Decreased plasma tryptophan and tryptophan/large neutral amino acid ratio in patients with neuroleptic-resistant schizophrenia: relationship to plasma cortisol concentration.

Tryptophan is the precursor of kynurenine and kynurenic acid, an α-7 nicotinic acetylcholine receptor antagonist and a N-methyl-D-aspartate (NMDA) receptor antagonist, both of which have been implicated in schizophrenia (SCH), as well as of serotonin. Glucocorticoids can activate the tryptophan-kynurenine pathway and lower plasma tryptophan concentrations. Some previous studies have reported decreases in the plasma tryptophan concentration and the tryptophan/large neutral amino acid (LNAA) ratio, a measure reflecting the brain tryptophan concentration, in patients with SCH. However, the influence of plasma cortisol, which has been reported to be increased in patients with SCH, on plasma tryptophan levels has not been examined in prior studies. Thus, we examined plasma tryptophan concentrations, tryptophan/LNAA ratios, and their relationships with plasma cortisol concentrations in treatment-resistant SCH (TR-SCH) patients, in non-treatment-resistant SCH (NTR-SCH) patients, and in normal controls (NC). Plasma tryptophan concentrations were significantly lower in TR-SCH patients (n=74) than in NTR-SCH patients (n=85) and NC subjects (n=55). In addition, tryptophan/LNAA ratios were significantly lower in TR-SCH patients than in NC subjects. No difference was observed in either measure between NTR-SCH patients and NC subjects. Tryptophan/LNAA ratios and plasma tryptophan concentrations showed a significant negative correlation and a trend-level correlation, respectively, with plasma cortisol concentrations in TR-SCH patients, but not in NTR-SCH patients or in NC subjects. These results suggest the tryptophan-kynurenine pathway may be particularly relevant to TR-SCH and that this may be influenced by the activity of the hypothalamic-pituitary-adrenal axis.