Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder
Research Highlights
► Depressed patients have reduced prefrontal gray matter compared to healthy controls. ► Those abnormalities localize to the visceromotor network implicated in depression. ► Depressed patients in remission show no areas of reduced gray matter. ► Greater gray matter might be associated with better clinical outcome.
Introduction
Voxel-based morphometry (VBM) is a fully automated method for analyzing neuromorphological MRI data that allows unbiased investigation of inherent differences in brain structure between clinical and control samples. This approach has been applied to identify neuromorphometric abnormalities in various neurodegenerative and psychiatric disorders, including major depressive disorder (MDD) (Ridgway et al., 2008, Ashburner and Friston, 2000). Structural abnormalities in MDD as reported in the VBM literature encompass regions belonging to the visceromotor network, including the orbitofrontal (OFC), subgenual prefrontal (SGPFC) and anterior cingulate cortices, and the hippocampus/amygdala complex (Tang et al., 2007, Wagner et al., 2008, Vasic et al., 2008, Leung et al., 2009, Frodl et al., 2008a, Treadway et al., 2009). However, the findings reported have been inconsistent, potentially due to experimental design differences across studies pertaining to patient selection, statistical power, or neuromorphometric methodology (Konarski et al., 2008). In addition, many published studies have used relatively small sample sizes (Tang et al., 2007, Wagner et al., 2008, Vasic et al., 2008, Leung et al., 2009, Treadway et al., 2009) or have not applied corrections for multiple testing (Tang et al., 2007, Wagner et al., 2008, Vasic et al., 2008, Leung et al., 2009). For example, decreased gray matter in the anterior cingulate cortex (ACC) has been described by some (Tang et al., 2007, Vasic et al., 2008) but not other studies (Pizzagalli et al., 2004), and the portion of the anterior cingulate affected has differed across the positive studies. Similarly, reduced amygdalar and hippocampal volume has been reported by some (Tang et al., 2007, Wagner et al., 2008), but not other studies (Frodl et al., 2008a, Treadway et al., 2009). According to recent evidence, hippocampal abnormalities might extend to treatment-naïve, first-episode MDD subjects, providing further evidence of the key role of this structure in the pathophysiology of depression (Zou et al., 2010).
It is noteworthy that in a study which employed a relatively large sample size (77 MDD patients and 77 healthy controls) and where statistical correction for multiple testing was used (Frodl et al., 2008a), structural gray matter (GM) reductions in MDD subjects were evident in cortical regions but not in subcortical structures, with the exception of the thalamus. However, most of the patients (79%) enrolled in this study were receiving antidepressant drugs at the time of scanning, potentially limiting the interpretability and generalizability of the results, particularly given previous evidence that these agents upregulate neurotrophin expression (Duman and Monteggia, 2006), contribute to neuronal remodeling (Bessa et al., 2009) and protect against gray matter loss (Lavretsky et al., 2005, Sheline et al., 2003). Therefore, whether prolonged periods of clinical remission or ongoing treatment with antidepressant medications influence gray matter volume or density remains unclear. Previous studies have shown that GM volumetric reductions associated with MDD persist in the subgenual anterior cingulate cortex (sgACC) after a mean of 4 months of effective antidepressant drug treatment (Drevets et al., 1997), while other reports suggest that chronic antidepressant treatment might protect against further gray matter loss in brain region involved in mood-regulation, such as the orbitofrontal cortex and the hippocampus (Lavretsky et al., 2005, Sheline et al., 2003). Nevertheless, reductions in hippocampal gray matter persisted in unmedicated MDD subjects despite a prolonged period of clinical remission (Neumeister et al., 2005). Potentially highlighting the importance of clinical remission in preventing further reductions in GM, the results of a 3-year longitudinal study showed that depressed patients who experience stable clinical remission have less GM decline in the left hippocampus, left anterior cingulate, left dorsomedial prefrontal cortex and bilateral dorsolateral prefrontal cortex than patients who do not remit (Frodl et al., 2008b). In this study the proportion of subjects receiving antidepressant treatment did not differ between remitters and non-remitters, suggesting a potential link between greater gray matter and better clinical outcome independently from drug treatment. Notably, most of the patients participating in this study were receiving antidepressant medication at the time of first scan and a large proportion of them continued treatment throughout the follow-up period, thus limiting the interpretation of the findings. Nevertheless, taken together the results of these studies suggest that effective antidepressant drug treatment may protect against progressive GM loss without reversing extant reductions in GM volume, and raise the hypothesis that MDD patients who develop either less or no GM atrophy during depressive episodes show better outcomes during treatment.
Providing further support to the hypothesis that morphometric abnormalities might be related to illness chronicity and poor clinical outcome in depressed patients, in another VBM study Li and colleagues found that only patients who continued being symptomatic after a 6-week course of antidepressant treatment showed pre-treatment reductions in the dorsal anterolateral prefrontal cortex GM compared to healthy subjects, while these abnormalities were not apparent in subjects who experienced symptomatic remission (Li et al., 2010). However, it should be noted that those findings reflect acute response to antidepressant treatment rather than stable adaptive changes reflecting sustained clinical improvement.
The aim of the present study was to investigate GM abnormalities in unmedicated, currently-depressed patients and unmedicated patients with MDD in full remission using VBM. We hypothesized that currently depressed patients would show GM reductions relative to healthy controls and to persistently remitted MDD subjects in brain areas involved in the extended visceromotor network of structures that supports mood regulation (Drevets et al., 2008). Regional white matter (WM) differences between groups also were investigated.
Section snippets
Participants
Fifty-eight unmedicated patients who met DSM-IV criteria for a current major depressive episode (MDE) and either recurrent or chronic MDD (dMDD), twenty-seven remitted, unmedicated patients with a past history of at least two MDEs who currently met DSM-IV criteria for recurrent MDD in full remission (rMDD), and one hundred seven healthy controls (HC) participated (Table 1). Patients in remission with a history of single MDE were excluded from the study as well as dMDD patients who presented
Demographic data
Demographic and clinical characteristics of the participants appear in Table 1.The mean age and gender distribution did not significantly differ across the HC, dMDD and rMDD groups. The dMDD and rMDD groups did not significantly differ on illness duration or proportion of subjects who were drug-naïve, while we observed a significantly longer time without medications for the rMDD compared to the dMDD subjects. While three weeks and three months were the minimal drug-free periods for being
Discussion
This study constitutes the largest morphometric study of unmedicated MDD subjects and the first to include a sample of unmedicated MDD subjects in full remission. The currently depressed subjects showed reduced prefrontal cortical GM volume and density as compared to both HC subjects and remitted MDD subjects. The areas of decreased GM in dMDD patients versus healthy controls (Table 2, Table 3) localize to the areas of the superior, middle and inferior frontal gyri corresponding to the
Conclusions
In conclusion, in a relatively large sample of unmedicated subjects with MDD, we found neuromorphometric abnormalities in the prefrontal cortex, the anterior cingulate cortex, the insula and other regions belonging to the visceromotor network. Unmedicated MDD subjects in full remission did not show similar evidence of reduced GM, but instead demonstrated areas of increased GM relative both to healthy and depressed controls. Our study design was cross-sectional, so it remains unclear whether the
Financial disclosures
The author(s) declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. The authors declare that over the past 1 year WCD has received compensation from Pfizer Pharmaceuticals for consulting.
Dr. Zarate is listed as a
Acknowledgments
This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health.
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