Pharmacogenetics of antidepressant medication intolerance.
Murphy GM Jr, Kremer C, Rodrigues HE and Schatzberg AF;
Commented by , 21 Nov 2003
Aim of the Study
This study sought to identify genetic markers for antidepressant intolerance in older adults with major depression, and to compare this with the effects of known genetic variation in cytochrome P450.
Background
Some patients experience side effects with antidepressants, others do not. Variation in the cytochrome P450 2D6 (CYP2D6) gene encoding debrisoquine hydroxylase may account for this via a pharmacokinetic mechanism: impaired hepatic metabolism leading to higher plasma concentrations hence more side effects. However, genetically determined differences in (5-HT) receptor proteins may also contribute to the observed variation via a pharmacodynamic mechanism.
Method
The study was an 8-week, double-blind randomised trial comparing mirtazepine and paroxetine conducted at 18 outpatient clinics in the United States. All subjects (paroxetine n = 124, mirtazepine n = 122) were age 65 +, free of major medical problems for 3 months, met DSM-IV criteria for major depression, had Mini-Mental State Examination scores > 25th percentile for their age, and scored 18 + on the 17-item Hamilton Depression Rating Scale.
Other concurrent medications were continued. Patients were treated with paroxetine (increasing to 40 mg per day) or mirtazepine (increasing to 45 mg per day) under a standardised regime; higher doses being used if there was no improvement in depression.
Genomic DNA was extracted from blood samples and analysed for CYP2D6 alleles and polymorphism in the HTR2A gene which codes for postsynaptic 5-HT receptor proteins. Paroxetine and mirtazepine blood concentrations were analysed by accepted chromatographic assays.
The reasons for any treatment discontinuations were carefully documented. The number of subjects discontinuing because of adverse events relative to genotype and treatment, plus the effect of genotype on mood improvement relative to drug, baseline and study centre, were analysed by a number of statistical techniques.
Results
Discontinuations and side effect severity to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype, which codes for a protein in the 5-HT2A receptor.
By contrast, HTR2A 102T/C genotype had no effect on mirtazepine side effects.
CYP2D6 genotype did not predict treatment outcome for either medication. There was no significant difference between the treatment groups in the frequencies of CYP2D6 genotype groups, nor any interaction between concurrent medication and study medication.
Discussion
These findings suggest that pharmacodynamic differences among patients due to variant 5-HT2A receptors are more important than pharmacokinetic variation in cytochrome P450, in determining paroxetine intolerance. The CNS postsynaptic 5-HT2A receptor is implicated in SSRI side effects such as sleep disruption, circadian rhythm disturbance, and sexual dysfunction. The 5-HT2A receptor is also found on smooth muscle cells in the gut and blood vessels.
HTR2A variation may alter receptor numbers, affinity, or signal transduction. Unlike paroxetine, mirtazepine blocks 5-HT2A receptors, preventing interaction with serotonin thus negating any genetic variation.
This important and well-designed study provides a rational (genetic) explanation for the apparently idiosyncratic intolerance to paroxetine experienced by some depressed patients. Whether similar genetic variation applies to the pharmacodynamics of other antidepressants, and whether pharmacogenetic markers can be used in clinical practice to predict antidepressant outcome requires further study.