Depression Study Suggests a Model for the Neurological Basis of Psychotherapy

Jacquelyn K. Beals, PhD

October 29, 2007 (San Diego) �?A new study has provided preliminary evidence that similar neurobiological mechanisms underlie psychotherapy and pharmacotherapy. The study found an association between genotypic variation in 2 receptors associated with antidepressant response and patients' responses to cognitive behavioral therapy (CBT).

Specific polymorphisms of HTR2A (a serotonin receptor) and NTRK2 (a receptor for brain-derived neurotrophic factor, or BDNF), as well as their interactions, appear to predict the effectiveness of CBT in patients with unipolar depression.

The study was presented here at the American Society of Human Genetics 57th Annual Meeting by Amelia Kotte, MS, a PhD candidate in the joint program in clinical psychology, Department of Psychology, San Diego State University; Department of Psychiatry, University of California, San Diego; and Veterans' Affairs Healthcare System, La Jolla, California.

The study enrolled 65 veterans who had taken a 16-week CBT program for unipolar depression within the past 5 years. Participants permitted access to their charts to determine their response to CBT as tracked with the Beck Depression Inventory (BDI), a 21-item self-report rating inventory. Each subject had 60 cc of blood drawn for genotyping. The initial gene candidates included GNB3, SERT, COMT, NTRK2, and HTR2A �?genes associated with mood disorders. Only NTRK2 and HTR2A were eventually shown to have a significant association with CBT responses.

A significant effect was found for NTRK2 [F(1,65) = 4; P = .05], and a significant interaction was identified between NTRK2 and HTR2A [F(2,59) = 3.8; P = .03]. The AA genotype of NTRK2 predicted a better response to CBT than that which occurred with the AG or GG genotypes. The interaction of HTR2A (GG) with NTRK2 (GG) was also associated with a better (lower) BDI score than was the combination of HTR2A (AA and AG) with NTRK2 (GG).

Ms. Kotte suggested that NTRK2 expression might modify serotonin activity by increasing neural plasticity, a mechanism that may be involved in antidepressant treatments. CBT treatment may also modulate serotonin receptors. She proposed a model in which NTRK2 expression in the brain influences BDNF (which interacts with the serotonin system), thereby modulating neural plasticity in the hippocampus and limbic regions.

Asked whether patients will soon be screened for their genetic profile before referral to certain treatment modalities, Ms. Kotte thought it would be done "sometime in the future, but we don't know how long it's going to take �?[5 or 10] years from now."

Her advisor, John R. Kelsoe, MD, from the Laboratory of Psychiatric Genomics. Department of Psychiatry, University of California, San Diego, and Veterans Affairs Healthcare System, La Jolla, California, told Medscape Pathology that availability of genetic screening "is going to be driven by patients who want to know answers and probably pushed a little bit ahead of the envelope. But I think it's starting to happen."

Michael S. Phillips, PhD, Canada research chair in translational pharmacogenomics, director of pharmacogenomics, Genome Quebec, and associate professor at the University of Montreal, Quebec, Canada, a comoderator of the session, also discussed the study with Medscape Pathology, saying, "There's more and more evidence suggesting that mechanistically, drugs are metabolized by different pathways, and there are genetic underpinnings.... It's not unheard of to think that if there are compounds within in the body that are going to be metabolized or modified, that there's genetic variation in there. We're all different levels of cascades of the same pathways."

He concluded, "The pharmacodynamic mechanisms are very much about the drug �?its pathways, and the pathophysiology. What we're going to start to see in the future, or starting even now, is that in early clinical studies or even in preclinical studies, people are starting to use genetics...to better characterize their patients."

Ms. Kotte disclosed a financial affiliation with John R. Kelsoe Psynomics, Inc.

Dr. Kelsoe is the founder of John R. Kelsoe Psynomics, Inc.

American Society of Human Genetics 57th Annual Meeting: Abstract 175. Presented October 26, 2007.

Medscape Medical News 2007. © 2007 Medscape