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
