Edward Craighead, PhD provided funding to treat non-remitters to the first treatment with combination medication and psychotherapy, to allow follow-up of patients for up to two years to identify predictors of recurrence, and to add patients to the sample to adequately power these studies. Additional support was received from PHS Grant UL1 Abstract Background: Acylcarnitines have important functions in mitochondrial energetics and β oxidation, and have been implicated to play a significant role in metabolic functions of the brain.This retrospective study examined whether plasma acylcarnitine profiles can help biochemically distinguish the three phenotypic subtypes of major depressive disorder (MDD)-(core depression (CD+), anxious depression (ANX+), and neurovegetative symptoms of melancholia (NVSM+))-following treatment with a selective serotonin reuptake inhibitor (SSRI). Methods:Depressed outpatients (n=240) from the Mayo Clinic Pharmacogenomics Research Network were treated with citalopram or escitalopram for eight weeks. Plasma samples collected at baseline and eight weeks post-treatment were profiled for multiple-, short-, medium-and longchain acylcarnitine levels using AbsoluteIDQ®p180-Kit and LC-MS. Linear mixed effects models were used to examine whether acylcarnitine levels discriminate the clinical phenotypes at baseline or eight weeks post-treatment, and whether temporal changes in acylcarnitine profiles differ between groups. Results: At baseline, significantly lower concentrations of short-and long-chain acylcarnitines were found in CD+ and NVSM+ compared to ANX+, and the shortchain acylcarnitines remained lower after eight weeks. At eight weeks, the medium-and longchain acylcarnitines were significantly lower in NVSM+ compared to ANX+. Regarding changes baseline to week eight, short-chain acylcarnitine levels significantly increased in CD+ and ANX+, and medium-and long-chain acylcarnitines significantly decreased in NVSM+ and CD+. Conclusions: In depressed patients treated with SSRIs, β -oxidation and mitochondrial energetics as evaluated by levels and changes in acylcarnitines may provide the biochemical basis of the clinical heterogeneity of MDD, especially when combined with clinical characteristics. 7