Clozapine Group Research Articles

Blood serum levels of CART peptide in patients with schizophrenia on clozapine monotherapy

CART (cocaine- and amphetamine-regulated transcript) is an endogenous inhibitor of food intake. We compared fasting serum CART levels in subjects with schizophrenia on clozapine monotherapy (n=24) with sex- and age-matched healthy controls (n=24). CART levels were higher in the clozapine group (262.76±359.91 vs. 90.40±169.90pg/mL). CART levels were higher in subjects with metabolic syndrome compared to subjects without metabolic syndrome in the clozapine group (415.63±416.93 vs. 122.62±237.17pg/mL, n=12 and 12, respectively) and in the whole study group (377.73±401.09 vs. 88.58±172.35pg/mL, n=16 and 32, respectively). In the control group CART levels were higher in subjects with total body fat lower than the target maximum compared to subjects with total body fat below the target maximum (121.71±154.91 vs. 66.32±182.96pg/mL, n=14 and 10, respectively). CART levels did not correlate with age, weight, BMI, abdominal, waist and hip circumferences, WHR, blood pressure, laboratory tests, clozapine dose, antipsychotic or clozapine treatment duration, body composition, and markers of insulin resistance in the study group. Further studies are required to confirm whether increased levels of circulating CART are compensatory in response to treatment-induced weight gain and abdominal obesity or a primary feature of schizophrenia.

Sex-dependent metabolic alterations of rat liver after 12-week exposition to haloperidol or clozapine.

Antipsychotic drugs are known to have sex-dependent effects on metabolic homeostasis. Liver plays a crucial role in drug degradation as well as in glucose and lipid metabolism. The present study examines the influence of clozapine and haloperidol on metabolic liver parameters. Over 12 weeks, male and female Sprague-Dawley rats were fed ground pellets containing clozapine or haloperidol. Liver mass was weighed and liver index calculated. Liver transaminases (ALAT, ALP), malondialdehyde, glucose, triglycerides, total cholesterol, HDL-cholesterol, and glycogen were determined. Finally, SREBP-1 and SREBP-2 as well as neutral fat deposits were examined. In male rats fed with clozapine, we found increased liver mass correlated with an increased liver index, high triglyceride levels, a high ratio of SREBP-1, and an elevated neutral fat distribution. Male and female haloperidol treated rats showed decreased liver mass and increased neutral fat deposition. Malondialdehyde was increased in all rats receiving antipsychotic medication indicating elevated oxidative stress. In both male and female clozapine treated rats, we found glycogen depletion related to decreased glucose levels in females. While liver transaminases were unchanged in the clozapine group, ALAT was elevated after haloperidol treatment in both sexes. Chronic clozapine intake exerts sex-dependent effects on hepatic metabolism. Although haloperidol has been shown to change fewer metabolic parameters, it causes oxidative stress and neutral fat deposits in liver tissue in both sexes.

Serum levels of AgRP protein in patients with schizophrenia on clozapine monotherapy.

Aim: Agouti-related peptide (AgRP) is one of the hypothalamic hormones that works by increasing appetite and decreasing metabolism, thus leading to weight gain. The aim of the study was to find out if AgRP level in subjects with schizophrenia on clozapine monotherapy is higher compared with healthy controls. Methodology: We determined fasting serum AgRP levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy, age- and sex-matched controls. Biochemical and anthropometric measurements were combined with body composition analysis. Results: There was no difference for AgRP levels between patients taking clozapine and control group (15.00±8.65 vs. 15.33±6.82 pg/mL, p =0.37). We found negative correlations between AgRP levels and total body fat (r =−0.34 and −0.48 in the whole study group and clozapine group, respectively) and positive correlations with lean body mass (r =0.38 and 0.49 in the whole study group and clozapine group, respectively), body water (r =0.34 and 0.49 in the whole study group and clozapine group, respectively) and basal metabolic rate (r =0.42 both in the clozapine and control groups). There were no correlations with age, height, weight, body mass index, fat mass index, abdominal, waist or hip circumferences, waist-hip ratio, blood pressure, total cholesterol, HDL, LDL, triglycerides, uric acid, glucose, insulin, clozapine dose or treatment duration, duration of treatment with antipsychotics and markers for insulin resistance. Conclusion: We cannot conclude that treatment with clozapine is associated with increased level of AgRP. We did not find previously described differences in AgRP levels between obese and non-obese subjects or associations between AgRP and various metabolic parameters.

Serum levels of desacyl ghrelin in patients with schizophrenia on clozapine monotherapy.

Desacyl ghrelin is a hormone that might be a functional inhibitor of ghrelin, a potent hunger-stimulating peptide. We determined fasting serum desacyl ghrelin levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy, age- and sex-matched controls. Biochemical and anthropometric measurements were combined with body composition determined using bioelectric impedance analysis. There were no differences in desacyl ghrelin levels between patients taking clozapine and the control group (272.09 ± 137.96 vs 259.62 ± 140.91 pg/mL, z = 0.17, P = 0.87). In the clozapine group, there were no differences between men and women for ghrelin levels (246.66 ± 123.17 vs 295.39 ± 151.77 pg/mL, z = -0.98, P = 0.32). In the clozapine group, fasting serum levels of ghrelin negatively correlated with waist-to-hip ratio (WHR) (r = -0.45, P = 0.03) and ionized calcium (r = -0.45, P = 0.03). Levels of ghrelin were lower in patients with WHR above World Health Organization-defined cut-off points (246.84 ± 114.34 [Q1 = 152.18, Q2 = 220.92, Q3 = 327.85] vs 400.30 ± 123.36 [Q1 = 283.73, Q2 = 414.03, Q3 = 485.8] pg/mL, z = 2.52, P = 0.01). In the clozapine group, there were no correlation with age, height, weight, body mass index, abdominal circumference, waist circumference, hip circumference, WHR, blood pressure, total cholesterol, high-density lipoproteins, low-density lipoproteins, triglycerides, uric acid, homocysteine, glucose, insulin, clozapine dose, duration of treatment with antipsychotics, duration of treatment with clozapine, total fat, target fat, basal metabolic rate, target weight, lean weight, body water, homoeostasis model assessment of insulin resistance (HOMA) 1-IR, HOMA2-IR and quantitative insulin sensitivity check index. Based on our results, we cannot conclude that treatment with clozapine affects levels of desacyl ghrelin. Also, in our study population we did not confirm previously described associations between desacyl ghrelin and various metabolic parameters.

Effect of antipsychotic drugs on gene expression in the prefrontal cortex and nucleus accumbens in the spontaneously hypertensive rat (SHR)

Antipsychotic drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs is dependent upon the dopaminergic D2 blockade, but they also modulate other neurotransmitter pathways. The exact mechanisms underlying the clinical response to APDs are not fully understood. In this study, we compared three groups of animals for the expression of 84 neurotransmitter genes in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Each group was treated with a different APD (risperidone, clozapine or haloperidol), and with a non-treated group of spontaneously hypertensive rats (SHRs), which is an animal model for schizophrenia. This study also explored whether or not differential expression was regulated by DNA methylation in the promoter region (PR). In the clozapine group, we found that Chrng was downregulated in the NAcc and six genes were downregulated in the PFC. In the haloperidol group, Brs3 and Glra1 were downregulated, as was Drd2 in the clozapine group and Drd3, Galr3 and Gabrr1 in the clozapine and haloperidol groups. We also encountered four hypermethylated CG sites in the Glra1 PR, as well as three in the risperidone group and another in the haloperidol group, when compared to non-treated rats. Following the APD treatment, the gene expression results revealed the involvement of genes that had not previously been described, in addition to the activity of established genes. The investigation of the involvement of these novel genes can lead to better understanding about the specific mechanisms of action of the individual APDs studied.

A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics.

IntroductionAtypical 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.MethodsThe 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.ResultsPON(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.ConclusionsIn 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.

Upregulation of dopamine D3, not D2, receptors correlates with tardive dyskinesia in a primate model

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to centrally active dopamine D2 receptor antagonists, including antipsychotic drugs and metoclopramide. The classical dopamine D2 receptor supersensitivity hypothesis in TD, which stemmed from rodent studies, lacks strong support in humans. To investigate the neurochemical basis of TD, we chronically exposed adult capuchin monkeys to haloperidol (median, 18.5 months; n = 11) or clozapine (median, 6 months; n = 6). Six unmedicated animals were used as controls. Five haloperidol-treated animals developed mild TD movements, and no TD was observed in the clozapine group. Using receptor autoradiography, we measured striatal dopamine D1, D2, and D3 receptor levels. We also examined the D3 receptor/preprotachykinin messenger RNA (mRNA) co-expression, and quantified preproenkephalin mRNA levels, in striatal sections. Unlike clozapine, haloperidol strongly induced dopamine D3 receptor binding sites in the anterior caudate-putamen, particularly in TD animals, and binding levels positively correlated with TD intensity. Interestingly, the D3 receptor upregulation was observed in striatonigral neurons. In contrast, D2 receptor binding was comparable to controls, and dopamine D1 receptor binding was reduced in the anterior putamen. Enkephalin mRNA widely increased in all animals, but to a greater extent in TD-free animals. These results suggest for the first time that upregulated striatal D3 receptors correlate with TD in nonhuman primates, adding new insights to the dopamine receptor supersensitivity hypothesis. The D3 receptor could provide a novel target for drug intervention in human TD.

PT054 The safety and efficacy of prednisolone in preventing re-accumulation of ascites among EMF patients at Mulago Hospital: A randomised clinical trial(pilot)

3,p<0.001). Nine (9%) clozapine patients and no healthy controls or non-clozapine patients, had LVEF <50%. In the clozapine group, multivariate analysis showed elevated neutrophil countand low HDL-cholesterolasthe onlyindependentassociationswithimpairedLS. Platelet count, D-dimer and fibrinogen levels did not differ between controls and patients with schizophrenia.Incontrast,theoverallcoagulationpotential(54.0� 12.6vs45.9� 9.1,p¼0.002), overallhaemostaticpotential(12.6� 5.8vs7.2� 3.7,p<0.001),andoverall fibrinolyticpotential (76.6� 9.8% vs 84.9� 6.4%,p<0.001) were all significantly different in patients with schizophrenia compared to controls and were unaffected by clozapine use. Conclusion: Asymptomatic LV impairment is common in patients with schizophrenia receiving long-term clozapine, and is associated with neutrophilia and low plasma HDL suggesting an inflammatory link. There is also a hypercoagulable and hypofibrinolytic state in patients with schizophrenia unrelated to specific clozapine use. Disclosure of Interest: V. Chow: None Declared, T. Yeoh: None Declared, A. C. C. Ng: None Declared, T. Pasqualon: None Declared, E. Scott: None Declared, T. Chung: None Declared, L. Thomas: None Declared, J. Curnow Consultancy for: Haematology consultative services to Novartis for the clozaril patient monitoring service, D. Celermajer: None Declared, L. Kritharides: None Declared

EPA-1059 – Metabolic syndrome in patients with schizophrenia: polypharmacy with first generation antipsychotics vs. clozapine alone

Background To establish the prevalence of metabolic syndrome and its parameters in group of patients with schizophrenia in polypharmacy – receiving first generation antipsychotics versus clozapine alone treated group. Subjects and methods 48 outpatients with schizophrenia divided into two groups: the first group of 21 patients in polypharmacy with first generation antipsychotics, and the second group of 27 patients treated with clozapine alone were assessed for the presence of metabolic syndrome. We used logistic regression models to assess the relationship between metabolic syndrome and antipsychotic therapy, gender and age. Results metabolic syndrome was found in 52.1% of all subjects. Compared to first generation antipsychotics polypharmacy, the monopharmacy with clozapine was associated with elevated rates of metabolic syndrome (28.6% vs. 70.4%, p= 0.004). With regard to particular parameters of metabolic syndrome, the elevated plasma triglycerides were significantly more present in subjects within Clozapine group (p=0.03). Logistic regression analysis showed that female gender (p= 0.004), older age (p=0.56), and clozapine treatment (p= 0.005) were significantly associated with metabolic syndrome. Discussion Results of this study are consistent with other studies, which showed that patients receiving Clozapine are at higher risk for metabolic abnormalities. Conclusion Compared to polypharmacy with first generation antipsychotics, the higher prevalence of metabolic syndrome is found in patients treated with Clozapine alone. The most prevalent metabolic disorder is dyslipidemia. Female gender, older age, clozapine treatment are significantly associated with metabolic syndrome.

Detection of plasma clozapine concentration in psychosis disorder inpatients receiving comedications

Objective To investigate the effect of various comedications on the plasma concentration of clozapine(CLZ) in inpatients with psychosis disorder.MethodsHigh performance liquid chromatography(HPLC) was used to analyze serum CLZ and norclozapine(N-CLZ) concentrations in 571 psychosis patients.The influence of commedication on plasma CLZ concentration was analyzed using SPSS 17.0 software while considering the dosage of CLZ and the comedications with 12 drugs most often used in combination with CLZ.ResultsThe CLZ dosage,plasma CLZ concentration and plasma N-CLZ concentration in the comedication group were significantly lower than those in pure CLZ group(P 0.01).The CLZ dosage in groups of comedications with clonazepam,paroxetine,venlafaxine,aripiprazole,quetiapine and risperidone were significantly lower than that of pure CLZ group(P 0.05,P 0.01).Comedication with clonazepam,lithium carbonate,valproate and quetiapine significantly decreased the plasma concentration of CLZ(P 0.05,P 0.01).Comedication with clonazepam,lithium carbonate,valproate,sertraline,quetiapine and risperidone significantly decreased the plasma concentration of N-CLZ(P 0.05,P 0.01).Spearman's correlation analysis found that there were significant positive correlations among any two of dosage CLZ,concentration of CLZ and concentration of N-CLZ in CLZ group(P 0.05,P 0.01).ConclusionSome commonly-used antipsychotics have impact on plasma CLZ concentration.Drug monitoring and dosage regulation of CLZ should be stressed among patients comedicated with clozapine combined with other antipsychotics,so as to timely regulate the dosage of CLZ.

Chronic effects of clozapine administration on insulin resistance in rats: Evidence for adverse metabolic effects

Chronic treatment with the atypical antipsychotics clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia and insulin resistance diabetes. The present study mainly aimed to investigate possible mechanisms underlying clozapine-induced hyperglycemia. Male Wistar albino rats were randomly divided into two groups (each consists of 12 rats). The first group received clozapine orally at a dose of 10mg/kg body weight daily for 6 weeks, while the other group received the drug vehicle only and served as the control group. At the end of the six weeks, hyperglycemia, hyperinsulinemia and insulin resistance, as indicated by Homeostatic model assessment of insulin resistance (HOMA-IR), were observed in the clozapine group as compared with the control group. This disturbance in glucose regulation was associated with non-significant changes in body weight, serum cortisol level, and hepatic glycogen content. The Clozapine group showed a significant increase in hepatic phosphorylase activity and in the gene expression level of hepatic glucose-6-phosphatse (G6Pase) enzymes compared to the control group. It can be concluded that clozapine-induced hyperglycemia and insulin resistance occur in a manner mostly independent of weight gain, and may be attributed to an increase in hepatic phosphorylase activity and increased expression level of G6Pase.

Obsessive compulsive symptoms in patients with Schizophrenia on Clozapine and with Obsessive Compulsive disorder: A comparison study

Obsessive compulsive symptoms are commonly reported in those with schizophrenia. Clozapine has previously been reported to induce, aggravate and alleviate these symptoms. It is unclear if these are similar to the symptoms experienced by those with obsessive compulsive disorder. This study describes the obsessive compulsive symptom profile of a population of patients with schizophrenia treated with clozapine (n=62) and compares this with patients with Obsessive Compulsive Disorder (n=35). All participants were attending an outpatient community mental health service. The Obsessive Compulsive Inventory (which measures the frequency and associated distress of a range of “behavioural” and “cognitive” symptoms), the Hospital Anxiety and Depression Scale and a demographic questionnaire were completed. In addition the schizophrenia group treated with clozapine completed the Brief Psychiatric Rating Scale. The OCD group reported significantly more symptoms for all OCI subscales compared to the clozapine group. Overall fourteen (22%) of the schizophrenia treated with clozapine group had clinically significant total OCI scores. Two (3%) had documented OCS pre clozapine. De novo OCS was reported in twelve (19%) cases. Nine (11%) had documented OC symptoms pre-clozapine while only two (3%) had symptoms after clozapine was initiated. In terms of OC symptom profile, the clozapine group scored highest on the Doubting scale, a cognitive symptom whereas the OCD group scored highest on Washing, a behavioural symptom. Both groups reported greater distress with cognitive rather than behavioural symptoms. Medication including clozapine dose was not correlated with symptom severity. Anxiety correlated highly with obsessive compulsive symptoms in the Clozapine group but not the OCD group. Within the Clozapine group, Obsessing correlated highly with Unusual Thought Content. Findings suggest that obsessive compulsive symptoms in the Clozapine group may reflect a subtype of 'schizo-obsessive' disorder.

Therapeutic potential of histamine H4 receptor agonists in triple‐negative human breast cancer experimental model

The presence of the histamine H₄ receptor (H₄R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H₄R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model. Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H₄R agonists were employed: histamine (5 mg kg⁻¹), clozapine (1 mg kg⁻¹) and the experimental compound JNJ28610244 (10 mg kg⁻¹). Data indicate that developed tumours were highly undifferentiated, expressed H₄R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H₄R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis. Histamine through the H₄R exhibits a crucial role in tumour progression. Therefore, H₄R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.

Twenty-Four Months of Antipsychotic Treatment in Children and Adolescents With First Psychotic Episode

The Child and Adolescent First-Episode Psychosis Study is a longitudinal study of early-onset first psychotic episodes. This report describes the naturalistic psychopharmacological treatment administered during a 24-month follow-up period, as well as discontinuation rates, reasons for discontinuation, and adverse effects. The sample comprised 110 patients, aged 9 to 17 years, with a first psychotic episode. Pharmacological treatment, changes, reasons for discontinuation, and the UKU (Udvalg for Kliniske Undersogelser) Side Effect Rating Scale were registered at 6, 12, and 24 months of follow-up. Second-generation antipsychotics, especially risperidone, quetiapine, and olanzapine, were the most commonly used. The discontinuation rate was 44.5% at 6 months, 59.1% at 12 months, and 70.9% at 24 months. Discontinuation rates or reasons for discontinuation (adverse reaction, insufficient response, and other) did not differ significantly between antipsychotics. At 6 months, significant differences were found in body mass index increase and body mass index z score increase, which were higher with olanzapine, and in neurological effects, which were higher with risperidone; at 12 and 24 months, these differences were no longer significant. High maintenance rates were found in the clozapine group, although they had higher scores on the autonomic subscale of the UKU. A long follow-up period reveals high discontinuation rates similar to those observed in adults, particularly during the first year. No differences were found between antipsychotics. Differences in adverse effects were found at 6 months but not subsequently after changes in treatment. Clozapine had a high maintenance rate, and its tolerability was comparable to that of other antipsychotics.

Randomized trial of clozapine vs. risperidone in treatment-naïve first-episode schizophrenia: Results after one year

In first-episode patients with psychosis, clozapine may be potentially valuable as an initial treatment seeking to limit early on clinical and cognitive deterioration. Nevertheless, until recently its restricted use has limited the study of this possibility. Our research group is developing a non-commercial, multicentric and open label study on the differential efficacy between clozapine and risperidone in first-episode schizophrenia. In this paper, we present the results related to clinical variables after a one-year follow-up. So far, we have recruited 30 patients diagnosed with schizophrenia or schizophreniform disorder with illness duration of less than two years. The patients had not received any previous treatment and they were randomized to treatment with clozapine or risperidone. Our results indicate that on average, patients on clozapine adhered to their original treatment for a longer time period than patients on risperidone. By last observation carried forward (LOCF) analysis, patients on clozapine and risperidone displayed similar clinical improvements, although marginally greater improvements in positive and total symptoms scores were found in the clozapine group. At the 12-month point we observed a marginal improvement in negative symptom scores in patients on clozapine. Subjective secondary effects, as measured with the Udvalg for KliniskeUndersøgelser (UKU) scale, correlated negatively with negative symptoms at follow-up. Our data, although preliminary, suggest that clozapine may have a slightly superior efficacy in the initial year of treatment of first-episode treatment-naïve patients with schizophrenia, and this can be explained for the most part by greater adherence to this treatment.

Effect of combined treatment with clozapine and metformin on fasting blood glucose, insulin level, and expression of the glucose transporter-2 (GLUT2) in Sprague-Dawley rats.

BackgroundAntipsychotic medications can cause an increase in blood glucose and the development of type II diabetes. Metformin may ameliorate these side effects.ObjectiveAssess whether or not metformin reduces the abnormalities in glucose metabolism that occur with use of the antipsychotic clozapine.MethodsEighteen adult Sprague-Dawley (SD) rats were divided into three groups that were intragastrically administered saline, clozapine (20 mg/kg), or a combination of clozapine (20 mg/kg) and metformin (78 mg/kg) for 28 days. Fasting blood glucose was assessed at baseline and every seven days thereafter. The animals were euthanized on the 28th day at which time aortic blood was obtained to assess blood insulin and C-peptide by radioimmunoassay, and pancreatic tissue samples were collected and used to determine the expression of the glucose transporter-2 (GLUT2) by real-time polymerase chain reaction (RT-PCR) and Western Blot.ResultsFasting blood glucose in the clozapine group was significantly higher at the 14th, 21st, and 28th day compared to baseline, but rats receiving clozapine and metformin only had significantly elevated levels on the 14th day of treatment. However, repeated measures ANOVA found no statistically significant differences in blood glucose levels over time between the three groups (p=0.136). Multiple comparison tests found that the mean insulin level in the clozapine+metformin group was significantly lower than the levels in the clozapine and saline groups. There were statistically significant differences in the expression of GLUT2 mRNA (clozapine+metformin group < clozapine group < saline group) and in the expression of GLUT2 protein (clozapine+metformin group, clozapine group < saline group).ConclusionThis study found a non-significant increase in fasting blood glucose in SD rats treated with clozapine that was partially counteracted by concurrent administration of metformin. Rats administered clozapine showed the expected decrease in the expression of GLUT2, but concurrent administration of metformin and clozapine for 28 days did not show the expected normalization of the expression levels of GLUT2.

Switching From Clozapine to Zotepine in Patients With Schizophrenia

Clozapine is the most effective antipsychotic for patients with treatment-refractory schizophrenia, but many adverse effects are noted. Clinicians usually hesitate to switch from clozapine to other antipsychotics because of the risk of a re-emergence or worsening of the psychosis, although empirical studies are very limited. Zotepine, an atypical antipsychotic with a pharmacologic profile similar to clozapine, was found to be an effective treatment for patients with treatment-resistant schizophrenia in Japan. This 12-week study is the first prospective, randomized, and rater-blind study to investigate the efficacy and tolerability of switching from clozapine to zotepine. Fifty-nine patients with schizophrenia, who had taken clozapine for at least 6 months with a Clinical Global Impression-Severity score of at least 3, were randomly allocated to the zotepine and the clozapine groups. At the end of the study, 52 patients (88%) had completed the trial. The 7 withdrawal cases were all in the zotepine group. The final mean (SD) dose of zotepine and clozapine was 397.1 (75.7) versus 377.1 (62.5) mg/d, respectively. Patients in the zotepine group showed a significant increase in the Brief Psychiatric Rating Scale [mean (SD), 4.7 (8.7) vs -1.3 (6.3); P = 0.005], more general adverse effects as revealed by the Udvalg for Kliniske Undersogelser Rating Scale [mean (SD), 1.74 (3.9) vs -0.2 (2.8); P = 0.039], more extrapyramidal adverse effects as demonstrated by the Simpson and Angus Scale [mean (SD), 1.29 (3.5) vs 0.17 (2.1); P = 0.022], an increased use of propranolol (37.1% vs 0%, P < 0.0001) and anticholinergics (25.7% vs 0%, P = 0.008), and an increased level of prolactin (29.6 vs -3.8 ng/ mL, P < 0.0005), compared with the clozapine group. The results suggested that switching from clozapine to zotepine treatment should be done with caution.

Haloperidol-induced striatalNur77expression in a non-human primate model of tardive dyskinesia

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to antipsychotic drugs. As several modern (so-called atypical) antipsychotic drugs are common offenders, combined with the widening clinical indications for prescription as well as exposure of vulnerable individuals, TD will remain a significant drug-induced unwanted side effect. In addition, the pathophysiology of TD remains elusive and therapeutics are difficult. Based on rodent experiments, we have previously shown that the transcriptional factor Nur77 (also known as nerve growth factor inducible gene B or Nr4a1) is induced in the striatum following antipsychotic drug exposure as part of a long-term neuroadaptive process. To confirm this, we exposed adult capuchin (Cebus apella) monkeys to prolonged treatments with haloperidol (median 18.5months, N=11) or clozapine (median 6months, N=6). Six untreated animals were used as controls. Five haloperidol-treated animals developed mild TD movements similar to those found in humans. No TD was observed in the clozapine group. Postmortem analysis of Nur77 expression measured by in situ hybridization revealed a stark contrast between the two drugs, as Nur77 mRNA levels in the caudate-putamen were strongly upregulated in animals exposed to haloperidol but were spared following clozapine treatment. Interestingly, within the haloperidol-treated group, TD-free animals showed higher Nur77 expression in putamen subterritories compared with dyskinetic animals. This suggests that Nur77 expression might be associated with a reduced risk of TD in this experimental model and could provide a novel target for drug intervention.

1369 – Efficacy, tolerability and remission in switching antipsychotics study: nineteen years of schizophrenia

Background Despite their proven efficacy and tolerability, many patients are often switched among antipsychotics therapies due to the lack of therapeutic response. Many physicians begin to switching antipsychotics with the original intention to discontinue the drug, and, continue with another therapy. Several new antipsychotics available allow us to improve the long- term therapy. Methods Nineteen year open label study in ‘ real world ’ setting in 121 inpatients with schizophrenia (DSM-III -> DSM-IV-TR) observed first time in 1992 in a neuropsychiatric centre and subsequently clinically evaluated until 2011; data collected and compared to switching between antipsychotics (from haloperidol to clozapine, risperidone, olanzapine, quetiapine, aripiprazole). At baseline: epidemiogical and biological parameters, PANSS, QLindex and, subsequently, with CGI-S scores during every clinical visit of control [T1 → T7]. The overall analysis carried out with EZAnalyze(c) ver.3.0. Results In the clozapine group remission rates were higher than other groups; Interrupted therapy: 27.62% of patients with risperidone, 34.85% with quetiapine. A consistent number of patients (8.04%), who have suspended the ‘first’ therapy with haloperidol, have assumed again the therapy with haloperidol toT7. Outcome was good in 28.4%,intermediate in 50,1% and poor in 21%. CGI-S T7 vs T0 (Severity of illness= p: 0,0066; Global improvement = p: 0,02844; Efficacy index =p: 0,00597) Conclusion Study suggested that most clinically stable outpatients with schizophrenia maintain remission states after being switched to atypical antipsychotics; a T7 (19 years) a consistent number of patients assumed again haloperidol with satisfactory rate of 51.18% then previous pharmacological treatments with a atypical antipsychotics.

Electroconvulsive Therapy and Clozapine in Adolescents With Schizophrenia Spectrum Disorders

To evaluate the safety and effectiveness of the combination of electroconvulsive therapy (ECT) and clozapine compared to ECT with other antipsychotics or benzodiazepines in a sample of adolescents diagnosed with schizophrenia spectrum disorders. Data regarding 28 adolescent subjects aged 13 to 18 with diagnoses of schizophrenia spectrum disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision and treated with ECT were retrospectively collected. Twelve subjects were also treated with clozapine and 16 with other antipsychotics or benzodiazepines during ECT course and follow-up. Electroconvulsive therapy parameters and adverse effects were assessed using a systematic protocol. Positive and Negative Syndrome Scale and Clinical Global Impression scores before ECT and after acute ECT, and rate of rehospitalization during 1-year follow-up were used to assess effectiveness. Response was defined as a 20% decrease in Positive and Negative Syndrome Scale scores. No differences were observed in the mean charge needed to induce seizure and electroencephalographic duration, but there was a slight difference in the current used. The nonclozapine group showed greater restlessness and agitation, although no differences were found in other adverse effects. The percentage of responders was similar: 66.7% in the clozapine group and 68.8% in the nonclozapine group. However, the rate of rehospitalization was lower in the patients treated with clozapine during 1-year follow-up (7.1%) compared to that of the nonclozapine group (58.3%) (P = 0.009). The main findings of this study were that combining ECT with clozapine, compared to ECT with other antipsychotics or benzodiazepines, was safe and that both treatments were equally effective. Charges needed to induce seizure were similar in both groups. Patients treated with clozapine during 1-year follow-up had a lower rate of rehospitalization.