While schizophrenia and bipolar disorder have been assumed to share phenotypic and genotypic features, there is also evidence for overlapping brain structural correlates, although it is unclear whether these relate to shared psychotic features. In this study, we used voxel-based morphometry (VBM8) in 34 schizophrenia patients, 17 euthymic bipolar I disorder patients (with a history of psychotic symptoms), and 34 healthy controls. Our results indicate that compared to healthy controls schizophrenia patients show grey matter deficits (p < 0.05, FDR corrected) in medial and right dorsolateral prefrontal, as well as bilaterally in ventrolateral prefrontal and insular cortical areas, thalamus (bilaterally), left superior temporal cortex, and minor medial parietal and parietooccipital areas. Comparing schizophrenia vs. bipolar I patients (p < 0.05, FDR corrected) yielded a similar pattern, however, there was an additional significant reduction in schizophrenia patients in the (posterior) hippocampus bilaterally, left dorsolateral prefrontal cortex, and left cerebellum. Compared to healthy controls, the deficits in bipolar I patients only reached significance at p < 0.001 (uncorr.) for a minor parietal cluster, but not for prefrontal areas. Our results suggest that the more extensive prefrontal, thalamic, and hippocampal deficits that might set apart schizophrenia and bipolar disorder might not be related to mere appearance of psychotic symptoms at some stage of the disorders.
Brain structural changes have been demonstrated in schizophrenia and bipolar disorder and interest has grown regarding areas of spatial overlap, in particular as both disorders share some clinical features and risk genes (Thaker, 2008). Given that brain structural changes are a putative endophenotype of schizophrenia and possibly bipolar disorder as well, the comparison of changes occurring in both disorders is of particular interest in understanding putative biomarker characteristics, for example with respect to specificity to a particular disorder or symptom characteristics.
Initial comparative studies have suggested that patients with schizophrenia might show volume loss in middle prefrontal and thalamic regions (McIntosh et al., 2004), and in total hippocampal volume (McDonald et al., 2006). Another study suggested more widespread prefrontal and temporal grey matter loss in schizophrenia, but not in bipolar disorder, for which sparing of cortical changes was observed (McDonald et al., 2005).
Subsequently, studies applying voxel-based morphometry (VBM) have been conducted to compare patients with schizophrenia and bipolar disorder. There has been some support from the notion of these initial studies that fronto-temporal grey matter deficits are more extensive in schizophrenia than in (psychotic) bipolar disorder (Brown et al., 2011, Molina et al., 2011, Ivleva et al., 2012 and Yuksel et al., 2012), but results have been rather inconclusive for the thalamus and hippocampus, which had been as further focus of earlier studies.
Another approach to compare brain structural changes has been to conduct meta-analyses of VBM studies in these disorders (Bora et al., 2012): the results indicate that the observed changes within the prefrontal areas may differ in location, with schizophrenia showing reductions in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) vs. fronto-insular reductions in bipolar disorder. Another aspect of this meta-analysis, which has been highlighted by a subsequent review of meta-analyses by Crow et al., is the issue of laterality (Crow et al., 2013): these authors identified a pattern of diverging laterality, which might be explained by the gender ratio across studies. Indeed, the meta-analysis by Bora et al. shows that the changes in bipolar disorder mostly manifest in the right hemisphere (e.g. right fronto-insular cortex, right subgenual/medial prefrontal, and right ACC/medial prefrontal cortex), while changes in schizophrenia studies more frequently show changes in right hemisphere structures (Bora et al., 2012). Differences in gender composition, esp. higher rates of male patients with schizophrenia, who might show more severe illness, might be a contributing factor.
However, such meta-analyses are limited as they normally do not include direct comparison between schizophrenia and bipolar disorder groups, and because it is also difficult to control for the numerous smaller systematic differences across studies, such as gender imbalance, details of VBM pre-processing and analyses. In fact, the current meta-analyses (Ellison-Wright and Bullmore, 2010, Yu et al., 2010 and Bora et al., 2012) do not take into account those original studies (mostly published after these meta-analyses), which directly compare schizophrenia vs. bipolar disorder cohorts, and they do not take into account the heterogeneity within the patient samples (esp. the bipolar cohorts), which often include both bipolar I and II patients, as well as those with and without psychotic symptoms.
In this study, we aimed to add new insight to the ongoing study of brain structural differences between schizophrenia and bipolar disorder. We focused on comparing schizophrenia patients with a subgroup of bipolar disorder patients with (previous) psychotic symptoms, using an updated version of VBM, as implemented in the VBM8 toolbox, and restricting recruitment of patient to those in remission. Based on the cited previous studies, we hypothesised that schizophrenia patients would show volume reductions in DLPFC, thalamus, and hippocampus, exceeding those seen in (euthymic) bipolar disorder patients.
