Debrisoquine hydroxylase genetic polymorphism and neuroleptic induced acute dystonic reaction among psychiatric patients, Muhimbili National Hospital

Abstract

Acute dystonic reactions (ADR) are the earliest and most dramatic extra- pyramidal side effects resulting from neuroleptic therapy due to inhibitory effects on dopaminergic receptor activity in the limbic system. They usually occur within the first few days of starting treatment and are characterised by involuntary tonic and/or clonic contractions of muscle groups, especially those of the head and neck, producing intermittent or sustained abnormal postures. Common motor presentations of ADR are torticollic, trismus, blepharospasm and dystonias of the trunk and limbs. Metabolism is the major determinant of the pharmacological and toxicological effects of administered neuroleptic drugs that is in turn determined by cytochrome P450 (CYP450) status. There is an association between CYP450 genotypes and the clinical responses to neuroleptic drugs (phenotype) including occurrences of extra-pyramidal side effects, which are more pronounced in persons with poor metaboliser (PM) status. To verify whether poor metaboliser (PM) of debrisoquine hydroxylase (CYP2D6) are susceptible to develop ADR in an in-patient sample of 98 persons with mental disorders (64 males and 34 females), allele status for CYP2D6*1, *2, *3, *4, *5 and *17 as well as geno duplication was determined by allele-specific PCR, long-PCR and restriction fragment length polymorphism analysis (RFLP). All the patients were screened and enrolled to the study if they developed ADR within two weeks of admission (N=49) and a sample matched by age, sex, vu

previous neuroleptic drug use and dosage that did not develop AOR in this time frame was enrolled as controls The results revealed a predominantly young population of mean age 28.732:.S0 6.95, a large proportion (n=60) clinically diagnosed to have schizophrenia, while 38 were suffering from bipolar affective disorder. A significantly higher proportion of patients with AOR had PM status (allele variants: CYP206*41*4, *4/*5 and *5/*5) compared to those that did not develop AOR (chi. sq. = 9.5-19.39; p=O.OO). On the other hand a higher proportion of patients that did not develop AOR had extensive metaboliser status (CYP206*11*1 allele variant), compared to patients that developed AOR this variation being marginally significant at a chi. sq of 12.3 (p=O.05). The alleles noted to be most significantly associated with AOR were CYP206*17 and CYP206*5 VIII