Metabolic adverse effects in clozapine-treated patients with schizophrenia

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Arvo building, auditorium F115, address: Lääkärinkatu 1


The field of science of the dissertation is Psychiatry.

The opponent is Professor Jarmo Hietala (University of Turku). Professor Esa Leinonen acts as the custos.

The language of the defence is Finnish. 


Metabolic adverse effects in clozapine-treated patients with schizophrenia : Cytokine and adipokine alterations, neuropeptide Y, and genetic associations

Objective: Patients with schizophrenia are characterized by high prevalence of obesity, smoking, substance use, cardiovascular disease, and suicidality with an approximately twice the standardized mortality ratio. Cardiovascular disease is a major cause of excess deaths in this patient group. Weight gain is a common side effect of many atypical antipsychotics, with metabolic consequences and comorbidity, social stigmatization and nonadherence. Clozapine is an atypical antipsychotic drug, with unique effects on treatment resistant schizophrenia. Clozapine has been consistently associated with weight gain and a high prevalence of metabolic syndrome. The mechanisms behind obesity and metabolic comorbidity in patients with schizophrenia are not fully understood, whether they are associated with medication, common genetic background, or schizophrenia-related defect in satiety regulation. There is a need for biomarkers for antipsychotic-induced weight gain, sufficiently sensitive and specific to account for metabolic syndrome and disturbed food intake behaviors. Both schizophrenia, obesity and metabolic syndrome are all associated with a chronic low-grade inflammatory state with abnormalities in several inflammatory cytokines and adipokines. The results so far from studies on cytokine and adipokine alterations and their associations with obesity or metabolic syndrome and schizophrenia are inconsistent, with substantial heterogeneity between populations and medications. Likewise, in terms of genetic association studies, the study samples have been limited, heterogeneous and have yielded inconclusive results. 

In this study markers of obesity and metabolic comorbidity, inflammatory markers and genetic associations were investigated in a sample of patients with treatment resistant schizophrenia on clozapine treatment. 

Materials and methods: 190 patients with schizophrenia on clozapine treatment completed a questionnaire eliciting, among others, estimated weight and height, trend in weight change (marked increase, slight increase, no change, decrease), weight gain in kilograms during clozapine treatment, and smoking. Information on past medical and psychiatric history and duration of clozapine treatment was collected from patient records. Blood samples were taken for the analysis of serum clozapine concentration, glucose, insulin, HDL-cholesterol, triglycerides, cytokines, and adipokines (IL-6, IL-1Ra, TNF-α, hs-CRP, leptin, adiponectin, resistin, adipsin), and neuropeptide Y, and for the genetic association study of SNPs LEP rs7799039, ADIPOQ rs1501299, HTR2C rs1414334, and NPY and arcuate nucleus NPY neuron receptor genes (21 genes and 215 SNPs). Two historical control samples (n=903, n=502) were available for reference of clinical markers and a sample of blood donors (n=395) for the genotype analysis of LEP, ADIPOQ and HTR2C genes. 

Results: The presence of metabolic risk factors and morbidity was substantial, including overweight/obesity, smoking, hypertriglyceridemia, low HDL-cholesterol, high HOMA-IR, low adiponectin levels, elevated hs-CRP levels and elevated IL-1Ra levels. As expected, gender differences were found in many of the cytokines and adipokines studied. Weight gain during clozapine treatment explained the obesity of the present patients. Women with weight gain had the highest levels of leptin. Weight gain among male patients was associated with low adiponectin levels. Elevated IL-1Ra was a sensitive marker of metabolic comorbidity in this patient population. Among female patients high IL-6 levels were associated with obesity, and with levels of leptin. Adipsin levels were linked to levels of leptin in both genders. Levels of resistin were associated with levels of IL-1Ra, and trend-like with hs-CRP and TNF-α, and with low levels of HDL-cholesterol in male patients. Levels of NPY were also associated with resistin. The levels of resistin were higher among smokers than non-smokers, and correlated with IL-1Ra and hs-CRP among smokers.

Conclusion: There are cytokine and adipokine alterations in patients with treatment resistant schizophrenia on clozapine treatment. Some of these were gender dependent and related to risk of metabolic comorbidity. Levels of leptin, weight gain during clozapine treatment, and inflammatory markers related to metabolic comorbidity (IL-6, IL-1Ra) showed a marked interaction, especially among female patients. In male patients low adiponectin level was a more specific marker of metabolic comorbidity and clozapine-induced weight gain. As a biomarker of systemic inflammation resistin may have a role as a marker of cardiovascular comorbidity, especially among male patients. The results of the present study do not support a major role of genetic polymorphisms LEP rs7799039, ADIPOQ rs1501299 and HTR2C rs1414334 in the regulation of serum leptin and adiponectin levels or weight gain. Serum NPY level does not seem to be a potential biomarker for antipsychotic-induced weight gain. Moreover, in genes encoding arcuate nucleus NPY neuron receptors serum NPY level alterations were not associated with the polymorphisms studied. 
In clinical practice, excess cardiovascular morbidity and mortality associated with schizophrenia are a concern. Further effort should be invested in the prevention and treatment of metabolic abnormalities and smoking cessation among these patients.


The dissertation is published in the publication series of Acta Universitatis Tamperensis; 2239, Tampere University Press, Tampere 2016. ISBN  978-952-03-0293-1, ISSN 1455-1616. The dissertation is also published in the e-series Acta Electronica Universitatis Tamperensis; 1739, Tampere University Press 2016. ISBN  978-952-03-0294-8, ISSN 1456-954X.

Additional information

Jari-Pekka Klemettilä,