Genetic Variation May Impact Response To Antidepressants

HOLLYWOOD, FLA—Researchers participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial have identified three gene polymorphisms that affect response to the antidepressant citalopram, according to Francis McMahon, MD, who reported the findings at the 45th Annual Meeting of the American College of Neuropsychopharmacology. The three markers are for polymorphisms in the genes HTR2A (which encodes the serotonin 2A receptor), GRIK4 (which encodes KA1, a kainate-type glutamate receptor), and BCL2 (which encodes a mitochondrial membrane protein thought to protect against neuronal death). “Our data demonstrate that the three genes we have found must play a key role in the action of antidepressants such as citalopram. They don’t tell us just how this happens. That will require future work,” Dr. McMahon told Neuro­Psychiatry Reviews. Dr. McMahon is Chief of Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health in Bethesda, Maryland.

Treatment-Resistant Genes
Genetic analysis was included in the STAR*D protocol design because the researchers hoped it would point the way toward better treatments for the 50% of patients for whom antidepressants are not effective, particularly those whose symptoms are inadequately controlled despite trying several medications. “Individual variation in outcome may have a partial genetic basis,” Dr. McMahon said. “Outcome and side-effect patterns vary less between illness episodes than between individuals. The outcome of treatment may run in families, and small samples have suggested that genetic variants may influence outcome. Genetic markers are not altered by disease or treatment and thus are ideal ‘biomarkers,’ and genetic findings might reveal aspects of etiology.”

Comparitive Study
The researchers’ objective was to study a large group of patients who were all treated with the same antidepressant medication and followed longitudinally, as well as to genotype a large number of genetic markers and to test for associations between outcomes and genotypes. The STAR*D cohort included 1,953 patients with major depression, all of whom were treated initially with citalopram. The investigators genotyped 768 single nucleotide polymorphisms (SNPs) in 68 candidate genes. Dr. McMahon said the candidate genes were chosen “to cover all of the major hypotheses: serotonin, norepinephrine, dopamine, glutamate, neurotrophins, and previously reported genes.”

Patients in the trial were treated according to a standardized protocol beginning with citalopram as initial monotherapy, then switching to sustained-release bupropion, cognitive therapy, sertraline, or extended-release venlafaxine or supplementing citalopram with sustained bupropion, buspirone, or cognitive therapy. If this was still not adequate, the patient could switch to mirtaza­pine or nortriptyline, or add lithium, sertraline, extended-release venlafaxine, or (with sustained-release bupropion) add triiodothy­ronine. If this was not adequate, level 4 care called for a switch to tranylcypromine or mirtazapine combined with extended-release venlafaxine.

Patients were classified according to outcome phenotypes on the Quick Inventory of Depressive Symptomatology (QIDS): remitters, with a final QIDS score of 5 or less, and responders, with a greater than 50% reduction in baseline QIDS. Intolerant patients were excluded from the analysis, along with those whose outcome was ambiguous.

“So far we have detected a significant and reproducible association between response to citalopram treatment and markers in HTR2A, which encodes the serotonin 2A receptor, as well as GRIK4, which encodes a kainate-type glutamate receptor,” Dr. McMahon said.

For example, the HTR2A marker can have AA, AG, or GG genotypes. The STAR*D data show that patients with the AA genotype improve more rapidly in response to antidepressant treatment and retain that advantage over time, compared to patients with either of the other two genotypes. The researchers also found that the HTR2A A allele was about seven times more common in white participants than in black participants. “We need to consider genetic factors along with psychosocial issues as we try to figure out why antidepressants don’t help black patients as much as they should,” Dr. McMahon said.
Overall, nonresponse rates were about 30% for patients with any HTR2A allele, but less than half that for patients who had both HTR2A and BCL2 alleles, or BCL2 and both GRIK4 alleles.

Personalizing Antidepressant Therapy Might Be Effective
Dr. McMahon said that genetic markers might be useful for identifying patients at risk for adverse effects and for matching medications with patients most likely to benefit from them, as well as for identifying novel drug targets through both downstream and upstream effects. “Our goal is to achieve much better prediction of who will and won’t respond and who is likely to suffer unacceptable side effects,” Dr. McMahon told NeuroPsychiatry Reviews. “Even then, it will also be necessary to develop a way to obtain the results of genetic marker tests during the initial visit, at the point of service. That is when the information will be most useful as a guide for clinical decision making,” he said.

—Janis Kelly

Suggested Reading
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.

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