Genomic Predictors of Response to Antidepressant Treatment in Geriatric Depression Using Genome-Wide Expression Analyses: A Pilot Study
Helen Lavretsky, MD; Ascia Eskin, MS; Stan Nelson, PhD; and Steve W. Cole, PhD
From the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles; the Semel Institute for Neuroscience and Human Behavior; the Cousins Center for Psychoneuroimmunology, and UCLA Human Genetics.
This poster presentation was supported by NIMH grants K24 MH086481 and R-01 MH077650.
Background: Geriatric depression is commonly associated with insufficient antidepressant response. It is important to understand the genetic basis of treatment resistance and preferential response to antidepressants with dopaminergic or serotonergic properties.
Methods: 20 older adults with major depression (age 60 and older) were randomized to receive 16 weeks of treatment with methylphenidate + placebo, citalopram + placebo, or citalopram + methylphenidate. The doses of methylphenidate ranged between 10–30 mg per day, and citalopram doses ranged between 20–40 mg per day. Genome-wide transcriptional profiling was carried out on peripheral blood mononuclear cell samples obtained at baseline and post-intervention. Microarrays were run on the Illumina platform, Human HT-12_V4, and quantile normalized.
Results: Among 20 subjects, 7 subjects failed to respond to treatment and 13 subjects were rapid responders. The expression of two genes in the dopamine and serotonin pathways, SNCA (2.18 higher; P=0.036) (alpha-synuclein gene implicated in Parkinson’s disease (SNCA) that binds dopamine transporter and is involved in the regulation of dopamine release and transport) and CA1 (2.53 times higher; t=0.029)(Carbonic anhydrase is involved in respiratory function and interacts with serotonin pathways) was higher at baseline in nonresponders. Treatment with methylphenidate upregulated genes—G-protein coupled protein signaling pathway involved in cellular aging (GPR175) and glutamate receptor NMDA protein 1 (GRINA).
Conclusions: The present results suggest a unique genetic signature in responders and non-responders to antidepressant treatment in the dopaminergic and serotonergic pathways that may allow prediction of individual treatment resistance. Treatment with methylphenidate resulted in upregulation of genes in the glutamatergic and G-protein signaling pathways, also important for neuroplasticity and brain aging. Our results will need to be replicated in larger samples with the use of additional specific biomarkers of the identified pathways.
To discuss genetic predictors of treatment resistance in geriatric depression
To discuss differences in gene expression with dopaminergic or serotonergic treatment
Lavretsky H, Kim MD, Kumar A, et al. Combined treatment with methylphenidate and citalopram for accelerated response in the elderly: an open trial. J Clin Psychiatry. 2003:64(12):1410–1414. PubMed
Lavretsky H, Siddarth P, Wong ML, et al. Dopamine and serotonin transporter genetic polymorphisms: clinical features and treatment response in geriatric depression. Int J Ger Psychiatry. 2007;22(7):1–5.