Our findings demonstrate that prefrontal, anterior paralimbic, and ventral striatal hypometabolism is present in bipolar depression. This network of structures has been consistently implicated in contributing to affective processing in health and having dysfunction in patients with mood disorders. This study demonstrates cerebral metabolic changes in a sample of bipolar disorder outpatients that more closely resembles those seen in clinical practice as opposed to inpatients with rapid cycling having only more treatment-resistant forms of the disorder. In Ketter et al.’s (2001)
study, participants were treatment-resistant and predominantly (81%) rapid cycling inpatients, and thus may have exhibited changes some of which were unique to such a population. Although some findings may be confined to treatment resistant and/or rapid cycling inpatient populations, our findings indicate that hypometabolism in the DLPFC (BA 9, 10, 46) that extended into the inferior (BA 44), middle (BA 10), and superior aspects of the prefrontal cortex apply in a sample of outpatients not specifically selected for rapid cycling or treatment resistance.
Our study provides evidence of an association between bipolar depression and absolute hypometabolism extended into the prefrontal cortex (BA 10/11), anterior cingulate cortex (BA 24/32), and the SGPFC (BA 25). Our findings regarding the SGPFC replicate those of Drevets et al. (Drevets et al., 1997
), who also reported decreased SGPFC metabolism in depressed bipolar patients relative to healthy controls. In the present study, the difference in metabolic rates between bipolar depressed patients and controls was more robust than that reported by Drevets et al., perhaps because of increased statistical power related to larger sample size or more severe depression in our sample.
Ketter et al. (2001)
reported that in their full sample of bipolar patients with a wide range of severity of depression, regions with inverse correlations between HAM-D scores and absolute metabolism that overlapped the middle frontal gyrus finding noted in the current study, but were more widespread. They also found direct correlations between HAM-D scores and relative metabolism in subcortical structures that were not seen in the current study. The more extensive correlational findings in Ketter et al.’s study could be related to their larger sample size and a greater range of severity of depression. However, it is also possible that the differences between our findings and those of Ketter et al. could reflect either pathological or compensatory changes associated with a more chronic, treatment-resistant course. Again, in view of our preliminary data regarding this issue, an adequately powered study comparing these distinct subgroups of bipolar disorder patients is needed to address these differences.
The present study partially replicated the findings of Kimbrell et al. (2002)
, who obtained FDG-PET scans from a sample of inpatients and outpatients diagnosed with varying degrees of severity of unipolar depression. A subsample of their more depressed (HAM-D ≥ 22) unipolar patients compared to healthy controls had decreased absolute metabolism in right DLPFC and bilateral medial prefrontal cortex and anterior paralimbic areas (around and encompassing the amygdala), bilateral temporal lobes (right more so than left) following the Sylvian fissure, and the insula.
Previous work employed various imaging conditions, subject populations, and provided variable results. We provide a tabular summary of previous cerebral metabolic studies of bipolar depression in . Most (Baxter et al., 1985
; Buchsbaum et al., 1986
; Martinot et al., 1990
), but not all (Tutus et al., 1998
), studies have demonstrated decreased prefrontal metabolism in bipolar depression. Of note however, Tutus et al. (1998)
employed a different radiotracer (99m
Tc-HMPAO) than used in all the remaining studies (FDG), which may have contributed to their failure to detect prefrontal hypometabolism. We did not find evidence of relative hypermetabolism in the left amygdala as reported in some (Drevets, 1999
; Drevets et al., 2002
) but not all (Abercrombie et al., 1998
) prior studies of unipolar major depressive disorder. Ketter et al. found relative but not absolute increases in amygdala metabolism in treatment-resistant primarily rapid-cycling bipolar inpatients. It is possible that our sample size did not afford sufficient power to detect differences in amygdala metabolism, but our sample size was twice that of one study that reported increased amygdala metabolism (Drevets et al., 2002
) and less than that of another (Siegle et al., 2006
). Perhaps hypermetabolism in the amygdala is more common in unipolar depression than in bipolar depression or not as robust a finding as prefrontal hypometabolism.
Summary of cerebral metabolic studies of bipolar depression
In addition to the above-mentioned metabolic changes in structures implicated in affective processing, we also found absolute hypometabolism in the right precuneus. Appreciation of the functions of this region of association cortex is only beginning to emerge, but its high resting metabolic rate that decreases during non-self-referential goal-directed actions suggests it may contribute to self-consciousness, and self-related mental representations during rest (Cavanna and Trimble, 2006
). Thus, dysfunction in this region could be related to negativistic distortions of self that are observed in depressed bipolar disorder patients.
There are some factors that limit the generalizability of our findings. Resting FDG-PET is advantageous because it is unlikely to perturb cerebral metabolism as would task performance. However, resting scans have the drawback that subjects may engage in variable mental activities while resting. Though our sample size is larger than some prior imaging studies of depression, it is possible that it was not sufficiently large to enable us to detect more subtle regional differences. Similarly, the extent of the some of the regions of differential metabolism might differ somewhat with a larger sample.
The present study provides additional evidence of decreased cerebral metabolism in bipolar depression in the bilateral DLPFC, with the left side exhibiting a greater decrease relative to control subjects than the right. Moreover, we found that hypometabolism in bipolar depression extended to the bilateral insula, prefrontal cortices, anterior cingulate, and subgenual prefrontal cortex, and had regional correlations with degree of depression. In contrast, we failed to detect subcortical anterior paralimbic relative metabolic increases seen in some other studies. The absence of the latter finding could be related to sample size limitations in our study or differences in clinical features across studies. The patients in our sample were medication-free for at least 2 weeks, which lessens the possibility that our findings reflect treatment effects. Because our sample had a more varied composition that previous ones, our findings are not restricted to particular subpopulations of bipolar disorder. In summary, our data support the hypothesis that decreased prefrontal hypometabolism is a crucial and relatively robust finding in bipolar depression that is evident across different clinical samples, and even in samples such as the current study that include outpatients not specifically selected for treatment resistance or rapid cycling.