BACKGROUND: Lysophosphatidic acid (LPA) is involved in numerous biological processes, including neurodevelopment, chronic inflammation, and immunologic response in the central nervous system. Autotaxin (ATX) is a secreted enzyme that produces LPA from lysophosphatidylcholine (LPC). Previous studies have demonstrated decreased protein levels of ATX in cerebrospinal fluid (CSF) of patients with major depressive disorder (MDD). Based on them, the current study investigated the levels of lysophospholipids species (LPLs) including LPA and related metabolic enzymes in CSF of patients with MDD and schizophrenia (SCZ). METHODS: The levels of LPLs and related metabolic enzymes were measured with either liquid chromatography-tandem mass spectrometry or enzyme-linked immunosorbent assay. Japanese patients were diagnosed with DSM-IV-TR. CSF was obtained from age- and sex-matched healthy controls (HC) (n = 27) and patients with MDD (n = 26) and SCZ (n = 27). RESULTS: Of all LPLs, the levels of LPA 22:6 (LPA - docosahexaenoic acid (DHA)) were significantly lower in patients with MDD and SCZ than in HC. These levels were negatively correlated with several clinical symptomatic scores of MDD, but not those of SCZ. In addition, the levels of LPA 22:6 were significantly correlated with the levels of LPC 22:6 among all of three groups. On the other hand, the levels of LPA 22:6 were not correlated with ATX activity in patients with MDD and SCZ. CONCLUSION: The lower levels of LPA 22:6 in patients with MDD and SCZ suggests an abnormality of LPA 22:6 metabolism. In addition, several depressive symptoms in patients with MDD were significantly associated with the lower levels of LPA 22:6, suggesting an involvement of LPA 22:6 in the pathophysiology of MDD.