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Peptides regulate neuroendocrine and limbic system functioning in animals. Both systems show major disturbances in the affective disorders. Only thyrotropin releasing hormone (TRH), luteinizing hormone releasing hormone (LHRH), melanocyte stimulating hormone inhibiting factor (MIF-I), and 1-desamino-8-D-arginine vasopressin (DDAVP) have been administered to affectively ill patients. The thyroid stimulating hormone (TSH) response to TRH is blunted (≤5 μU/ml) in some patients during depression and mania and in alcoholics. The blunted response may be an important tool in the diagnosis of depression and mania. Together with other demonstrated endocrine abnormalities, the blunted TSH response suggests a profound alteration in the physiological relationship between the central nervous system and the anterior pituitary in affective illness. Behaviorally, TRH, LHRH, DDAVP, and MIF-I have general activating effects in humans that have not yet been demonstrated to be restricted to or specific to affective illness. The interpretation of peptide challenges, however, in the study of affective illness is obfuscated by the small number of patients used and the multiple sites that peptides at pharmacological doses may affect.