• We reviewed the literature to determine the characteristics of corticosteroid-induced mental disturbances. We conclude that (1) while dosage may be correlated to the risk of developing mental disturbances, neither dosage nor duration of treatment seems to affect the time of onset, duration, severity, or type of mental disturbances; (2) euphoria, depression, and psychotic reactions are the common manifestations of corticosteroidinduced mental disturbances; (3) females seem to be more prone to these disturbances than males; (4) patients with past mental illness are not necessarily predisposed to such disturbances; and (5) corticosteroid-induced mental disturbances are usually reversible on dose reduction or discontinuation of the drug. At present there are no simple models to explain the psychotic reactions, anxiety, or agitation seen in corticosteroidinduced mental disturbances.

Side Effects of Corticosteroid Therapy: Psychiatric Aspects

Quantitative aspects of tryptophan metabolism in humans and other species: a review.

There is evidence for disturbances of indolealkylamine metabolism and of the pituitary-adrenal system in depression. Animal experiments indicate that these disturbances may be metabolically related through the enzyme tryptophan pyrrolase, synthesis of which depends upon adrenal activity. The possible significance of these changes in the development of depressive illness is discussed, as well as the therapeutic implications.

Tryptophan pyrrolase--a biochemical factor in depressive illness?

1 Two mechanisms have been proposed to explain the decline in brain tryptophan and 5-hydroxytryptamine (5-HT) after administration of hydrocortisone and the subsequent induction of liver pyrrolase. These are depletion of tryptophan by high rates of tryptophan catabolism and inhibition of tryptophan uptake by elevated levels of the tryptophan catabolite, kynurenine.2 The increase in plasma kynurenine after hydrocortisone injection (25 mg/kg) was small, and kynurenine, at a concentration ten fold greater, did not inhibit tryptophan uptake by brain as measured by the Oldendorf technique. Thus, inhibition of tryptophan uptake by kynurenine is not an important mechanism in the control of brain tryptophan and 5-HT.3 The decline in brain tryptophan after hydrocortisone was comparable to that seen in other tissues, which comprise more than half of the body weight of a rat.4 The total decline in free tryptophan stores in whole animals treated with hydrocortisone was estimated to be about 450 mug. This amount of tryptophan would be catabolized by tryptophan pyrrolase in about 20 min, when the enzyme is induced, according to an earlier estimate of the rate of tryptophan catabolism in vivo.5 Tryptophan pyrrolase activity remains high for much longer than 20 min, suggesting that there is net protein catabolism, which releases tryptophan and prevents non-protein tryptophan levels falling very far.6 These results demonstrate that the decline in brain tryptophan and 5-HT after hydrocortisone is caused by depletion of tryptophan stores due to the high activity of tryptophan pyrrolase. However, our data suggest that this effect is diminished by release of tryptophan from proteins. Thus, peripheral protein metabolism may be an important factor in the control of brain tryptophan levels and 5-HT synthesis.

Mechanism of decline in rat brain 5-hydroxytryptamine after induction of liver tryptophan pyrrolase by hydrocortisone: roles of tryptophan catabolism and kynurenine synthesis

Tryptophan is an indispensable amino acid in animal nutrition. Without it young animals cease to grow, and adult animals can no longer maintain nitrogen equilibrium. Hence, dietary intake is ultimately the starting point for any consideration of the regulation of the content of this amino acid in the CNS. Dietary deficiency of tryptophan results quickly in a decrease in the content of this amino acid in brain (Gessa et al., 1974; Dickerson and Pao, 1975). This depletion also accounts for the known decrease in tissue 5-hydroxytryptamine (5-HT, serotonin), including that of the brain (Eber and Lembeck, 1958; Gal and Drewes, 1962; Culley et al., 1963). Some species (e.g., pig and rat) can use D-tryptophan for part of their nutritional requirement (Baker et al., 1971) presumably converting it by way of oxidative deamination followed by asymmetric transamination to the L-amino acid. The rat can use the α-keto analogue of tryptophan for growth, but this compound is not as effective as the amino acid itself (Pond et al., 1964).

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Papers

Effect of chronic administration of cortisone on the tryptophan induced changes in amine levels in the rat brain.