Anto Praveen Rajkumar, R (2013) Studies on the Association between Genetic Polymorphisms and Clozapine Drug Response in Treatment Resistant Schizophrenia. Doctoral thesis, The Tamil Nadu Dr. M.G.R. Medical University, Chennai.
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Abstract
Despite clozapine’s superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost as well as variable clinical outcomes mandate a clinical need to predict its treatment response. Cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine. Antagonism of serotonin 5HT3A receptor contributes to the superior clinical efficacy of clozapine. Hence, this research investigated the associations between various clinical variables, four single nucleotide polymorphisms in CYP1A2 gene (rs2069514, rs35694136, rs2069526 and rs762551) as well as two SNP in HTR3A gene (rs1062613 and rs2276302) and treatment responses as well as adverse events of clozapine in patients with TRS. 101 consecutive patients with TRS, on stable doses of clozapine, were recruited into this research. The following clinical assessment instruments were employed: Brief Psychiatric Rating Scale, Abnormal Involuntary Movements Scale, Addenbrooke’s Cognitive Examination- Revised, WHO Disability Assessment Scale-II, Childhood and Recent Traumatic Events Scale, and Premorbid Assessment Scale. Serum clozapine levels were determined by using high performance liquid chromatography. The four CYP1A2 SNPs were genotyped by Polymerase Chain Reaction and restriction fragment length polymorphisms method. The two HTR3A SNPs were genotyped by direct DNA sequencing. Clozapine response was defined by six varying outcome definitions. A case-control design framework was adopted and appropriate multivariate statistics were employed. Past history of catatonia, smoking, hyper-somnolence and cognitive dysfunction were significantly associated with non-response to clozapine. Outcome definitions of non-response to clozapine influenced its association with the clinical predictors. While employing nonparametric multiple robust regression models, oral clozapine dose, high caffeine consumption and Valproate co-medication were significantly associated with serum clozapine levels. A dosing nomogram was developed including these clinical predictors for serum clozapine levels. Results of this research revealed that the four CYP1A2 gene SNPs were not significantly associated with clozapine treatment response, adverse effects, serum clozapine levels or with disability status of the participants. Minor alleles of HTR3A gene SNPs, rs1062613 and rs2276302, were significantly associated with good clinical response to clozapine, after appropriate corrections for multiple testing. However, these pharmacogenetic associations varied depending on the employed outcome definition for response to clozapine. A pharmacogenetic model including both HTR3A gene SNPs could explain only 13.8% of variability observed in the responses to clozapine, while a combined clinical predictors and HTR3A pharmacogenetic association model could explain 38% of variability observed in the responses to clozapine among the patients with TRS. CONCLUSIONS: Clinical variables are useful to predict response to clozapine and to model a dosing nomogram for serum clozapine levels. Smoking is a potentially modifiable risk factor for non-response to clozapine. Importance of caffeine consumption and Valproate co-medication should be considered during clozapine dose adjustments to enhance its therapeutic response and safety profile. As the four CYP1A2 gene single nucleotide polymorphisms do not help to predict the clinical response to clozapine, routine screening for them prior to starting clozapine is currently unwarranted. Combined clinical and pharmacogenetic models could predict responses to clozapine better than HTR3A pharmacogenetic associations alone. The results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions. This research indicates that future pharmacogenetic studies should evaluate associated clinical variables. It highlights the need for consensus criteria to define treatment outcomes in pharmacogenetic studies of schizophrenia. Schizophrenia is not a single disease. It is a heterogeneous group of clinical disorders. The inherent heterogeneity within the clinical category of treatment-resistant schizophrenia obscures the search for the clinical and pharmacogenetic predictors for its response to clozapine. Syndrome sub-categorization employing biological variables is desired to achieve the etiological homogeneity of schizophrenia (300). Appropriate biological markers, defining the response to clozapine, have to be identified for developing better prediction models with clinical and pharmacogenetic predictors. Until we identify such biological markers, we need reliable consensus research criteria, which will be analogous to the prevailing diagnostic criteria, to define treatment responses for pharmacogenetic studies of schizophrenia. There should be a consensus on which domains of schizophrenia should be assessed and on which assessment instruments should be employed to assess those domains. After developing such consensus criteria, all pharmacogenetic studies of schizophrenia should employ them a priori to define treatment outcomes. As explanatory pluralism is the need of the hour in psychiatry (297), it is high time to reduce the wide gulf between the clinical and pharmacogenetic research on this topic. Combining clinical and pharmacogenetic predictors may identify many patients, who are more likely to benefit with clozapine, and may prevent the unnecessary exposure of many potential non-responders to serious adverse effects. Future longitudinal studies, investigating both clinical and pharmacogenetic factors together with consensus outcome definitions, are desired to predict response to clozapine among patients with treatment-resistant schizophrenia. Ethnic differences in the serum levels and the clinical responses of clozapine are known to exist among the Asian patients with schizophrenia (67). However, systematic searches of electronic databases have not yielded any Indian studies examining the pharmacogenetic associations of clozapine. This research has provided new data on the CYP1A2 as well as 5HT3A allele frequencies, clinical as well as pharmacogenetic predictors of responses to clozapine and on the clinical proxy measures of serum clozapine levels among Indian patients with treatment-resistant schizophrenia. These data may contribute towards improving the management of patients with treatment-resistant schizophrenia in India.
| Item Type: | Thesis (Doctoral) |
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| Uncontrolled Keywords: | Association, Genetic Polymorphisms, Clozapine, Drug Response, Treatment, Resistant, Schizophrenia. |
| Subjects: | Respiratory Medicine > Psychiatry > Respiratory Medicine > Psychiatry |
| Depositing User: | Subramani R |
| Date Deposited: | 17 Jun 2017 05:14 |
| Last Modified: | 22 Sep 2022 09:48 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/32 |
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