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Clozapine is the gold standard for treatment-resistant schizophrenia; however, its superior efficacy is accompanied by potentially serious adverse events (neutropenia, seizures, constipations, pneumonia), many of which are also concentration-dependent. As such, clozapine dose titration should be guided by therapeutic drug monitoring (TDM). However, access to TDM is often limited. The present study describes a new deep neural network that can predict the concentrations, toxicity and therapeutic dose range for clozapine and norclozapine. The model was trained on basic clinical data (biological sex, age, clozapine daily dose, BMI, CRP and number of CYP 1A2 and 3A4 substrates, inhibitors and inducers) from 69 patients treated with different clozapine doses. Our findings provide the training efficacy data for the model, as well as an analysis of clozapine and norclozapine blood concentrations in a test group of three additional patients, to demonstrate its practical capabilities. The model is licensed on a free and permissive 2-Clause BSD license and is available to all clinicians; it can be accessed as a web application, available at https://csk.umed.pl/clotop., Competing Interests: Declaration of competing interest Nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The aim of this study is to analyze whether clozapine serum concentration may affect fasting serum levels of several appetite regulating peptides: CART, PYY(1-36), NPY, AgRP, des-acylated ghrelin, leptin and obestatin. Serum concentration of clozapine and fasting serum levels of des-acylated ghrelin, neuropeptide Y (NPY), agouti-related protein (AgRP), peptide YY (PYY(1-36)), cocaine- and amphetamine-regulated transcript (CART), leptin and obestatin were measured in 30 subjects with schizophrenia on clozapine monotherapy. Leptin concentration was negatively correlated with clozapine dose (r = -0.53, p = 0.002), while NPY concentration was negatively correlated with clozapine concentration (r = -0.55, p = 0.01). Correlations with other peptides were not significant. We cannot conclude that serum concentration of clozapine is directly associated with increased or decreased level of appetite-regulating peptides., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Metabolic syndrome (obesity, glucose intolerance, insulin resistance and dyslipidaemia) is a well-known adverse effect of most antipsychotics. It is particularly common in patients treated with olanzapine and clozapine. Currently, the mechanisms underlying its development are not completely understood., Case Report: We present a case of improved body composition (reduced amount of total body fat and visceral adipose tissue), anthropometric measurements (body weight, waist, abdominal and hip circumferences) and lipid profile in a 31-year-old man with schizophrenia following discontinuation of clozapine. During a combined treatment with clozapine, flupentixol and ziprasidone, a routine laboratory test revealed a severe dyslipidaemia (triglycerides > 1800 mg/dL; > 20.3 mmol/L), despite previous lipid-lowering therapy. This abnormality completely recovered after clozapine has been discontinued., Conclusions: Clozapine may cause severe, but reversible metabolic abnormalities, including obesity and hypertriglyceridaemia. Atypical antipsychotic-related lipid abnormalities may have a very rapid onset, occur in relatively young patients, with severe lipid derangements and have potential serious complications. This case confirms how important is to monitor metabolic parameters in patients taking antipsychotics. Discontinuation or switching to another antipsychotic medication may improve components of the metabolic syndrome.

Background: We tested the hypothesis that uric acid levels are higher in subjects with schizophrenia treated with clozapine than in healthy control and they correlate with anthropometric measurements, laboratory tests and results of bioimpedance analysis of body composition., Methods: Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed., Results: There was no difference of fasting uric acid concentrations between clozapine and control groups (4.5 ± 1.4 vs. 4.3 ± 1.3 mg/dl, P = 0.87). Regarding the whole group, uric acid levels were significantly higher in men (5.2 ± 1.2 vs. 3.6 ± 0.9, P < 0.001). Uric acid levels correlated with weight (R = 0.58, P = 0.003), body mass index (BMI; R = 0.49, P = 0.01), abdominal circumference (R = 0.45, P = 0.03), waist circumference (R = 0.47, P = 0.02), waist-to-hip ratio (R = 0.42, P = 0.04), insulin (R = 0.50, P = 0.01), homoeostasis model assessment of insulin resistance 2 (HOMA2-IR; R = 0.49, P = 0.01), basal metabolic rate (R = 0.56, P = 0.004), lean body mass (R = 0.55, P = 0.005) and body water (R = 0.55, P = 0.005). There were no significant differences of uric acid levels for smoking status, impaired fasting glucose, abdominal obesity, obesity/overweight and dyslipidemia. Uric acid levels did not correlate with age, duration of clozapine treatment, clozapine dose, leg circumference, systolic blood pressure, diastolic blood pressure, total body fat, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), homocysteine, corrected calcium, glucose and homoeostasis model assessment of insulin resistance 1 (HOMA1-IR)., Conclusions: We did not find significant differences in blood uric acid levels between subjects with schizophrenia and controls. Association with weight, BMI, abdominal and waist circumferences, insulin levels and insulin resistance may support uric acid role as an important cardiovascular risk factor. Association with lean weight may explain why men have higher levels of uric acid than women.

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.

Objective: Neuropeptide Y (NPY) is one of the hypothalamic hormones that works by increasing appetite and decreasing metabolism, leading to weight gain. We checked whether NPY level in subjects with schizophrenia on clozapine is higher compared with healthy controls., Methods: We determined the fasting NPY levels of 24 subjects with schizophrenia on clozapine monotherapy and 24 age- and sex-matched healthy controls., Results: There was no difference for NPY between the clozapine group and the control group (mean [SD], 323.33 [138.50] vs 295.83 [25.28] pg/mL, P = 0.25). Neuropeptide Y was higher in women in the clozapine group (376.00 [162.15] vs 275.45 [96.99] pg/mL, P = 0.048) but not in the control group (P = 0.31) or in the whole study group (P = 0.20). We found no correlations between NPY and age, weight, body mass index, fat mass index, body circumferences, blood pressure, waist-to-hip ratio, levels of cholesterol, high-density lipoproteins, low-density lipoproteins, triglycerides, uric acid, calcium, homocysteine, glucose, insulin, insulin resistance, treatment duration, dose of clozapine, body composition, or basal metabolic rate., Conclusions: We cannot conclude that treatment with clozapine is associated with increased level of NPY. We did not find previously described differences in NPY for obesity or associations between NPY and metabolic parameters.

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±169.90 pg/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±237.17 pg/mL, n=12 and 12, respectively) and in the whole study group (377.73±401.09 vs. 88.58±172.35 pg/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±182.96 pg/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., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aim: Desacyl ghrelin is a hormone that might be a functional inhibitor of ghrelin, a potent hunger-stimulating peptide., Methods: 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., Results: 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., Conclusion: 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., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

Objective: We tested the hypothesis that fasting blood glucose and insulin levels are higher in schizophrenic subjects on clozapine monotherapy compared with healthy controls and they correlate with anthropometric measurements, laboratory tests and body composition., Methods: Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed., Results: Patients taking clozapine had higher fasting levels of glucose (103.5±31.6 vs. 87.8±11.7mg/dL, z=-2.03, p=0.04), there was no difference for insulin concentrations and markers of insulin resistance. In the clozapine group glucose levels correlated with clozapine dose (R=-0.43, p=0.03), while insulin levels correlated with weight (R=0.66, p<0.001), body mass index (R=0.54, p=0.007), abdominal (R=0.53, p=0.007) and waist (R=0.43, p=0.04) circumference, total body fat (R=0.51, p=0.01), and uric acid levels (R=0.50, p=0.01). In the clozapine group insulin levels were lower in subjects with body mass index <25kg/m(2) (7.0±3.3 vs. 13.4±8.8μU/mL, p=0.04) and in subjects without abdominal obesity (6.3±2.4 vs. 13.3±8.6μU/mL, p=0.03)., Conclusions: We found higher blood glucose levels in subjects taking clozapine and no differences in blood insulin levels between subjects with schizophrenia and controls. Associations between blood insulin levels and abdominal/waist circumferences support the role of abdominal obesity as an important risk factor of insulin resistance., (Copyright © 2014 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

We tested the hypothesis that homocysteine levels are higher in blood of schizophrenic subjects on clozapine monotherapy than in healthy controls and they correlate with anthropometric measurements, laboratory tests and results of bioimpedance analysis of body composition. Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed. Regarding the whole group, homocysteine levels were significantly higher in men (17.0 ± 3.4 vs. 12.1 ± 4.0 μmol/L, p = 0.009). Homocysteine levels correlated with waist circumference (R = 0.58, p = 0.003), waist-to-hip ratio (R = 0.57, p = 0.003), basal metabolic rate (R = 0.48, p = 0.01), lean body mass [kg] (R = 0.53, p = 0.008), body water [L] (R = 0.53, p = 0.008) and triglycerides (R = 0.57, p = 0.003). There were no significant differences of homocysteine levels for impaired fasting glucose, abdominal obesity, obesity/overweight, and dyslipidemia. Homocysteine levels did not correlate with age, treatment duration, clozapine dose, weight, body mass index, abdominal circumference, blood pressure, total body fat, cholesterol, high density lipoproteins, low density lipoproteins, uric acid, calcium, glucose, insulin, homoeostasis model assessment of insulin resistance 1, and homoeostasis model assessment of insulin resistance 2. We did not find significant differences in blood homocysteine levels between subjects with schizophrenia and controls. Association with waist circumference may support homocysteine role as an important cardiovascular risk factor. Association with lean weight may explain why men have higher levels of homocysteine than women.

More than 20 atypical antipsychotics are authorized worldwide. Ten of these are authorized and available in Poland. Asenapine, registered in the treatment of manic episodes in the course of bipolar disorder, is the last atypical authorized in Poland. Moreover, several substances are being studied (in preclinical or clinical studies). Thirteen atypicals authorized outside Poland are discussed in the paper (to a degree according to their clinical significance): iloperidone, paliperidone, lurasidone, blonanserin, zotepine, perospirone, clocapramine, clotiapine, mosapramine, carpipramine, nemonapride, sultopride, remoxipride, as well as four substances being currently studied: bifeprunox, pimavanserin, vabicaserin and cariprazine. Only one, the oldest substance of this group - clozapine - maintains its special position among a vast array of atypical antipsychotic medications. Although it was discovered more than 40 years ago, we still have no other drug of comparable efficacy. Moreover, more data indicate that the traditional division of antipsychotics into first and second generation is losing its raison d'être - mainly due to lack of data supporting clinical superiority of the latter. However, increasing awareness of psychiatrists of the harmful effects of new antipsychotic medications (particularly in terms of metabolic complications) motivates researchers to search for safer medications. As a result, new substances combining the advantageous profile of clinical activities with a good or at least acceptable safety profile are being developed. Nevertheless, there is still a vast unmet need for more effective (particularly in treatmentrefractory cases) and better tolerated antipsychotic medications. [ABSTRACT FROM AUTHOR]