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RationaleDesigner receptors exclusively activated by designer drugs (DREADDs) are a tool for "remote control" of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist.ObjectivesSecond-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit.MethodsMale and female TH:Cre + rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons of TH:Cre + rats. All rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in counterbalanced order.ResultsAll three CNO doses reduced operant rewards earned in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest J60 dose tested significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre + rats were correlated and were present in both sexes.ConclusionsFindings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

Rationale: Clozapine N-oxide (CNO) has been developed as a ligand to selectively activate designer receptors exclusively activated by designer drugs (DREADDs). However, previous studies have revealed that peripherally injected CNO is reverse-metabolized into clozapine, which, in addition to activating DREADDs, acts as an antagonist at various neurotransmitter receptors, suggesting potential off-target effects of CNO on animal physiology and behaviors. Recently, second-generation DREADD agonists compound 21 (C21) and JHU37160 (J60) have been developed, but their off-target effects are not fully understood. Objectives: The present studies assessed the effect of novel DREADD ligands on reward-seeking behavior. Methods: We first tested the possible effect of acute i.p. injection of low-to-moderate (0.1, 0.3, 1, 3 mg/kg) of CNO, C21, and J60 on motivated reward-seeking behavior in wild-type mice. We then examined whether a high dose (10 mg/kg) of these drugs might be able to alter responding. Results: Low-to-moderate doses of all drugs and a high dose of CNO or C21 did not alter operant lick responding for a reward under a progressive ratio schedule of reinforcement, in which the number of operant lick responses to obtain a reward increases after each reward collection. However, high-dose J60 resulted in a total lack of responding that was later observed in an open field arena to be due to a sedative effect. Conclusions: This study provides definitive evidence that commonly used doses of CNO, C21, and J60 have negligible off-target effects on motivated reward-seeking but urges caution when using high doses of J60 due to sedative effects. [ABSTRACT FROM AUTHOR]

Rationale: Repeated chemogenetic stimulation is often employed to study circuit function and behavior. Chronic or repeated agonist administration can result in homeostatic changes, but this has not been extensively studied with designer receptors exclusively activated by designer drugs (DREADDs). Objectives: We sought to evaluate the impact of repeated DREADD activation of dopaminergic (DA) neurons on basal behavior, amphetamine response, and spike firing. We hypothesized that repeated DREADD activation would mimic compensatory effects that we observed with genetic manipulations of DA neurons. Methods: Excitatory hM3D(Gq) DREADDs were virally expressed in adult TH-Cre and WT mice. In a longitudinal design, clozapine N-oxide (CNO, 1.0 mg/kg) was administered repeatedly. We evaluated basal and CNO- or amphetamine (AMPH)-induced locomotion and stereotypy. DA neuronal activity was assessed using in vivo single-unit recordings. Results: Acute CNO administration increased locomotion, but basal locomotion decreased after repeated CNO exposure in TH-CrehM3Dq mice relative to littermate controls. Further, after repeated CNO administration, AMPH-induced hyperlocomotion and stereotypy were diminished in TH-CrehM3Dq mice relative to controls. Repeated CNO administration reduced DA neuronal firing in TH-CrehM3Dq mice relative to controls. A two-month CNO washout period rescued the decreases in basal locomotion and AMPH response. Conclusions: We found that repeated DREADD activation of DA neurons evokes homeostatic changes that should be factored into the interpretation of chronic DREADD applications and their impact on circuit function and behavior. These effects are likely to also be seen in other neuronal systems and underscore the importance of studying neuroadaptive changes with chronic or repeated DREADD activation. [ABSTRACT FROM AUTHOR]

Rationale: Clozapine is a unique medication with a potential role in the treatment of severe borderline personality disorder (BPD). Objectives: The review examines the effectiveness of clozapine as a medication for management for severe BPD with high risk of suicide, violence or imprisonment, and aims to help guide clinical practice in managing severe BPD. Methods: A database search of the terms "Clozapine" AND "BPD"; "Antipsychotics" AND "BPD"; "Clozapine" AND "Borderline Personality Disorder"; and "Antipsychotics" AND "Borderline Personality Disorder" were performed in CINAHL, Cochrane Library, Embase, Medline, PsychINFO, PubMed, and Web of Science. Full-text articles of clinical clozapine use for BPD were included for review. Results: A total of 24 articles consisting of 1 randomised control trial, 10 non-controlled trials, and 13 case reports were identified. Most of the studies reported benefits from clozapine when used for severe BPD. Many of the studies focused on clozapine use in BPD patients at high risk of suicide. Results from these non-controlled and case reports support the use of clozapine in patients with severe BPD at high risk of suicide. Conclusion: There may be a role for clozapine in treating severe treatment refractory BPD, especially for those patients at high risk of suicide and frequent hospitalisations. [ABSTRACT FROM AUTHOR]

Rationale: Availability of the dopamine and noradrenaline precursor tyrosine is critical for normal functioning, and deficit in tyrosine transport across cell membrane and the blood-brain barrier has been reported in bipolar disorder and schizophrenia. Clozapine and lithium are two psychoactive agents used to treat psychosis, mood disorders and suicidal behavior, but their mechanism of action remains largely unknown. Objective: To characterize immediate and delayed differences in tyrosine uptake between healthy controls (HC) and bipolar patients (BP) and see if these differences could be normalized by either clozapine, lithium or both. A second objective was to see if clozapine and lithium have additive, antagonistic or synergistic effects in this. Method: Fibroblasts from five HC and five BP were incubated for 5 min or 6 h with clozapine, lithium, or combination of both. Radioactive labelled tyrosine was used to quantify tyrosine membrane transport. Results: There was significantly reduced tyrosine uptake at baseline in BP compared to HC, a deficit that grew with increasing incubation time. Clozapine selectively increased tyrosine uptake in BP and abolished the deficit seen under baseline conditions, while lithium had no such effect. Combination treatment with clozapine and lithium was less effective than when clozapine was used alone. Conclusions: There was significant deficit in tyrosine transport in BP compared to HC that was reversed by clozapine but not lithium. Clozapine was more effective when used alone than when added together with lithium. Potential clinical implications of this will be discussed. [ABSTRACT FROM AUTHOR]

Rationale: Clozapine has proven to be superior to other antipsychotic drugs in the treatment of schizophrenia but is under-prescribed due to its potentially severe side effects. Clozapine-induced sialorrhea (CIS) is a frequent and extremely uncomfortable side effect, which remains understudied. Objectives: To examine the prevalence of diurnal and nocturnal CIS in a sample of patients treated with clozapine, and to evaluate its impact on quality of life. Methods: We conducted a cross-sectional, observational study of 130 patients with schizophrenia spectrum disorders treated with clozapine. The prevalence of CIS was evaluated via specific sialorrhea scales. None of the patients included in the study was receiving a specific treatment for hypersalivation during the study period. Possible associations between sialorrhea and clinical and quality of life variables were analyzed. Results: Of 130 subjects, 120 (92.3%) suffered from CIS. Eighty-one (62.31%) suffered from diurnal CIS, 115 (88.56%) from nocturnal CIS, and 85 (65.38%) suffered from both. Significant positive associations between quality of life and diurnal CIS (B = 0.417; p = 2.1e − 6, R2 = 0.156) and nocturnal CIS (B = 0.411; p = 7.7e − 6, R2 = 0.139) were detected. Thirty per cent of the subjects reported a moderate to severe negative impact of sialorrhea on their quality of life. Conclusions: The present study suggests that CIS is highly prevalent in patients with schizophrenia and has an important impact on quality of life in one-third of our sample. Therefore, the inclusion of a systematic evaluation and treatment of CIS in standard clinical practice is highly recommended. Trial registration: Clinical Trials (https://clinicaltrials.gov) under reference NCT04197037. [ABSTRACT FROM AUTHOR]

Rationale: Though clozapine is recommended for treatment of tardive dyskinesia (TD) relating to the use of antipsychotic medications, studies comprehensively investigating the treatment effect of clozapine on TD are still limited. Objectives: This review examines the effectiveness of clozapine as an intervention for tardive dyskinesia and dystonia in patients with all psychiatric conditions. Effectiveness of clozapine, duration to exert the effect and dosage used were also analysed. Methods: A search in the PubMed, PsycINFO and clinicaltrials databases was performed, using the search terms "Clozapine" AND "dyskinesia" OR "dystonia". Full-text articles that reported the use of clozapine to treat abnormal involuntary movements and were written in English were included. Results: A total of 48 studies were identified, of which 13 were clinical trials and 35 were case reports. Significant improvement was seen in 86.7% of patients with schizophrenia spectrum disorders (average dose of clozapine = 355 mg/day) and 93% of patients with other psychiatric disorders (average dose of clozapine = 152.5 mg/day). Patients with other psychiatric diagnoses had faster improvement than the patients with schizophrenia spectrum disorders. Variation in improvements and dosage were also seen in the clinical trials. Conclusion: Results suggested an overall effectiveness of clozapine in the treatment of TD for patients with a range of psychiatric conditions. Different response time and clozapine dosage were seen in patients with different psychiatric conditions, suggesting different treatment protocols are required for different conditions. Most of the studies identified are of inadequate qualities, highlighting the need for high quality studies to provide clearer evidence. [ABSTRACT FROM AUTHOR]

Rationale: Though numerous studies demonstrate the superiority of clozapine (CLZ) for treatment of persistent psychotic symptoms that are characteristic of treatment-refractory schizophrenia (TRS), what remains unknown are the neural and molecular mechanisms underlying CLZ's efficacy. Recent work implicates increased corticostriatal functional connectivity as a marker of response to non-CLZ, dopamine (DA) D2-receptor blocking antipsychotic drugs. However, it is undetermined whether this connectivity finding also relates to CLZ's unique efficacy, or if response to CLZ is associated with changes in striatal DA functioning. Objective: In a cohort of 22 individuals with TRS, we examined response to CLZ in relation to the following: (1) change in corticostriatal functional connectivity; and (2) change in a magnetic resonance-based measure of striatal tissue iron (R2'), which demonstrates utility as a proxy measure for elements of DA functioning. Methods: Participants underwent scanning while starting CLZ and after 12 weeks of CLZ treatment. We used both cortical and striatal regions of interest to examine changes in corticostriatal interactions and striatal R2' in relation to CLZ response (% reduction of psychotic symptoms). Results: We first found that response to CLZ was associated with an increase in corticostriatal connectivity between the dorsal caudate and regions of the frontoparietal network (P < 0.05, corrected). Secondly, we observed no significant changes in striatal R2' across CLZ treatment. Conclusion: Overall, these results indicate that changes in corticostriatal networks without gross shifts in striatal DA functioning underlies CLZ response. Our results provide novel mechanistic insight into response to CLZ treatment. [ABSTRACT FROM AUTHOR]

Rationale and objective: In this study, we hypothesized that the chronic use of clozapine affects cytokine expression and has a greater effect on female patients than on male patients. The aims of this study were to detect (1) whether serum cytokine levels were altered in patients with chronic schizophrenia after clozapine treatment compared with age- and sex-matched healthy controls, (2) whether there was a gender difference in serum cytokine levels after clozapine treatment, and (3) whether there was a correlation between serum cytokine levels and clozapine daily dosage in patients with schizophrenia. Methods: Forty-nine inpatients with schizophrenia treated with clozapine and fifty-three sex- and age-matched healthy controls were recruited. The patients' psychiatric symptoms were measured by the Positive and Negative Syndrome Scale (PANSS). Blood samples from both patients and healthy controls were collected. Serum IL-1β, IL-2, IL-6, IL-17, IFN-γ, and TNF-α levels were measured in duplicate by sandwich enzyme-linked immunosorbent assay. Results: We found that chronic clozapine treatment in patients with schizophrenia resulted in the abnormal expression of serum cytokines, such as IL-2, IL-6, IL-17, and TNF-α, compared with the healthy controls. In addition, there was a gender difference in the abnormal expression of cytokines between male and female patients with schizophrenia. In the female group, IL-2 serum levels were lower than those in the male group. Interestingly, there was a positive correlation between serum IL-2 levels and the daily clozapine dosage in female patients with schizophrenia. Conclusion: Findings from our study have shown clear evidence that clozapine had a greater effect on immune function in female patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale Traf2- and Nck-interacting kinase (TNIK), a member of germinal center kinase (GCK) family, has been implicated as a risk factor in schizophrenia and bipolar disorder as well as the action of antipsychotics. TNIK is an essential activator of Wnt/β-catenin signaling pathway which has been identified involved in the mechanism underlying the effects of antipsychotics. Thus, the effects of TNIK on antipsychotics may be achieved by influencing Wnt/β-catenin signaling pathway proteins. Objectives and methods In the current study, the effects of up- or downregulated TNIK on β-catenin, T-cell factor 4 (TCF-4), glycogen synthase kinase-3β (GSK3β), and phosphorylated GSK3β (p-GSK3β) were examined in the human glioma U251 cells. Then, we observed the effects of antipsychotics (clozapine and risperidone) on the above proteins and evaluated the role of differentially expressed TNIK on antipsychotic-treated cell groups. Results The result showed that clozapine treatment decreased β-catenin and TCF-4 levels in U251 cells, and risperidone had the similar effects on β-catenin and p-GSK3β. The downregulated TNIK using siRNA impeded the regulation of antipsychotics on Wnt pathway proteins via increasing the expression levels of TCF-4, β-catenin, or p-GSK3β, whereas the upregulated TNIK made no significant change. Conclusions The influence of TNIK on the effects of antipsychotics may be partly through Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Rationale and objective: Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders. Methods: We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue. Results: Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients' BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α. Conclusion: Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators. [ABSTRACT FROM AUTHOR]

Rationale: Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile. Objective: This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs. Methods: Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded. Results: A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119–0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918–0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110–0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = − 0.164, 95% CI − 0.529–0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI − 0.203–0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305–0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948–0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261–0.377, p = 0.025). Conclusions: Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs. [ABSTRACT FROM AUTHOR]

Rationale: There is a need to develop animal models of schizophrenia-like behaviors that have both construct and predictive validity. Recently, a neonatal phencyclidine (PCP) and post-weaning social isolation dual-hit model was developed; however, its face and predictive validities need to be further investigated. Objective: The aims of this study were to extend the characterization of the behavioral changes occurring in the neonatal PCP and post-weaning social isolation dual-hit rat model and to evaluate the effects of chronic treatment with clozapine on signs related to schizophrenia. Methods: Male Wistar rat pups were treated with PCP (10 mg/kg s.c.) on postnatal days (PND) 7, 9, and 11. Starting from weaning, neonatal PCP-treated rat pups were socially isolated, while control saline-treated rats were group housed. At adulthood, rats were assessed using behavioral tasks evaluating locomotor activity, social recognition, prepulse inhibition, and reversal learning. Clozapine (3 mg/kg i.p.) was administered daily starting from a week before behavioral tests and until the end of the study. Results: Neonatal PCP-treated and post-weaning social isolated (PCP-SI) rats displayed persistent and robust locomotor hyperactivity as well as social recognition impairment. The latter could not be explained by variations in the motivation to interact with a juvenile rat. Weak-to-moderate deficits in prepulse inhibition and reversal learning were also observed. Chronic treatment with clozapine attenuated the observed locomotor hyperactivity and social recognition deficits. Conclusion: The PCP-SI model presents enduring and robust deficits (hyperactivity and social recognition impairment) associated with positive symptoms and cognitive/social deficits of schizophrenia, respectively. These deficits are normalized by chronic treatment with clozapine, thereby confirming the predictive validity of this animal model. [ABSTRACT FROM AUTHOR]

Background: Hypersalivation and drooling are commonly reported in clozapine-treated patients. Current management strategies have been evaluated using subjective measures. Many case reports describe the successful use of atropine in the treatment of the condition. Aims: To measure the effect and safety of sublingual atropine on nocturnal unstimulated saliva secretion. Secondary aims were to evaluate the patient's satisfaction with the atropine effect on hypersalivation (or sialorrhea), drooling, and sleep. Method: Twenty-one clozapine-treated patients with hypersalivation, or drooling, were randomised to take a single 600-μg dose of sublingual atropine drops or a matching placebo. The saliva secretion was measured over 5 min at baseline and 2 h after the administration of the study medication. Results: Sublingual atropine reduced the saliva secretion significantly more than the placebo (mean difference = − 57.21%, 95% CI: − 104.30, − 10.11, P = 0.02). A significant decrease in standing pulse rate was recorded in the participants in the atropine group (− 5.8 (− 9.54, − 2.15), P = 0.002). Subjectively, more patients in the atropine group found their pillow to have less saliva the following morning and found their sleep to be better. Conclusions: Sublingual atropine drops significantly reduces nocturnal unstimulated clozapine-induced saliva secretion. More research is required to compare the effect of sublingual atropine with other anticholinergic medications and different dosage forms. Trial registration: ACTRN12618000051246 [ABSTRACT FROM AUTHOR]

Rationale and objectives: Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT2C receptor and histaminergic H1 receptor are involved in aspects of feeding behaviour, the effect of clozapine on feeding may be linked to its action at these receptors. Methods: We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT2C and histaminergic H1 receptors on the same schedule. Clozapine reliably increased responding for food, even when rats had ad libitum access to food. The effect of clozapine on responding for food was reproduced by combined (but not individual) antagonism of the serotonin 5-HT2C and histaminergic H1 receptors. Conclusion: These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT2C and histaminergic H1 receptors. [ABSTRACT FROM AUTHOR]

Background: Antipsychotic-induced weight gain has been especially related to clozapine and olanzapine. Underlying mechanisms in relation to food preferences with an increased food craving and consumption of specific nutrients have not been extensively studied in patients with serious mental illness (SMI). We aim to describe specific food preferences (craving) and subsequent food consumption in SMI patients starting clozapine, as well as their possible relation to weight and body mass index (BMI). Methods: An observational prospective follow-up study (18 weeks) was conducted in a cohort of 34 SMI patients who started clozapine due to resistant-psychotic symptoms. Anthropometric measures, Food Craving Inventory (FCI), and a food consumption frequency questionnaire were evaluated at baseline, weeks 8 and 18 of treatment. Statistical analysis included generalized estimating equations models with adjustment for potential confounding factors. Results: No longitudinal changes over time were found across the different food craving scores after 18 weeks of treatment. However, adjusted models according to BMI status showed that the normal weight (NW) group presented an increased score for the "complex carbohydrates/proteins" food cravings (− 0.67; 95% CI [− 1.15, − 0.19]; P = 0.010), while baseline scores for "fast-food fats" cravings were significantly higher in the overweight/obese (OWO) group in comparison with NW patients (NW, 2.05; 95% CI [1.60, 2.49]; OWO, 2.81, 95% CI [2.37, 3.25]; P = 0.016). When considering if food craving could predict weight gain, only increments in "fast-food fats" cravings were associated (β = − 5.35 ± 1.67; 95% CI [− 8.64, − 2.06]; P = 0.001). Conclusions: No longitudinal differences were found for any of the food craving scores evaluated; however, in the NW group, food craving for "complex carbohydrates/proteins" changed. Thus, changes in "fast-food fats" cravings predicted weight increase in this sample. Interventions targeting food preferences may help to mitigate weight gain in patients starting treatment with clozapine. [ABSTRACT FROM AUTHOR]

Objective: This study examined the effect of adjunctive telmisartan on body metabolism in clozapine- or olanzapine-treated patients with schizophrenia. Method: Each subject had been on stable dose of olanzapine or clozapine for at least 1 month. In a 12-week randomized, double-blind, placebo-controlled study, subjects received either telmisartan (80 mg once per day) or placebo. The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated based on fasting blood levels of insulin and glucose. Fasting blood levels of triglycerides and cholesterols, as well as serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were measured. The whole-body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline and repeated at week 12. Results: Fifty-four subjects were randomized and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). There were no significant differences between the two groups in week 12 changes for HOMA-IR or fasting triglycerides (− 0.18 ± 1.24 vs 0.39 ± 1.39, p = 0.181; − 26 ± 76 vs − 10 ± 81 mg/dL, p = 0.679, respectively) (telmisartan vs placebo). Further, there were no significant between group differences in week 12 changes for other fasting lipids, body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's > 0.100). The DXA assessment showed no significant differences between the two groups in week 12 changes for fat mass, lean mass, or total mass (p's > 0.100). Conclusion: In the present study, adjunctive treatment of telmisartan did not seem to improve body metabolism in schizophrenia patients receiving olanzapine or clozapine. The implications for future studies were discussed. ClinicalTrials.gov identifier NCT00981526. [ABSTRACT FROM AUTHOR]

Background: Clozapine is the most effective medication for the positive symptoms of treatment-refractory schizophrenia. Although clozapine use is associated with fewer admissions, less is known about the impact of clozapine cessation on hospitalisation. Aims: The aims of this study were to investigate whether clozapine-reduced psychiatric inpatient admissions and bed days, and investigate patient factors associated with these changes from a sample of 1906 people commenced on clozapine. Methods: All people commencing clozapine during an acute hospitalisation over a 10-year period in Queensland, Australia, were included in this retrospective cohort study. A mirror image design was used to compare psychiatric bed days and hospitalisations 2 years before and after clozapine treatment, and the impact of clozapine continuation or early cessation. Changes in psychiatric bed days and hospitalisations were analysed using linear regression, adjusting for the duration on clozapine, sex, age, indigenous status, country of origin and time to clozapine commencement. Results/outcomes: There was a significant reduction in bed days (29.55 days vs 24.46 days, p < 0.001) and admissions (2.27 vs 1.87 < 0.001) associated with clozapine commencement. This remained significant among clozapine continuers, but not among those with early cessation. Longer duration on clozapine was associated with greater reductions in psychiatric bed days and admissions. Age, sex and time to clozapine commencement, indigeneity and country of origin did not impact outcomes. Conclusion/interpretation: Longer clozapine therapy led to a greater reduction in psychiatric bed days and hospitalisations. Early cessation was associated with a return to pre-clozapine levels of bed days and admissions. [ABSTRACT FROM AUTHOR]

Background: Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic of hallucinogenic 5-HT2A receptor agonists. However, the role of mGlu2 in the behavioral effects induced by antipsychotic drugs remains poorly understood. Here, we tested antipsychotic-like behavioral phenotypes induced by the atypical antipsychotic clozapine in mGlu2-KO mice and wild-type control littermates.Methods: Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated.Results: The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion.Conclusion: These findings further support the existence of a functionally relevant crosstalk between 5-HT2A and mGlu2 receptors in different preclinical models of antipsychotic activity. [ABSTRACT FROM AUTHOR]

Rationale: Clozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia.Methods: Using data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993-2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia.Results: There were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five reported deaths from neutropenia and cardiomyopathy.Conclusions: The rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial. [ABSTRACT FROM AUTHOR]

Rationale: We recently introduced a new rat model of emotional hyperthermia in which a salient stimulus activates brown adipose tissue (BAT) thermogenesis and tail artery constriction. Antipsychotic drugs, both classical and second generation, act to reduce excessive assignment of salience to objects and events in the external environment. The close association between salient occurrences and increases in body temperature suggests that antipsychotic drugs may also reduce emotional hyperthermia. Objectives: We determined whether chlorpromazine, clozapine, and risperidone dose dependently reduce emotionally elicited increases in BAT thermogenesis, cutaneous vasoconstriction, and body temperature in rats. Methods: Rats, chronically instrumented for measurement of BAT and body temperature and tail artery blood flow, singly housed, were confronted with an intruder rat (confined within a small wire-mesh cage) after systemic pre-treatment of the resident rat with vehicle or antipsychotic agent. BAT and body temperatures, tail blood flow, and behavioral activity were continuously measured. Results: Clozapine (30 μg-2 mg/kg), chlorpromazine (0.1-5 mg/kg), and risperidone (6.25 μg-1 mg/kg) robustly and dose-relatedly reduced intruder-elicited BAT thermogenesis and tail artery vasoconstriction, with consequent dose-related reduction in emotional hyperthermia. Conclusions: Chlorpromazine, a first-generation antipsychotic, as well as clozapine and risperidone, second-generation agents, dose-dependently reduce emotional hyperthermia. Dopamine D receptor antagonist properties of chlorpromazine do not contribute to thermoregulatory effects. Interactions with monoamine receptors are important, and these monoamine receptor interactions may also contribute to the therapeutic effects of all three antipsychotics. Thermoregulatory actions of putative antipsychotic agents may constitute a biological marker of their therapeutic properties. [ABSTRACT FROM AUTHOR]

Clozapine is the gold standard medication for treatment refractory schizophrenia, but unfortunately, its use is also associated with many adverse metabolic side effects. There may be a strong genetic component to the development of these adverse effects. We undertook a systematic review to examine the evidence for genetic variation being associated with secondary metabolic outcomes in patients with schizophrenia on clozapine, under both longitudinal and cross-sectional study designs. We limited studies to those examining patients definitely taking clozapine, unlike prior reviews that have examined metabolic effects of patients taking a range of antipsychotic medications. We found associations with outcomes such as increases in BMI and metabolic syndrome for variants in genes such as LEP and HTR2C. Meta-analysis of rs381328 in HTR2C revealed that the presence of the T allele led to a 0.63 kg/m (95% CI − 1.06 to − 0.19; p = 0.005) decrease in BMI compared to the C allele. Study and population heterogeneity and lack of statistical power among reviewed articles mean that evidence is lacking to warrant prophylactic genotyping of patients commencing clozapine to predict those at increased risk of developing adverse metabolic effects. Further efforts to establish collaborative consortia, consensus around study design and replication studies in independent populations should be encouraged. [ABSTRACT FROM AUTHOR]

Rationale: Clozapine (CLZ) is an effective treatment for schizophrenia, producing improvements in both negative symptoms and cognitive impairments. Cognitive impairments can be modelled in animals by ketamine (KET) and assessed using the attentional set-shift task (ASST). Objective: Our first aim was to determine whether CLZ improves cognitive function and reverses KET-induced cognitive impairments using the ASST. Our second aim was to assess dose dependency of these effects. Results: Our findings demonstrate that acute as well as sub-chronic administration of KET cause cognitive deficits observed as increase in number of trails and errors to reach the criterion in the EDS phase. CLZ 0.3 mg/kg reversed the effects of both acute and sub-chronic KET, with no effects on locomotor activity. However, clozapine's effect after sub-chronic administration of dose 0.3 mg/kg was not as explicit as in the case of acute treatment. Moreover, administration of 1 mg/kg CLZ to KET-treated mice induced or enhanced deficits in the extra-dimensional shift phase compared to 1 mg/kg CLZ administration to mice not receiving KET. Locomotor activity test showed sedation effects of CLZ 1 mg/kg after acute treatment; therefore, effect of CLZ 1 mg/kg on KET-induced cognitive deficits was not evaluated in the attentional set-shift task (ASST) test. Conclusions: The present findings support dose-dependent effects of CLZ to reverse KET-induced cognitive deficits. The observed dose dependency may be mediated by activation of different receptors, including monomers and/or heterodimers. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) psychosis is encountered in as many as 50% of patients with advanced disease. Treatment options for PD psychosis are few. In fact, only clozapine and pimavanserin have shown efficacy in randomised controlled trials. Clinicians are often reluctant to prescribe the former, due to the risk of agranulocytosis, while the latter is not widely available yet. Because it is already clinically available and exhibits high affinity for serotonin 2A receptors, a target with which both clozapine and pimavanserin interact, we hypothesised that the anti-depressant mirtazapine might be effective to alleviate PD psychosis. Methods: Here, we tested the anti-psychotic potential of mirtazapine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Five MPTP-lesioned marmosets exhibiting psychosis-like behaviours were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with mirtazapine (0.1, 1 and 10 mg/kg) or vehicle. We also tested the effect of mirtazapine on L-DOPA-induced dyskinesia. Results: The addition of mirtazapine 10 mg/kg to L-DOPA reduced psychosis-like behaviours by 50% (P < 0.05) and dyskinesia by 29% (P < 0.01), when compared to L-DOPA/vehicle. Importantly, the antipsychotic and antidyskinetic effects of mirtazapine were achieved without hindering L-DOPA anti-parkinsonian action. Conclusions: Our results suggest that mirtazapine may be effective to alleviate PD psychosis and, because the drug is clinically available, clinical trials that would assess its anti-psychotic efficacy in PD could be rapidly undertaken, hopefully leading to a new treatment option for this debilitating condition. [ABSTRACT FROM AUTHOR]

Rational: Prepulse inhibition (PPI) is suppression of the startle reflex by a weaker sensory stimulus (prepulse) preceding the startling stimulus. In people with schizophrenia, impairment of attentional modulation of PPI, but not impairment of baseline PPI, is correlated with symptom severity. In rats, both fear conditioning of prepulse and perceptually spatial separation between the conditioned prepulse and a noise masker enhance PPI (the paradigms of attentional modulation of PPI). Objectives: As a neurodevelopmental model of schizophrenia, isolation rearing impairs both baseline PPI and attentional modulations of PPI in rats. This study examined in Sprague-Dawley male rats whether neonatally blocking N-methyl- d-aspartate (NMDA) receptors specifically affects attentional modulations of PPI during adulthood. Results: Both socially reared rats with neonatal exposure to the NMDA receptor antagonist MK-801 and isolation-reared rats exhibited augmented startle responses, but only isolation rearing impaired baseline PPI. Fear conditioning of the prepulse enhanced PPI in socially reared rats, but MK-801-treated rats lost the prepulse feature specificity. Perceptually spatial separation between the conditioned prepulse and a noise masker further enhanced PPI only in normally reared rats. Clozapine administration during adulthood generally weakened startle, enhanced baseline PPI in neonatally interrupted rats, and restored the fear conditioning-induced PPI enhancement in isolation-reared rats with a loss of the prepulse feature specificity. Clozapine administration also abolished both the perceptual separation-induced PPI enhancement in normally reared rats and the fear conditioning-induced PPI enhancement in MK-801-treated rats. Conclusions: Isolation rearing impairs both baseline PPI and attentional modulations of PPI, but neonatally disrupting NMDA receptor-mediated transmissions specifically impair attentional modulations of PPI. Clozapine has limited alleviating effects. [ABSTRACT FROM AUTHOR]

Rationale: In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient. Objectives: The aim of this study was to find out whether elevated serum levels (≥5 mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone. Methods: Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5 mg/l) and pathological (>5 mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis. Results: Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine ( n = 33, P < 0.01) and risperidone ( n = 40, P < 0.01). A trend for an increase was found for quetiapine ( n = 32, P = 0.05). Median increases were 48.0 % (clozapine), 11.9 % (quetiapine), and 24.2 % (active moiety of risperidone), respectively. Conclusions: In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations. [ABSTRACT FROM AUTHOR]

Rationale: New clozapine optimization strategies are warranted, as some patients do not achieve sufficient response and experience various adverse effects. Fluvoxamine is a potent CYP1A2 inhibitor and may increase the ratio of clozapine to its primary metabolite N-desmethylclozapine (NDMC). Objectives: This study aims to review all pharmacodynamic effects and the adverse effect profile of changing the clozapine/NDMC ratio with adjunctive fluvoxamine. Methods: MEDLINE, Embase, and the Cochrane Library were searched with the search terms 'clozapine' and 'fluvoxamine' without any time limit. Language was restricted to English, Scandinavian, Polish, and German. Studies were sorted for relevance based on title and abstract. Clinical recommendations of potential indications/effects were graded as level A, B, C, or D depending on studies of high, moderate, low, or very low quality, respectively. Results: Based on data from 24 case reports/series, seven cohort studies, and two randomized controlled trials, 241 patients were studied. Evidence ( A) supported that adjunctive fluvoxamine increased clozapine plasma levels. This may increase the probability of response in patients, where sufficient clozapine plasma levels cannot be achieved. Adjunctive fluvoxamine reduced metabolic adverse effects of clozapine ( B) but not agranulocytosis risk ( B). Although depressive or obsessive-compulsive symptoms may improve, a SSRI with no CYP1A2 inhibition should rather be used ( C). No studies investigated the effect of adjunctive fluvoxamine to minimize clozapine rebound psychosis ( D) or to reduce the effects of smoking on clozapine plasma levels ( D). Conclusions: Adjunctive fluvoxamine may have clinical potentials for optimizing clozapine treatment but further clinical studies are warranted to explore the clinical implications. [ABSTRACT FROM AUTHOR]

Rationale: Ketamine, an N-methyl- d-aspartate receptor (NMDAR) antagonist, causes locomotor hyperactivity, aberrant prepulse inhibition and impaired reversal learning among other deficits. There are numerous clinical and pre-clinically uses of NMDAR antagonists and a growing need to characterize their neurobehavioral effects. Objectives: The present study was designed to characterize 1) ketamine's effect on incremental repeated acquisition (IRA), a procedure that taps multiple neurobehavioral functions and has performance measures correlated with IQ in humans, and 2) the extent to which clozapine (CLZ) and haloperidol (HAL) block ketamine's detrimental effects. Methods and Results: In experiment 1 (Exp. 1), BALB/c mice nose-poked under an IRA procedure for sucrose pellets. Systemic ketamine (1-30 mg/kg) dose-dependently decreased measures of cognitive and motor function. CLZ pretreatment (CLZ 0.1-4.0 mg/kg) dose-dependently attenuated ketamine-induced (30 mg/kg) deficits; the effective dose range of CLZ was 0.3-1.0 mg/kg. HAL pretreatment (0.01-0.1 mg/kg) did not attenuate any ketamine-induced deficits. In experiment 2 (Exp. 2), BALB/c mice lever-pressed under an IRA procedure for sweetened condensed milk. Ketamine (30 mg/kg) produced a global impairment in the IRA procedure and CLZ pretreatment (0.3-1.0 mg/kg) dose-dependently attenuated that impairment; motor-based performance recovered to a greater extent than cognitive performance. When tested alone, these doses of CLZ had little effect on IRA performance. Conclusions: These findings support the notion that CLZ is more effective than HAL at blocking ketamine-induced deficits. The IRA procedure may be beneficial for distinguishing the efficacy of drugs that seek to alleviate deficits in complex behavior that result from acute NMDAR antagonism. [ABSTRACT FROM AUTHOR]

Rationale: Prior research has not systematically investigated the effects of systemic antipsychotic drugs on operant response acquisition, specifically their behavioural microstructure, reinforcement blunting and relative potency in acquisition compared to performance once operant responding has stabilized. Objectives: This study aims to systematically investigate the effects of systemically administered clozapine, metoclopramide, haloperidol and risperidone during free operant response acquisition and performance. Methods: Following magazine training, food-restricted male Wistar rats lever pressed for food reward in 15 min daily operant conditioning sessions. Results: All drugs suppressed operant response acquisition and performance. Risperidone and metoclopramide, but not clozapine or haloperidol, suppressed operant responding more potently during acquisition than performance. The dopamine D2-like receptor antagonists haloperidol and metoclopramide that affect the ventral and dorsal striatum blunted reinforcement and decreased inactive lever presses in acquisition. In contrast, the atypical antipsychotics clozapine and risperidone that affect the ventral striatum and prefrontal cortex failed to decrease inactive lever presses during acquisition, suggesting a possible decision-making deficit. Haloperidol decreased active lever pressing over performance days. The drugs did not appear to affect rats' sensitivity to active lever press outcome, even though they suppressed active lever pressing. Conclusions: Results suggest that reinforcement impact during operant acquisition is dependent on dopamine D2 receptors while drugs affecting, among other areas, the prefrontal cortex produce a deficit in ability to suppress inactive lever press responses. [ABSTRACT FROM AUTHOR]

Rationale: Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect. Objective: The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats. Methods: 2,5-dimethoxy-4-iodo-amphetamine (DOI, a preferential 5-HT agonist) or quinpirole (a preferential dopamine D agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance disruptive effect of clozapine were tested. Results: Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance. Conclusions: Acute behavioral effect of clozapine can be enhanced by activation of the D receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT receptors in the mPFC. [ABSTRACT FROM AUTHOR]

Introduction: Atypical antipsychotics have significantly improved the quality of life for schizophrenic patients. Despite their beneficial effects, these antipsychotics induce weight gain, diabetes, and dyslipidemia. The aims of this study were to investigate the antioxidative activity of paraoxonase and assess lipid profile as a cardiovascular risk factor in patients with schizophrenia under long-term clozapine or risperidone treatment. Methods: The study included 66 patients with schizophrenia under clozapine or risperidone treatment and 19 healthy control subjects. Serum paraoxonase activities against paraoxon (PON(PO)), phenylacetate (PON(PA)), dihydrocoumarin (PON(DHC)), serum Trolox equivalent antioxidant activity (TEAC), antioxidant gap (GAP), and lipid profile were determined. Results: PON(DHC) activity was reduced in both antipsychotic drug-treated groups (clozapine 43.46 ± 1.06 U/ml, p < 0.001; risperidone 50.57 ± 1.54 U/ml, p < 0.01; control 52.27 ± 1.34 U/ml). A similar pattern was observed for the PON(DHC)/HDL-cholesterol (HDLC) ratio. On the contrary, PON(PO) and PON(PA) were increased in the treated group, but the corresponding paraoxonase/HDLC ratios were not significantly different from controls, except for PON/HDLC in the clozapine group. TEAC and GAP were only decreased in the clozapine-treated group. Conclusions: In patients with schizophrenia, clozapine or risperidone treatment had different effects on various paraoxonase activities. The results of the present study suggest that patients with schizophrenia might be at increased risk for metabolic and cardiovascular disease related to reduced PON(DHC), TEAC, and GAP. [ABSTRACT FROM AUTHOR]

The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug's effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug's therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Rationale: We have discovered that rats at the age of 18 months begin to twitch their heads spontaneously (spontaneous head twitching, SHT). To date, no one has described this phenomenon., Objectives: The purpose of this study was to characterize SHT pharmacologically and to assess some possible mechanisms underlying SHT., Methods: Wistar male rats were used in the study. Animals at the age of 18 months were qualified as HSHT (SHT ≥ 7/10 min observations) or LSHT (SHT < 7/10 min observations). Quantitative real-time PCR with TaqMan low-density array (TLDA) approach was adopted to assess the mRNA expression of selected genes in rat's hippocampus., Results: HSHT rats did not differ from LSHT rats in terms of survival time, general health and behavior, water intake, and spontaneous locomotor activity. 2,5-dimethoxy-4-iodoamphetamine (DOI) at a dose of 2.5 mg/kg increased the SHT in HSHT and LSHT rats, while ketanserin dose-dependently abolished the SHT in the HSHT rats. The SHT was reduced or abolished by olanzapine, clozapine, risperidone, and pimavanserin. All these drugs have strong 5-HT2A receptor-inhibiting properties. Haloperidol and amisulpride, as antipsychotic drugs with a mostly dopaminergic mechanism of action, did not influence SHT. Similarly, escitalopram did not affect SHT. An in-depth gene expression analysis did not reveal significant differences between the HSHT and the LSHT rats., Conclusions: SHT appears in some aging rats (about 50%) and is permanent over time and specific to individuals. The 5-HT2A receptor strongly controls SHT. HSHT animals can be a useful animal model for studying 5-HT2A receptor ligands., (© 2022. The Author(s).)

Rationale: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a major role in neurogenesis and neuroplasticity, and in the modulation of several neurotransmitter systems including the dopaminergic system. There are mixed reports about the association between the BDNF Val66Met polymorphism, schizophrenia, and treatment response to antipsychotic drugs. Objectives: The present study evaluated the association of the BDNF Val66Met polymorphism with treatment response to atypical antipsychotic olanzapine in schizophrenia and the possible predictive value of the BDNF Val66Met genotype status in treatment response to antipsychotic medication. Methods: The study included 590 ethnically homogenous Caucasian patients with schizophrenia (diagnosed using the SCID), 40.2 ± 12.0 years old, treated with olanzapine monotherapy (10-20 mg/day), or with other antipsychotics such as risperidone (3-6 mg/day), clozapine (100-500 mg/day), haloperidol (3-115 mg/day), fluphenazine (4-25 mg/day), and quetiapine (50-800 mg/day). Patients were subdivided into responders and non-responders according to a 50 % reduction in the Positive and Negative Syndrome Scale (PANSS) total and subscale scores after 8 weeks of treatment. Results: The results, corrected for possible effects of gender and age, showed a significant association between the BDNF Val66Met polymorphism and treatment response to olanzapine in patients. The Val/Val genotype was observed more frequently in treatment responders to olanzapine, and this genotype was associated with an improvement in clinical symptoms. Conclusions: Our results suggest that BDNF Val66Met variants might influence the response to 8 weeks of monotherapy with olanzapine, in a relatively large sample of patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: Antipsychotic dosage is generally adjusted by physicians depending on the stability of the patient and the response to that particular drug. Our hypothesis is that patients with previous suicide attempt are prescribed higher doses of antipsychotics. Objective: We examined the dosage and patterns of antipsychotic use in regard to past suicidal behaviour. Methods: For this study, 304 subjects with schizophrenia spectrum disorders between the ages of 18 and 75 were recruited. A cross-sectional assessment was used for this study, in which data were collected from each patient through an interview and self-report questionnaires. The percentages of the Compendium of Pharmaceuticals and Specialties (CPS) maximum recommended daily dose were applied to standardize antipsychotic dosages across different treatments. We compared the standardized dosage of antipsychotics in schizophrenics with previous suicide attempts and those who have never attempted suicide. Results: Applying the ANCOVA, our preliminary results show no significant difference ( P = 0.467) in antipsychotic dosage in the attempters and non-attempters. The prescribed clozapine dosage fails to show a significant relationship with suicidal history ( P >0.05). Conclusions: In summary, our analysis does not show antipsychotic dosage adjustment based on past suicide attempt, after controlling for the current suicidal ideation and hopelessness. [ABSTRACT FROM AUTHOR]

Rationale: Metabolic syndrome (MetS) has consistently been identified as an adverse effect of long-term treatment with atypical antipsychotics (AAPs) such as clozapine. Elevated serum homocysteine concentration has been found to act as an independent risk factor for MetS, and catechol-O-methyltransferase (COMT) catalyzes the homocysteine metabolism. We accordingly hypothesized that COMT dysregulation may confer the susceptibility to MetS induced by AAPs, potentially in a gender-specific manner, because the interaction effects of COMT and gender have been consistently reported. Objectives: This study aimed at determining the prevalence and influence of COMT on MetS among a population undergoing long-term clozapine treatment. Methods: A total of 468 schizophrenia patients taking clozapine were divided into two groups, those experiencing MetS and non-MetS. We genotyped three functional variants (rs4633, rs4680, and rs4818) in COMT and measured the serum levels of fasting homocysteine, glucose, triglyceride (TG), and high-density lipoprotein cholesterol. Results: MetS was found in 202/468 (43.2 %) of all the patients, with 40.2 % prevalence (138/343) in males and 51.2 % (64/125) in females. Patients with MetS had notably higher metabolic parameters than those without MetS. The mean levels of homocysteine in patients with MetS were significantly higher than those without MetS. We found a positive association between the rs4680 polymorphism and the serum triglyceride levels (corrected P = 0.024). Further analysis revealed that the rs4680 Met allele was significantly associated with increased triglyceride levels among female patients ( P = 0.009), but not among males ( P = 0.07). Conclusions: Our findings suggest a potential association between rs4680 in COMT and elevated TG levels, particularly among female patients. [ABSTRACT FROM AUTHOR]