اثر الکتروشوک درمانی بر روی بیوپترین و اسیدهای آمینه خنثی بزرگ در افسردگی شدید مقاوم در برابر دارو

Biopterin, neopterin and the large neutral amino acids (LNAA), i.e. phenylalanine, tyrosine, tryptophan, isoleucine, leucine and valine were measured in plasma of 20 severely depressed inpatients before and after a course of electroconvulsive therapy (ECT). These patients showed a significantly lower plasma biopterin concentration at baseline in comparison with healthy controls. After treatment an increase in biopterin was found, which was statistically significant in the depressed patients with psychotic features. The plasma phenylalanine–tyrosine ratio, which previously increased, normalised after ECT. Mean tryptophan concentration was lower in depressed patients than in normal controls. The patients who responded to ECT showed an increase in the tryptophan concentration and its ratio (tryptophan/LNAA) after treatment. Our results suggest that ECT increases biopterin, which probably results in synthesis of amino acids, especially tyrosine. Furthermore, ECT seems to increase cerebral tryptophan availability because of less tryptophan catabolism parallel with biopterin activation. More research is required to see if biopterin could be useful as a biological marker for the depressive state in this subgroup of patients, because this compound seems to play an important role in the etiology and treatment of depression.

The metabolism of biogenic amines has been hypothesised to play a key role in the pathophysiology of affective disorders. A functional deficiency of cerebral norepinephrine and serotonin is still the most widely accepted model for understanding the biology of depression and the therapeutic action of antidepressant treatments (Van Praag, 1982). Tetrahydrobiopterin (BH4) is the essential co-factor for the hydroxylation of phenylalanine, tyrosine and tryptophan, which is the rate-limiting step in the formation of dopamine, norepinephrine and serotonin, respectively (Kapatos et al., 1993 and Levine, 1988). Independent from its function as co-factor for the hydroxylation, BH4 also enhances the release of these neurotransmitters from nerve terminals (Mataga et al., 1991 and Wolf et al., 1991). A link between BH4 and both nitric oxide, a neuroendocrine modulator of the HPA axis, and the immune system has been hypothesised (van Amsterdam and Opperhuizen, 1999) BH4 is synthesised de novo from guanosine triphosphate (GTP), which is converted to dihydroneopterin triphosphate (NHPT3). The latter is converted by a series of tetrahydro intermediates to BH4. The concentration of cellular BH4 is dependent on this pathway and a salvage mechanism that converts quinonoid dihydrobiopterin to BH4 by the enzyme dihydropteridine reductase. Hydrolysis of NHPT3 yields dihydroneopterin, which is excreted in urine with its oxidative product neopterin, as are BH4 and its oxidative products, dihydrobiopterin and biopterin (Levine, 1988) (Fig. 1). Full-size image (2 K) Fig. 1. Biosynthesis of tetrahydrobiopterin and its effect on the hydroxylation of phenylalanine, tyrosine and tryptophan. Figure options Increased neopterin secretion is a sensitive marker of activation of cell-mediated immunity. Interferon-gamma, which is produced and secreted by activated T cells, is probably the most important activator of pteridine synthesis and release by activated cells of the monocyte/macrophage lineage (Hüber et al., 1984 and Maes et al., 1994). Immune activation not only increases synthesis of pteridines but also tryptophan catabolism through induction of indoleamine-2,3-dioxygenase (IDO) and will therefore, influence serotonin metabolism (Maes et al., 1993). There is evidence for immune-activation in depression (Maes et al., 1994). Indeed, plasma levels of tryptophan and the ratio of tryptophan to the sum of amino acids, which compete for the same cerebral uptake mechanism, i.e. phenylalanine, tyrosine, isoleucine, leucine and valine, have been found to be lower in depressed subjects than in normal control subjects (DeMyer et al., 1981 and Møller, 1985). Many studies have focused on the catecholamine hypothesis of depression (Schildkraut, 1965). Recent challenge studies have renewed interest in this theory (Berman et al., 1999). Levels of phenylalanine and tyrosine have been studied in depressed patients. A lower tyrosine level or a lower tyrosine ratio to competing amino acids is often reported. Antidepressant medication seems to have no effect on these measures (e.g. Møller et al., 1981). Anderson reported a reduction of the ratio of phenylalanine to tyrosine after response to ECT, suggestive of increased hydroxylation by BH4 after treatment (Anderson et al., 1994). Because of its role in dopamine, norepinephrine and serotonin metabolism, BH4 has been studied in depressed patients. Contradictory results have been reported (Abou-Saleh et al., 1995, Anderson et al., 1992, Blair et al., 1984, Bonaccorso et al., 1998, Coppen et al., 1989, Duch et al., 1984 and Garbutt et al., 1985). In these studies, however, urinary biopterin was measured. As can be expected from the metabolism and excretion of BH4, plasma measurements are not comparable with these results. Hashimoto and Knapp found an increased plasma biopterin in depressed patients (Hashimoto et al., 1990 and Knapp and Irwin, 1989). Methodological factors make these and several other studies difficult to compare. The population was often not well defined or not very restricted. ‘Major depression’ could represent too broad a spectrum of pathology for studying a biological marker. Besides, in these studies patients were using several psychotropic drugs. The same problems arise when studying neopterin, as mentioned above a known marker of immunity. An increase in the concentration of neopterin could be expected in plasma of depressed patients. However, recently O'Toole found no significant difference in plasma neopterin between patients and normal controls, while Maes and Dunbar found increased levels in urine (Dunbar et al., 1992, Maes et al., 1994 and O'Toole et al., 1998). Studying strictly selected, severely depressed, medication-free inpatients, we tried to answer the following questions: (1) Is the plasma concentration of biopterin lowered in this population, compared to normal controls, and is the neopterin concentration increased? (2) Are certain clinical features like psychotic symptoms or the response to treatment related to even lower concentrations of biopterin? (3) Is there an increase in plasma biopterin after effective treatment (ECT) with a reverse tendency for plasma neopterin? (4) Are the concentrations of the amino acids, on which tetrahydrobiopterin acts as a co-factor, changed before and after treatment? More specifically, is the phenylalanine–tyrosine-ratio, a known measure for hydroxylation activity of BH4, higher in the depressed population in comparison with normal controls and is this ratio lowered after successful treatment? And is tryptophan or the tryptophan ratio decreased before treatment and increased after that?