Effects Of Clozapine Research Articles

Modulation of neuronal morphology by antipsychotic drug: Involvement of serotonin receptor 7

Antipsychotic drugs (APDs) are the primary pharmacological treatment for schizophrenia, a complex disorder characterized by altered neuronal connectivity. Atypical or second-generation antipsychotics, such as Risperidone (RSP) and Clozapine (CZP) predominantly block dopaminergic D2 and serotonin receptor 2A (5-HT2A) neurotransmission. Both compounds also exhibit affinity for the 5-HT7R, with RSP acting as an antagonist and CZP as an inverse agonist. Our study aimed to determine whether RSP and CZP can influence neuronal morphology through a 5-HT7R-mediated mechanism. Here, we demonstrated that CZP promotes neurite outgrowth of early postnatal cortical neurons, and the 5-HT7R mediates its effect. Conversely, RSP leads to a reduction of neurite length of early postnatal cortical neurons, in a 5-HT7R-independent way.Furthermore, we found that the effects of CZP, mediated by 5-HT7R activation, require the participation of ERK and Cdk5 kinase pathways. At the same time, the modulation of neurite length by RSP does not involve these pathways.In conclusion, our findings provide valuable insights into the morphological changes induced by these two APDs in neurons and elucidate some of the associated molecular pathways. Investigating the 5-HT7R-dependent signaling pathways underlying the neuronal morphogenic effects of APDs may contribute to the identification of novel targets for the treatment of schizophrenia.

Clozapine use at a specialised psychiatric hospital in Johannesburg.

Clozapine is the gold standard medication for treatment-resistant psychosis, with robust evidence supporting its efficacy in multiple symptom domains. However, clozapine's side effect profile contributes to its underutilisation and discontinuation. This study aimed to explore the magnitude of clozapine use and describe factors that impact on its effective use among in-patients. Tara Hospital, a specialised psychiatric hospital in Johannesburg. This was a retrospective, cross-sectional file review of clozapine-treated patients admitted over the 2-year study period. Data variables included: demographics, clinical information, discharge prescription, clozapine-related side effects and details of clozapine discontinuation, where applicable. A cohort of 33.2% of patients from Tara's biological wards received a trial of clozapine. Participants experienced anti-cholinergic clozapine-related side effects that included weight gain (79.5%), tachycardia (35.2%) and constipation (35.2%). Clozapine was discontinued in 13.7% of participants, and no life-threatening side effects or deaths occurred. Significantly more use of flupenthixol decanoate (64.3% vs. 30.7%; p = 0.0322) and anticholinergics (35.7% vs. 11.4%; p = 0.0474) occurred in the clozapine-discontinued group. Polypharmacy rates were high for psychiatric and non-psychiatric medications. One-third of patients received clozapine trials, most of whom continued at discharge. Although side effects occurred frequently, life-threatening side effects did not. Clozapine monitoring protocols, side effect rating scales, pre-emptive management of side effects, lifestyle interventions and clinician education may improve outcomes of clozapine use. The use of plasma clozapine levels may be beneficial. This study expands our limited knowledge regarding current clozapine prescribing trends in South Africa.

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia.

Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine's wide-ranging superior efficacy - for treatment-resistant schizophrenia (TRS) and beyond - and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients' benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine's unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine's full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

Clozapine Reduces Recurrent Suicidal and Self-Injurious Behavior in Treatment-Refractory Incarcerated Individuals.

This retrospective review examines clozapine's effects on treatment-refractory incarcerated individuals (N = 23) with recurrent thoughts of self-harm and/or self-injurious behavior. Emergent suicide risk assessments and days on suicide watch were assessed for the 3 months pre- and post-clozapine treatment. Total suicide assessments fell from 73 pre- to 14 post-clozapine, with a median of 2 assessments (interquartile range [IQR]: 1,5) pre-clozapine compared with 0 (IQR: 0,1) post-clozapine (p < 0.0001). Total days on suicide watch decreased from 104 days pre- to 32 post-clozapine, with a median of 3 days (IQR: 0,9) pre-clozapine compared with 0 (IQR: 0,0) post-clozapine (p = 0.0012). Emergency room visits and medical hospitalizations decreased substantially for all months of treatment. Clozapine treatment was associated with marked reductions in self-injurious thoughts and behaviors in high-risk incarcerated individuals.

Clinical Audit of Clozapine Prescribing Practice and Monitoring Process in an Australian Community Mental Health Service

AimsClozapine, a well-established treatment of choice for treatment-resistant schizophrenia is known to reduce suicidality, lessen the risk of tardive dyskinesia and reduce relapse risk. It contributes to a higher quality of life by reducing cognitive clouding. Patients taking Clozapine have improved social and work functioning. But Clozapine's significant side effects require regular, intense monitoring to minimize mortality and morbidity. To improve current practice of clozapine prescribing and monitoring, a systematic audit of service practices against guidelines of local hospital / Monash Health Clozapine patient management guidelines and the Royal Australian and New Zealand College of Psychiatrists (RANZCP) clinical practice guidelines will identify any deficits and inform measures to overcome them.MethodsAn audit was conducted to compare the current clozapine prescribing practice and monitoring process compared with local hospital / Monash Health Clozapine patient management guidelines and RANZCP clinical practice guidelines among clozapine prescribed patients in an Australian community mental health service.ResultsMedical records of thirty-three eligible adult patients on clozapine were audited. All the patients were prescribed dosages within the recommended daily clozapine range. Clozapine was used for appropriate indications (treatment of treatment resistant-schizophrenia or schizoaffective disorder). Of the 33 patients, clozapine level was subtherapeutic on 54.5% of patients. 54.5% of patients were on an adjunct psychotropic with clozapine. Aripiprazole and sodium valproate were used by eight patients each, and nine patients were identified using selective serotonin reuptake inhibitors. The most common side effect was hypersalivation (57.6%), followed by weight gain (39.4%), sedation (21.2%) and constipation (12.1%). Monthly weight monitoring, physical examination, medical officer monthly review and full blood examination, at 97% compliance met these standards. However, monitoring of Body Mass Index (BMI) (66.7%) and six-monthly consultant reviews (42.4%) showed poor compliance (&lt;70%) with the standards. Most metabolic blood investigations were in moderate compliance (70–90%) except for relatively high compliance for lipid profile (90.1%). Monitoring cardiac functions by echocardiogram were only 75.8% met the standard.ConclusionMost patients in this clinic receive recommended monthly monitoring practice but for BMI monitoring, six-monthly consultant review, most blood investigations and annual or 2 yearly echocardiogram findings indicated need for improvement. Polypharmacy of psychotropics increases the side effect burden and further increases the need to closely monitor the physical health and prescriptions of this cohort of patients. The next stage of this project will involve a codesign approach to developing a response to these findings that will be outlined here.

Anti-aggressive effects of clozapine in involuntarily committed black patients with severe mental illness

IntroductionPatients with severe mental illness are falsely characterized as aggressive by the media, perpetuating stigma. While exaggerated, some patients with severe mental illness are more aggressive without treatment. Clozapine may have a unique anti-aggressive effect in patients with schizophrenia-related disorders, independent of antipsychotic or sedative effects. Limited data in forensic and involuntary committed patients is currently available. PurposeThis study evaluates clozapine's effects on hostility and aggression in court-ordered Black patients. MethodsThis study analyzes a subgroup of Black patients from a larger prospective 24-week open-label clozapine study. All patients were involuntarily committed and enrolled from two participating state psychiatric hospitals. The primary outcome measured was total use of ‘as needed’ (PRN) or ‘immediate need’ (STAT) medications for aggression/hostility. Secondary outcomes included number and duration of seclusion and restraint (S/R) episodes, and changes in Brief Psychiatric Rating Scale (BPRS) hostility factor score. ResultsSixty-nine patients were included in our analysis. Significant reductions were noted in PRN/STAT medication use over time (χ2 = 6.90; p = 0.008) and the BPRS hostility factor score was reduced by 30% over the 24 weeks (F = 4.34, df = 62, p = 0.002). ConclusionsTreatment with clozapine effectively reduced hostility and aggression within this cohort of involuntarily committed Black patients with mental illness compared to baseline. Specifically, it helped lower the total number of PRN/STAT medication administrations and improved clinician-rated hostility factor scores on the BPRS. Our findings are pertinent as data in forensic settings is lacking and Black patients have been infrequently included in large prospective clinical trials with clozapine. ClinicalTrials.gov identifierNCT02404155.

Clozapine induces astrocyte-dependent FDG-PET hypometabolism.

Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35mgkg-1) for 6weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.

Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study.

Background: Cognitive disorders associated with schizophrenia are closely linked to prefrontal cortex (PFC) dysfunction. Administration of the non-competitive NMDA receptor antagonist ketamine (KET) induces cognitive impairment in animals, producing effects similar to those observed in schizophrenic patients. In a previous study, we showed that KET (20 mg/kg) induces cognitive deficits in mice and that administration of clozapine (CLZ) reverses this effect. To identify biochemical mechanisms related to CLZ actions in the context of KET-induced impairment, we performed a biochemical analysis using the same experimental paradigm—acute and sub-chronic administration of these drugs (0.3 and 1 mg/kg). Methods: Since the effect of CLZ mainly depends on G-protein-related receptors, we used the Signaling PathwayFinder Kit to identify 84 genes involved in GPCR-related signal transduction and then verified the genes that were statistically significantly different on a larger group of mice using RT-PCR and Western blot analyses after the administration of acute and sub-chronic drugs. Results: Of the 84 genes involved in GPCR-related signal transduction, the expression of six, βarrestin1, βarrestin2, galanin receptor 2 (GalR2), dopamine receptor 2 (DRD2), metabotropic glutamate receptor 1 (mGluR1), and metabotropic glutamate receptor 5 (mGluR5), was significantly altered. Since these genes affect the levels of other signaling proteins, e.g., extracellular signal-regulated kinase 1/2 (ERK1/2), G protein-coupled receptor kinase 2 (Grk2), and G protein-gated inwardly rectifying potassium 3 (Girk3), we determined their levels in PFC using Western blot. Most of the observed changes occurred after acute treatment with 0.3 mg/kg CLZ. We showed that acute treatment with CLZ at a lower dose significantly increased βarrestin1 and ERK1/2. KET treatment induced the upregulation of βarrestin1. Joint administration of these drugs had no effect on the βarrestin1 level. Conclusion: The screening kit we used to study the expression of GPCR-related signal transduction allowed us to select several important genes affected by CLZ. However, the obtained data do not explain the mechanism of action of CLZ that is responsible for reversing KET-induced cognitive impairment.

Clozapine initiation in the Belfast Health and Social Care Trust (BHSCT)

AimsThe aim of this project is to improve the quality of documentation and recording of the assessment and monitoring of patients commencing clozapine in BHSCT.BackgroundClozapine is an effective treatment for patients with schizophrenia who have not responded to at least two other antipsychotics. Due to clozapine's significant side effect profile patients must be carefully assessed prior to treatment initiation with close monitoring of their physical observations and reported side effects during initiation.The BHSCT Clozapine Pathway currently uses a Clozapine Assessment Integrated Care Pathway (ICP) common to inpatient and outpatient clozapine titrations and a Clozapine Titration ICP which varies slightly between inpatient and outpatient titrations.MethodThe Clozapine ICPs of patients commenced on clozapine in BHSCT in a 9 month period commencing January 2019 were reviewed. Handwritten clinical records were used to collect data on rates of completion of all aspects of the pathway.These results were used to identify areas of the pathway that were being poorly completed and the “Method for Improvement Model” used to trial changes to the pathway using Plan-Do-Study-Act (PDSA) cycles.Result20 patients in BHSCT were commenced on clozapine in the 9 month period. 1 Clozapine Initiation Pathway could not be located; therefore data were collected on 19 patients. 2 patients were initiated in the community and 17 patients initiated as inpatients.The results showed that sections of the Clozapine Assessment ICP were poorly completed; for example only 27% of the “Patient Baseline Preparation Checklist” were complete, with 60% partially complete and 13% completely blank.In the inpatient clozapine titration ICP the physical observations record was complete in only 20% of patients and the side effects monitoring record complete in only 13% of patients. Conversely the physical observations and side effects monitoring records were complete in 100% (n = 2) of patients.ConclusionBHSCT Clozapine Pathways were being poorly completed, with outpatient pathways being completed better than inpatient pathways. Analysis of the data shows that repetition of information in various parts of the pathway leads to gaps in documentation.Parts of the pathway that were poorly completed have been redesigned and the impact of these changes assessed using the PDSA cycle method. It is hoped that this along with education of staff will lead to an improvement in the assessment and monitoring of patients being commenced on clozapine.

Clozapine affects the pharmacokinetics of risperidone and inhibits its metabolism and P-glycoprotein–mediated transport in vivo and in vitro: A safety attention to antipsychotic polypharmacy with clozapine and risperidone

Antipsychotic polypharmacy (APP), as one maintenance treatment strategy in patients with schizophrenia, has gained popularity in real-world clinical settings. Risperidone (RIS) and clozapine (CLZ) are the most commonly prescribed second-generation antipsychotics, and they are often used in combination as APP. In this study, the pharmacokinetics of RIS and CLZ in rats were examined after co-administration to explore the reliability and rationality of co-medication with RIS and CLZ. In addition, the effects of CLZ on RIS metabolism and transport in vitro were investigated. The results illustrated that in the 7-day continuous administration test in rats, when co-administered with CLZ, the area under curve and peak concentrations of RIS were increased by 2.2- and 3.1-fold at the first dose, respectively, increased by 3.4- and 6.2-fold at the last dose, respectively. The metabolite-to-parent ratio of RIS was approximately 22% and 33% lower than those of RIS alone group at the first and last doses, respectively. Moreover, CLZ significantly increased RIS concentrations in the brain (3.0–4.8 folds) and cerebrospinal fluid (2.1–3.5 folds) in rats, which was slightly lower than the impact of verapamil on RIS after co-medication. Experiments in vitro indicated that CLZ competitively inhibited the conversion of RIS to 9-hydroxy-RIS with the inhibition constants of 1.36 and 3.0 μM in rat and human liver microsomes, respectively. Furthermore, the efflux ratio of RIS in Caco-2 monolayers was significantly reduced by CLZ at 1 μM. Hence, CLZ may affect the exposure of RIS by inhibiting its metabolism and P-glycoprotein-mediated transport. These findings highlighted that APP with RIS and CLZ might increase the plasma concentrations of RIS and 9-hydroxy-RIS beyond the safety ranges and cause toxic side effects.

Clozapine in epilepsy and psychosis: effects on seizures and metabolic profile

Clozapine (CZP) is an antipsychotic used in resistant psychosis, but has adverse metabolic effects and is associated with new onset or worsening of epileptic seizures (ES). There is not enough information available regarding its effect on metabolic variables and on ES in patients with epilepsy. To describe the effect of CZP on the metabolic and hematologic profiles, and on ES in patients with epilepsy and with psychosis and/or aggressive behavior. A case series of patients with epilepsy and psychosis and/or aggressive behavior that received CZP with an 18-week follow-up. Clinical records were assessed from 2008-2018. 30 patients with epilepsy that received CZP were included. A paired analysis (Student’s t-test or Wilcoxon signed rank test) was performed with metabolic variables (glucose, cholesterol, and triglycerides), hematologic variables, weight, body mass index (BMI), and monthly ES before and after CZP administration. The median age to CZP initiation was 31.9 ± 16.07 years. Median CZP dosage was 193 mg/day. There were changes on BMI (p = 0.001; 3.2 kg/m2 increase, median = 3.08), triglycerides (p = 0.002) and glucose (p = 0.030). Weight increase was 7 kg (p = 0.292; median = 4 kg). Monthly ES mean was decreased from 4.9 (median = 2) to 2.04 (median = 1; p = 0.001). This study provide information regarding the security profile of CZP in patients with epilepsy with psychosis and/or aggressive behavior. A decrease on monthly ES was observed, as well as moderate increases in triglycerides, glucose and BMI, which coincide with that described by other authors.

The relationship between plasma levels of clozapine and N-desmethyclozapine as well as M1 receptor polymorphism with cognitive functioning and associated cortical activity in schizophrenia

Studies that examined the effect of clozapine on cognitive functions in schizophrenia provided contradictory results. N-desmethylclozapine (NDMC) is the major metabolite of clozapine and have procognitive effects via agonistic activity in the M1 cholinergic receptors. The rs2067477 polymorphism in the M1 receptors may play role in cognitive profile in schizophrenia. We investigated the association of plasma clozapine (PClz), NDMC (PNdmc) levels and the rs2067477 polymorphism with cognitive functions and cortical activity measured by functional near infrared spectroscopy during the N-Back task in subjects with schizophrenia (N = 50) who are under antipsychotic monotherapy with clozapine. We found that PClz and PNdmc levels were negatively, PNdmc/PClz ratio was positively correlated with immediate recall score in the Rey Auditory Verbal Learning Test. PNdmc/PClz ratio was positively correlated with cortical activity during the N-back task. M1 wild-type group (CC: wild-type) produced higher cortical activity than M1 non wild-type group (CA: heterozygote / AA: mutant) in cortical regions associated with working memory (WM). These results suggest that individual differences in clozapine's effect on short term episodic memory may be associated with PClz and PNdmc. Higher activity in the M1 wild-type group may indicate inefficient use of cortical resources and/or excessive use of certain cognitive strategies during WM performance.

Constipation screening in people taking clozapine: A diagnostic accuracy study

ObjectiveClozapine is the favoured antipsychotic for treatment-refractory schizophrenia but its safe use requires careful adverse-effect management. Clozapine-induced gastrointestinal hypomotility (CIGH or ‘slow-gut’) is one of the most common and serious of clozapine's adverse effects. CIGH can lead to paralytic ileus, bowel obstruction, gastrointestinal ischaemia, toxic megacolon, and death. Enquiring about constipation is a simple and commonly used screening method for CIGH but its diagnostic accuracy has not previously been assessed. MethodsFirst, we examined the reliability of asking about constipation compared with asking about Rome constipation criteria in inpatients treated with clozapine (n = 69). Second, we examined the diagnostic accuracy of (1) self-reported constipation and (2) the Rome criteria, compared with the reference standard of gastrointestinal motility studies. ResultsAfter 30 motility tests, it was clear constipation screening had very poor diagnostic properties in this inpatient group and the study was terminated. Although 73% of participants had objective CIGH on motility testing, only 26% of participants self-reported constipation, with sensitivity of 18% (95% CI: 5–40%). Specificity and positive predictive values were higher (95% CI: 63–100% and 40–100%, respectively). Adding in Rome criteria improved sensitivity to 50% (95% CI: 28.2–71.8%), but half the cases were still missed, making this no more accurate than tossing a coin. ConclusionsCIGH is often silent, with self-reported constipation having low sensitivity in its diagnosis. Treating CIGH based on self-reported symptoms questions will miss most cases. However, universal bowel motility studies are impractical. In the interests of patient safety, prophylactic laxatives are suggested for people taking clozapine.

Effect of Clozapine on Proton Magnetic Resonance Spectroscopy Findings in Hippocampus.

The purpose of this study was to investigate the effect of clozapine on proton magnetic resonance spectroscopy (1H-MRS) findings in hippocampus in patients with schizophrenia. In addition, the relationship between the change in 1H-MRS findings and the change in psychopathology and neurocognitive functions was evaluated. Patients with schizophrenia (n=16) were assessed with the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale (CGI), a neurocognitive test battery and 1H-MRS at baseline, and twelve weeks after the initiation of clozapine. Healthy controls (n=8) were assessed once with a neurocognitive test battery and 1H-MRS. Bilateral multivoxel and left single voxel NAA/Cr, Cho/Cr, MI/Cr was calculated in the hippocampi. After 12 weeks of clozapine treatment, PANSS and CGI scores decreased; immediate recall, cumulative learning subtests of the Rey Auditory Verbal Learning Test, Category Verbal Fluency Test and Wechsler Memory Scale's visual reproduction delayed subtest scores increased significantly. Compared with healthy controls and patients after clozapine, hippocampi multivoxel and single voxel NAA/Cr, Cho/ Cr, MI/Cr ratios were not different in patients before clozapine. No significant correlations between change in 1H-MRS metabolite ratios and change in psychopathology, neurocognitive functions were detected. This study is the first longitudinal study to investigate the effect of clozapine in hippocampus with 1H-MRS. There were no significant changes in 1H-MRS findings in hippocampi after twelve weeks of clozapine treatment. Clozapine's effect in hippocampus should be investigated further in longer follow up studies with larger samples to reach a final conclusion.

Opposite clozapine and ziprasidone effects on the reactivity of plasma albumin SH-group are the consequence of their different binding properties dependent on protein fatty acids content

Antipsychotic drugs interfere with the antioxidant defense system provoking complex and often toxicological effects. Here we examined differences in plasma albumin reduced free thiol (SH) group content and its reactivity as a consequence of clozapine (CLZ) and ziprasidone (ZIP) binding. Chronic administration of CLZ reduced, whereas treatment with ZIP increased albumin-SH content in rats. Regardless of the ratio of stearic acid (SA) bound to protein, in vitro binding of ZIP to human serum albumin (HSA) increased both the SH group level and reactivity. In contrast, the effect of CLZ on HSA-SH reactivity was dependent on HSA to SA molar ratio. CLZ binding was accompanied by an increase in HSA-SH reactivity in samples with normal, but a reduction of its reactivity level with higher SA/HSA ratio, compared to drug-free samples. We demonstrate by steady-state fluorescence quenching studies that an increase in SA binding to HSA is associated with a significant reduction of binding constant for both antipsychotics. In addition, this is the first report of quantitative characterization of ZIP binding to HSA. Our findings suggest that albumin-SH content and reactivity is modulated by ZIP towards an increased antioxidant defense capacity in circulation, as opposed to CLZ, which can contribute to the safer, more effective treatment of schizophrenia.

Clozapine and all-cause mortality in treatment-resistant schizophrenia: a historical cohort study.

ObjectiveLarge‐scale epidemiological studies have demonstrated a protective effect of clozapine on mortality in people with schizophrenia. Clozapine is reserved for use in patients with treatment‐resistant schizophrenia (TRS), but evidence of clozapine's effect on mortality exclusively within TRS samples is inconclusive. Hence, we aimed to investigate the effect of clozapine use on all‐cause mortality in TRS patients.MethodsA historical patient cohort sample of 2837 patients, who met criteria for TRS between 1 Jan 2008 and 1 Jan 2016, were selected from the South London and Maudsley NHS Foundation Trust (SLAM) electronic health records (EHR). The national Zaponex Treatment Access System (ZTAS) mandatory monitoring system linked to the SLAM EHR was used to distinguish which patients were initiated on clozapine (n = 1025). Cox proportional hazard models were used, adjusting for sociodemographics, clinical monitoring, mental and physical illness severity and functional status.ResultsAfter controlling for potential confounders, the protective effect of clozapine on all‐cause mortality was significant (adjusted hazard ratio 0.61; 95% confidence interval 0.38–0.97; P = 0.04).ConclusionsClozapine reduces the risk of mortality in patients who meet criteria for TRS. We provide further evidence that improving access to clozapine in TRS is likely to reduce the mortality gap in schizophrenia.

Clozapine impact on c-Fos expression in mild stress preconditioned male rats exposed to a novelty stressor.

Clozapine (CLZ) stimulates several brain areas some of them being sensitive to stress. Aim of the present study was to reveal whether 7-day CLZ administration may: (1) activate the selected forebrain areas; (2) modulate response of these structures to a single forced swimming episode (FSW); (3) modulate response of these structures to FSW after 13-day preconditioning with mild unpredictable stress complex (CMS). Used groups of male Wistar rats: (a) vehicle or CLZ treated for 7days; (b) vehicle or CLZ treated for 7days and on the 7th day exposed to FSW; (c) CMS exposed for 13days, from the 8th day injected with vehicle or CLZ and on the 14th day exposed to FSW. Vehicle or CLZ (10mgkg-1 day-1 in 0.1% acetic acid) were administered intraperitoneally. c-Fos quantification was performed 90min after FSW in the medial prefrontal cortex (mPFC), dorsolateral (dLS) and ventrolateral (vLS) septum, dorsolateral (DLStr) and dorsomedial (DMStr) striatum, nucleus accumbens shell (NAc shell) and core (NAc core), and hypothalamic paraventricular nucleus (PVN). In unstressed animals CLZ increased c-Fos expression in the mPFC, vLS, and PVN. After a single FSW, CLZ decreased the number of c-Fos immunoreactive cells in the vLS, DMStr, NAc shell, and NAc core. In CMS rats, CLZ suppressed c-Fos immunoreactivity in response to FSW in the PVN. Our data indicate that CLZ elicits different impact on neuronal activities in the brain areas studied and modifies the response of these structures to stress. CLZ effect seems to be affected by stress duration.

Unique Effects of Clozapine: A Pharmacological Perspective.

Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.

Abstract P321: Clozapine-induced Hypertension: Role of the Dopamine Type 4 Receptor (D4R) in Human Renal Proximal Tubule Cells (RPTC)

Clozapine (CLZ), a potent D 4 R antagonist that is an effective antipsychotic drug for the treatment of schizophrenia, is associated with hypertension. The hypertensive side effect of CLZ may be through inhibition of the D 4 R because germline deletion of D 4 R in mice causes hypertension. The hypertension caused by germline deletion of D 4 R may, in part, be due to increased renal expression of the angiotensin type 1 receptor (AT 1 R) and renal expression of sodium exchangers, transporters, and pumps, e.g., NHE3, NKCC2, NCC, and Na + K + /ATPase, α subunit. CLZ administered subcutaneously (20mg/kg/day/x3 days, n=5) in mice induced hypertension, shifted the pressure-natriuresis plot to the right, and increased the renal expressions of NCC and Na + K + /ATPase, α subunit, relative to vehicle-treated mice (n=5). Activation of D 4 R decreased AT 1 R expression and Na + K + /ATPase activity in rat renal proximal tubule cells (RPTCs). Therefore, we studied two groups: subjects 18 to 75 years old with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder treated with CLZ for &gt;2 months (CLZ, N=32) and untreated healthy controls ( HC , N=20) without psychiatric illness. There were no significant differences in blood pressure (BP) between the two groups since more than half of the CLZ participants received antihypertensive medication. We studied RPTCs cultured from the participant’s urine (CLZ, N=18; HC, N=9) and treated those cells with 100 nM CLZ. CLZ decreased D 4 R expression in both HC and CLZ groups ( HC , VEH 1.04±0.17 vs CLZ 0.73±0.09, n=9, paired t-test, P&lt;0.05; CLZ, VEH 1.02±0.09 vs CLZ 0.75±0.06, n=16, paired t-test, P&lt;0.01). CLZ also increased reactive oxygen species (Rosstar550 assay) in the HC but not CLZ-treated group ( HC , VEH 0.92±0.07 vs CLZ 1.02±0.09, n=8, paired t-test , P&lt;0.05; CLZ VEH 1.09±0.18 vs CLZ 1.07±0.18, n=14). The density of plasma membrane AT 1 R tended to be higher in CLZ-treated hypertensive (CLX HP) than the CLZ-treated normotensive participants (CLZ NP): ( HC , 0.28±0.08 n=8; CLZ NP, 0.10±0.02 n=4; CLZ HP, 0.81±0.31 n=7). Thus, CLZ may induce hypertension through a D 4 R/AT 1 R-mediated mechanism similar to that reported in D 4 R knockout mice. Additional studies will determine if CLZ increases sodium transport in human RPTCs.

Clozapine induced blood dyscrasias and a therapeutical approach

IntroductionClozapine is a neuroleptic commonly used in treatments resistant to schizophrenia. However, despite the benefits, clozapine might cause some serious side effects. Hence, it is of the utmost necessity to keep an exacting control of the patients.ObjectivesTo study some of the therapeutical approaches to the treatment of clozapine induced neutropenia and agranulocytosis.MethodsReview of some articles in Mental Health Journals.ResultsThe treatment with clozapine, substratum of aminergic and muscarinic receptors, entails a 0.9% risk of causing agranulocytosis, and approximately a 2.7% risk of causing neutropenia. Both occur, over 80% of them, during the first 18 weeks of treatment. Thus, before starting it, it is necessary to draw some blood and analyze the complete blood count (CBC). Also, we must analyze CBCs weekly during the first 18 weeks. Other dyscrasias like leukopenia, leukocytosis, anaemia, eoshinophilia, thrombocythaemia or thrombocytopenia can also be observed. When agranulocytosis appears, it can be treated by discontinuing the clozapine treatment, but also using granulocyte-colony stimulating factor or lithium, both separated or combined with clozapine. Lithium produces reversible leukocytosis onceplasma levels of &gt; 0.4 mmol/L are reached. Despite the simultaneous treatment with lithium, clozapine can trigger some neurological side effects, it seems that seizure risk remains invariable.ConclusionsSome of the clozapine's side effects, like neutropenia or agranulocytosis, are potentially lethal. Their treatment consists of discontinuing clozapine or initiating granulocyte-colony stimulating factor or lithium. These are good options that can give rise to a later continued treatment with clozapine.Disclosure of interestThe authors have not supplied their declaration of competing interest.