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Background This study compared diurnal variation in mood and regional cerebral metabolic rate of glucose (rCMRglc) in depressed and healthy subjects. Methods Depressed and healthy subjects were investigated using [ 18 F]-fluoro-deoxyglucose positron emission tomography scans during morning and evening wakefulness. All subjects completed subjective mood ratings at both times of day. Statistical parametric mapping was used to compare rCMRglc between the two groups across time of day. Results Depressed patients showed evening mood improvements compared with healthy subjects. Compared with healthy subjects, depressed patients showed smaller increases in rCMRglc during evening relative to morning wakefulness in lingual and fusiform cortices, midbrain reticular formation, and locus coeruleus and greater increases in rCMRglc in parietal and temporal cortices. Depressed patients had hypermetabolism in limbic-paralimbic regions and hypometabolism in frontal and parietal cortex at both times of day compared with healthy subjects. Conclusions Variation in rCMRglc differs across times of day in depressed and healthy subjects. In depressed patients, evening mood improvements were associated with increased metabolic activity in ventral limbic-paralimbic, parietal, temporal, and frontal regions and in the cerebellum. This increased metabolic pattern during evening wakefulness may reflect partial normalization of primary and compensatory neural systems involved in affect production and regulation.