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Planning subsequent treatment strategies based on early responses rather than waiting for delayed antidepressant action can be helpful. We identified genetic markers for later non-remission in patients exhibiting poor early improvement using whole-exome sequencing data of depressive patients treated in a naturalistic manner. Among 1000 patients, early improvement at 2 weeks (reduction in Hamilton Depression Rating Scale [HAM-D] score ≥ 20%) and remission at 12 weeks (HAM-D score ≤ 7) were evaluated. Gene- and variant-level analyses were conducted to compare patients who did not exhibit early improvement and did not eventually achieve remission (<i>n</i> = 126) with those who exhibited early improvement and achieved remission (<i>n</i> = 385). Genes predicting final non-remission in patients who exhibited poor early improvement (<i>COMT, PRNP</i>, <i>BRPF3</i>, <i>SLC25A40,</i> and <i>CGREF1</i> in males; <i>PPFIBPI</i>, <i>LZTS3, MEPCE, MAP1A,</i> and <i>PFAS</i> in females; <i>ST3GAL5</i> in the total population) were determined. Among the significant genes, variants in the <i>PRNP</i> (rs1800014), <i>COMT</i> (rs6267), <i>BRPF3</i> (rs200565609), and <i>SLC25A40</i> genes (rs3213633) were identified. However, interpretations should be made cautiously, as complex pharmacotherapy involves various genes and pathways. Early detection of poor early improvement and final non-remission based on genetic risk would be helpful for decision-making in a clinical setting.