Long-term Clozapine Treatment Research Articles

The Involvement of PGRMC1 Signaling in Cognitive Impairment Induced by Long-Term Clozapine Treatment in Rats

Introduction: Progesterone receptor component 1 (PGRMC1) has been identified as a potential target in atypical antipsychotic drug-induced metabolic disturbances as well as neuroprotection in the central nervous system. In our study, we aimed to figure out the essential role of PGRMC1 signaling pathway underlying clozapine-induced cognitive impairment. Methods: In male SD rats, we utilized recombinant adeno-associated viruses (BBB 2.0) and the specific inhibitor of PGRMC1 (AG205) to regulate the expression of PGRMC1 in the brain, with a special focus on the hippocampus. Treatments of clozapine and AG205 were conducted for 28 days, and subsequent behavioral tests including modified elevated plus maze and Morris water maze were conducted to evaluate the cognitive performance. Hippocampal protein expressions were measured by Western blotting. Results: Our study showed that long-term clozapine administration led to cognitive impairment as confirmed by behavioral tests as well as histopathological examination in the hippocampus. Clozapine inhibited neural survival through the PGRMC1/EGFR/GLP1R-PI3K-Akt signaling pathway, leading to a decrease in the downstream survival factor, brain-derived neurotrophic factor (BDNF), and simultaneously promoted neural apoptosis in the rat hippocampus. Intriguingly, by targeting at the hippocampal PGRMC1, we found that inhibiting PGRMC1 mimics, while its upregulation notably mitigates clozapine-induced cognitive impairment through PGRMC1 and its downstream signaling pathways. Conclusion: PGRMC1-overexpression could protect hippocampus-dependent cognitive impairment induced by clozapine. This effect appears to arise, in part, from the upregulated expression of PGRMC1/EGFR/GLP1R and the activation of downstream PI3K-Akt-BDNF and caspase-3 signaling pathways.

The case of a geriatric female experiencing frequent falls and epileptic seizures during long-term low-dose clozapine and extended-release bupropion treatment

There are few reports describing the incidence of seizures in patients prescribed a combination of clozapine and bupropion for the treatment of psychiatric disorders, despite the known drug-drug interaction associated with concomitant use. We report the case of a 67-year-old geriatric woman who experienced multiple falls and seizures while receiving a low daily dose of clozapine 200 mg and bupropion extended-release (XL) 150 mg. There was no recurrence of seizure activity after discontinuation of bupropion and initiation of an antiepileptic drug, divalproex. This case report suggests that bupropion in combination with low-dose clozapine may increase the risk of seizures in elderly patients.

As-Required Filgrastim for Late-Onset Neutropenia Complicating Long-Term Clozapine Treatment: a Case Report.

Clozapine is considered the most effective antipsychotic for schizophrenia, but it can cause neutropenia and even agranulocytosis. We describe the first case in Hong Kong involving the use of filgrastim, a recombinant form of human granulocyte colony-stimulating factor, to enable clozapine continuation therapy for a severely ill patient with treatment-resistant schizoaffective disorder who developed recurrent neutropenia after almost 20 years of continuous clozapine therapy. Therefore, clinical vigilance is important, regardless of clozapine treatment duration. Filgrastim can facilitate long-term clozapine therapy in patients with clozapine-induced neutropenia.

Vortex keratopathy after photorefractive keratectomy in a patient on long-term clozapine treatment

Background: Vortex keratopathy is a corneal entity characterized by corneal deposits at the level of the basal epithelium in the form of a whorl-like pattern in the interpalpebral portions of the cornea. Medications such as amiodarone, chloroquine, hydroxychloroquine, indomethacin, phenothiazines, ibuprofen, and naproxen bind to the cellular lipids of the basal epithelial layer of the cornea, producing a characteristic whorl pattern. Here, we report a case of bilateral central vortex keratopathy with slight vision impairment 3 weeks after uneventful photorefractive keratectomy (PRK) in a woman on long-term clozapine treatment.
 Case Presentation: A 42-year-old woman presented to the outpatient clinic for refractive surgery for the correction of bilateral moderate myopia. Her best-corrected distance visual acuity was 20 / 20 in both eyes. She had been on antipsychotic clozapine tablets 400 mg / day for the past 6 years to manage a psychiatric disorder. On detailed preoperative slit-lamp examination, her corneas were clear, with perilimbal conjunctival pigmentations. Other ocular examination results were unremarkable. At the 3-week follow-up after an uneventful PRK, her uncorrected distance visual acuity was 20 / 25 in the right eye and 20 / 20 in the left eye, with complaints of slightly unclear vision in both eyes. Slit-lamp examination revealed bilateral corneal subepithelial deposits in a whorl-like pattern reminiscent of vortex keratopathy. The deposits were restricted to the epithelial and subepithelial regions and did not extend to the stroma without evident stromal haze. Dilated fundus examination results were normal bilaterally. Despite excellent refractive outcomes and visual acuity in both eyes, she was dissatisfied and complained of unclear vision. She was administered with lubricating eye drops and placed on regular follow-ups. At the 4-month follow-up, the vortex lines were cleared centrally, and she reported improvement in vision. Anterior-segment optical coherence tomography of the cornea revealed no epithelial deposits in the central part of the cornea and residual deposits in the temporal peripheral cornea, indicating clearing of the deposits from the central cornea and explaining the subjective improvement in vision. Her final best-corrected distance visual acuity was 20/20 in both eyes with an unremarkable ocular examination.
 Conclusions: Our case indicates a potential causal relationship between long-term clozapine treatment and development of temporary, visually significant vortex keratopathy after uneventful PRK. Further large-scale studies are required to verify the causal relationship between the long-term clozapine administration and the development of vortex keratopathy following surface ablation photorefractive procedures.

Correlation of Orexin-A and brain-derived neurotrophic factor levels in metabolic syndrome and cognitive impairment in schizophrenia treated with clozapine

Orexin-A and brain-derived neurotrophic factor (BDNF) are implicated in regulating metabolic syndrome (MetS) and cognitive impairment of schizophrenia. However, the associations among them remains unclear. Here, we aimed to investigate the relationship between Orexin-A levels, BDNF, MetS, clinical symptom profile, and cognitive function in schizophrenia patients following long-term clozapine treatment. We measured Orexin-A and BDNF levels in 140 schizophrenia patients with and without MetS. We assessed clinical symptoms on the Positive and Negative Syndrome Scale and cognitive function by the assessment of Neuropsychological Status (RBANS), and examined their associations with Orexin-A. Patients with MetS had significantly lower Orexin-A levels and higher coding test, attention span and delayed retention in RBANS (P < 0.05). Correlation analysis showed that Orexin-A was associated with BDNF, TG, HDLC, PANSS active social avoidance and emotional withdrawal significantly. Besides, Orexin-A significantly interacted with BDNF for metabolic and cognitive profiles including waist circumference, delayed retention and list recognition. Logistic regression analysis showed that Orexin-A level (odds ratio [OR] = 0.380, 95% confidence interval [CI]: 0.151–0.952, P = 0.039) and total illness duration (OR = 0.932, 95% CI: 0.875–0.991, P = 0.025) were predictive variables of MetS. However, there was no significant relationship between Orexin-A and cognitive function after adjustment for age, sex and educational levels. Totally, a lower plasma Orexin-A level seems to be related to metabolic parameters more than cognitive profiles. The interaction of Orexin-A with BDNF may be partly responsible for worse MetS and better cognition of elderly schizophrenia, but the causal relationship needs further clarification.

Long-term Use of Clozapine is Protective for Bone Density in Patients with Schizophrenia

Low bone mineral density (BMD) prevails among patients with schizophrenia. Antipsychotics use plays an important role in BMD. Previous cross-section study suggests that clozapine treatment may benefit BMD of women with schizophrenia. However, the effect of long-term clozapine therapy on BMD remains unknown. This prospective study compared clozapine and non-clozapine antipsychotics in long-term effects on BMD among both men and women with schizophrenia. Patients with schizophrenia and age-matched healthy individuals were enrolled from two centers. All patients, including clozapine receivers and non-clozapine antipsychotics recipients, kept clinically stable with unchanged antipsychotics and doses for at least 6 months at enrollment and during the follow-up period. BMD was examined by dual-energy X-ray absorptiometer upon enrollment and at 1- or 3-year follow-up. Thorough clinical and laboratory variables were measured too. The mean BMD of patients receiving clozapine was higher than that of the non-clozapine patients at both enrollment and follow-up. Overall, the patients in the clozapine group gained BMD, while those in the non-clozapine group lost BMD after 1–3 years (p = 0.015). There was no significant difference of BMD change between clozapine-treated patients and healthy controls. Factors associated with BMD change in the clozapine group included calcium level (B = −0.607, p = 0.021) and T3 level (B = −0.077, p = 0.007). This longitudinal study suggests that long-term clozapine treatment may protect BMD compared to prolactin-raising and non-clozapine prolactin-sparing antipsychotics among patients with schizophrenia. Future prospective studies are warranted to testify whether switching from non-clozapine antipsychotics to clozapine can rescue BMD.

Correlation of DRD2 mRNA expression levels with deficit syndrome severity in chronic schizophrenia patients receiving clozapine treatment.

Schizophrenia is a complex, severe, chronic psychiatric disorder, and the associated deficit syndrome is widely regarded as an important clinical aspect of schizophrenia. This study analyzed the relationship of deficit syndrome severity with the mRNA levels of members of signaling pathways that associate with the pathophysiology of schizophrenia, including the dopamine D2 receptor (DRD2), protein kinase B (AKT1), and phosphoinositide-3 kinase (PI3KCB), in peripheral blood leukocytes (PBLs) of 20 healthy controls and 19 chronic schizophrenia patients with long-term clozapine treatment. The DRD2 expression levels in chronic schizophrenia group were statistically higher than those in controls (t=2.168, p=0.037). Moreover, in chronic schizophrenia group, correlations were observed between the expression levels of DRD2 and PI3KCB (r=0.771, p<0.001), DRD2 and AKT1 (r=0.592, p=0.008), and PI3KCB and AKT1 (r=0.562, p=0.012) and between the DRD2 mRNA levels and the Proxy for the Deficit Syndrome score (r=0.511, p=0.025). In control group, the correlation between PI3KCB expression levels and DRD2 expression levels was only observed (r=0.782, p<0.001). In conclusion, a correlation was observed between increased deficit syndrome severity and elevated expression levels of DRD2 in PBLs of chronic schizophrenia patients receiving long-term clozapine treatment.

Tachycardia in patients treated with clozapine versus antipsychotic long-acting injections.

Tachycardia is a known adverse effect during clozapine treatment. However, prevalence reported differs widely between studies and hitherto there are no studies comparing clozapine-treated patients with a similar control group. The present study was carried out to assess the prevalence of tachycardia in patients treated with clozapine and antipsychotic long-acting injections (LAI). Data on heart rate (HR), concomitant medication, and relevant anthropometric and laboratory measurements were collected for all clozapine-treated patients (n=174) in a defined catchment area and compared with data on patients treated with LAI (n=87). In total, 33% of patients on long-term clozapine treatment had tachycardia (HR>100) compared with 16% in the LAI group (P<0.001). The mean HR was 91 in the clozapine group and 82 in the LAI group (P<0.001). Clozapine dose correlated with HR. The majority of patients with HR more than 100 received no specific treatment for tachycardia. In conclusion, the prevalence of tachycardia was twice as high in patients treated with clozapine as in a similar patient group with severe schizophrenia spectrum disorder. The tachycardia was in many cases clinically unnoticed. Tachycardia during antipsychotic treatment is a common phenomenon that must be monitored for actively and, when noticed, further investigated and treated.

Risk of New-Onset Diabetes After Long-Term Treatment With Clozapine in Comparison to Other Antipsychotics in Patients With Schizophrenia.

It has been suggested that clozapine has one of the largest diabetic effects of all atypical antipsychotics. To confirm these findings, we examined retrospectively the risk of new-onset diabetes in long-term clozapine treatment compared to treatment with other antipsychotics in a matched control population with schizophrenia or schizoaffective disorder. Ninety-four adult patients with schizophrenia or schizoaffective disorder who had been treated with clozapine for 5 years or longer were matched on age, diagnosis, and sex to 94 patients without any use of clozapine. The groups were followed up for as long as 20 years. The cumulative incidence of new detection of diabetes in the clozapine group was 22.3% (mean follow-up, 12.3 years; absolute risk difference, 6.3%; 95% confidence interval, -4.9% to 17.5%). An additional rigorous analysis of the 83 matched pairs with normal glucose measurement before end point showed a significant risk difference between the 2 groups (21.7% compared with 8.4%) but may have been biased against clozapine. We conclude that definitive evidence showing a clinically significant larger risk for new-onset diabetes after long-term treatment with clozapine in comparison to other antipsychotics is lacking.

Clozapine Improves Memory Impairment and Reduces Aβ Level in the Tg-APPswe/PS1dE9 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive degenerative condition. In order to treat AD, the use of a "drug repositioning" or "repurposing" approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for the treatment of psychosis and behavioral symptoms, and several animal models have shown the effects of these potential disease-modifying compounds. In this study, we examined whether long-term clozapine treatment could reduce amyloid beta (Aβ) deposition and cognitive impairment in transgenic mice of AD, Tg-APPswe/PS1dE9. AD mice were fed clozapine at 20mg/kg/day for 3months from 4.5months of age. Intake of clozapine improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of AD mice. Clozapine upregulated Trk, brain-derived neurotrophic factor, cyclin-dependent kinase-5, and p35 in the cortex and hippocampus of AD mice and activated AMP-activated protein kinase (AMPK). As a downstream effector of AMPK, beta-secretase expression was decreased by clozapine administration. Moreover, clozapine-phosphorylated synapsin I at Ser9 and Ser549 sites in the hippocampus and cortex of AD mice, which may be involved in synaptic strength. This study suggests that as one of candidate for multi-target approach of AD treatment, clozapine is proposed as a therapeutic drug for treatment of AD patients.

CYP1A2polymorphism −1545C &gt; T (rs2470890) is associated with increased side effects to clozapine

BackgroundCytochrome P450 1A2 gene (CYP1A2) polymorphisms have been suggested to be associated with increased side effects to antipsychotics. However, studies on this are scarce and have been conducted with either various antipsychotics or only in small samples of patients receiving clozapine. The aim of the present study was to test for an association between the CYP1A2 −1545C > T (rs2470890) polymorphism and side effects in a larger sample of patients during long-term clozapine treatment.MethodsA total of 237 patients receiving clozapine treatment completed the Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) assessing clozapine-induced side effects. Of these patients, 180 completed the questionnaire satisfactorily, agreed to provide a blood sample, and were successfully genotyped for the polymorphism.ResultsThe TT genotype of CYP1A2 polymorphism −1545C > T (rs2470890) was associated with significantly more severe side effects during clozapine treatment (p = 0.011). In a subanalysis, all seven types of side effects (sympathicotonia–tension; depression–anxiety; sedation; orthostatic hypotension; dermal side effects; urinary side effects; and sexual side effects) appeared numerically (but insignificantly) more severely among TT carriers. In addition, use of mood stabilizers was more common among patients with the TT genotype (OR = 2.63, p = 0.004).ConclusionsThis study has identified an association between the CYP1A2 polymorphism −1545C > T (rs2470890) and the occurrence of more severe clozapine side effects. However, these results should be regarded as tentative and more studies of larger sample sizes will be required to confirm the result.

Asymptomatic left ventricular dysfunction with long-term clozapine treatment for schizophrenia: a multicentre cross-sectional cohort study

ObjectivesPatients with schizophrenia treated with clozapine are at risk of acute myocarditis and dilated cardiomyopathy. However, there are no data on the prevalence of subclinical cardiomyopathy or its associations.Methods100 consecutive...

Metabolic syndrome in patients taking clozapine: prevalence and influence of catechol-O-methyltransferase genotype

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. This study aimed at determining the prevalence and influence of COMT on MetS among a population undergoing long-term clozapine treatment. 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. 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). Our findings suggest a potential association between rs4680 in COMT and elevated TG levels, particularly among female patients.

White Blood Cell Monitoring During Long-Term Clozapine Treatment

Late-onset agranulocytosis is rare during treatment with clozapine, especially in monotherapy. The authors describe a case of agranulocytosis that emerged after 19 years of continuous clozapine monotherapy. The discovery of the agranulocytosis was due to the lifelong white blood cell counts that are now required for clozapine treatment. Despite the fact that this requirement probably saved the life of this patient, this monitoring is not evidence-based because the incidence of agranulocytosis does not exceed that of conventional antipsychotic drugs, for which no such requirement exists. For mentally competent and adequately informed patients, the Netherlands Clozapine Collaboration Group now permits quarterly monitoring after the first 6 months of clozapine treatment.

TNF-α −308 G>A polymorphism and weight gain in patients with schizophrenia under long-term clozapine, risperidone or olanzapine treatment

Atypical or second-generation antipsychotics (SGAs) are associated with excessive body weight gain (BWG) and other components of metabolic syndrome. Among all SGAs, clozapine and olanzapine are known to cause the most significant weight gain, followed by risperidone and quetiapine. The genetic variant of tumor necrosis factor α ( TNF-α), −308 G>A polymorphism (rs1800629), has been implicated in clozapine-induced BWG in several studies. We hypothesized that TNF-α −308 G>A polymorphism has a general effect on SGA-induced BWG. The present study was conducted to examine the association between TNF-α −308 G>A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics (SGAs). A total of 500 patients with schizophrenia treated with clozapine ( n = 275), olanzapine ( n = 79) or risperidone ( n = 146) for an average of 49.9 months were recruited. Subjects with an increase in weight of more than 7% from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG. The association between TNF- α −308 G>A polymorphism and BWG was studied, and the effect of non-genetic factors such as baseline BMI, SGA treatment duration and SGA type on the association was controlled by logistic regression. The results revealed that there was no significant association between BWG and TNF-α −308 G>A polymorphism (GG/GA/AA or GG/GA+AA) in each separate SGA group or collectively. These findings suggest that TNF-α −308 G>A polymorphism does not play a major role in SGA-induced weight gain.

The prevalence and clinical‐demographic correlates of diabetes mellitus in chronic schizophrenic patients receiving clozapine

To examine the prevalence and correlates of diabetes in a large sample of Chinese patients with schizophrenia on long-term clozapine treatment, because this population previously has received little systematic study. Two hundred and six inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition schizophrenia criteria were recruited in a cross-sectional naturalistic study, and compared with 615 healthy control subjects matched for age, sex, education, and body mass index (BMI). The patient's psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Diagnoses of diabetes were established through review of medical records and fasting blood glucose testing, or an oral glucose tolerance test. Diabetes mellitus was more common in patients than in the normal controls (22.3% vs 6.2%) (odds ratio = 4.37, confidence interval (CI) 2.76-6.92, p < 0.001). The prevalence of diabetes increased with age across five age-groups as compared with normal controls (X(2) = 18.0, df = 4, p = 0.001). The PANSS total score and sub-scores showed no differences between the diabetic and non-diabetic groups. Logistic regression in the patients revealed significant associations between diabetes and a family history of diabetes (p < 0.001), age (p < 0.01), and BMI (p < 0.05). Long-term clozapine treatment was associated with an increased and clinically important risk of diabetes mellitus in Chinese chronic schizophrenic patients, which is consistent with previous reports in Western populations.

Left Ventricular Dysfunction and Low Grade Inflammation in Schizophrenic Patients Receiving Long-term Clozapine Treatment: A 2D-Speckle Tracking Echocardiographic Study

improvement in their mean pulmonary arterial pressures at sixmonths (41.3± 17.8 vs 21.7± 2.5mmHg).Onepatient has successfully been transplanted and the remaining two patients remain stable on thewaiting list for cardiac transplantation. Conclusion: This analysis shows that patients with endstageheart failure due to hypertrophic cardiomyopathydo benefit from continuous centrifugal flow LVAD therapy. doi:10.1016/j.hlc.2011.05.174

Genetic association between TNF‐α −308 G&gt;A polymorphism and longitudinal weight change during clozapine treatment

The aim of the study was to investigate the association between genetic variation in the tumor necrosis factor-alpha (TNF-alpha) gene and longitudinal weight change during long-term clozapine treatment. Fifty-five patients with refractory schizophrenia treated with clozapine for 8 years were recruited. Gender, age, treatment response to clozapine in the first 14 months, baseline BMI, clozapine dose, concomitant use of mood stabilizers and other antipsychotics, and -308 G > A polymorphism in the human TNF-alpha gene were analyzed using generalized estimating equations. In addition to having a lower baseline BMI (p = 0.0013) and a longer treatment time (p = 0.050), the -308 GG carriers gained significantly more weight than the -308 A allele carriers (p = 0.0084) during 8 years of clozapine treatment, after controlling for other non-genetic factors. The -308 G > A genetic variant of the TNF-alpha gene is associated with longitudinal weight change during clozapine treatment. Follow-up duration is an important factor to consider when performing pharmacogenetic study of clozapine-induced weight gain.

S28-02 - Impact of gene polymorphisms on pharmacokinetics and pharmacodynamics of olanzapine and clozapine

Treatment with antipsychotic drugs is, despite the introduction of many new compounds, far from optimal in a large proportion of patients. Apart from lack of or insufficient response, various adverse drug reactions often limit the use of otherwise efficient drugs, and increase the risk of non-compliance and poor treatment outcome. Thus, there is considerable need for individualized treatment in order to maximize the therapeutic outcome. This variability in drug response may be related to both pharmacokinetic and pharmacodynamic factors, many of which are genetically regulated. In the presentation, the contribution of allelic variability in genes coding for drug metabolic enzymes (CYP2D6, CYP1A2 and others) and transport proteins (ABCB1), as well as drug targets, to the pharmacokinetics and clinical effects of atypical antipsychotics will be discussed, using olanzapine and clozapine as model drugs. While CYP2D6 had no influence, carriage of two CYP1A2 allelic variants was associated with higher dose-adjusted plasma concentrations of clozapine and its metabolite desmethylclozapine. Patients with elevated insulin levels more frequently carried the *1C and *1D alleles, had higher plasma drug levels, higher blood lipids and HOMA-IR compared to patients with normal insulin levels. Associations were found between HTR2C and HTR2A haplotypes and increased BMI and C-peptide levels. A HTR2C haplotype was also shown to be significantly more frequent among obese than non-obese patients on long-term clozapine treatment. The data illustrate the need of an integrated approach involving both pharmacokinetic and -dynamic aspects in pharmacogenetic studies aiming at personalized antipsychotic treatment.

Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients

Despite clozapine's unique effectiveness in patients with schizophrenia, a number of adverse effects have been recognised including abnormalities in lipid and glucose metabolisms. A high clozapine level in red blood cells (RBCs) and disturbed anti-oxidant enzyme activities in blood from schizophrenic patients prompted us to investigate lipid status and anti-oxidant enzyme defence in the blood of chronic schizophrenic patients on long-term clozapine therapy. Plasma lipids, RBC anti-oxidant enzyme activities and haemoglobin (Hb) content were measured using established procedures in a group of eighteen chronically-medicated (average 630 days of therapy) schizophrenic patients receiving clozapine (average dose of 295 mg/day) and data were compared with those from a group of eighteen well-matched normal controls. Significantly higher levels of plasma triglycerides (by 47%, p<0.01) and total cholesterol and phospholipids (by 8% and 11%, respectively p<0.05) in patients were found. CuZn-superoxide dismutase (SOD1) activity was markedly higher (by 35%, p<0.001) while selenium-dependent glutathione peroxidase (GSH-Px1) activity was markedly lower (by 41%, p<0.001) in patients. In addition, metHb and HbA1c levels in patients were significantly higher (by 58% and 25%, respectively p<0.001). SOD1 activity was negatively correlated (p<0.001) to GSH-Px1 activity in patients. The findings support the view that ongoing oxidative stress may be a mechanism by which clozapine induces some adverse effects that increase the risk of diabetes and metabolic syndrome. If valid, this would indicate that in parallel with long-term clozapine treatment, schizophrenic patients could be encouraged to make some lifestyle changes to limit the detrimental effects of the medication.