Psychiatry and Addiction Medicine
LEARNING OBJECTIVES
It is now possible to use genetic testing to minimize adverse responses to psychiatric medications and to increase the probability of identifying medications that will be more likely to provide a therapeutic response for an individual patient.1 It has been known for many years that variations in drug-metabolizing enzyme genes (DME genes), such as the cytochrome P450 2D6 gene (CYP2D6), are associated with differential pharmacokinetic profiles for psychotropic medications.2 While individual clinical laboratories began testing for drug-metabolizing genes before 2004, the FDA approval of the AmpliChip developed by Roche Diagnostics was a landmark event that facilitated the utilization of clinical genotyping in a greatly expanded number of clinical settings.3
DRUG-METABOLIZING ENZYME GENES RELEVANT FOR GUIDING TREATMENT WHEN USING PSYCHOTROPIC MEDICATIONS
Variations in the DME genes have been shown to alter the responses of patients to psychotropic medications. Specifically, the cytochrome P450 family of genes has been studied extensively. Five of the many cytochrome P450 genes that are particularly relevant for the management of psychotropic medications will be reviewed.
The Cytochrome P450 2D6 Gene
The CYP2D6 was the first DME gene that was widely tested to identify poor metabolizers. Additionally, the identification of ultrarapid metabolizers of 2D6 substrate medications has proven to be clinically useful. There are more than 70 medications that are currently metabolized by the 2D6 enzyme. Many of these drugs are widely used psychotropic medications.
CYP2D6 is located on the 22nd chromosome and codes for the CYP2D6 enzyme. It is highly variable and there are currently more than 100 formally recognized variants. These CYP2D6 allelic variants have been classified as being upregulated, normal, deficient, or completely inactive. A variety of methodologies for predicting 2D6 phenotypes based on CYP2D6 genotypes have been suggested. However, the most widely used methodologies for pheno-type specification are designed to identify patients as having one of four metabolic capacities. These categories are usually labeled as poor, intermediate, extensive (i.e., normal), and ultrarapid.
There is considerable variability in the allele frequency of 2D6 gene variants based on the ancestral origin of a population. For example, the completely inactive *3 allele is essentially found only in European populations. Similarly, the deficient *17 allele is primarily found in sub-Saharan Africa populations. Yet another example is the *10 allele, which is the most common allele found in Japanese populations.4
The results of pharmacogenomic testing provide an estimate of a metabolic capacity phenotype. However, a more active genotype can produce a CYP2D6 enzyme that is subsequently inhibited as a consequence of a drug interaction. Strong inhibition of patients who have one or even two normal CYP2D6 alleles can result in decreased metabolic capacity. However, poor metabolizers who have two inactive copies of the 2D6 gene have no 2D6 metabolic capacity. Consequently, the metabolism of these individuals cannot be further inhibited.
While many antidepressant medications are metabolized to some degree by the 2D6 enzyme, there are five antidepressants that are primarily metabolized by 2D6. These include two selective serotonin reuptake inhibitors, fluoxetine and paroxetine, the selective norepinephrine reuptake inhibitor venlafaxine, and two tricyclic antidepressants, desipramine and nortriptyline.
Similarly, many antipsychotic medications have some 2D6 enzyme involvement in their metabolism. However, there are five antipsychotic medications that are predominantly metabolized by 2D6. These include four typical antipsychotic medications, chlorpromazine, thioridazine, haloperidol, and perphenazine, as well as the atypical antipsychotic medication, risperidone.
Atomoxetine is a medication that is used for the treatment of attention deficit hyperactivity disorder. The primary mode of metabolism of atomoxetine is also by the 2D6 enzyme. Caution in using atomoxetine is advised in patients who are poor CYP2D6 metabolizers, given that they may achieve a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose. Consequently, poor metabolizers are at a higher rate for the adverse effects when prescribed standard doses of atomoxetine.5
Some analgesics such as codeine and tramadol are prodrugs. A prodrug is an inactive compound and must be transformed to an active metabolite in order to have a therapeutic effect. In the case of codeine, its active metabolite is morphine. A patient must have some CYP2D6 metabolic capacity for this transformation from codeine to morphine to take place.
A primary consideration in treatment of patients with 2D6 substrate medications is that those patients who have diminished metabolic capacity must be treated with lower than traditional doses. Conversely, patients who have ultrarapid CYP2D6 metabolic capacity are unlikely to respond to treatment with 2D6 substrate medications at traditional doses.
The Cytochrome P450 2C19 Gene
The cytochrome P450 2C19 gene (CYP2C19) is a large gene that codes for an enzyme containing 490 amino acids. CYP2C19 is somewhat less variable than 2D6. However, there are CYP2C19 alleles that are upregulated, normal, have decreased metabolic activity, or are completely inactive. Like CYP2D6, CYP2C19 has dramatic variation in allelelic distributions based on geographical ancestry. For example, patients who are of Asian ancestry are more likely to have intermediate or poor metabolic 2C19 phenotypes than patients of European ancestry.
Both citalopram and escitalopram are primarily metabolized by the 2C19 enzyme as are imipramine and amitripty-line. In contrast to the 2D6 enzyme, the 2C19 enzyme usually plays a relatively minor role in the metabolism of antipsychotic medications.
The Cytochrome P450 1A2 Gene
The cytochrome P450 1A2 gene (CYP1A2) is the only commonly genotyped cytochrome P450 enzyme drug-metabolizing gene that is easily inducible. CYP1A2 is located on chromosome 15 and codes for the 1A2 enzyme composed of 516 amino acids. Allele frequency of the inducible CYP1A2 allele (i.e.,*1F) has been reported to be approximately 33% in populations of European ancestry. The most common inducer of 1A2 activity is tobacco smoke.
Fluvoxamine is an antidepressant that is primarily metabolized by the 1A2 enzyme. However, the CYP1A2 enzyme also plays a role in the metabolism of duloxetine, clomipramine, and imipramine. The 1A2 enzyme plays an important role in the metabolism of both clozapine and olanzapine. Given that alleles of this gene are inducible when patients are exposed to tobacco smoke, induction can result in clinical complications of acutely psychotic patients who have an enhanced 1A2 metabolic capacity.
The Cytochrome P450 2B6 Gene
The cytochrome P450 2B6 gene (CYP2B6) is located on chromosome 19 and consists of 27,098 nucleotides. CYP2B6 codes for the 2B6 enzyme composed of 491 amino acids. It is the primary enzyme for the metabolism of bupropion, which is used both as an antidepressant and to decrease craving for nicotine.6
A specific polymorphism of CYP2B6 has been demonstrated to result in a coding change that decreases the functionality of the enzyme. Patients with the T allele of this polymorphism are less likely to respond to bupropion treatment.7 CYP2B6 also may influence nicotine replacement therapy as it can metabolize nicotine.
The Cytochrome P450 2A6 Gene
The cytochrome P450 2A6 gene (CYP2A6) is located on chromosome 19 and consists of 6,909 nucleotides. CYP2A6 codes for the 2A6 enzyme that is composed of 494 amino acids. It plays a major role in the metabolism of nicotine and consequently slow CYP2A6 metabolizers are able to achieve higher levels of plasma nicotine when taking standard nicotine replacement therapy.
PHARMACOGENOMIC TARGET GENES RELEVANT FOR GUIDING TREATMENT WHEN USING PSYCHOTROPIC MEDICATIONS
The term “target gene” refers to those genes that code for proteins that play a role in the pharmacodynamic response of patients to medications. A pharmacodynamic response requires that the patient have an adequate exposure to the medication. The most common target genes of interest for psychiatric pharmacogenomic testing are neurotransmitter transporter genes and neurotransmitter receptor genes. The effectiveness of a transporter molecule to facilitate the “reuptake” of a neurotransmitter to the interior of the neuron has implications for psychotropic medications that influence the reuptake process. For example, the serotonin transporter protein is the primary target of selective serotonin reuptake inhibitors. As a consequence of this inhibition, the concentration of serotonin in the neural cleft is increased with the objective of achieving a decrease in the severity of depressive symptoms. Neurotransmitter receptors, similarly, are variable and this variation can result in differences in their sensitivity to medications. Genetic variance has been associated with variation in sensitivity.
Serotonin Transporter Gene
The serotonin transporter gene (SLC6A4) is the most widely studied pharmacogenomically relevant target gene that has been demonstrated to predict the probability of psychotropic medication response. SLC6A4 is located on chromosome 17 and codes for the serotonin transporter protein that plays a primary role in the reuptake of serotonin in the neural synapse.
The most widely studied variant of SLC6A4 is the indel promoter polymorphism, which is frequently referred to as 5HTTLPR. This indel consists of a variant that is either 43 or 44 base pairs (bp) in size. There are actually many variations of both the long allele and the short allele. Furthermore, there has been some evidence that there is an interaction between a single nucleotide polymorphism (SNP) (i.e., rs25531) located immediately upstream of the indel polymorphism and the activity level of the long allele of the transporter protein.
Yet another significant variant of SLC6A4 is a variable number tandem repeat (VNTR) located in intron 2. This variant is sometimes referred to as the STin2 VNTR. Four variants of this VNTR have been reported. The most common alleles are the 10- and 12-repeat.
Variations in SLC6A4 allele frequencies occur across ancestral populations. For example, the long allele of the indel polymorphism occurs with an allele frequency of approximately 82% in African American populations. In contrast, the frequency of the long allele is only 20% in Japanese populations.
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