Tryptophan depletion studies depression

Possibly the best evidence suggesting involvement of norepinephrine and serotonin in major depressive disorder devolved from depletion studies (Delgado et al., 1990). In these stndies, patients who have responded to treatment for depression are given procedures, which deplete brain levels of serotonin or norepinephrine. Serotonin levels are decreased by nse of a low monoamine diet, followed by a drink which inclndes all the amino acids except the serotonin precnrsor tryptophan. Norepinephrine levels are depleted by administration of alpha-methylparatyrosine. In patients who had responded to treatment with a serotonergic antidepressant, depletion of serotonin cansed a prompt and dramatic, but brief reoccurrence of the symptoms of major depression. In patients who had responded to treatment with a noradrenergic antidepressant, depletion of norepinephrine caused a relapse into depression. The converse was not true in other words, serotonin depletion did not canse relapse in patients who responded to noradrenergic antidepressants, and vice versa. 

The involvement of the central nervous system serotonin function in the pathogenesis and treatment of affective disorders has been a subject of intensive research during the past 30 years.33 36 Studies using serotonin precursors and agonists as pharmacologic probes and measurements of cerebrospinal fluid monoamine metabolite levels indicated that alterations in central nervous system serotonin function may be involved in the pathophysiology of depression. Since the synthesis of serotonin depends on dietary intake of the precursor tryptophan, many studies have utilized tryptophan depletion techniques by which patients were fed a tryptophan-free diet for various time intervals. 

Delgado et al.20 studied the behavioral effects of rapid (24 h) tryptophan depletion in patients in antidepressant-induced remission. Patients receiving antidepressants leading to remission were then given a tryptophan-free amino acid drink, and they experienced a depressive relapse. Free plasma tryptophan level was negatively correlated with the depression score during acute tryptophan depletion. A number of other studies on the effects of tryptophan depletion on relapse of depression after treatment confirmed the previous findings.37 11... 

Sharma et al.69 utilized the acute tryptophan depletion paradigm to evaluate patients with schizophrenia under controlled conditions. They observed no clinical or statistically significant improvement in symptoms compared to baseline when tryptophan depletion was imposed. The authors considered that their findings with schizophrenic or schizoaffective patients (treated but still symptomatic) may differ from those in untreated symptomatic patients. Other studies with the effects of tryptophan depletion differ markedly in treated remitted vs. untreated symptomatic depressed patients.20 70... 

In general, the results of experimental studies in patients with PMS have given mixed results on whether there is lowered serotonin function in these patients. Menkes et al.84 reported that acute tryptophan depletion aggravated symptoms, particularly irritability, for women with PMS compared to controls. Ellenbogen et al.85 reported that tryptophan depletion caused a modest lowering of mood in healthy women without PMS and with no family history of depression. On the other hand, Benkelfat et al.86 reported no lowering of mood in healthy male subjects with no history of depression. 

A recent study showed that immunotherapy with IFN-a was follov ed by an increase of depressive symptoms and serum kynurenine concentrations on the one hand, and reduced concentrations of tryptophan and serotonin on the other hand (Bonaccorso et al., 2002). The kynurenine/tryptophan ratio, which reflects the activity of IDO, increased significantly. Changes in depressive symptoms v ere significantly positively correlated vdth kynurenine and negatively correlated with serotonin concentrations (Bonaecorso etal., 2002). This study and others (Capuron et al., 2003) clearly show that the IDO activity is increased by IFN, leading to an increased kynurenine production and a depletion of tryptophan and serotonin. The further metabolism of kynurenine, however, seems to play an additional crucial role for the psychopathological states. 

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