Hippocampal volume and verbal memory performance in late-stage bipolar disorder

Abstract

Studies about changes in hippocampal volumes in subjects with bipolar disorder (BD) have been contradictory. Since the number of manic episodes and hospitalization has been associated with brain changes and poor cognitive outcomes among BD patients, we have hypothesized that these variables could clarify this issue. We stratified subjects with BD in early (BD-Early), intermediate (BD-intermediate) and late (BD-Late) stages as a function of number of manic episodes and prior hospitalization. Then, we compared their hippocampal volumes and California Verbal Learning Test-II (CVLT-II) scores with healthy controls (HC) using the general linear model. A total of 173 subjects were included in the study (112 HC, 15 BD-Early, 30 BD-Intermediate, and 16 BD-Late). We found a significant group effect on hippocampus volume (F(3,167) = 3.227, p = 0.024). Post-hoc analysis showed that BD-Late subjects had smaller hippocampus than HC (p = 0.017). BD-Early and BD-Intermediate subjects showed no significant difference in hippocampus volume compared to HC and BD-Late subjects. The CVLT trial 1 to 5 scores were significantly different across the groups (F(3,167) = 6.371, p < 0.001). Post-hoc analysis showed that BD-Intermediate (p = 0.006) and BD-Late (p = 0.017) subjects had worse memory performance during immediate recall than HC, while the performance difference between BD-Early subjects and HC was not significant (p = 0.208). These findings add to the notion that BD is a neuroprogressive disorder with brain changes and cognitive impairment according to prior morbidity (number of manic episodes and hospitalization). Also, they suggest that hippocampus is a brain marker and a potential therapeutic target for patients at late stage.

Introduction

Lifetime prevalence of bipolar disorder (BD) is 2.1% worldwide, with subthreshold forms affecting another 2.4% (Merikangas et al., 2007). BD is associated with cognitive impairment even during periods of euthymia (Martínez-Arán et al., 2004, Barrett et al., 2009). Emergent evidence from systematic reviews in the field suggests an association between the number of manic episodes as well as psychiatric hospitalizations with neurocognitive decline (Robinson and Ferrier, 2006), particularly verbal memory impairment (Martínez-Arán et al., 2004). Not only cognition seems to be impaired in portion as a function of number of mood episodes in BD. There is evidence of overall brain atrophy in bipolar patients with multiple-episodes and a cross-sectional study showed that lateral ventricles were significantly larger in bipolar patients with multiple-episodes as compared to first-episode patients or healthy controls (Strakowski et al., 2002). Also, a recent study showed decreased volume of corpus callosum in BD women with more than 10 episodes and at least one psychiatric hospitalization (Lavagnino et al., 2015).

Hippocampus is essential for the acquisition, consolidation and retrieval of memory (Eichenbaum, 2000), which places it as an interesting structure to study the relations among cognitive impairment, brain changes, and number of manic episodes. However, studies of hippocampal volumes in BD patients have been contradictory so far, showing no changes (Brambilla et al., 2003, Altshuler et al., 2000, Bertolino et al., 2003), smaller volumes (Blumberg et al., 2003, Bearden et al., 2008), and even larger volumes in BD patients as compared to controls (Javadapour et al., 2010, van Erp et al., 2012). In addition, six meta-analyses did not show changes in hippocampal volumes in patients with BD (McDonald et al., 2004, Videbech and Ravnkilde, 2004, Kempton et al., 2008, Arnone et al., 2009, Bora et al., 2010, Ellison-Wright and Bullmore, 2010).

Thus we hypothesize that reduced hippocampal volumes and poorer verbal memory performance can be identified in patients with multiple episodes and hospitalizations but not in patients with fewer and less severe episodes. We set forth to assess hippocampal volume and verbal memory according to number of manic episodes and hospitalization in BD.