and the serotonin partial agonist reuptake inhibitor, vortioxetine, exhibit higher binding affinity to 5-HT7 than other conventional antipsychotics and antidepressants. To date, the initially expected rapid onset of antidepressant effects—in comparison with conventional antidepressants or mood-stabilising antipsychotics—due to 5-HT7 inhibition has not been observed with lurasidone and vortioxetine; however, several clinical studies suggest that 5-HT7 inhibition likely contributes to quality of life of patients with schizophrenia and mood disorders via the improvement of cognition. Furthermore, recent preclinical studies reported that 5-HT7 inhibition might mitigate antipsychotic-induced weight gain and metabolic complication by blocking other monoamine receptors. Further preclinical studies for the development of 5-HT7 modulation against neurodevelopmental disorders and neurodegenerative diseases have been ongoing. To date, various findings from various preclinical studies indicate the possibility that 5-HT7 modifications can provide two independent strategies. The first is that 5-HT7 inhibition ameliorates the dysfunction of inter-neuronal transmission in mature networks. The other is that activation of 5-HT7 can improve transmission dysfunction due to microstructure abnormality in the neurotransmission network—which could be unaffected by conventional therapeutic agents—via modulating intracellular signalling during the neurodevelopmental stage or via loss of neural networks with aging. This review attempts to describe the current and novel clinical applications of 5-HT7 modulation based on preclinical findings. Full article

Antipsychotic-induced weight gain (AIWG) is a serious adverse effect. Studies have linked genetically-predicted CYP2D6 metabolic capacity to AIWG. The evidence, however, is ambiguous. We performed multiple regression analyses examining the association between genetic-predicted CYP2D6 metabolic capacity and AIWG. Analyses were based on previously unpublished data from an RCT investigating the clinical utility of routine genotyping of CYP2D6 and CYP2C19 in patients with schizophrenia. A total of 211 patients, corresponding to 71% of the original study population, were included. Our analyses indicated an effect of genetically predicted CYP2D6 metabolic capacity on AIWG with significant weight gain in both CYP2D6 poor metabolizers (PMs) (4.00 kg (95% CI: 0.80; 7.21)) and ultrarapid metabolizers (UMs) (6.50 kg (95% CI: 1.03; 12.0)). This finding remained stable after adjustment for covariates (PMs: 4.26 kg (0.88; 7.64), UMs: 7.26 kg (1.24; 13.3)). In addition to the CYP2D6 metabolic capacity, both baseline body mass index (−0.24 (95% CI: −0.44; −0.03)) and chlorpromazine equivalents per day (0.0041 (95% CI: 0.0005; 0.0077)) were statistically significantly associated with weight change in the adjusted analysis. Our results support that the genetically predicted CYP2D6 metabolic capacity matters for AIWG. Full article

(1) Background: The second-generation antipsychotics (SGAPs) induce metabolic and inflammatory side effects, but documentation of their effects on the liver and kidneys is scarce. Aim: To study the three-year fluctuation of selected markers of renal and hepatic function in forensic psychiatric patients receiving SGAPs for more than five years. (2) Methods: Thirty-five forensic psychiatric patients (N = 35) were classified into two groups according to the type of SGAPs used for their treatment and the relevant risk of weight gain and metabolic complications. The three-year medication history, anthropometric data and biochemical data relevant to renal and hepatic function were retrieved from the individual medical files, specifically: serum levels of urea, uric acid, creatinine, alkaline phosphatase and amylase; the liver function enzymes, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and gamma-glutamyl transpeptidase(γ-GT), and also the inflammatory index C-reactive protein (CRP). (3) Results: The patients receiving the SGAPs with a low risk for weight gain showed no significant fluctuation in the biochemical markers over the three-year period. The patients receiving the SGAPs with a high risk for weight gain showed significant differences between at least two measurements of uric acid (p = 0.015), SGOT (p = 0.018) and SGPT (p = 0.051). They showed significantly higher levels of creatinine in the third year compared to the second year (p = 0.029), and SGOT in the second year compared to the first (p = 0.038), and lower levels of SGPT in the third year compared to the second (p = 0.024). (4) Conclusion:In addition to consideration of possible metabolic and inflammatory complications, the choice of an antipsychotic drug for long-term treatment should also take into account the risk of hepatotoxicity and kidney damage. Full article

Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED₃₀ (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED₃₀ (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments. Full article

Background: The usage of antipsychotics (APs) is the most robust and scientifically based approach in the treatment of schizophrenia spectrum disorders (SSDs). The efficiency of APs is based on a range of target receptors of the central nervous system (CNS): serotoninergic, dopaminergic, adrenergic, histaminergic and cholinergic. Metabolic disorders are the most severe adverse drug reactions (ADRs) and lead to cardiovascular diseases with a high rate of mortality in patients with SSDs. Neuropeptide Y receptor Y5 (NPY5R) is known in the chain of interaction to target receptors for APs, agouti-related peptide receptors and proopiomelanocortin receptors. We studied the association of the single-nucleotide variants (SNVs) rs11100494 and rs6837793 of the NPY5R gene, and rs16147, rs5573, rs5574 of the NPY gene, with metabolic disorders in Russian patients with SSDs. Methods: We examined 99 patients with SSDs (mean age—24.56 years old). The mean duration of APs monotherapy was 8 weeks. The biochemical blood test included levels of glucose, cholesterol, lipoproteins, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein and albumin. Anthropometry included weight, height, waist circumference and hip circumference. We used real-time PCR to study the carriage of major and minor alleles of the SNV rs11100494 (1164C>A) of the NPY5R gene (chromosome localization—4q32.2). Group 1 comprised 25 patients with SSDs taking APs with a change in body weight of more than 6% since the start of APs therapy. Group 2 comprised 74 patients with SSDs taking APs with a change in body weight of less than 6% since the start of APs therapy. Results: We show the significance of genetic risk factors (carriage of major allele C of SNV rs11100494 of the NPY5R gene) for the development of AP-induced weight gain in Russian patients with SSDs. The allele C predisposes to AP-induced weight gain (OR = 33.48 [95% CI: 12.62; 88.82], p-value < 0.001). Additionally, the results of our study demonstrate that first-generation APs (FGAs) are more likely to cause an increase in serum transaminase levels but are less likely to increase body weight. Second-generation APs (SGAs) are more likely to cause weight gain and changes in serum glucose levels. Conclusion: Our study shows the predictive role of the allele C of SNV rs11100494 of the NPY5R gene in the development of AP-induced weight gain. However, we did not find a significant association between biochemical markers and this SNV in Russian patients with SSDs. Full article

Excessive weight gain and cardiometabolic dysfunction are common and clinically relevant side effects of antipsychotic medications. In this pilot study, we aimed to establish the feasibility of using metformin and its effectiveness in managing antipsychotic-induced weight gain in patients with first-episode psychosis (FEP) on follow-up with the Singapore Early Psychosis Intervention Programme in a 24-week, randomized, double-blind, placebo-controlled trial, to ascertain the effects of metformin discontinuation on body weight and evaluate the safety and tolerability of metformin. Participants between the ages of 16 and 40 with FEP assessed as clinically stable and who had gained ≥5% of their pre-drug weight after initiation of the antipsychotic treatment were recruited from outpatient clinics between April 2015 and April 2018. Seventeen participants met all the inclusion criteria and were randomized to receive metformin (n = 8) or the placebo (n = 9) at Week 0, with follow up assessments at Weeks 3, 6, 12, 24, and 36. Metformin was generally well-tolerated. Participants in the metformin arm were able to control their weight better than participants receiving the placebo, an effect that did not persist after discontinuation. Our results support the use of metformin as a safe and tolerable weight control measure in a typical outpatient sample of young people with FEP. Full article