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Background: Alcohol use disorder (AUD) is a significant co-morbidity in patients with schizophrenia. Clozapine offers some benefits in treating patients with refractory schizophrenia and AUD, but co-medicating with disulfiram is also common. Procedures: We report two cases where co-medicating with disulfiram led to a significant increase in clozapine serum levels. Findings: Clozapine serum levels decreased to one-third in Patient 1 when disulfiram was discontinued and started to increase again when disulfiram was reintroduced. Patient 2 developed toxic serum levels of clozapine during disulfiram treatment combined with heavy coffee drinking and symptoms reminiscent of neuroleptic malignant syndrome. Conclusions: Clozapine and disulfiram are both metabolized by cytochrome P450 CYP1A2 and clinically relevant interaction through this shared pathway is possible.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Purpose/background A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. Methods/procedures Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. Findings/results The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). Implications/conclusions Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

Background During clozapine treatment, diarrhea is a rare but clinically relevant adverse effect. Cases of microscopic colitis and eosinophilic colitis have been previously reported. Procedures We present 4 patients who developed severe diarrhea in early weeks of clozapine therapy. Findings Two patients had significant peripheral eosinophilia 1 week after diarrhea symptoms. One of these patients also had Charcot-Leyden crystals in stool afterward, confirming the presence of eosinophils in the gut lumen. One of our patients had a confirmed microscopic colitis and later also neutropenia, which required treatment. Conclusions Charcot-Leyden crystals in stool may be associated with concurrent diarrhea and eosinophilia during clozapine treatment, which is a previously unreported finding. Occurrence of blood dyscrasias with diarrhea symptoms during clozapine treatment needs further investigation to understand the possible shared mechanisms.

Metabolic syndrome and related cardiovascular risk factors are well-known comorbidities among patients with schizophrenia. Biomarkers of these antipsychotic-associated metabolic adverse effects and antipsychotic-induced weight gain are needed. Glucagon-like peptide-1 (GLP-1) is involved in insulin secretion, regulation of satiety, inhibition of food intake, and inhibition of gastric emptying. GLP-1 also induces reduction in body weight. Visfatin/ NAMPT/ PBEF is an adipocytokine secreted by several cells and tissues. Increased plasma visfatin levels have been associated with overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases, low grade inflammation, and proinflammatory markers. Associations between antipsychotic-induced weight gain and serum visfatin and GLP-1 levels have been little studied in patients with schizophrenia. The aim of the present study was to test the possible role of serum GLP-1 and visfatin level alterations as markers of weight gain in association with metabolic and inflammatory markers in 190 patients (109 male, 81 female) with schizophrenia on clozapine treatment. High serum levels of GLP-1 correlated significantly with higher levels of visfatin, leptin, insulin, HOMA-IR, higher BMI, and weight change among men. Associations between serum visfatin levels and BMI or weight change were not found in the present patients. Serum GLP-1 level seems to be a marker of metabolic risk factors among men with schizophrenia on clozapine treatment. Female patients may be more sensitive to suppressive effects of clozapine on GLP-1 secretion. Patients on clozapine would benefit from GLP-1 agonists as preventive treatment. publishedVersion

BACKGROUND Clozapine impairs gastrointestinal motility owing to its anticholinergic and antiserotonergic properties. This commonly leads to constipation and potentially to more severe complications such as bowel obstruction and ischemia. The aim of this study was to determine whether genetic variations in the genes encoding muscarinic and serotonergic receptors (CHRM2, CHRM3, HTR2, HTR3, HTR4, and HTR7) explain the variations in incidence of constipation and anticholinergic symptoms during clozapine treatment. Genes associated with opiate-induced constipation were also included in this analysis (TPH1, OPRM1, ABCB1, and COMT). PROCEDURES Blood samples from 176 clozapine-treated, Finnish, white patients with schizophrenia were genotyped. Constipation and anticholinergic symptoms were rated using the Liverpool University Neuroleptic Side Effect Rating Scale self-report questionnaire. In total, 192 single-nucleotide polymorphisms (SNPs) were detected and grouped to formulate a weighted genetic-risk score (GRS). RESULTS No significant associations between individual SNPs or GRSs and constipation or laxative use were observed. A GRS of 19 SNPs in CHRM2, CHRM3, HTR3C, HTR7, ABCB1, OPRM1, and TPH1 was associated with anticholinergic symptoms in a generalized linear univariate model, with body mass index, clozapine monotherapy, and GRS as explaining variables (permuted P = 0.014). Generalized linear univariate model analysis performed on the opiate-induced constipation-associated SNPs and a single CHRM3 SNP revealed an association between anticholinergic symptoms and a score of 8 SNPs (adjusted P = 0.038, permuted P = 0.002). CONCLUSIONS Two GRSs are able to predict the risk of anticholinergic symptoms in patients receiving clozapine and possibly an increased risk of gastrointestinal hypomotility.

Tausta ja tavoitteet. Klotsapiinia pidetään tällä hetkellä tehokkaimpana antipsykoottisena lääkkeenä. Haittavaikutukset rajoittavat kuitenkin sen käyttöä. Sedaatio on yleisin haittavaikutus ja syy klotsapiinihoidon keskeyttämiselle. Klotsapiinin aiheuttama syljenerityksen lisääntyminen on toiseksi yleisin kiusallinen haittavaikutus, jota voi ilmetä etenkin öisin. Ummetus ja suolen toiminnan hitaus ovat myös yleisiä, ja nämä voivat johtaa pahimmillaan vaikeisiin komplikaatioihin kuten suolitukokseen. Annosvakioiduissa klotsapiinin ja norklotsapiinin seerumin pitoisuuksissa on vaihtelua potilaiden välillä johtuen geneettisistä ja ympäristövaikutteisista syistä. Korkeammat klotsapiinipitoisuudet ovat kaiken kaikkiaan yhteydessä haittaoireiden lisääntymiseen ja kouristusriskiin. Farmakogeneettisen tiedon avulla voidaan mahdollisesti ennustaa tulevaisuudessa lääkehoidon haittavaikutuksia ja tämä tieto voi myös auttaa haittavaikutusten mekanismien tunnistamisessa. Tämän tutkimuksen tavoitteena oli tutkia, ovatko 1) syljenerityksen lisääntyminen, 2) sedaatio, 3) ummetus ja muut antikolinergiset oireet ja 4) klotsapiini- ja norklotsapiinipitoisuudet, pitoisuusannossuhde tai klotsapiiniannos yhteydessä yhden nukleotidin polymorfismeihin (single nucleotide polymorphism, SNP) geeneissä, jotka liittyvät haittavaikutusten farmakologisiin mekanismeihin. Aineisto ja menetelmät. Yhteensä 237 suomalaista skitsofreniaa sairastavaa potilasta, joilla oli käytössä klotsapiinilääkitys, osallistui tutkimukseen. Potilaat täyttivät arviointiasteikon haittaoireiden voimakkuuksien arvioimiseksi (Liverpool University Neuroleptic Side Effect Rating Scale, LUNSERS). Verinäytteistä määritettiin klotsapiini- ja norklotsapiinipitoisuudet sekä potilaiden genotyypit. SNP:t analysoitiin kolmella periytyvyysmallilla (additiivinen, resessiivinen ja dominantti) erikseen ja ryhmissä muodostaen painotettuja geneettisiä riskipisteytyksiä (weighted genetic risk score, GRS). GRS:ien nollajakauman arvioimiseksi ja GRS-tulosten validoimiseksi käytettiin permutaatiotestausta. Tulokset. Adrenoseptori alfa-2a -geenin (ADR2A) rs1800544 oli yhteydessä lisääntyneeseen syljeneritykseen. Kahdeksan SNP:ia histamiini-N-metyylitransferaasigeenissä (HNMT), jotka olivat voimakkaassa kytkentäepätasapainossa keskenään (LD, r2=1), olivat yhteydessä sedaatioon. Antikolinergisten oireiden ja kolinergisen muskariinisen M3 -geenin (CHRM3) rs685548:n välillä ja kahden GRS:n välillä löytyi assosiaatiot. Kahdessa GRS:ssä oli SNP:ejä seuraavista geeneistä: serotoniinireseptori 5-HT4 ja 5-HT7 (HTR4, HTR7), tryptofaanihydroksylaasi 1 (TPH1), CHRM2 ja CHRM3, ATP binding cassette subfamily B member 1 (ABCB1) ja opioidireseptori μ1 (OPRM1). Assosiaatioita klotsapiinin farmakokineetisen vaihtelun tai klotsapiiniannoksen ja tutkittujen SNP:ien sytokromi P450 geeneistä, ABCB1-geenistä ja ATP binding cassette subfamily G member 2 (ABCG2) -geenistä välillä ei löytynyt. 4 SNP:n GRS oli trenditasolla yhteydessä sedaation määrän vaihteluun ja havaittiin myös trendi 5 SNP:n GRS:n yhteydestä siihen, oliko potilaalla käytössä matalampi (100-300mg) vai korkeampi (350-800mg) annos klotsapiinia, mikä voi liittyä vaihteluun hoitovasteen saavuttamisessa. Johtopäätökset. Tutkimuksessa löydettiin assosiaatioita klotsapiinin aiheuttaman syljenerityksen lisääntymisen, sedaation ja antikolinergisten oireiden ja tutkittujen geneettisten polymorfismien välillä. Löydettyjä markkereita ei voida suoraan soveltaa työkaluina kliinisessä työssä, mutta yhdistettynä mahdollisiin tuleviin löydöksiin näitä työkaluja on mahdollista kehittää. Farmakogenetiikalla ja farmakogenomiikalla tulee olemaan tulevaisuudessa tärkeä rooli lääketurvallisuuden ja hoitomyöntyvyyden edistämisessä estäen mahdollisia vakavia komplikaatioita. Background and aims. Clozapine is currently regarded as the most efficient antipsychotic drug for patients with schizophrenia, but its adverse effects limit its use. Sedation is the most common adverse effect and leading reason for discontinuing clozapine. Clozapine-induced sialorrhea (CIS) is the second most common adverse effect, which may be bothersome, especially at night-time. Constipation and gastrointestinal hypomotility are also common, and may lead to severe, even life-threatening complications such as ileus. The dose-standardized concentrations of clozapine and norclozapine vary between patients due to environmental and genetic reasons. Higher concentrations are associated with a higher burden of adverse effects and especially the risk of seizures. With the aid of pharmacogenetic information adverse effects could be predicted in the future. Pharmacogenetic findings could possibly also lead to better understanding of the mechanisms behind the adverse effects. The aims of this study were to study if 1) sialorrhea, 2) sedation, 3) constipation and other anticholinergic symptoms and 4) clozapine and norclozapine concentrations, concentration/dose-ratio or clozapine dose are associated with single nucleotide polymorphisms (SNPs) in genes related to the pharmacological mechanisms of the adverse effect. Material and methods. A total of 237 Finnish clozapine-treated patients with schizophrenia participated in the study. Patients completed the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). Blood samples were taken, from which clozapine and norclozapine concentrations were analysed and patients genotyped. SNPs were analysed in three heritability models (additive, recessive and dominant) separately and in groups forming weighted genetic risk scores (GRSs). Permutation tests were performed for estimating the null distribution of the GRSs and for validating the GRS results. Results. Adrenoceptor alpha-2a gene (ADRA2A) rs1800544 was associated with CIS. Eight SNPs in high linkage disequilibrium (LD, r2 = 1) in the histamine N-methyltransferase (HNMT) gene were associated with sedation. Anticholinergic symptoms were associated with cholinergic muscarinic receptor 3 gene (CHRM3) rs685548 and two GRSs with SNPs from 5-hydroxytryptamine (serotonin) receptor 5-HT4 and 5-HT7 genes (HTR4, HTR7), tryptophan hydroxylase 1 gene (TPH1), cholinergic muscarinic receptor M2 and M3 genes (CHRM2 and CHRM3, ATP binding cassette subfamily B member 1 gene (ABCB1) and opioid receptor μ1 gene (OPRM1). No associations were found between studied SNPs from cytochrome P450 enzyme genes, ABCB1 gene and ATP binding cassette subfamily G member 2 gene (ABCG2) and variations in clozapine pharmacokinetics or clozapine dose. A trend-level association between a GRS of 4 SNPs and the sedation factor score (p=0.066) was observed. A GRS of 5 SNPs also predicted on a trend-level whether the patient received a lower (100-300mg) or higher (350-800mg) dose of clozapine (p=0.074). This might be related to variation in treatment response. Conclusions. Associations were found between CIS, sedation and anticholinergic symptoms and the genetic polymorphisms studied. The findings in this study are not directly applicable into tools for clinical use, but in combination with other findings in the future could aid in the development of such tools. Pharmacogenetics and pharmacogenomics have an important role in promoting drug safety and better adherence to drug therapy, possibly preventing severe complications.

Clozapine is associated with subjectively unpleasant or clinically serious side-effects, which may affect treatment adherence. The aims of the study were to explore the association of clozapine+ norclozapine serum concentration and other factors with subjective side-effects in schizophrenia patients.In this cross-sectional study, 237 patients with a diagnosis of schizophrenia, schizo-affective or other non-organic psychoses completed the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), a self-report scale measuring side-effects of antipsychotics and a clinical questionnaire. Clozapine+ norclozapine serum concentration of 190 patients was measured. Of the patients 80 (33.7%) were on antipsychotic combination therapy.Higher clozapine+ norclozapine concentrations were associated with the depression-anxiety factor of LUNSERS and antipsychotic combination treatments were associated with sympatichotonia-tension factor. Younger patients reported sedation more often than older patients.According to the present results, high clozapine concentrations were associated with depression-anxiety symptoms, but the causality remains unknown.

Objective Clozapine-induced sialorrhea (CIS) is a common, inconvenient and socially stigmatizing adverse effect. The pathophysiology of CIS may be related to the effect of clozapine on the muscarinic and adrenergic receptors as well as the disruption of the circadian rhythms. The aim of this study was to find out if polymorphisms in muscarinic M1 and M3 receptor genes (CHRM1 and CHRM3), adrenoceptor alpha 2A gene (ADRA2A) or clock circadian regulator gene (CLOCK) are associated with CIS. Methods Two hundred and thirty-seven clozapine-treated Finnish schizophrenia patients were genotyped for CHRM1, CHRM3, CLOCK and ADRA2A polymorphisms, and their salivary dysfunction was assessed with two questions. Twenty-six of these patients had previously been on medication to treat CIS. Comparisons of the genotypes between patients with excessive versus non-excessive salivation were analysed. Genotype distributions between patients and control group and haplotypes were also studied. Results CHRM1, CHRM3 and CLOCK polymorphisms and haplotypes were not associated with CIS. ADRA2A (rs1800544) genotype was associated with CIS (p = 0.029). In patients with CIS, CC genotype (n = 103) was more common than in G-allele carriers (n = 79) (p = 0.013, OR 2.13, 95% CI: 1.17–3.88). No differences were found in the distributions of genotypes between patients and controls. Conclusions ADRA2A genotype was associated with CIS. Copyright © 2014 John Wiley & Sons, Ltd.

Aim: To investigate INSIG2's association with obesity, weight change and serum lipid profile during clozapine treatment. Materials & methods: Subjects with schizophrenia (n = 190) were genotyped, identifying seven SNPs. Genetic risk scores (GRSs) were calculated to adiponectin, high-density lipoprotein cholesterol, triglycerides and weight gain. Results: In the model for weight gain, SNPs rs12151787, rs17047733 and rs10490626 were selected. Explanatory variables were BMI (p = 5.05 × 10-5), age (p = 0.003) and GRS (p = 2.81 × 10-5, p = 0.0002 after permutation). No GRS resulted for adiponectin or high-density lipoprotein cholesterol. Rs2161829 and rs10490620 were selected for triglycerides; this GRS was insignificant after permutation. Conclusion: INSIG2 plays a role in weight gain and obesity during clozapine treatment.

Sedation is a common adverse effect of clozapine treatment, which may be partly related to clozapine binding to histamine receptors in the central nervous system. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the histaminergic system are associated with sedation in clozapine-treated patients. The study population comprised 237 clozapine-treated, Finnish, Caucasian patients that were diagnosed with schizophrenia and 176 were genotyped using Illumina HumanCoreExome-12 BeadChip. Sedation levels were assessed using self-rating questions from the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). The relationships between 55 different SNPs in the histaminergic system and adverse sedation effects were examined. SNPs were analyzed separately, and in groups, to formulate a genetic risk score (GRS). A permutation test was performed to avoid type I errors. Eight linked SNPs (r2 = 1) in the HNMT gene were also associated with sedation according to the GLM, adjusted for age, gender and BMI (false-discovery-rate-adjusted p = 0.013). An association on a trend level between a GRS of four different SNPs (recessive histamine N-methyltransferase HNMT rs2737385, additive histamine receptor H1 rs1552498, dominant HRH1 rs17034063 and recessive amine oxidase, copper containing 1 AOC1 rs6977381) and sedation was found (permuted p-value = 0.066) in a generalized linear model (GLM) incorporating age, gender and body mass index (BMI; adjusted R2 = 0.22). Polymorphisms in genes encoding histamine receptors or enzymes related to histamine metabolism may explain individual variation in sedative effects experienced during clozapine treatment.

BackgroundAntipsychotic-induced weight gain (AIWG) leads to metabolic consequences and comorbidity, social stigmatization and nonadherence in patients with schizophrenia. Neuropeptide Y (NPY) has an important role in appetite and body weight regulation. Associations between AIWG and serum NPY levels, and genetic polymorphisms (SNPs) associated with its serum levels have been little studied in these patients.Subjects and methodsAssociations between serum NPY concentration and other metabolic and inflammatory markers, and 215 SNPs in 21 genes (NPY gene, NPY receptor genes and genes encoding arcuate nucleus NPY neuron receptors) were studied in 180 patients with schizophrenia on clozapine treatment.ResultsThe serum levels of NPY correlated with levels of resistin (r = 0.31, P < 0.001) and age (r = 0.22, P = 0.003). In the general linear univariate model the best-fitting model with explanatory factors age, serum resistin level, serum insulin level, BMI and gender explained 18.0% (P < 0.001) of the variance of serum NPY. Genetic risk score (GRSNPY) analysis found twelve significant (P < 0.05) serum NPY concentration related SNPs among α7 nicotinic acetylcholine receptor gene CHRNA7, insulin receptor gene INSR, leptin receptor gene LEPR, glucocorticoid receptor (GR) gene NR3C1, and NPY gene. However, after permutation test of gene score the predictive value of GRSNPY remained non-significant (P = 0.078).ConclusionsSerum NPY level does not seem to be a feasible biomarker of AIWG. Serum NPY level alterations are not significantly associated with the candidate gene polymorphisms studied.

Clozapine-induced sialorrhea (CIS) is a common, inconvenient and socially stigmatizing adverse effect. The pathophysiology of CIS may be related to the effect of clozapine on the muscarinic and adrenergic receptors as well as the disruption of the circadian rhythms. The aim of this study was to find out if polymorphisms in muscarinic M1 and M3 receptor genes (CHRM1 and CHRM3), adrenoceptor alpha 2A gene (ADRA2A) or clock circadian regulator gene (CLOCK) are associated with CIS.Two hundred and thirty-seven clozapine-treated Finnish schizophrenia patients were genotyped for CHRM1, CHRM3, CLOCK and ADRA2A polymorphisms, and their salivary dysfunction was assessed with two questions. Twenty-six of these patients had previously been on medication to treat CIS. Comparisons of the genotypes between patients with excessive versus non-excessive salivation were analysed. Genotype distributions between patients and control group and haplotypes were also studied.CHRM1, CHRM3 and CLOCK polymorphisms and haplotypes were not associated with CIS. ADRA2A (rs1800544) genotype was associated with CIS (p = 0.029). In patients with CIS, CC genotype (n = 103) was more common than in G-allele carriers (n = 79) (p = 0.013, OR 2.13, 95% CI: 1.17-3.88). No differences were found in the distributions of genotypes between patients and controls.ADRA2A genotype was associated with CIS.