In vivo relationship between serotonin 1A receptor binding and gray matter volume in the healthy brain and in major depressive disorder.

Serotonin 1A (5-HT1A) receptors mediate serotonin trophic role in brain neurogenesis. Gray matter volume (GMV) loss and 5-HT1A receptor binding alterations have been identified in major depressive disorder (MDD). Here we investigated the relationship between 5-HT1A receptor binding and GMV in 40 healthy controls (HCs) and, for the first time, 47 antidepressant-free MDD patients using Voxel-Based Morphometry and [11C]WAY100635 Positron Emission Tomography. Values of GMV and 5-HT1A binding (expressed as BPF, one of the types of binding potentials that refer to displaceable or specific binding that can be quantified in vivo with PET) were obtained in 13 regions of interest, including raphe, and at the voxel level. We used regression analysis within each group to predict GMV from BPF, while covarying for age, sex, total gray matter volume and medication status. In the HCs group, we found overall a positive correlation between terminal field 5-HT1A receptor binding and GMV, which reached statistical significance in regions such as hippocampus, insula, orbital prefrontal cortex, and parietal lobe. We observed a trend towards inverse correlation between raphe 5-HT1A autoreceptor binding and anterior cingulate GMV in both groups, and a statistically significant positive correlation between raphe 5-HT1A binding and temporal GMV in MDD. Analysis of covariance at the voxel-level revealed a trend towards interaction between diagnosis and raphe 5-HT1A binding in predicting GMV in cerebellum and supramarginal gyrus (higher correlation in HCs compared with MDD). Our results replicated previous findings in the normative brain, but did not extend them to the brain in MDD, and indicated a trend towards dissociation between MDD and HCs in the relationship of raphe 5-HT1A binding with postsynaptic GMV. These results suggest that 5-HT1A receptors contribute to altered neuroplasticity in MDD, possibly via effects predating depression onset.

Transcranial Magnetic Stimulation of Left Dorsolateral Prefrontal Cortex Induces Brain Morphological Changes in Regions Associated with a Treatment Resistant Major Depressive Episode: An Exploratory Analysis.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is an FDA-approved antidepressant treatment but little is known of its mechanism of action. Specifically, downstream effects of TMS remain to be elucidated. OBJECTIVE/HYPOTHESIS: This study aims to identify brain structural changes from TMS treatment of a treatment resistant depressive episode through an exploratory analysis. METHODS: Twenty-seven subjects in a DSM-IV current major depressive episode and on a stable medication regimen had a 3T magnetic resonance T1 structural scan before and after five weeks of standard TMS treatment to the left dorsolateral prefrontal cortex. Twenty-seven healthy volunteer (HVs) subjects had the same brain MRI acquisition. Voxel-based morphometry was performed using high dimensional non-linear diffusomorphic anatomical registration (DARTEL). RESULTS: Six clusters of gray matter volume (GMV) that were lower in pre-treatment MRIs of depressed subjects than in HVs. GMV in four of these regions increased in MDD after TMS treatment by 3.5-11.2%. The four brain regions that changed with treatment were centered in the left anterior cingulate cortex, the left insula, the left superior temporal gyrus and the right angular gyrus. Increases in the anterior cingulate GMV with TMS correlated with improvement in depression severity. CONCLUSIONS: To our knowledge, this is the first study of brain structural changes during TMS treatment of depression. The affected brain areas are involved in cognitive appraisal, decision-making and subjective experience of emotion. These effects may have potential relevance for the antidepressant action of TMS.

Omega-3 polyunsaturated fatty acid supplementation and white matter changes in major depression.

White matter abnormalities are implicated in major depressive disorder (MDD). As omega-3 polyunsaturated fatty acids (PUFAs) are low in MDD and affect myelination, we hypothesized that PUFA supplementation may alleviate depression through improving white matter integrity. Acutely depressed MDD patients (n = 16) and healthy volunteers (HV, n = 12) had 25-direction diffusion tensor imaging before and after 6 weeks of fish oil supplementation. Plasma phospholipid omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and omega-6 PUFA arachidonic acid (AA) levels were determined before and after supplementation using high-throughput extraction and gas chromatography and expressed as a percentage of total phospholipids (PUFA%). Fractional anisotropy (FA) was computed using a least-squares-fit diffusion tensor with non-linear optimization. Regression analyses were performed with changes in PUFA levels or Hamilton Depression Rating Scale scores as predictors, voxel-wise difference maps of FA as outcome, covariates age and sex, with family-wise correction for multiple comparisons. Increases in plasma phospholipid DHA% (but not EPA% or AA%) after fish oil predicted increases in FA in MDD but not HV, in a cluster including genu and body of the corpus callosum, and anterior corona radiata and cingulum (cluster-level p < 0.001, peak t-score = 8.10, p = 0.002). There was a trend for greater change in FA in MDD responders over nonresponders (t = -1.874, df = 13.56, p = 0.08). Decreased depression severity predicted increased FA in left corticospinal tract and superior longitudinal fasciculus (cluster-level p < 0.001, peak t-score = 5.04, p = 0.0001). Increased FA correlated with increased DHA% and decreased depression severity after fish oil supplementation suggests therapeutic effects of omega-3 PUFAs may be related to improvements in white matter integrity.

Cortical thickness differences between bipolar depression and major depressive disorder.

OBJECTIVES: Bipolar disorder (BD) is a psychiatric disorder with high morbidity and mortality that cannot be distinguished from major depressive disorder (MDD) until the first manic episode. A biomarker able to differentiate BD and MDD could help clinicians avoid risks of treating BD with antidepressants without mood stabilizers. METHODS: Cortical thickness differences were assessed using magnetic resonance imaging in BD depressed patients (n = 18), MDD depressed patients (n = 56), and healthy volunteers (HVs) (n = 54). A general linear model identified clusters of cortical thickness difference between diagnostic groups. RESULTS: Compared to the HV group, the BD group had decreased cortical thickness in six regions, after controlling for age and sex, located within the frontal and parietal lobes, and the posterior cingulate cortex. Mean cortical thickness changes in clusters ranged from 7.6 to 9.6% (cluster-wise p-values from 1.0 e-4 to 0.037). When compared to MDD, three clusters of lower cortical thickness in BD were identified that overlapped with clusters that differentiated the BD and HV groups. Mean cortical thickness changes in the clusters ranged from 7.5 to 8.2% (cluster-wise p-values from 1.0 e-4 to 0.023). The difference in cortical thickness was more pronounced when the subgroup of subjects with bipolar I disorder (BD-I) was compared to the MDD group. CONCLUSIONS: Cortical thickness patterns were distinct between BD and MDD. These results are a step toward developing an imaging test to differentiate the two disorders.