Findings from Arnone et al's ^{Reference Arnone, Cavanagh, Gerber, Lawrie, Ebmeier and McIntosh1} systematic review and meta-analysis of magnetic resonance imaging (MRI) studies suggest that patients with bipolar disorder are characterised, in comparison with healthy controls, by significant reductions of whole-brain and prefrontal lobe volumes and by enlargement of lateral ventricles and globus pallidus, although most of the brain changes detected in bipolar disorder do not seem to be diagnostically specific and some clinical variables, such as patients' age, duration of illness and pharmacological treatment, appear to be relevant in determining the magnitude of observed effect sizes.

These findings are not completely consistent our own recent meta-analysis ^{Reference Vita, De Peri and Sacchetti2} of MRI studies in first-episode bipolar disorder. Our study did not evidence whole-brain volume deficits in first-episode bipolar disorder compared with healthy controls. This may indicate that a progressive decrease of whole-brain volume occurs over the course of the disease, and might be detectable only when multi-episode or chronic cases are considered. This is confirmed by the correlation found between gray matter loss and duration of illness in the meta-regression performed by Arnone et al ^{Reference Arnone, Cavanagh, Gerber, Lawrie, Ebmeier and McIntosh1} and by the results of longitudinal studies demonstrating gray matter volume loss over time in the prefrontal cortex in young adults with bipolar disorder ^{Reference Kalmar, Wang, Spencer, Edmiston, Lacadie and Martin3} or of cross-sectional comparisons between first- and multiple-episode bipolar disorder showing more severe brain abnormalities in patients with multiple episodes of illness. ^{Reference Strakowski, DelBello, Zimmerman, Getz, Mills and Ret4}

On the other hand, we did find a significant decrease of total white matter volume in first-episode bipolar disorder, while Arnone et al ^{Reference Arnone, Cavanagh, Gerber, Lawrie, Ebmeier and McIntosh1} failed to obtain the same finding in their analysis of a larger number of studies mainly conducted in patients with chronic illness. This may indicate that alterations in white matter normal growth may constitute early and primary abnormalities in bipolar disorder, consistent with some preliminary evidence of the association between patterns of disturbed structural white matter integrity in bipolar disorder and genetic liability for the illness. ^{Reference Chaddock, Barker, Marshall, Schulze and Hall5} In order to explain the lack of white matter volume reduction in chronic illness, it could be hypothesised either that other, more generalised brain changes may override white matter abnormalities over the course of the disease, or that white matter changes may be attenuated by treatment or, again, may be less sensitive to the later effects of ageing. Indirect support for this idea derives from the finding of smaller volumetric differences in the temporal lobes in bipolar disorder with increasing age, duration of illness and use of mood stabilisers, ^{Reference Arnone, Cavanagh, Gerber, Lawrie, Ebmeier and McIntosh1} the only discrete brain volume including white matter analysed in the meta-regressions performed by Arnone et al.

In conclusion, the finding of different brain abnormalities in chronic v. first-episode bipolar disorder supports the notion of different pathophysiological trajectories of specific brain morphological characteristics over the course of the disease and emphasises the need for further longitudinal studies aimed at addressing specifically the issue of the time of appearance and course of individual brain abnormalities in bipolar disorder, from which may derive a better understanding of the pathogenesis of the disease itself.