Structural changes in subcortical nuclei may underlie clinical symptoms of mood disorders. The goal was to determine whether macrostructural changes exist in brain areas assumed to be involved in regulation of mood and whether such changes differ between major depressive disorder and bipolar disorder. A case-control design was used to compare volumes of all major subcortical nuclei. Brains of patients with major depressive disorder (n = 9) or bipolar disorder (n = 11) or of individuals without a neuropsychiatric disorder (n = 22) were included. Exclusion criteria were a history of substance abuse or histological signs of neurodegenerative disorders. Volumes of the striato-pallidal nuclei, of the hypothalamus, thalamus, amygdala, hippocampus and basal limbic forebrain were determined in the right and left hemisphere by planimetry of 20 mum whole brain serial paraffin sections. Comparisons between patients with bipolar disorder, major depressive disorder and controls showed a significant (Lambda = 0.35, F(20,56) = 1.93, P = 0.028) overall difference in volumes of all investigated regions with strong effect sizes ( f > 0.40) contributed by the hypothalamus, external pallidum, putamen and thalamus. As compared to controls, a strong effect size (f > 0.40) was found in the bipolar group for smaller volumes of the hypothalamus, external pallidum, putamen and thalamus,whereas in patients with major depressive disorder a strong effect size was only found for a smaller volume of the external pallidum. In conclusion our data suggest that pathways presumably involved in mood regulation have structural pathology in affective disorders with more pronounced abnormalities in bipolar disorder.
Alterations of GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Gamma-aminobutyric acid (GABA) acts via binding to A and B receptors, whereas the B receptor is G protein-coupled. Glutamic acid decarboxylase (GAD) is the key enzyme of GABA synthesis. Immunohistochemical staining of GAD 65/67-immunoreactive neurons was performed in dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, superior temporal cortex, hippocampus formation, and mediodorsal thalamus with consecutive determination of neuronal density in 20 brains of patients with mood disorders (P) and 19 controls (C). In the patients' group were 11 patients with bipolar disorder (BD) and 9 patients with major depressive disorder (MDD). The data were tested statistically using analysis of variance (ANOVA) and post hoc Tukey tests. ANOVA revealed significant differences among the groups (C, BD, MDD) in dorsolateral prefrontal cortex, orbitofrontal cortex, superior temporal cortex, and hippocampus. Post hoc tests demonstrated higher neuronal densities in unipolar patients compared with bipolar patients and controls in dorsolateral prefrontal cortex, superior temporal cortex, and hippocampus. In the orbitofrontal cortex, a higher neuronal density was found in bipolar and unipolar patients compared with controls. In mood disorder patients, dose equivalents of antidepressants given prior to death correlated positively with the neuronal density in superior temporal cortex and hippocampus. The current data on GAD 65/67 point to a dysregulation of the GABAergic system in mood disorders. Possibly, existing deficits of GABAergic neurotransmission will be compensated or overcompensated by antidepressants. Additionally, albeit speculative, an imbalance between GABA production and transport might be of relevance.
Results indicate that patients with primary mood disorders have a circumscribed numerical neuronal deficiency in the dorsal raphe. This structural deviation may contribute to impaired serotonergic innervation of brain regions which are involved in the pathology of mood disorders.
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