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Background: Alzheimer's disease (AD) is a neurodegenerative condition leading to memory loss, cognitive impairment, and neuropsychiatric symptoms. Second-generation antipsychotics (SGAs) are commonly used to manage these neuropsychiatric symptoms, but their safety profile in patients with AD requires further investigation. Objective: The objective was to evaluate the safety of SGAs in patients with AD by analyzing adverse drug reactions (ADRs) using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: This study conducted a comprehensive analysis of FAERS data from 2014 to 2023, focusing on ADRs in patients with AD treated with SGAs such as risperidone, quetiapine, olanzapine, clozapine, and aripiprazole. Descriptive, disproportionality, time, and dose analysis were performed using the Bayesian confidence propagation neural network, Weibull, and physiologically based pharmacokinetic model. Results: Out of 1289 patients with AD treated with SGAs, the most common ADRs involved the nervous system, gastrointestinal system, and cardiac disorders. Disproportionality analysis identified significant positive signals in cardiac, renal, and vascular systems. Quetiapine, risperidone, and olanzapine showed more positive signals compared with clozapine and aripiprazole. Time analysis indicated that cardiovascular ADRs occurred randomly, whereas renal ADRs increased with prolonged use. Dose analysis suggested that small doses of SGAs did not elevate the risk of multiple cardiac, renal, or vascular ADRs. Conclusion and Relevance: The study underscores the importance of monitoring for ADRs, particularly in the cardiac and renal systems, when using SGAs in patients with AD. Future research incorporating more comprehensive clinical data is warranted to support safe and rational drug utilization. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a severe psychiatric condition that affects approximately 24 million people worldwide. The complex pathophysiology of schizophrenia presents various challenges for researchers and doctors. Therefore, it is crucial to curate robust pharmacotherapy for patients with schizophrenia to ease their symptoms. Establishing proper standards for patient care requires an ammunition of research studies done on the disease and its therapy, upon which health-care practitioners can rely for future patient care. Unfortunately, there is a void of adequate research studies done on understanding the prescription patterns of schizophrenia in India, especially in rural areas. To improve patient outcomes, there is a need for increased research on this particular subject. Aim: The aim of this study was to assess the prescription pattern of antipsychotics in patients with schizophrenia at a tertiary care hospital in rural Karnataka. Setting and Design: This is an observational study carried out in MVJ Medical College and Research Hospital, Bengaluru, India. Materials and Methods: The study included a total of 139 inpatients, regardless of their age and sex, who had been diagnosed with schizophrenia. The study was conducted for a period of 6 months, from February 2022 to July 2022. Data collection involved a case record form (CRF) designed for assessing treatment patterns. An investigator was assigned to the Department of Psychiatry, where patients with schizophrenia were discovered and after reviewing their medication chart, necessary data were filled into the CRF. The obtained data were then compiled and assessed. Results: Paranoid schizophrenia was the major subclass (90.0%). The prescription pattern showed that second-generation antipsychotics (SGAs) were prescribed more than first-generation antipsychotics (FGAs), 112 (81.29%) and 41 (29.5%) prescriptions, respectively. In SGAs, tablet olanzapine received the most prescriptions which was 42 (30.22%). Tablet haloperidol was the major FGA to be prescribed receiving 18 prescriptions (12.95%). This study also included the assessment of combination drugs which showed that tablet risperidone + tablet trihexyphenidyl was the most prescribed combination drug 118 (78.43%). Conclusion: Our study showed that our findings aligned with several similar studies and also differed from a few, underscoring the need for further research and individualized treatment approaches to manage this complex psychiatric disorder.

Abstract Background Schizophrenia (SCZ) shares high clinical relevance with the immune system, and the potential interactions of psychopharmacological drugs with the immune system are still an overlooked area. Here, we aimed to identify whether the second-generation antipsychotics (SGA) monotherapy or combined therapy of SGA with other psychiatric medications influence the routine blood immunity biomarkers of patients with SCZ. Methods Medical records of inpatients with SCZ from January 2019 to June 2023 were retrospectively screened from June 2023 to August 2023. The demographic data and peripheral levels of cytokines (IL-2, IL-4, IL-6, TNF-α, INF-γ, and IL-17 A), lymphocyte subtype proportions (CD3+, CD4+, CD8 + T-cell, and natural killer (NK) cells), and thyroid autoimmune antibodies (thyroid peroxidase antibody (TPOAb), and antithyroglobulin antibody (TGAb)) were collected and analyzed. Results 30 drug-naïve patients, 64 SGA monotherapy (20 for first-episode SCZ, 44 for recurrent SCZ) for at least one week, 39 combined therapies for recurrent SCZ (18 with antidepressant, 10 with benzodiazepine, and 11 with mood stabilizer) for at least two weeks, and 23 used to receive SGA monotherapy (had withdrawn for at least two weeks) were included despite specific medication. No difference in cytokines was found between the SGA monotherapy sub-groups (p > 0.05). Of note, SGA monotherapy appeared to induce a down-regulation of IFN-γ in both first (mean [95% confidence interval]: 1.08 [0.14–2.01] vs. 4.60 [2.11–7.08], p = 0.020) and recurrent (1.88 [0.71–3.05] vs. 4.60 [2.11–7.08], p = 0.027) episodes compared to drug-naïve patients. However, the lymphocyte proportions and thyroid autoimmune antibodies remained unchanged after at least two weeks of SGA monotherapy (p > 0.05). In combined therapy groups, results mainly resembled the SGA monotherapy for recurrent SCZ (p > 0.05). Conclusion The study demonstrated that SGA monotherapy possibly achieved its comfort role via modulating IFN-γ, and SGA combined therapy showed an overall resemblance to monotherapy.

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities, including visceral obesity, dyslipidemia, and insulin resistance. In this regard, visceral white adipose tissue (vWAT) plays a critical role, influencing energy metabolism, immunomodulation, and oxidative stress. Adipose-derived stem cells (ADSCs) are key players in these processes within vWAT. While second-generation antipsychotics (SGAs) have significantly improved treatments for mental health disorders, their chronic use is associated with an increased risk of MetS. In this study, we explored the impact of SGAs on ADSCs to better understand their role in MetS and identify potential therapeutic targets. Our findings reveal that olanzapine disrupts lipid droplet formation during adipogenic differentiation, impairing insulin receptor endocytosis, turnover, and signaling. SGAs also alter the endolysosomal compartment, leading to acidic vesicle accumulation and increased lysosomal biogenesis through TFEB activation. PKCζ is crucial for the SGA-induced nuclear translocation of TFEB and acidic vesicle formation. Notably, inhibiting PKCζ restored insulin receptor tyrosine phosphorylation, normalized receptor turnover, and improved downstream signaling following olanzapine treatment. This activation of PKCζ by olanzapine is driven by increased phosphatidic acid synthesis via phospholipase D (PLD), following G protein-coupled receptor (GPCR) signaling activation. Overall, olanzapine and clozapine disrupt endolysosomal homeostasis and insulin signaling in a PKCζ-dependent manner. These findings highlight SGAs as valuable tools for uncovering cellular dysfunction in vWAT during MetS and may guide the development of new therapeutic strategies to mitigate the metabolic side effects of these drugs. [ABSTRACT FROM AUTHOR]

Background: Older‐age bipolar disorder (OABD) is commonly defined as bipolar disorder in individuals aged 60 or more. There have been no studies to examine temporal trends in the pharmacological treatment of OABD. We aimed to investigate prescription changes among OABD patients discharged from two public mental hospitals in Taiwan from 2006 to 2019. Methods: OABD patients discharged from the two study hospitals, from 1 January 2006 to 31 December 2019 (n = 1072), entered the analysis. Prescribed drugs at discharge, including mood stabilisers (i.e., lithium, valproate, carbamazepine, and lamotrigine), antipsychotics (i.e., second‐ and first‐generation antipsychotics (SGAs and FGAs)), and antidepressants, were investigated. Complex polypharmacy was defined as the use of three or more agents among the prescribed drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran‐Armitage Trend test. Results: The most commonly prescribed drugs were SGAs (72.0%), followed by valproate (48.4%) and antidepressants (21.7%). The prescription rates of SGAs, antidepressants, antidepressants without mood stabilisers, and complex polypharmacy significantly increased over time, whereas the prescription rates of mood stabilisers, lithium, FGAs, and antidepressants plus mood stabilisers significantly decreased. Conclusions: Prescribing patterns changed remarkably for OABD patients over a 14‐year period. The decreased use of lithium and increased use of antidepressants did not reflect bipolar treatment guidelines. Future research should examine whether such prescribing patterns are associated with adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background We report the final results of treatment with aripiprazole, blonanserin, and paliperidone from the Japan Useful Medication Program for Schizophrenia (JUMPs), a 104-week naturalistic study. Methods JUMPs was an open-label, three-arm, randomized, parallel-group, 104-week study. Patients aged ≥ 20 years with schizophrenia requiring antipsychotic treatment or a switch from previous therapy were enrolled. The primary endpoint was treatment discontinuation rate over 104 weeks. Secondary endpoints included remission rate, Personal and Social Performance (PSP), safety, Positive and Negative Syndrome Scale (PANSS), and quality of life (QOL; EuroQol-5 dimension). Results In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). Treatment discontinuation rates (aripiprazole, 80.5%; blonanserin, 81.2%; paliperidone, 71.4%) were not significantly different (p = 0.2385) among the treatment groups at 104 weeks; comparable outcomes were observed for endpoints, including remission (42.9%, 46.7%, and 45.8%), PANSS, and safety. In the overall cohort, while the improvement in the PSP total score at Week 104 was not significantly different from baseline, a significant improvement (p

Background: We report the final results of treatment with aripiprazole, blonanserin, and paliperidone from the Japan Useful Medication Program for Schizophrenia (JUMPs), a 104-week naturalistic study. Methods: JUMPs was an open-label, three-arm, randomized, parallel-group, 104-week study. Patients aged ≥ 20 years with schizophrenia requiring antipsychotic treatment or a switch from previous therapy were enrolled. The primary endpoint was treatment discontinuation rate over 104 weeks. Secondary endpoints included remission rate, Personal and Social Performance (PSP), safety, Positive and Negative Syndrome Scale (PANSS), and quality of life (QOL; EuroQol-5 dimension). Results: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). Treatment discontinuation rates (aripiprazole, 80.5%; blonanserin, 81.2%; paliperidone, 71.4%) were not significantly different (p = 0.2385) among the treatment groups at 104 weeks; comparable outcomes were observed for endpoints, including remission (42.9%, 46.7%, and 45.8%), PANSS, and safety. In the overall cohort, while the improvement in the PSP total score at Week 104 was not significantly different from baseline, a significant improvement (p < 0.05) in QOL and total PANSS scores (including all subscales) was observed at Week 104 compared with baseline. Multivariable analysis identified a shorter disease duration and a higher chlorpromazine-equivalent antipsychotic dosage level (≥ 1000 mg) before switching to monotherapy as predictors of treatment discontinuation. Conclusions: The 104-week treatment outcomes were comparable between groups; the overall trend of improvement in remission rate, safety, and QOL suggests the importance of continued treatment. Clinical trial registration: UMIN-Clinical Trials Registry UMIN000007942 (public release date: 14/05/2012). Key points: • The follow-up (104-week) results of the JUMPs study showed that the rate of treatment discontinuation (range: 71–81%) and resolution of symptoms (range: 43–47%) were similar among Japanese patients with schizophrenia treated with aripiprazole, blonanserin, and paliperidone. • Continued second-generation antipsychotic treatment (104-week) contributes to the maintenance of remission, social functioning, and QOL. • Treatment discontinuation is likely to get affected by shorter disease duration and higher dose of antipsychotics (chlorpromazine-equivalent antipsychotic dosage level: ≥1000 mg) before switching to single treatment with any of the three second-generation antipsychotics. [ABSTRACT FROM AUTHOR]

Converging evidence has suggested that treatment augmentation with a second-generation atypical antipsychotic (SGA) may improve treatment outcomes in major depressive disorder (MDD) patients after an incomplete response to a first-line antidepressant. Cariprazine is a recently approved SGA for MDD augmentation. Herein, we evaluate both continuous (ie, change in depressive symptom severity scores over time) and categorical (ie, remission and response rates) outcomes. Following a full-text review, four randomized controlled trials (RCTs) were included in our meta-analysis, while five studies were included for a qualitative review. Risk ratios (RRs) were calculated for all included randomized controlled studies to determine the relative response and remission rates of cariprazine compared to placebo augmentation. The RR for all-cause dropout was also determined as a proxy for overall acceptability. Two studies found a statistically significant treatment response using cariprazine augmentation. One study observed depressive symptom remission for cariprazine compared to placebo. Our random-effects model revealed moderate antidepressant effects of cariprazine, with a standardized mean difference (SMD) in Montgomery–Åsberg Depression Rating Scale (MADRS) scores of −1.79 (95% CI): −2.89, −0.69). Our pooled response RR and remission RR were calculated as 1.21 (95% CI: 1.05, 1.39, P =0.008) and 0.99 (95% CI: 0.84, 1.17, P =0.91), respectively. The RR for response was statistically significant (P <0.05). However, the RR for remission was not statistically significant. The findings from our meta-analysis include a variable magnitude of effects. Evidence suggests cariprazine may be an effective treatment for MDD; however, further results are needed to clarify this relation. [ABSTRACT FROM AUTHOR]

Worldwide, acute antipsychotic poisoning results in high morbidities and mortalities. Though extrapyramidal syndromes are commonly associated, the extent of extrapyramidal syndromes in relation to the severity of antipsychotic poisoning has not been addressed yet. Thus, this study aimed to assess the Global Dystonia Rating Scale (GDRS) as an unfavorable outcomes predictive tool in acute antipsychotic poisoning. A cross-sectional study included 506 antipsychotic-poisoned patients admitted to Tanta University Poison Control Center, Egypt, over three years was conducted. The mean GDRS was 9.1 ± 16.7 in typical antipsychotic poisoning, which was significantly higher than that of atypical antipsychotics (4.2 ± 11.5) (p = 0.003). Patients with GDRS> 20 showed significantly higher liability for all adverse outcomes (p < 0.05). However, poisoning with typical antipsychotics was associated with significantly more cardiotoxicity (p = 0.042), particularly prolonged QRS (p = 0.005), and intensive care unit (ICU) admission (p = 0.000). In contrary to the PSS, which failed to predict the studied adverse outcomes, GDRS significantly predicted all adverse outcomes (p < 0.000) for all antipsychotic generations. In atypical antipsychotics, GDRS above three accurately predicted cardiotoxicities, prolonged QTc interval, and respiratory failure with Area under curves (AUC) of 0.937, 0.963, and 0.941, respectively. In typical antipsychotic poisoning, at higher cutoffs (7.5, 27.5, 18, and 7.5), cardiotoxicities, prolonged QTc interval, and respiratory failure were accurately predicted (AUC were 0.974, 0.961, and 0.960, respectively). GDRS is an objective, substantially useful tool that quantifies dystonia and can be used as an early reliable predictor of potential toxicity in acute antipsychotic poisoning. [ABSTRACT FROM AUTHOR]

Aims Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders. Methods This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium (n = 1028), valproate (n = 3580), olanzapine (n = 797), quetiapine (n = 1975) or risperidone (n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy. Results Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5–7.6), 8.4 (7.4–9.5), 11.1 (8.3–14.9), 7.4 (6.0–9.2) and 12.0 (9.3–15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33–3.22]) and risperidone (1.66 [1.08–2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54–6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62–6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk. Conclusion Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD. [ABSTRACT FROM AUTHOR]

Abstract Aims Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders. Methods This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium (n = 1028), valproate (n = 3580), olanzapine (n = 797), quetiapine (n = 1975) or risperidone (n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers

Abstract Background There is growing concern regarding teratogenic effect of antipsychotics. Previous research assessing association between antipsychotics and congenital malformations (CMs) yielded mixed results and were all derived from Western countries. We aimed to examine risk of major and organ/system-specific CMs associated with prenatal antipsychotic exposure in Hong Kong. Methods This population-based study identified women aged 15–50 years who delivered their first/singleton child between 2003–2018 from public healthcare service database. Propensity score (PS)-weighted logistic-regression analyses were performed to examine risk of CMs following first-trimester exposure to antipsychotic classes (second- and first-generation antipsychotic; SGA and FGA) and six most frequently-prescribed individual antipsychotics. Results Of 465,069 women, 419 and 420 redeemed ≥1 prescription of SGA and FGA during first-trimester, respectively. Prevalence of any CMs was 4.9% (95%CI:4.9–5.0%) in unexposed-infants, 9.1% (6.7–12.3%) in SGA-exposed infants, and 6.2% (4.3–9.0%) in FGA-exposed infants. SGA exposure (adjusted-odds-ratio: 2.11 [95%CI:1.19–3.86]) was associated with increased risk of CMs. This finding was consistent with sensitivity analyses addressing exposure misclassification and confounding by treatment indication, but not with PS-matched sensitivity analysis. Elevated risk of CMs was observed in infants exposed to high-dose olanzapine (7.50 [1.65–36.13]) and high-dose quetiapine (15.03 [4.86–56.72]), but with wide-CIs. Organ/system-specific malformations were not associated with SGA, FGA or individual antipsychotics. Conclusion We observed a small increased risk of major malformations associated with SGA, but was not consistently affirmed in sensitivity analyses, precluding firm conclusions. Research with large sample size clarifying comparative safety of individual antipsychotics on specific malformations is warranted.

Background: Among antipsychotics, sialorrhea is most associated with clozapine, and when it occurs, it is uncomfortable, socially stigmatizing, and can contribute to medication non-adherence. Risperidone has a generally negligible muscarinic activity compared to clozapine, and yet, multiple reports of severe sialorrhea associated with risperidone have been reported. Case presentation: This case report describes risperidone-induced sialorrhea that was unintentionally masked by simultaneous clonidine administration that was intended to treat hypertension. Interestingly, sialorrhea was present but mild when clonidine was present; however, when risperidone was further titrated and clonidine removed, a significant worsening of sialorrhea developed. Sialorrhea did not respond to treatment with anticholinergic medication. Conclusion: The pathophysiology of antipsychotic-induced sialorrhea is complex and varies between antipsychotics. Risperidone-induced sialorrhea is suspected of having prominent adrenergic pathophysiology that is likely composed of highly viscoelastic saliva (high protein content), differing from the more commonly encountered clozapine-induced sialorrhea. Risperidone-induced sialorrhea is reported as more likely to respond to dose reduction and treatment with α2-adrenergic receptor agonists or β-adrenergic receptor antagonists and less likely to respond to anticholinergic (antimuscarinic) medications. [ABSTRACT FROM AUTHOR]

Background There is limited knowledge of whether cognitive-behavioral therapy (CBT) or second-generation antipsychotics (SGAs) should be recommended as the first-line treatment in individuals at clinical high risk for psychosis (CHRp). Hypothesis To examine whether individual treatment arms are superior to placebo and whether CBT is non-inferior to SGAs in preventing psychosis over 12 months of treatment. Study Design PREVENT was a blinded, 3-armed, randomized controlled trial comparing CBT to clinical management plus aripiprazole (CM + ARI) or plus placebo (CM + PLC) at 11 CHRp services. The primary outcome was transition to psychosis at 12 months. Analyses were by intention-to-treat. Study Results Two hundred eighty CHRp individuals were randomized: 129 in CBT, 96 in CM + ARI, and 55 in CM + PLC. In week 52, 21 patients in CBT, 19 in CM + ARI, and 7 in CM + PLC had transitioned to psychosis, with no significant differences between treatment arms (P  = .342). Psychopathology and psychosocial functioning levels improved in all treatment arms, with no significant differences. Conclusions The analysis of the primary outcome transition to psychosis at 12 months and secondary outcomes symptoms and functioning did not demonstrate significant advantages of the active treatments over placebo. The conclusion is that within this trial, neither low-dose aripiprazole nor CBT offered additional benefits over clinical management and placebo. [ABSTRACT FROM AUTHOR]

ABSTRACT Olanzapine is one of the most effective medicines available for stabilizing schizophrenia spectrum disorders. However, it has been reported to show the greatest propensity for inducing body weight gain and producing metabolic side effects, which cause a great burden in patients with psychiatric disorders. Since the gut microbiota has a profound impact on the initiation and development of metabolic diseases, we conducted a longitudinal study to explore its role in olanzapine-induced obesity and metabolic abnormalities. Female Sprague-Dawley rats were treated with different doses of olanzapine, and metabolic and inflammatory markers were measured. Olanzapine significantly induced body weight gain (up to a 2.1-fold change), which was accompanied by hepatic inflammation and increased plasma triglyceride levels (up to a 2.9-fold change), as well as gut microbiota dysbiosis. Subsequently, fuzzy c-means clustering was used to characterize three clusters of longitudinal trajectories for microbial fluctuations: (i) genera continuing to increase, (ii) genera continuing to decrease, and (iii) genera temporarily changing. Among them, Enterorhabdus (r = 0.38), Parasutterella (r = 0.43), and Prevotellaceae UCG-001 (r = 0.52) positively correlated with body weight gain. In addition, two MetaCyc metabolic pathways were identified as associated with olanzapine-induced body weight gain, including the superpathway of glucose and xylose degradation and the superpathway of l-threonine biosynthesis. In conclusion, we demonstrate that olanzapine can directly alter the gut microbiota and rapidly induce dysbiosis, which is significantly associated with body weight gain. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by olanzapine. IMPORTANCE Olanzapine is one of the most effective second-generation antipsychotics for stabilizing schizophrenia spectrum disorders. However, olanzapine has multiple drug-induced metabolic side effects, including weight gain. This study provides insight to the gut microbiota target in olanzapine-induced obesity. Specifically, we explored the longitudinal gut microbiota trajectories of female Sprague-Dawley rats undergoing olanzapine treatment. We showed that olanzapine treatment causes a dynamic alteration of gut microbiota diversity. Additionally, we identified three genera, Parasutterella, Enterorhabdus, and Prevotellaceae UCG-001, that may play an important role in olanzapine-induced obesity. In this case, the supply or removal of specific elements of the gut microbiota may represent a promising avenue for treatment of olanzapine-related metabolic side effects.

BackgroundAmong antipsychotics, sialorrhea is most associated with clozapine, and when it occurs, it is uncomfortable, socially stigmatizing, and can contribute to medication non-adherence. Risperidone has a generally negligible muscarinic activity compared to clozapine, and yet, multiple reports of severe sialorrhea associated with risperidone have been reported.Case presentationThis case report describes risperidone-induced sialorrhea that was unintentionally masked by simultaneous clonidine administration that was intended to treat hypertension. Interestingly, sialorrhea was present but mild when clonidine was present; however, when risperidone was further titrated and clonidine removed, a significant worsening of sialorrhea developed. Sialorrhea did not respond to treatment with anticholinergic medication.ConclusionThe pathophysiology of antipsychotic-induced sialorrhea is complex and varies between antipsychotics. Risperidone-induced sialorrhea is suspected of having prominent adrenergic pathophysiology that is likely composed of highly viscoelastic saliva (high protein content), differing from the more commonly encountered clozapine-induced sialorrhea. Risperidone-induced sialorrhea is reported as more likely to respond to dose reduction and treatment with α2-adrenergic receptor agonists or β-adrenergic receptor antagonists and less likely to respond to anticholinergic (antimuscarinic) medications.

Long-acting injectable antipsychotics are one of the mainstays of long-term treatment for schizophrenia. The production of the first classical long-acting injectable antipsychotics began in the 1970s and their use expanded, only to decline with the advent of second-generation oral antipsychotics with new properties. Taking advantage of the beneficial properties of second-generation antipsychotics, including their neuroprotective effect, with 100% certainty of adherence, is made possible by the current range of long-acting injectable second-generation antipsychotics. In the Czech Republic, the first second-generation antipsychotic in this dosage form was registered in 2003, and four active substances are currently available, the prescription of which remains limited by reimbursement restrictions. The costs for health insurers have been gradually increasing over 20 years and have tripled when comparing 2014-2022. The first generic long-acting injectable antipsychotic drugs are currently being marketed, the arrival of which will bring about a decline in reimbursement from public health insurance in this important segment of psychopharmacological treatment, theoretically allowing its further expansion towards appropriate patients. [ABSTRACT FROM AUTHOR]

Background and Objectives: Periodontitis is a highly prevalent disease in psychiatric patients, including those undergoing symptomatic treatment with second-generation antipsychotics. Some of these drugs, such as clozapine (CLO) and olanzapine (OLA), have prominent metabolic effects such as weight gain, hyperglycemia, and dyslipidemia, which are risk factors for periodontitis. In addition to the metabolic effects, there are reports of changes in salivary flow, gingival bleeding, and caries. In this context, we aimed to evaluate if the metabolic effects of OLA and CLO alter periodontal parameters in an animal model of periodontitis without the environmental and psychosocial biases inherent to human diseases. Methods: In the first set of experiments, male and female adult Wistar rats received oral administration of CLO, OLA, or vehicle for 45 days. They were evaluated for body mass composition and weight gain, blood glucose parameters (fasting and glucose tolerance and insulin resistance tests), and lipid profile (HDL, total cholesterol, and triglycerides). In a second set of experiments, the same measurements were performed in female rats exposed to the antipsychotics for 45 days and ligature-induced periodontitis on the 30th day of treatment. Macroscopic measurements of exposed roots, microtomography in the furcation region of the first molar, and histological evaluation of the region between the first and second molars were evaluated to assess bone loss. Additionally, gingival measurements of myeloperoxidase activity and pro-inflammatory cytokine TNF-α were made. Results: Only females exposed to OLA had more significant weight gain than controls. They also exhibited differences in glucose metabolism. Ligature-induced periodontitis produced intense bone retraction without changing the density of the remaining structures. The bone loss was even higher in rats with periodontitis treated with OLA or CLO and was accompanied by a local increase in TNF-α caused by CLO. These animals, however, did not exhibit the same metabolic impairments observed for animals without periodontitis. Conclusion: The use of clozapine and olanzapine may be a risk factor for periodontal disease, independent of systemic metabolic alterations. [ABSTRACT FROM AUTHOR]

Xueying Zhang,1– 3,* Chen He,1– 3,* Peijun Ju,4,* Qingrong Xia,1– 3 Jianliang Gao,1– 3 Loufeng Zhang,1– 3 Xuequan Chen,1– 3 Hui Yuan,1– 3 Hua Gao,1– 3 Yang Zhang,1– 3 Junwei Yan,1– 3 Wen Xie,1– 3,* Cuizhen Zhu1– 3,* 1Affiliated Psychological Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Clinical Center for Psychiatry and Mental Health, Hefei Fourth People’s Hospital, Hefei, People’s Republic of China; 3Anhui Mental Health Center, Hefei, People’s Republic of China; 4Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Xie; Cuizhen Zhu, Affiliated Psychological Hospital of Anhui Medical University, No. 316 Huangshan Road, Shushan District, Hefei, Anhui, People’s Republic of China, Tel +86 13339102285 ; +86 13705535258, Fax +86 055163616000, Email xiewen0808@sina.com; zhucuizhen88@126.comPurpose: The study aimed to clarify the cognitive impairments of schizophrenia with metabolic syndrome while evaluating their potential as risk factors.Patients and Methods: We recruited 153 participants and divided them into three groups according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and the guideline standards for the prevention and treatment of dyslipidemia in Chinese adults in 2007 for metabolic syndrome, as follows: healthy control group (n = 47); nonmetabolic syndrome group (n = 58); and metabolic syndrome group (n = 48). Psychotic symptoms were evaluated using the Positive and Negative Syndrome Scale. Cognitive function and automatic thinking were estimated using the Montreal Cognitive Assessment Scale, Verbal Fluency Test, and Automatic Thoughts Questionnaire. Serum biochemical parameters were measured by automatic biochemistry analyzer.Results: One-way ANOVA analysis revealed that differential cognition impairments in schizophrenia patients compared to controls. Furthermore, results of multiple comparisons showed that more serious barriers in orientation, language fluency, and negative automatic thinking existed in the metabolic syndrome group than in the healthy and non-metabolic syndrome groups. Spearman correlation and stepwise linear regression analyses showed that psychopathological symptoms, high waist circumference, and high triglyceride were the predictive factors for negative automatic thoughts, orientation, and language fluency. Those results collectively revealed that high waist circumference, high triglyceride and negative automatic thinking had validity and effectiveness in predicting the cognitive function impairments of the metabolic syndrome group.Conclusion: The present findings strongly supported the notion that aberrant parameters of high waist circumference, high triglyceride and high negative automatic thoughts had validity and effectiveness predictive role for cognitive impairments in the schizophrenics with metabolic syndrome. The schizophrenia patients with metabolic syndrome should receive regular monitoring and adequate treatment for metabolic and psychological risk factors.Keywords: second-generation antipsychotics, negative symptoms, diet, Montreal Cognitive Assessment Scale, Verbal Fluency Test

Introduction: The management of pediatric bipolar disorder (PBD) requires pharmacotherapy to control acute symptoms, reduce relapse, prevent suicide, and improve psychosocial functioning. The purpose of this study was to investigate prescribing patterns among PBD patients discharged from two public mental hospitals in Taiwan, from 2006 to 2019. Methods: PBD patients discharged from the two study hospitals, from 1 January 2006 to 31 December 2019 (n = 420), were included in the analysis. Prescribed drugs at discharge, including mood stabilizers (i.e., lithium, valproate, carbamazepine, and lamotrigine), antipsychotics (i.e., second‐ and first‐generation antipsychotics, SGAs and FGAs), and antidepressants, were explored. Complex polypharmacy was defined as the use of 3 or more agents among the prescribed drugs. Time trends of each prescribing pattern were analyzed using the Cochran‐Armitage Trend test. Results: The most commonly prescribed psychotropic agents were SGAs (76.0%), followed by valproate (65.7%) and FGAs (24.8%). The prescription rates of SGAs, antidepressants, antidepressant plus antipsychotic, and antidepressant without mood stabilizer significantly increased over time, whereas the prescription rates of mood stabilizers, lithium, and FGAs significantly decreased. Discussions: Prescribing patterns changed greatly for PBD patients over time. However, much more evidence supporting the effectiveness of psychotropic agents in PBD patients is required. [ABSTRACT FROM AUTHOR]

The antipsychotics are used among pharmacological treatment of depression. Atypical antipsychotics have been used as monotherapy or adjunctively with antidepressants to treat depressive disorders with or without psychotic symptoms. The antidepressant effect of atypical antipsychotics involves regulation of monoamine, glutamate, gamma-aminobutyric acid, cortisol, and neurotrophic factors. To date, the United States Food and Drug Administration has approved aripiprazole and quetiapine slow-release tablets as adjunctive treatment for depressive disorders, and the combination of olanzapine and fluoxetine for the treatment of treatment-resistant depression. When using atypical antipsychotics in the treatment of depressed patients, clinicians need to monitor patients for the emergence of adverse effects, including hyperglycemia, weight gain, cholesterol levels, and extrapyramidal symptoms. These agents are effective for depression only at subantipsychotic doses. Receptor profiles predict that all second-generation antipsychotics will have anxiolytic effects as subantipsychotic doses but that all will be dysphorogenic at full antipsychotic doses (i.e. produce a depression-like clinical picture). The antidepressant effect appears to be unique to some agents. Also, despite the availability of a large number of antidepressants of different classes, a significant portion of patients do not achieve remission, and treatment resistance is common. This paper reviews the antipsychotics that are effective for the treatment of depressive disorders, and the pharmacological mechanisms of antipsychotics in the treatment of depressive disorders. [ABSTRACT FROM AUTHOR]

Psychiatric disorders are associated with cardiometabolic diseases, partly due to adverse drug effects with individual risk variabilities. Risperidone and sertraline are widely used for youths. Although they may be exposed to anthropometric changes, few data about this population exist. We evaluated the correlation between several blood parameters and body changes in a very small group of drug-naïve adolescents who had started risperidone or sertraline. We examined weight, waist circumference (WC), WC/height ratio and body mass index (BMI) at baseline (T0) and after at least three months of therapy (T1), and blood glucose and lipid profiles at T0. Here, we show significant increases in several anthropometric parameters in both groups, a negative correlation between HDL and ΔWC in the risperidone group and positive correlations between insulin and ΔBMI and between HOMA-IR and ΔBMI in the sertraline group. Despite the sample size, these results are important because it is difficult to study adolescents who are long-term-compliant with psychotropic drugs. This pilot study supports the importance of future large-scale investigations to understand the metabolic risk profiles of psychotropic drugs, their individual vulnerabilities and their underlying mechanisms. Simultaneous guideline-based psychiatric and metabolic interventions should be part of daily practice. [ABSTRACT FROM AUTHOR]

To assess the impact of the route of administration and doses of second-generation antipsychotics (SGAs) on treatment adherence, hospital admissions, and suicidal behaviour in patients with severe schizophrenia (Clinical Global Impression–Severity–CGI-S ≥ 5), we implemented an observational 5-year follow-up study. A total of 37.5% of the patients on oral antipsychotics (Aps) and 11.5% of those on long-acting injectables (LAIs) abandoned the treatment (p < 0.001). There were no differences in treatment discontinuation between the LAI-AP standard and high-dose groups. A total of 28.1% of the patients on oral Aps had at least one hospitalisation, as well as 13.1% of patients on LAIs (p < 0.001). There were fewer hospitalisations of patients on LAIs in the high-dose group (p < 0.05). Suicide attempts were recorded for 18% of patients on oral Aps but only for 4.6% of patients on LAIs (p < 0.001). No differences were found between the dosage groups on LAIs. Tolerability was good for all Aps and somewhat better for LAIs than oral Aps in terms of side effects (p < 0.05). There were no differences between the standard and high-dose groups. More patients discontinued treatment due to side effects in the oral AP group (p < 0.01). LAI SGA treatment was more effective than oral AP in terms of adherence and treatment outcomes for managing people with severe schizophrenia. Moreover, significant improvements were found that favour high-dose LAI SGA treatment for some of these patients. This study highlights the need to consider LAI antipsychotics and high-dose strategies for patients with severe schizophrenia. [ABSTRACT FROM AUTHOR]

Catatonia is a complex neuropsychiatric syndrome, occurring in the context of different psychiatric and neurodevelopmental disorders, in neurological and medical disorders, and after substance abuse or withdrawal. The relationship between Autism Spectrum Disorder (ASD), Schizophrenia Spectrum Disorders (SSDs) and catatonia has been previously discussed, with the three disorders interpreted as different manifestations of the same underlying brain disorder (the "Iron Triangle"). We discuss in this paper the diagnostic, clinical and therapeutic implications of this complex relationship in an adolescent with ASD, who presented an acute psychotic onset with catatonia, associated with mixed mood symptoms. Second-generation antipsychotics were used to manage psychotic, behavioral and affective symptoms, with worsening of the catatonic symptoms. In this clinical condition, antipsychotics may be useful at the lowest dosages, with increases only in the acute phases, especially when benzodiazepines are ineffective. Mood stabilizers with higher GABAergic effects (such as Valproate and Gabapentin) and Lithium salts may be more useful and well tolerated, given the frequent association of depressive and manic symptoms with mixed features. [ABSTRACT FROM AUTHOR]

Background: For bipolar disorder, a severe, recurring mental disorder, pharmacotherapy is a cornerstone of effective treatment. The purpose of this study was to investigate prescribing changes among patients with bipolar disorder discharged from two public psychiatric hospitals in Taiwan over a 14-year period.Methods: Patients with bipolar disorder discharged from the two study hospitals between 2006 and 2019 (n = 9071) were included in the analysis. Prescribed drugs for the treatment of bipolar disorder, including mood stabilizers (i.e., lithium, valproate, carbamazepine, and lamotrigine), any antipsychotics (i.e., second- and first-generation antipsychotics; SGAs & FGAs), and any antidepressants, were examined. Complex polypharmacy was defined as the use of 3 or more agents among the prescribed drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test.Results: The prescription rates of SGAs, any antidepressants, antidepressant monotherapy, antidepressants without mood stabilizers, and complex polypharmacy significantly increased over time, whereas the prescription rates of any mood stabilizers, lithium, carbamazepine, FGAs, and antidepressants plus mood stabilizers significantly decreased.Limitations: Treatment allocation is not randomized in a retrospective study. The diagnoses of bipolar disorder were based on clinical judgments. This was a hospital-based study.Conclusions: Substantial prescribing changes took place during the study period. The decreased use of lithium and the increased use of antidepressants were not in accordance with the evidence-based treatment and recommendations in treatment guidelines. Therefore, long-term outcomes of prescribing changes should be explored in the future. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) is a complex psychiatric disorder of multifactorial origin, in which both genetic and environmental factors have an impact on its onset, course, and outcome. Large variability in response and tolerability of medication among individuals makes it difficult to predict the efficacy of a chosen therapeutic method and create universal and precise guidelines for treatment. Pharmacogenetic research allows for the identification of genetic polymorphisms associated with response to a chosen antipsychotic, thus allowing for a more effective and personal approach to treatment. This review focuses on three frequently prescribed second-generation antipsychotics (SGAs), risperidone, olanzapine, and aripiprazole, and aims to analyze the current state and future perspectives in research dedicated to identifying genetic factors associated with antipsychotic response. Multiple alleles of genes involved in pharmacokinetics (particularly isoenzymes of cytochrome P450), as well as variants of genes involved in dopamine, serotonin, and glutamate neurotransmission, have already been identified as ones of significant impact on antipsychotic response. It must, however, be noted that although currently obtained results are promising, trials with bigger study groups and unified protocols are crucial for standardizing methods and determining objective antipsychotic response status. [ABSTRACT FROM AUTHOR]

Given the great importance of treating patients with bipolar disorder, the aim of this study was to compare the efficacy of aripiprazole with other second-generation antipsychotics in relieving acute symptoms of mania. In this study, 50 patients with bipolar I disorder, manic episode, were divided into two groups receiving aripiprazole (n = 25) and other second-generation antipsychotics (risperidone, olanzapine, and quetiapine) (n = 25) for 6 weeks. The disease severity was evaluated and compared according to YMRS and CGI criteria. The mean severity of mania according to YMRS and CGI, at week 0 in comparison with weeks 2, 4 and 6 in both groups was significantly different (p < 0.0001) and the treatment with Aripiprazole at week 2 (p < 0.0001) and 4 (p = 0.0002) was significantly better than the other second-generation antipsychotics. The two groups also showed an overall improvement in CGI-based results at weeks 4 and 6 (p = 0.002). In addition, the efficacy index for aripiprazole at weeks 4 (p = 0.011) and 6 (p < 0.0001) as well as disease improvement in the second (p < 0.0001) and fourth (p = 0.026) weeks after treatment were better than the other second-generation antipsychotics. Aripiprazole and other second-generation antipsychotics, 2 weeks after initiation of treatment, significantly reduced mania severity in patients with bipolar disorder, however, aripiprazole seems to be more efficient and faster for controlling mania in patients with bipolar disorder. Aripiprazole and other second-generation antipsychotics, 2 weeks after initiation of treatment, significantly reduced mania severity in patients with bipolar disorder. Comparison between the two drugs, aripiprazole showed a more beneficial role in the second and fourth weeks than second-generation antipsychotics. Due to the fact that the possible mechanisms involved in the role of aripiprazole have not been considered compared to other antipsychotics in patients with bipolar disorder, there is a need for more extensive studies in this field. [ABSTRACT FROM AUTHOR]

The study aim was to assess the abuse/misuse potential of second‐generation antipsychotics (SGAPs) using VigiBase data. We extracted individual case safety reports of "Drug abuse, dependence and withdrawal" involving SGAPs up to June 2018. We assessed disproportionate reporting by calculating the information component, considering the lower end of the 95% credibility interval for the information component (IC025), and the proportional reporting ratio. We identified 1683 individual case safety reports recorded as "abuse, dependence and withdrawal" involving SGAPs, mainly quetiapine (n = 1089) and olanzapine (n = 209). The disproportional reporting indicators highlighted an association between "Drug abuse and dependence", and quetiapine, olanzapine and ziprasidone, as indicated by the IC025 (2.263, 0.259 and 1.051, respectively) and proportional reporting ratio values (3.929, 1.020 and 1.334, respectively). The abuse/misuse potential is confirmed for quetiapine and olanzapine and highlighted for the first time for ziprasidone. Physicians should consider these risks when prescribing these antipsychotics, especially to patients with history of drug abuse. [ABSTRACT FROM AUTHOR]

Acute agitation and aggression create safety risks for both patients and staff, often leading to psychiatric emergencies. Quick and appropriate treatment is necessary to achieve safe and effective outcomes. Unfortunately, there are several factors that hinder timely interventions, such as medication shortages and delay in staff preparedness. Ultimately, the goal of managing acute agitation and aggression in the clinical setting is to de-escalate the situation and prevent harm to patients and staff. This article will explore useful interventions in realizing treatment goals for the management of agitation and aggression in adults while navigating limitations faced in practice.

Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia (SCZ), but SGAs may differ in the severity of side effects. Long-term studies are lacking, and previous observational studies have limitations, such as failure to account for confounding factors and short follow-up durations. To compare the long-term anthropometric and metabolic side effects of seven SGAs in a Chinese population, using a within-subject approach to reduce the risk of confounding. We collected longitudinal data of SGA prescriptions, concomitant medications, fasting blood glucose (BG), lipid profiles, and BMI in a cohort of 767 patients with SCZ, with follow-up lasting up to 18.7 years (median ∼6.2 years). A total of 192,152 prescription records were retrieved, with 27,723 metabolic measures analysed. Linear mixed models were used to estimate the effects of SGA on BG, lipid profiles and BMI. Besides studying the effects of SGA medications (as binary predictors), we also investigated the effects of SGA dosage on metabolic profiles. Considering SGA medications as binary predictors, clozapine and olanzapine were associated with the most substantial worsening of lipid profiles and BMI. A significant increase in BG was observed with clozapine only. Amisulpride, paliperidone and quetiapine were associated with worsened lipid profiles and increased BMI. Conversely, aripiprazole was associated with significant improvement in lipid profiles but a small increase in BMI. When SGA dosage was considered, the model showed consistent results overall. At the minimum effective dose, clozapine was associated with the most severe metabolic side effects, followed by olanzapine. Risperidone and aripiprazole showed the least metabolic side effects, with aripiprazole being significantly associated with lower lipids. This study clarified the long-term and dose-dependent effects of different SGAs on anthropometric and metabolic parameters in Chinese SCZ patients. Our findings may inform clinicians and SCZ patients of SGA choices. • Long-term effects of second-generation antipsychotics (SGAs) on metabolic profiles and BMI in schizophrenia patients. • Within-subject approach to reduce confounding factors in observational study of SGA side effects. • Dose-dependent effects of SGAs on blood glucose, lipid profiles, and BMI in Chinese schizophrenia cohort. • Clozapine and olanzapine associated with most substantial worsening of lipid profiles and BMI. • Aripiprazole associated with improved lipid profiles but small increase in BMI. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate factors associated with concomitant laxative use among elderly patients with schizophrenia, discharged on second‐generation antipsychotics (SGAs), from two large public psychiatric hospitals in Taiwan. Methods: Elderly patients with schizophrenia who were discharged between 2006 and 2019 and received SGA monotherapy at discharge were included in the analysis. Multivariate logistic regression was used to identify factors associated with regular laxative use at discharge. The Cochrane‐Armitage trend test was used to evaluate whether significant time trends existed for rates of laxative use at discharge. Results: A total of 2591 elderly patients with schizophrenia were discharged during the study period, and 1727 of 2591 patients who met the inclusion criteria were included for analysis. Of these 1727 patients, 732 (42.4%) also received concomitant laxatives. Female gender, mood stabiliser use and concomitant diabetes mellitus were found to be associated with increased laxative use. Among SGAs, clozapine was associated with the highest rate of laxative use, followed by zotepine, quetiapine, olanzapine and risperidone. Additionally, risperidone, amisulpride, aripiprazole, paliperidone and sulpiride were associated with comparable rates of laxative use. Laxative use rates grew over time from 30.8% in 2006 to 46.6% in 2019 (z = 4.83, P < 0.001). Conclusions: Laxative use is common in elderly schizophrenia patients treated with SGAs. In cases of clinically significant constipation, switching to an SGA with a lower risk for constipation, or discontinuing the use of mood stabilisers should be considered, if clinically feasible. [ABSTRACT FROM AUTHOR]

Antipsychotics used to treat schizophrenia can cause drug-induced liver injury (DILI), according to the Roussel Uclaf Causality Assessment Method. The role of oxidative stress in triggering injury in these DILI cases is unknown. We repeatedly administrated two second-generation antipsychotics, aripiprazole and olanzapine, at laboratory alert levels to study underlying mechanisms in stress prevention upon acute oxidative stress. The drugs were administered continuously for up to 8 weeks. For this, hepatoma Fao cells, which are suitable for metabolic studies, were used, as the primary hepatocytes survive in the culture only for about 1 week. Four stress responses—the oxidative stress response, the DNA damage response and the unfolded protein responses in the endoplasmic reticulum and mitochondria—were examined in H2O2-treated cells by antioxidant enzyme activity measurements, gene expression and protein quantification. Oxidant conditions increased the activity of antioxidant enzymes and upregulated genes and proteins associated with oxidative stress response in aripiprazole-treated cells. While the genes associated with DNA damage response, Gadd45 and p21, were upregulated in both aripiprazole- and olanzapine-treated cells, only aripiprazole treatment was associated with upregulation in response to even more H2O2, which also coincided with better survival. Endoplasmic reticulum stress-induced Chop was also upregulated; however, neither endoplasmic reticulum nor mitochondrial unfolded protein response was activated. We conclude that only aripiprazole, but not olanzapine, protects liver cells against oxidative stress. This finding could be relevant for schizophrenia patients with high-oxidative-stress-risk lifestyles and needs to be validated in vivo. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association between acute kidney injury (AKI) and use of second-generation antipsychotics (SGA) in older adults. Methods: In a population-based cohort study using Danish national registries, new users of SGAs (aged ≥ 65) were identified during 2005–2015. Each SGA user was matched to 10 population controls on age, sex, and the SGA initiation date. The outcome was incident AKI within 90 days after the index date. Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for potential confounders. Results: In the study, 36,581 new SGA users and 365,810 controls were included. The 90-day incidence rate of AKI was 4.38 and 1.70 per 1000 person-years among SGA users and controls, respectively, corresponding to a crude HR of 2.57 (1.79–3.68). The fully adjusted HR (aHR) was 1.43 (0.89–2.27) for all SGAs. The risk differed among individual drugs with aHRs for olanzapine 3.50 (1.20–10.23), quetiapine 1.62 (0.81–3.26), and risperidone 0.68 (0.28–1.64). In sensitivity analyses, the aHR declined to 1.24 (0.95–1.61) at 1-year follow-up. Conclusions: Olanzapine use was associated with a significantly increased 90-day AKI risk. For quetiapine, the risk was elevated but not significant, and risperidone had no association. CIs were wide and confounder adjustment largely impacted the estimates. Main limitations included residual confounding and incomplete recording of AKI diagnoses. [ABSTRACT FROM AUTHOR]

Despite methodological limitations, real-world studies might support clinicians by broadening the knowledge of antipsychotics' (APs) effectiveness and tolerability in different clinical scenarios and complement clinical trials. We conducted an extensive literature search in the PubMed database to evaluate the effectiveness and tolerability profiles of second-generation antipsychotics (SGAs) from real-world studies to aid clinicians and researchers in selecting the proper treatment for patients with schizophrenia and related disorders. The present review evidenced that SGAs demonstrated superior effectiveness over first-generation antipsychotics (FGAs) in relapse-free survival and psychiatric hospitalization rate and for treating negative symptoms. Persistence and adherence to therapy were higher in SGAs than FGAs. Most studies concluded that switching to long-acting injectables (LAIs) was significantly associated with a lower treatment failure rate than monotherapy with oral SGAs. Considerable improvements in general functionality, subjective well-being, and total score on global satisfaction tests, besides improved personal and social performance, were reported in some studies on patients treated with LAI SGAs. Clozapine was also associated with the lowest rates of treatment failure and greater effectiveness over the other SGAs, although with more severe side effects. Effectiveness on primary negative symptoms and cognitive deficits was rarely measured in these studies. Based on the data analyzed in the present review, new treatments are needed with better tolerability and improved effectiveness for negative, affective, and cognitive symptoms. [ABSTRACT FROM AUTHOR]

Second-generation antipsychotics (SGAs), in particular, olanzapine and clozapine, have been associated with the development of type 2 diabetes mellitus (T2D) and metabolic syndrome in individuals with schizophrenia. In this context, beta cell dysfunction is a plausible mechanism by which SGAs cause T2D. Herein, we analyzed the direct effects of olanzapine, a commonly prescribed SGA with diabetogenic properties, on the INS-1 (821/13) beta cell line and isolated pancreatic islets. Treatment of INS-1 beta cells with non-toxic concentrations of olanzapine (3–6 μM) during 4 h activated endoplasmic reticulum (ER) stress-mediated signaling by increasing PERK/eIF2α phosphorylation, IRE-1 phosphorylation and XBP-1 splicing. Moreover, glucose-stimulated insulin secretion (GSIS) was inhibited when olanzapine was present for 16 h. The insulin secretory function of INS-1 cells was restored by inhibiting olanzapine-induced ER stress with tauroursodeoxycholic acid (TUDCA). Similar effects of olanzapine with or without TUDCA on ER-stress-mediated signaling and GSIS were found in pancreatic islets from female mice. Our results indicate that early activation of ER stress in pancreatic beta cells is a potential mechanism behind the alterations in glucose homeostasis induced by olanzapine. [ABSTRACT FROM AUTHOR]

В статье представлен обновленный алгоритм терапии депрессии при биполярном аффективном расстройстве. Актуальность этой работы обусловлена не только высокой распространенностью и мощным дезадаптирующим влиянием заболевания, но также появлением новых лекарственных препаратов и формированием новых подходов к терапии. Прежде всего это касается ограничения использования антидепрессантов при лечении депрессии в рамках биполярного расстройства и расширения применения антипсихотиков второго поколения. Алгоритм основан на анализе данных литературы с учетом последних доказательных исследований, метаанализов и экспертных мнений. Выбор лекарственных средств для проведения тех или иных этапов терапии определяется степенью доказательности имеющихся о них данных.

Abstract Background It is well established that the different antipsychotics used for schizophrenia symptoms differ substantially in their side effects. However, relatively little is known about the impact of these side effects on functioning from the patient’s perspective. We aimed to understand how key side effects of second-generation antipsychotics impact the functioning and quality of life (QoL) of patients with schizophrenia. Methods This is a cross-sectional, web-based survey of patient-reported side effect burden of antipsychotic drugs in adults with schizophrenia. The survey was deployed in the United States, Canada, Australia, Spain, Italy, Norway, and Denmark. It included sociodemographic and clinical questions, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), and the Glasgow Antipsychotic Side-Effect Scale (GASS). Eight pre-defined key side effects classified as activating (“Shaky hands or arms,” “Restlessness,” and “Difficulty sleeping”), sedating (“Sleepy during the day”, “Feeling drugged or like a zombie,” and “Feeling dizzy/Fainted”) or other side effects (“Problems enjoying sex” and “Gaining weight”), and additional questions related to impacts on function and quality of life were asked. Results In total, 435 participants (mean age: 38 years, 53.8% female) were included. The total Q-LES-Q-SF score indicated overall medium satisfaction with their quality of life (score of 44.3; possible range 14–70). The most prevalent side effects were “Sleepy during the day” (83.2%), “Difficulty sleeping” (74.7%), “Dry mouth” (63.9%), “Problems enjoying sex” (53.4%) and “Gaining weight” (52.4%). Women reported the side effects of “Sleepy during the day”, “Problems enjoying sex” and “Gaining weight” more frequently than men. Key side effects impacted physical, social, occupational and psychological aspects of functioning. Patients with key side effects often felt frustrated by their experiences. Total Q-LES-Q-SF score showed a significant inverse correlation with the score of pre-defined groups of side effects indicating worse QoL in association with more severe key side effects in these patients. Conclusion Stable patients with schizophrenia taking second-generation antipsychotics live with many side effects, including activating and sedating side effects, sexual side effects, and weight gain. Presence of these side effects is associated with substantial impacts across all aspects of daily functioning and lower quality of life and satisfaction.

Introduction Long-acting injectable antipsychotics (LAIs) have emerged as a new therapeutic option to treat patients suffering a psychotic disorder. To date, there is a lack of studies regarding safety and clinical use pattern of LAIs in pregnant women. Objectives Provide evidence and real world clinical data of pregnant women with schizophrenia who have been treated with long-acting aripiprazole monohydrate (aripiprazole once monthly [AOM] condition) during their pregnancy. Methods Descriptive real-world clinical experiences of pregnant women in treatment with AOM. The information was obtained by reviewing electronic medical records and by direct clinical observation management. Results The first six case-series describing the pregnancy course of women with schizophrenia treated with AOM. All of them remained psychopathologically stable through pregnancy, and their infants became healthy with normal developmental milestones (Table 1). Table 1. Clinical characteristics of six case-reports. Mothers 1 2 3 4 5 6 Maternal/Pregnancy outcomes Age(years) 35 29 35 31 38 30 Diagnosis Schizophrenia Schizophrenia Schizophrenia Schizophrenia Schizophrenia Schizophrenia AOM(mg/days) 400-300 400-300 400-300 160 300 400 Type of delivery Eutocic. Eutocic, preterm Eutocic Eutocic Eutocic Eutocic Neonatal outcomes Weight(grams) 3300 1800 3140 3102 2940 3400 Gender Female Female Male Male Male Male Developmental Abnormalities (years) No(3) No(2) No( 0.17) No(2) No(2) No(1.5) Conclusions The favorable results in this case-series suggest that despite the lack of evidence on reproductive safety and treatment with AOM during pregnancy, this therapeutic option should be considered in pregnant women with schizophrenia. However, further research on the use of long-acting antipsychotics in pregnant women is needed. Disclosure No significant relationships.

Background: Adverse cutaneous drug reactions have been reported with most drugs, including antidepressants (ADs) and second-generation antipsychotics (SGAs). The lack of extensive research on the relationship between ADs and SGAs, and cutaneous toxicity remains troubling. Our study aimed to assess the cutaneous toxicity of ADs and SGAs and provide valuable insights for clinical applications and scientific investigations., Research Design and Methods: We conduct a pharmacovigilance study based of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database to analysis the relationship of ADs and SGAs and cutaneous adverse events. Reporting odds ratios (ROR) and information components (IC) were presented using statistical shrinkage transformation., Results: Comparing ACDRs to other ADRs, each AD (fluoxetine (ROR 025  = 1.49), fluvoxamine (ROR 025  = 1.14), paroxetine (ROR 025  = 1.49), escitalopram (ROR 025  = 1.79), sertraline (ROR 025  = 1.44), venlafaxine (ROR 025  = 1.46) and duloxetine (ROR 025  = 1.69)) showed significantly more cases. There was no association between SGA and cutaneous toxicity. The spectrum displayed strong signals in duloxetine-induced genital ulceration (IC 025  = 2.75) and amisulpride-induced conjunctivitis (IC 025  = 2.56)., Discussion: This study provides a valuable foundation for clinical practice and medication monitoring by thoroughly analyzing, methodically evaluating, and quantifying the potential dermal toxicity of ADs and SGAs.

Background: Many of the atypical antipsychotics induce metabolic side effects, limiting their use in clinical practice. Alpha-lipoic acid (ALA) was proposed as a new approach in schizophrenia to improve metabolic effects of atypical antipsychotics. The aim of the study is to evaluate the effect of ALA on metabolic and clinical parameters among schizophrenic subjects. Methods: 15 schizophrenic subjects, in stable atypical antipsychotic monotherapy were included in the study. ALA was administrated at the oral daily dose of 600 ​mg/d in addition to antipsychotic therapy. Metabolic, clinical, and psychopathological parameters were measured at typical antipsychotics. e initial screening, and after 12 weeks. Results: ALA produced a statistically significant reduction in QTc (p ​= ​0.012), blood glucose (p ​= 0.005), AST (p ​= ​0.021), γGT (p ​= ​0.035), CPK (p ​= ​0.005) and prolactinaemia (p ​= ​0.026). In contrast, there was a significant increase in HbA1c (p ​= ​0.026). No effects on body weight and blood lipid levels (triglycerides, total cholesterol, HDL, LDL) emerged. Conclusions: ALA treatment appeared to be effective for reducing diabetes risk, liver functionality parameters, hyperprolactinaemia and QTC interval. ALA appears to be safe as adjunctive components in schizophrenia.

Background Second-generation antipsychotics (SGAs) are used to treat children for mental health disorders but in some children they cause cardiometabolic complications including weight gain and type 2 diabetes. Genetic variants can place a child at risk of developing these metabolic complications. The fat mass and obesity-associated (FTO) rs9939609 A allele has been associated with obesity and dietary energy intakes in healthy children but its relation to metabolic complications in SGA-treated children is not known. Objectives This study investigated the association of the FTO rs9939609 variant and SGA treatment with cardiometabolic complications and dietary intakes in children with mental health disorders. Methods A cross-sectional population of children (≤18 y; n  = 506) with mental health disorders that were SGA-treated (n  = 197) and SGA-naïve (n  = 309) were recruited through the Department of Psychiatry at BC Children's Hospital. Dietary intakes were estimated using 3-d food records in a subset of children (n  = 73). Results Genotype frequencies were not different between SGA-treated (TT genotype 42.6%, TA genotype 38.6%, AA genotype 18.8%) and SGA-naïve (TT 41.1%, TA 39.5%, AA 19.4%) children. Children with the A allele had lower BMI z -sores compared with the TT genotype (0.84 ± 1.19 compared with 1.19 ± 1.36; P  = 0.005, adjusted for ethnicity). We observed an interaction between FTO genotype and SGA status on fasting glucose (P  = 0.036). SGA-naïve children with the A allele had higher fasting glucose than those with the TT genotype (4.96 ± 0.35 compared with 4.81 ± 0.35 mmol/L; P  = 0.001), in adjusted models (age, sex, ethnicity, and BMI z -score). This was not observed in SGA-treated children. Children with the A allele had higher daily total energy intakes compared with the TT genotype (1994 ± 619 compared with 1814 ± 484 kcal/d; P  = 0.048), in adjusted models (age, sex, ethnicity, and BMI z -score); no effect of SGA-treatment was observed. Conclusions Our findings suggest the A allele of the FTO rs9939609 variant is associated with higher BMI in children with mental health disorders, but only in those not treated with SGAs. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. Methods: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. Results: Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. Conclusions/interpretation: Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes. [ABSTRACT FROM AUTHOR]

Objective: Numerous studies have examined the association of antimanic medications with neurocognition in adults with bipolar disorder (BD). However, few studies have examined this topic in youth. Thus, we aimed to examine the association of lithium and second-generation antipsychotics (SGAs), the first-line antimanic medications for youth with BD, with neurocognition in a relatively large sample of youth with BD. Methods: Participants included 91 youth with BD-I, -II, or -Not Otherwise Specified, aged 13-20 years (n = 14 current lithium use, n = 51 current SGA use). We examined four tests from the Cambridge Neuropsychological Test Automated Battery: Intra/Extra Dimensional Set-Shifting Task (IED), Rapid Visual Information Processing Task (RVP), Stockings of Cambridge Test (SOC), and Affective Go/No-Go (AGN). Within-sample Z-scores were computed, and a global neurocognitive composite score and g factor derived from these tests comprised the primary outcomes. Multivariable analyses controlled for age, sex, and IQ. Results: Current lithium use was significantly associated with poorer cognitive flexibility/set-shifting (IED). After further controlling for lifetime comorbid attention-deficit/hyperactivity disorder and current depression symptoms in sensitivity analyses, the lithium finding was no longer significant. Current SGA use was significantly associated with greater affective processing bias (AGN). No significant findings survived correction for multiple comparisons. All other cognitive outcomes were not significantly associated with current lithium use, current SGA use, or total number of current medications. Conclusions: Treatment with lithium or SGAs was associated with minimal neurocognitive impairments, with small effect sizes in primary multivariable analyses. This study adds to the limited body of literature examining medication use in relation to neurocognition in youth with BD. While the current study cannot rule out associations of smaller effect size, present findings suggest that leading mood-stabilizing medications are not associated with frank neurocognitive impairments in youth with BD. [ABSTRACT FROM AUTHOR]

Background Augmentation with second-generation antipsychotics (SGAs) represents an evidence-based psychopharmacotherapeutic strategy recommended in case of insufficient response to the first-line antidepressant (AD) treatment in major depressive disorder (MDD). Comparative evidence regarding efficacy and prescription preferences of the individual SGAs is scarce. Methods In the scope of this European, multi-site, naturalistic cross-sectional investigation with retrospective assessment of treatment outcome, we compared sociodemographic and clinical characteristics of 187 MDD patients receiving either quetiapine (n = 150) or aripiprazole (n = 37) as augmentation of their first-line AD psychopharmacotherapy. Results Comorbid posttraumatic stress disorder and diabetes were significantly associated with aripiprazole augmentation in our primary and post-hoc binary logistic regression analyses. Furthermore, we identified an association between aripiprazole co-administration and the presence of additional psychotic features, higher rates of AD combination treatment, and a longer duration of psychiatric hospitalizations during the lifetime, which, however, lost significance after correcting for multiple comparisons. Regarding treatment outcome, we found a trend of higher response rates and greater reductions in severity of depressive symptoms in MDD patients dispensed quetiapine. Conclusions Factors associated with a more chronic and severe profile of MDD seem to encourage clinicians to choose aripiprazole over quetiapine, that was, however, administered in the majority of our MDD patients, which might reflect the current approval situation allowing to prescribe exclusively quetiapine as on-label augmentation in MDD in Europe. Given the retrospective assessment of treatment response, the markedly smaller proportion of patients receiving aripiprazole augmentation generally showing an unfavorable disease profile, and the partially heterogeneous statistical robustness of our findings, further studies are required to elaborate on our observation and to generate unambiguous recommendations regarding the choice of first-line SGA augmentation in MDD. [ABSTRACT FROM AUTHOR]

The antipsychotics are used among pharmacological treatment of depression. Atypical antipsychotics have been used as monotherapy or adjunctively with antidepressants to treat depressive disorders with or without psychotic symptoms. The antidepressant effect of atypical antipsychotics involves regulation of monoamine, glutamate, gamma-aminobutyric acid, cortisol, and neurotrophic factors. To date, the United States Food and Drug Administration has approved aripiprazole and quetiapine slow-release tablets as adjunctive treatment for depressive disorders, and the combination of olanzapine and fluoxetine for the treatment of treatment-resistant depression. When using atypical antipsychotics in the treatment of depressed patients, clinicians need to monitor patients for the emergence of adverse effects, including hyperglycemia, weight gain, cholesterol levels, and extrapyramidal symptoms. These agents are effective for depression only at subantipsychotic doses. Receptor profiles predict that all second‐generation antipsychotics will have anxiolytic effects as subantipsychotic doses but that all will be dysphorogenic at full antipsychotic doses (i.e. produce a depression-like clinical picture). The antidepressant effect appears to be unique to some agents. Also, despite the availability of a large number of antidepressants of different classes, a significant portion of patients do not achieve remission, and treatment resistance is common. This paper reviews the antipsychotics that are effective for the treatment of depressive disorders, and the pharmacological mechanisms of antipsychotics in the treatment of depressive disorders. [ABSTRACT FROM AUTHOR]