Poor evidence for putative abnormalities in cerebrospinal fluid neurotransmitters in patients with depression versus healthy non-psychiatric individuals: A systematic review and meta-analyses of 23 studies

Abstract

Background: Although investigated for decades, surprisingly no systematic review has ever been published on monoamines concentrations in cerebrospinal fluid (CSF) in major depressive disorder (MDD) versus healthy individuals (HC).

Methods: We did a systematic review and meta-analyses according to the PRISMA Statement based on comprehensive database searches for studies on CSF biomarkers of monoamines and their precursor and/or metabolites, and glutamine, glutamate and GABA in MDD versus HC. Risk of bias was systematically assessed.

Results: A total of 23 studies were included. Statistically significantly decreased levels between MDD and HC were found regarding CSF 5-HIAA (n = 2/13 (15%)), HVA (n = 2/11 (18%)), MHPG (n = 1/8 (13%)), and GABA (n = 2/4 (50%)), while increased levels were reported regarding NE (n = 1/2 (50%)), MHPG (n = 1/8 (13%)) and DOPEG (n = 1/1 (100%)). A majority of the studies found no statistically significant differences between MDD and HC regarding CSF 5-HIAA, HVA, NE, MHPG, glutamine, glutamate and GABA. Meta-analyses showed: 5-HIAA (-3.85, -8.89, 1.19, 0.14), HVA (-18.02, -30.99, -5.04, 0.01), MHPG (0.11, -2.96, 3.17, 0.95) and GABA (-33.20, -51.79, -14.62, 0.00) (mean difference, lower 95% CL, upper 95% CL, p-value). Most studies were influenced by risk of bias mainly due to small sample sizes, and not considering potential confounders as age, gender, severity of depression, body height and position during lumbar puncture, analytics of biomarkers and medication.

Conclusion: The evidence for CSF 5-HIAA, HVA, NE, MHPG, DOPEG and GABA being related to the pathophysiology of MDD is poor. Future controlled studies of monoamines or metabolites should validate the null i.e., that the concentrations of these compounds are not abnormal in MDD.

Keywords: Depression; Meta-analyses; Neurotransmitter; Pathophysiology; Systematic review.