Niko Seppälä

Cytokine and adipokine alterations in patients with schizophrenia treated with clozapine.

Metabolic syndrome is associated with both schizophrenia and antipsychotic medication, especially clozapine, with alterations in inflammatory cytokines and adipokines. However, the data in this field is heterogeneous and the sample sizes of the patients are limited. In this study we assessed the serum levels of cytokines/adipokines IL-6, IL-1Ra, hs-CRP and adiponectin, and components of metabolic syndrome in 190 patients with treatment resistant schizophrenia treated with clozapine. Substantial metabolic comorbidity was found in this patient group; overweight/obesity, smoking, hypertriglyceridemia, low HDL-cholesterol, high HOMA-IR, low adiponectin levels, elevated hs-CRP levels and elevated IL-1Ra levels. Elevated IL-1Ra levels are associated with insulin resistance, obesity and hypertriglyceridemia. Low adiponectin levels were associated with hypertriglyceridemia, low HDL cholesterol and high glucose, and in male patients also with obesity and high IL-1Ra levels. After controlling for confounding factors age and smoking, levels of IL-1Ra and hs-CRP associated with obesity, and the levels of IL-6 associated with obesity in female patients. We conclude that there are partly gender dependent cytokine and adipokine alterations in patients with schizophrenia on clozapine treatment associated with metabolic comorbidity. The genetic background of these cytokine alterations needs to be further investigated.

Effect of Anticholinergics in Preventing Acute Deterioration in Patients Undergoing Abrupt Clozapine Withdrawal

AbstractBackground: The most serious adverse effect of clozapine, agranulocytosis, was described for the first time in Finland in 1975. It caused the immediate withdrawal of clozapine from the market and immediate discontinuation of this medication in all patients. It is now known that abrupt withdrawal of clozapine may cause a rapid deterioration in psychotic symptoms. Objective: The aim of this retrospective study was to investigate the effect of abrupt clozapine withdrawal on psychiatric patients, and to examine whether anticholinergic drugs are effective in preventing acute deterioration. Materials and methods: We reviewed the hospital case records from Pitkäniemi Psychiatric Hospital, Tampere, Finland, of the 28 patients with schizophrenia who had been receiving clozapine and from whom it was abruptly withdrawn due to the withdrawal of the drug from the market in the summer of 1975. We assessed the incidence of deterioration and whether or not patients in whom this occurred were receiving anticholinergic drugs. Results: We found a rapid deterioration after clozapine withdrawal in almost half (46.4%; n = 13) of the patients. Patients receiving anticholinergic drugs (such as antiparkinsonians, tricyclic antidepressants and antipsychotics with anticholinergic properties) were significantly less likely to deteriorate than those not receiving these drugs (21.4% vs 71.4%, p = 0.008). The condition of the patients who deteriorated was poor for up to 1 month after discontinuation, but had improved slightly by the end of 1975. Conclusion: Anticholinergic medication should be considered for preventing possible symptom deterioration when clozapine is abruptly discontinued.

CYP1A2 polymorphism -1545C > 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.

Factors associated with subjective side-effects during clozapine treatment

Abstract Objective: 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. Methods: 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. Results: 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. Conclusion: According to the present results, high clozapine concentrations were associated with depression–anxiety symptoms, but the causality remains unknown.

Resistin as an inflammatory marker in patients with schizophrenia treated with clozapine

Abstract Background: Schizophrenia is associated with excess cardiovascular comorbidity and mortality related to lifestyle factors, such as lack of physical activity, poor diet, and smoking. The prevalence of metabolic syndrome is increased among patients with schizophrenia, with the highest rates among patients on clozapine treatment. Smoking, obesity, physical inactivity, airway inflammation and obstruction, and adipose tissue and inflammatory marker activation are related in systemic inflammation. Low-grade inflammation is also associated with schizophrenia. Adipokine resistin is a biomarker involving several acute and chronic inflammatory states. However, the inflammatory role of resistin is so far inconclusive and studies in schizophrenia are scanty. Aims: The aim of the present study was to explore the role of serum resistin as an inflammatory marker in patients with schizophrenia on clozapine treatment. Methods: Associations between serum levels of resistin and some other selected cytokines/adipokines (adiponectin, leptin, adipsin, IL-6, IL-1Ra, TNF-α, hs-CRP) and metabolic markers in 190 patients with schizophrenia on clozapine treatment were studied using a cross-sectional study design. Results: Among male patients especially, smokers had higher levels of resistin than non-smokers, and among smokers resistin levels were associated with IL-1Ra and hs-CRP levels. In the whole patient group levels of resistin associated with levels of IL-1Ra, and among male patients with low HDL-cholesterol. Conclusions: Resistin is a biomarker of systemic inflammation associated with smoking among patients with schizophrenia on clozapine treatment. Resistin might have a role as a marker of cardiovascular comorbidity.

Polymorphism in alpha 2A adrenergic receptor gene is associated with sialorrhea in schizophrenia patients on clozapine treatment

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.

Association study of arcuate nucleus neuropeptide Y neuron receptor gene variation and serum NPY levels in clozapine treated patients with schizophrenia

BACKGROUND Antipsychotic-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 METHODS Associations 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. RESULTS The 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). CONCLUSIONS Serum 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.

Smoking and weight among patients using clozapine

Abstract Background: Both obesity and smoking are common in schizophrenia patients taking clozapine, causing cardiovascular disease and premature deaths. Methods: Two hundred and thirty-seven patients with schizophrenia or related psychoses treated with clozapine completed the Liverpool University Neuroleptic Assessment Scale (LUNSERS) and a questionnaire including current height, weight, changes therein and smoking status. Aims: The aim of this study was to analyze weight and weight change in smoking and non-smoking patients taking clozapine. A possible interaction between obesity and smoking was explored. Results: No association was found between weight change and smoking status during clozapine treatment. There was no significant difference in body mass index (BMI) between non-smokers and smokers. In the analysis of covariance (ANCOVA) with BMI as the dependent variable, the best fitting model comprised age, sex, intensity of sedation, and reported amount of smoking as explanatory variables (ηp2= 0.116; P = 0.029; power = 0.750). None of the explanatory proportions of any single factor was significant. Conclusions: Estimated according to reported weight gain and BMI, no difference was found between smoking and non-smoking clozapine-treated patients. Number of cigarettes smoked explained BMI if age and sex were taken into account. This result is in line with the findings of some general population studies, where heavy smoking has been associated with a greater risk of obesity.

Histaminergic gene polymorphisms associated with sedation in clozapine-treated patients

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.