Seizures and myoclonus associated with antidepressant treatment: assessment of potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment with CYP2D6 inhibitors

Abstract

All adverse drug reaction reports labelled seizures or myoclonus during treatment with antidepressants and stored in the Swedish national database for spontaneous reporting of adverse drug reactions were reviewed in order to evaluate possible risk factors. The reporting physicians were contacted and asked for complementary information, and blood samples for determination of the CYP2D6 and CYP2C19 genotypes were obtained from patients available. In total, 25 cases of seizures and 7 cases of myoclonus were studied. The drugs included were maprotiline (n=8), mianserin (n=7), fluvoxamine (n=6), amitriptyline (n=3), clomipramine (n=3), citalopram (n=2), paroxetine (n=2) and lofepramine (n=1). Previously suggested predisposing factors were identified in all but four cases (87%). None of the 11 patients genotyped were found to be poor metabolizers with respect to the enzymes CYP2D6 or CYP2C19. Thus, neither the CYP2D6 nor the CYP2C19 genotype were found to be associated with the occurrence of seizures/myoclonus during treatment with antidepressants. However, 15 patients (47%) were concomitantly treated with drugs with potential inhibitory effects on CYP2D6, such as neuroleptics and dextropropoxyphene, and the patients might thus have been converted from the extensive metabolizer to the poor metabolizer phenotype during this treatment. Concomitant treatment with drugs decreasing the seizure threshold and/or inhibiting the metabolism of antidepressants appeared to be an important risk factor for the occurrence of seizures/myoclonus.

Myoclonus During Prolonged Treatment with Sertraline in an Adolescent Patient

“…A Medline review of the literature revealed an association between myoclonus and antidepressant agents including SSRIs (Spigset et al 1997). …”

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

“…Few studies provide quantitative data on adverse drug reactions. 49 induced seizures was reported in relation to CYP2D6 activity 145 and several studies showed a relationship between extrapyramidal side effects of antipsychotic drugs and CYP2D6 polymorphisms. 96,[146][147][148][149][150][151][152][153][154][155][156] However, compared to the large efforts made to evaluate pharmacokinetic differences due to CYP polymorphisms, few prospective studies on benefit of phenotyping or genotyping for therapeutic outcome have been conducted so far.…”

The CYP2C19 Enzyme Polymorphism

“…While tightly controlled study designs can highlight the influence of genetic variation on drug disposition, they may overstate or miss the true relevance of genetic variation where it may matter most, in the clinical environment. Several studies have attempted to relate CYP2C19 PM phenotype to xenobiotic toxicity [88][89][90][91][92]. However, only one study actually associated CYP2C19 PM phenotype with drug toxicity.…”