Interpretive Handbook

Treatment with specific antidepressant and antipsychotic medications is often guided empirically. Despite the wide array of drugs available for treatment, some patients do not initially respond to treatment, and others who respond early may eventually relapse or develop serious side effects. Antidepressant selection may be more effectively guided by genotyping polymorphic genes encoding several cytochrome P450 enzymes, the serotonin transporter, and the serotonin (5-hydroxytryptamine) receptors HTR2A and HTR2C.(1)

Drugs that bind to the serotonin receptors have a wide range of effects including altering the activation of the receptors, rendering them more or less sensitive to drug concentration, or blocking the receptor. Variations (polymorphisms) in the genes that encode for the serotonin receptor have been associated with different types of drug responses including:

-Allelic variation in the HTR2A gene has been reported to affect response to selective serotonin reuptake inhibitors (SSRI) resulting in increased drug levels and increased risk for adverse drug reactions.(2) Patients with polymorphic variants in the HTR2A/2C serotonin receptors may be considered for switching to non-SSRI antidepressants that block the type 2 receptors. Allelic variations in the HTR2A and HTR2C genes have been linked with response to the antipsychotic drug clozapine. The presence of the HTR2A receptor allele His452 has been reported to predict favorable response to clozapine therapy.(3)

-Treatment with atypical antipsychotics results in significant weight gain (2-3 kg/m[2]) in some patients. Weight gain has been positively correlated with a polymorphism in the promoter of HTR2C (-759C).(4)

-Allelic variation in the HTR2A and HTR2C genes has also been associated with increased risk of tardive dyskinesia in schizophrenic patients.(5,6)

-Allelic variation in the HTR2A gene and its promoter have been associated with improved effectiveness of citalopram in major depression disorder.

Guiding treatment choice of an (selective serotonin reuptake inhibitor) SSRI or non-SSRI antidepressant. Individuals homozygous for the IVS2+54538 A allele have improved probability of response to citalopram, in contrast to individuals homozygous or heterozygous for the IVS2 G allele. Individuals with major depression disorders are more likely to respond to citalopram if they are homozygous for the -1438G promoter allele.

Guiding treatment choice in individuals who have a drug-metabolizer phenotype discordant with CYP450 genotypes

Identifying patients who may benefit from treatment with the antipsychotic drug clozapine

Identifying those patients receiving atypical antipsychotic medications with excessive weight gain who may benefit by switching to different antipsychotic medications

An interpretive report will be provided.

Drug-drug interactions must be considered when dealing with heterozygous individuals.

This test does not detect polymorphisms other than those listed above.

The HTR2A gene is located on the long arm of chromosome 13 (13q). For patients with known hematologic disorders that involve deletion of 13q, call the laboratory for instructions.

An interpretive report will be provided.

1. Malhotra AK, Murphy GM Jr, Kennedy JL: Pharmacogenetics of psychotropic drug response. Am J Psychiatry 2004;161(5):780-796 

2. Murphy GM Jr, Kremer C, Rodrigues HE, et al: Pharmacogenetics of antidepressants medication intolerance. Am J Psychiatry 2003;160(10):1830-1835

3. Arranz MJ, Murno J, Birkett J, et al: Pharmacogenetic prediction of clozapine response. Lancet 2000;355(9215):1615-1616

4. Reynolds GP, Zhang ZJ, Zhang XB: Polymorphism of the promoter region of the serotonin 5-HT2C receptor gene and clozapine-induced weight gain. Am J Psychiatry 2003;160:677-679

5. Segman RH, Heresco-Levy U, Finkel B, et al: Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 2001;6(2):225-229

6. Segman RH, Heresco-Levy U, Finkel B, et al: Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility. Psychopharmacology 2000;152(4):408-413

7. Choi MJ, Kang RH, Ham BJ, et al: Serotonin receptor 2A gene polymorphism (-1438A->G) and short-term treatment response to citalopram. Neuropsychobiology 2005;52:155-162

8. McMahon FJ, Buervenich S, Charney D, et al: Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 2006;78:804-814