Glutamatergic Neurometabolite Levels in Bipolar Disorder: A Systematic Review and Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

Background: The glutamatergic system is thought to play an important role in the pathophysiology of bipolar disorder (BD). While there has been an increase in proton magnetic resonance spectroscopy studies examining this neurotransmission system, the results are inconsistent. Possible reasons for the inconsistency, including clinical features such as mood state and childhood versus adulthood age, were not addressed in previous meta-analyses. Methods: This systematic review and meta-analysis of proton magnetic resonance spectroscopy studies of BD included 40 studies, with 1135 patients with BD and 964 healthy control (HC) subjects. Results: Glutamate plus glutamine and glutamine levels in the anterior cingulate cortex of patients with BD were significantly elevated compared with those of HC subjects (standardized mean difference = 0.42, 0.48, respectively). Subgroup analyses showed that adult BD patients had significantly higher levels of glutamate plus glutamine than adult HC subjects, but this was not the case in pediatric patients. For mood states, anterior cingulate cortex glutamate plus glutamine levels were higher in patients with bipolar depression than those in HC subjects. Conclusions: Our results imply that glutamatergic dysfunction in the anterior cingulate cortex may be implicated in the pathophysiology of BD, which is most evident in adult BD patients and patients with bipolar depression.