Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.3 These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.
In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.
CYP2D6: Many variants
CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.4
Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).10
I the late 1970s, 2 groups of researchers noted unexpected serious adverse reactions in studies of debrisoquine,5 a sympatholytic antihypertensive drug, and sparteine,6 an antiarrhythmic and oxytocic alkaloid drug. They observed that 5% to 10% of patients were unable to efficiently metabolize debrisoquine and sparteine and went on to define a genetic polymorphism responsible for these metabolic differences. They also observed that metabolism of antidepressants, antipsychotics, and beta blockers also was defective in these patients.
Further investigations established that the enzyme responsible for debrisoquine metabolism was a cytochrome P450 (CYP) enzyme that is now termed CYP2D6.7 In addition to biochemical evidence, the colocalization of sparteine oxidation deficiency and of the CYP2D6 locus at chromosome 22q13.1 confirmed CYP2D6 as the target gene of the debrisoquine/sparteine polymorphism.8,9
CYP450 enzymes involved in biotransformation of SSRIs
|SSRI||Enzymes involved in biotransformation|
|Citalopram||CYP2C19, CYP2D6, CYP3A4|
|Escitalopram||CYP2C19, CYP2D6, CYP3A4|
|Fluoxetine||CYP2D6, CYP2C9, CYP2C19, CYP3A4|
|Sertraline||CYP2C9, CYP2C19, CYP2D6, CYP3A4|
|CYP: cytochrome P450; SSRI: selective serotonin reuptake inhibitors |
Source: Reference 10
Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.3 These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.11 PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.
Suicide and CYP2D6 status
The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.12 Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte12 found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.12 Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.16
A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.16 The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.17 The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.