THE CEREBRAL DIABETES PARADIGM FOR UNIPOLAR DEPRESSION

Unipolar depression, alcoholism and suicide have become more common ov er the past decades. Genetic studies have attempted to link (bipolar) affective disorder to the short arm of chromosome 11 (where the loci f or insulin, insulin growth factor (IGF), tyrosine hydroxylase (TH) and h-ras-oncogene are located) but these have failed. Since TH and the i nsulin receptor require phosphorylation by protein kinases, then a def ect of the h-ras-oncogene or its products (p21) could disorder both th ese systems and compromise catecholaminergic transmission in neurones and energy flow in glial cells. This could lead not only to a predispo sition to depression ('trait markers') but to neurotoxic damage, predi sposed by inadequate cytosol Mg2+ levels or hypometabolism. Tyrosine, tryptophan and phenylalanine hydroxylases all require tetrahydrobiopte rin (BH4) which allosterically regulates its own activity as well as t hat of these enzymes. Anything which impairs this cofactor could lead to overt depression in predisposed individuals, and the heterocyclic a mines are being increasingly implicated. These substances are derived from fried and broiled meats, azo food dyes, soft drinks and hard cand ies, but particularly from cigarette and petroleum fumes. The heterocy clic amines can inhibit aromatic-I-amino-acid-decarboxylase (AADC) as well as the hydroxylases reversibly, but BH4 is inhibited noncompetiti vely. Thus, susceptible individuals (those with inherited defective pr otein kinase phosphorylation) might be 'tipped over' by chronic exposu re to these neurotoxins. The rising incidence of unipolar depression-a ssociated morbidity could be significantly linked to increasing levels of heterocyclic amines in the developed nations.