SIR: Baumann et al.^R5W43261 recently published findings showing reduced volume of the external globus pallidus (GPe) in subjects with histories of unipolar and bipolar depression. The pallidal finding is of interest in light of previous results.

Depression is prominent in diseases that predominantly affect the globus pallidus, such as encephalitis lethargica^R5W43262 and Fahr's syndrome (FS).^R5W43263 There is some evidence suggesting predominant GPe involvement in FS.^R5W43263 In a study of focal subcortical lacunar infarcts, 89% of subjects with secondary major depression had pallidal lesions.^R5W43264 Left GPe lesions were significantly more common in these depressed subjects than in otherwise-identical control subjects. In another study, elderly depressed subjects had more pallidal and putaminal hyperintensities than nondepressed matched control subjects.^R5W43265 In another report, untreated depressed patients who committed suicide had selectively increased pallidal serotonin 5-HT_lD receptor binding.^R5W43266

The potential pathophysiological implications of these findings were set forth in our model of depression after pallidal lesions.^R5W43264 Briefly, dorsal GPe dysfunction disinhibits internal GP (GPi) neurons projecting to the parvocellular portion of the mediodorsal thalamus. This increases GPi inhibition of the thalamus, leading to reduced thalamocortical glutamatergic stimulation of dorsolateral prefrontal cortical areas. The model also predicts that increased ventral GPe inhibition on GPi neurons projecting to the magnocellular portion of the mediodorsal thalamus leads to enhanced ventral frontal inhibition on dorsolateral prefrontal cortex, resulting in depression. These states accord with metabolic data and structural findings in unipolar depression.^R5W43264 Consistent with this model, GPi stimulation^R5W43267 (inhibiting GPi) and ventroposterior pallidotomy^R5W43268 are reported to reduce depression in Parkinson's patients.

GPe abnormalities can be eclipsed by other structural pathology in neurological illness and are potentially subject to underascertainment. Careful attention to the GPe in depressive disorders, as undertaken in the study by Baumann et al., may further enhance our pathophysiological understanding of these conditions.