Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis

Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis


J Psychiatry Neurosci 2012;37(4):333-43

Tomas Hajek, MD, PhD; Miloslav Kopecek, MD, PhD; Cyril Höschl, MD; Martin Alda, MD

Hajek, Alda — Department of Psychiatry, Dalhousie University, Halifax, NS; Hajek, Kopecek, Höschl, Alda — Prague Psychiatric Centre, Department of Psychiatry and Medical Psychology, 3rd School of Medicine, Charles University, Prague, Czech Republic


Background: Smaller hippocampal volumes relative to controls are among the most replicated neuroimaging findings in individuals with unipolar but not bipolar depression. Preserved hippocampal volumes in most studies of participants with bipolar disorder may reflect potential neuroprotective effects of lithium (Li).

Methods: To investigate hippocampal volumes in patients with bipolar disorder while controlling for Li exposure, we performed a meta-analysis of neuroimaging studies that subdivided patients based on the presence or absence of current Li treatment. To achieve the best coverage of literature, we categorized studies based on whether all or a majority, or whether no or a minority of patients were treated with Li. Hippocampal volumes were compared by combining standardized differences between means (Cohen d) from individual studies using random-effects models.

Results: Overall, we analyzed data from 101 patients with bipolar disorder in the Li group, 245 patients in the non-Li group and 456 control participants from 16 studies. Both the left and right hippocampal volumes were significantly larger in the Li group than in controls (Cohen d = 0.53, 95% confidence interval [CI] 0.18 to 0.88; Cohen d = 0.51, 95% CI 0.21 to 0.81, respectively) or the non-Li group (Cohen d = 0.93, 95% CI 0.56 to 1.31; Cohen d = 1.07, 95% CI 0.70 to 1.45, respect ively), which had smaller left and right hippocampal volumes than the control group (Cohen d = –0.36, 95% CI –0.55 to –0.17; Cohen d = –0.38, 95% CI –0.63 to –0.13, respectively). There was no evidence of publication bias.

Limitations: Missing information about the illness burden or lifetime expos ure to Li and polypharmacy in some studies may have contributed to statistical heterogeneity in some analyses.

Conclusion: When expos ure to Li was minimized, patients with bipolar disorder showed smaller hippocampal volumes than controls or Li-treated patients. Our findings provide indirect support for the negative effects of bipolar disorder on hippocampal volumes and are consist ent with the putative neuroprotective effects of Li. The preserved hippocampal volumes among patients with bipolar disorder in most individual studies and all previous meta-analyses may have been related to the inclusion of Li-treated participants.

Submitted Oct. 4, 2011; Revised Dec. 30, 2011; Jan. 14, 2012; Accepted Jan. 17, 2012.

Acknowledgements: This study was supported by funding from the Canadian Institutes of Health Research, the Nova Scotia Health Research Foundation, the Ministry of Health of the Czech Republic (MZ0PCP2005) and a Dalhousie Clinical Research Scholarship to T. Hajek. The sponsors of the study had no role in the design or conduct of this study; in the collection, management, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript.

Competing interests: None declared.

Contributors: All authors designed the study, analyzed the data, reviewed the article and approved its publication. T. Hajek and M. Kopecek acquired the data. T. Hajek wrote the article.

DOI: 10.1503/jpn.110143

Correspondence to: T. Hajek, Department of Psychiatry, Dalhousie University, Queen Elizabeth II Health Sciences Centre, A.J. Lane Bldg., Room 3093, 5909 Veteran’s Memorial Lane, Halifax NS B3H 2E2;