Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis

Abstract

Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person’s subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings.

Association between plasma α‐aminobutyric acid and depressive symptoms in older community‐dwelling adults in Japan

“…glutamate and glycine) or as precursors of important neurotransmitters, such as catecholamines (from phenylalanine), histamine (from histidine), serotonin (from tryptophan) and γ-aminobutyric acid (from glutamate). Consistent with this, several studies have revealed associations between plasma amino acid patterns and depressive symptoms [5][6][7][8][9] however, the available evidence for older adults is less than that for younger populations. Because depressive symptoms in older adults differ from those of younger adults, the identification of the plasma amino acid signature of depressive symptoms in older adults is important not only for the development of a biomarker of geriatric depression, but also for understanding its pathophysiology.…”

Hikikomori : Multidimensional understanding, assessment, and future international perspectives

“…Microglia play crucial roles in brain inflammation via releasing free radicals and inflammatory cytokines, such as interleukin‐6 and tumor necrosis factor‐α, and activation of microglia has recently been proposed to exist in various psychiatric disorders, including schizophrenia, depression, bipolar disorder, and autism . In addition, microglial overactivation is proposed to exist in the brains of suicide victims and suicidal individuals, especially via the tryptophan–kynurenine pathway . As noted above, a recent epidemiological data analysis showed that hikikomori sufferers are more likely to have suicide risk, thus similar biological mechanisms via microglial activation may exist in hikikomori …”

Development and validation of the 22‐item Tarumi's Modern‐Type Depression Trait Scale: Avoidance of Social Roles, Complaint, and Low Self‐Esteem (TACS‐22)

“…Tryptophan metabolites, especially serotonin, have gathered greater attention in the endeavor to understand the pathophysiology of depression . In addition, metabolites of the tryptophan–kynurenine pathway are increasingly attracting interest . Just recently, we reported that plasma tryptophan is a possible diagnostic biomarker of MDD and that some of the tryptophan–kynurenine metabolites in plasma are related to severity of some depressive symptoms .…”