title: Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis.
abstract: 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, respectively), 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.
  
  
  CONCLUSIONS
  Missing information about the illness burden or lifetime exposure to Li and polypharmacy in some studies may have contributed to statistical heterogeneity in some analyses.
  
  
  CONCLUSIONS
  When exposure 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 consistent 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.
authors.affiliation: Department of Psychiatry, Dalhousie University, Halifax, NS, Canada. tomas.hajek@dal.ca
authors.forename: Tomas
authors.initials: T
authors.lastname: Hajek
authors.forename: Miloslav
authors.initials: M
authors.lastname: Kopecek
authors.forename: Cyril
authors.initials: C
authors.lastname: Höschl
authors.forename: Martin
authors.initials: M
authors.lastname: Alda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001284:Atrophy / Q000473:pathology; D001714:Bipolar Disorder / Q000188:drug therapy / Q000473:pathology*; D016022:Case-Control Studies; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D059906:Neuroimaging / Q000379:methods / Q000523:psychology / Q000706:statistics & numerical data*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D008094:Lithium