Little is known whether cholesterol levels affect depression treatment outcomes. We aimed to study the association between baseline and changes in blood cholesterol levels with drug-specific antidepressant response and long-term prognosis in patients with major depressive disorder (MDD). From the Danish site of the GENDEP trial, we included patients with MDD randomized to escitalopram or nortriptyline treatment. Total and free cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and depression severity using the Montgomery-Åsberg Depression rating scale (MADRS) were measured at baseline and after 26 weeks of treatment initiation. By linkage with nationwide registers, we analyzed psychiatric and cardiometabolic hospital contacts during the five years after the trial. We assessed the association of cholesterol levels with a) depression severity using linear and mixed effects regression analyses; and b) the register-based outcomes using Cox regression analyses. Among 78 patients (mean age 38 years, 74% women, mean MADRS score 28 [SD=4.5]), baseline cholesterol levels were not correlated with antidepressant response. Among 58 patients with measurements at week 0 and 26, cholesterol levels significantly increased in both treatment groups. Only in patients using escitalopram did the increase in total and free cholesterol and LDL correlate with improved antidepressant response. Baseline or changes in cholesterol were not associated with 5-year outcomes. Secondary analyses on a rather small sample. This study provides clinical insight into potential drug-specific associations between increases in cholesterol levels and antidepressant response to escitalopram but not nortriptyline. • Cholesterol levels increased during 26 weeks of antidepressant treatment • Among those treated with escitalopram, the increase correlated with improved response • We found no correlation between change in cholesterol and response in the nortriptyline group • Baseline or change in cholesterol levels were not associated with differential 5-year prognosis
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