Abstract
Growing evidence suggests that the glutamatergic modulator ketamine has rapid antidepressant effects in treatment-resistant depressed subjects. The anticholinergic agent scopolamine has also shown promise as a rapid-acting antidepressant. This study applied genome-wide markers to investigate the role of genetic variants in predicting acute antidepressant response to both agents. The ketamine-treated sample included 157 unrelated European subjects with major depressive disorder (MDD) or bipolar disorder (BD). The scopolamine-treated sample comprised 37 unrelated European subjects diagnosed with either MDD or BD who had a current Major Depressive Episode (MDE), and had failed at least two adequate treatment trials for depression. Change in Montgomery–Asberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAM-D) scale scores at day 1 (24 h post-treatment) was considered the primary outcome. Here, we conduct pilot genome-wide association study (GWAS) analyses to identify potential markers of ketamine response and dissociative side effects. Polygenic risk score analysis of SNPs ranked by the strength of their association with ketamine response was then calculated in order to assess whether common genetic markers from the ketamine study could predict response to scopolamine. Findings require replication in larger samples in light of low power of analyses of these small samples. Neverthless, these data provide a promising illustration of our future potential to identify genetic variants underlying rapid treatment response in mood disorders and may ultimately guide individual patient treatment selection in the future.
Highlights
The development of rapid-acting treatments for individuals with major depressive disorder (MDD) or bipolar depression who fail to respond to conventional antidepressant treatments is an urgent public health priority, because of the increased risk of suicide in patients with treatment-resistant depression[1,2,3]
Identifying the specific mechanisms and targets associated with antidepressant response to ketamine compared with scopolamine, as well as subgoups associated with treatment response, could facilitate personalized treatment selection in individuals with major depression
Previous studies have explored biomarkers of antidepressant response to ketamine via several avenues, including proton magnetic resonance spectroscopy (MRS) measures of glutamate, glutamine, Glx, and/or gamma-aminobutyric acid (GABA) levels; structural and functional magnetic resonance imaging (MRI);[17] positron emission tomography (PET) measures of metabotropic glutamatergic receptor binding;[18] magnetoencephalography (MEG) assessments of changes in synaptic plasticity;[19] polysomnography;[20] actigraphy;[21] and biochemical measures[22,23,24,25,26,27]
Summary
The development of rapid-acting treatments for individuals with major depressive disorder (MDD) or bipolar depression who fail to respond to conventional antidepressant treatments is an urgent public health priority, because of the increased risk of suicide in patients with treatment-resistant depression[1,2,3]. Accumulating evidence indicates that a single infusion of the glutamatergic modulator ketamine can produce rapid, robust, and relatively sustained antidepressant effects within hours in patients with both non-treatmentresistant and treatment-resistant MDD and bipolar depression[4,5,6,7,8,9,10,11]. Identifying the specific mechanisms and targets associated with antidepressant response to ketamine compared with scopolamine, as well as subgoups associated with treatment response, could facilitate personalized treatment selection in individuals with major depression. While the identification of biomarkers associated with response to rapid-acting antidepressants is clear in the early stages of testing and development, such biomarkers could eventually offer promising additions or alternatives to the traditional rating scales used to assess clinical severity and outcome in depression, as well as suggest key avenues for personalized treatment
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