Measurement of neopterin, kynurenine and tryptophan in sera of schizophrenic patients

Summary

Neopterin can be regarded as a sensitive marker of the activity of cellmediated immunity. In chronic schizophrenic outpatients as well as in acute schizophrenic inpatients neopterin values were found within the normal range. Acutely ill schizophrenic patients had lowest neopterin levels at the day of admission, showing significantly decreased values when being compared to matched controls. Kynurenine data showed the same development as neotperin whereas tryptophan levels were rather unchanged.

These results support the hypothesis of an immune dysfunction in the acute state of schizophrenia.

Immunology being involved in the pathophysiology or in the etiology of schizophrenia has been addressed in numerous studies and although the results are controversial there are at least three hypotheses left which can be supported by the most consistent immunologic findings:

• - an autoimmune process being involved in schizophrenic disorder (Knight, 1985; Ganguli, 1993, 1994)

• - a viral infection or even slow virus infection being the cause of schizophrenic illness (Goodall, 1932; Menninger, 1928; Crow, 1984; DeLisi und Crow, 1986)

• - an immunological dysregulation mainly refering to the T-cell system due to a yet unknown mechanism (Sperner-Unterweger, 1989; Hornberg, 1995; Rothermundt, 1996).

In the three outlined hypotheses the expected immunologic alterations are primarily refering to cell-mediated immunity (CMI). Assessing the activity of CMI, neopterin, a low molecular weight compound deriving biosynthetically from guanosine triphosphate can be regarded as a sensitive and validated marker (Fuchs, 1988). It is released in large quantities mainly by activated cells of the monocyte/macrophage lineage which have been stimulated by gamma-interferon (IFN-gamma) derived from activated T-cells (Huber, 1984; Werner, 1989; Wachter, 1992). Increased neopterin excretion in urine or in serum was demonstrated in diseases connected to cellular immune mechanisms (e.g., acute viral infections, graft vs. host disease, Aids) (Fuchs, 1988).

In two previous studies we measured urinary neopterin in chronic schizophrenic outpatients as well as in patients admitted to hospital due to acute schizophrenic psychosis (Sperner-Unterweger, 1989, 1992). For both patients groups neopterin levels were found within the normal range and the comparison between chronic schizophrenic patients and healthy controls did not show a statistically significant difference. Inpatients with acute symptomatology had lowest neopterin values at the day of admission, showing a statistically significant difference when being compared to healthy, sex- and age-matched controls (p < 0.01). After 7 days of treatment in hospital neopterin normalized and did not show any further differences in comparison to healthy probands. Evaluating the correlation between neopterin und psychopathology a positive correlation was found for patients suffering from chronic schizophrenia of the residual type whereas inpatients suffering from acute schizophrenia of the paranoid type showed a negative correlation (Sperner-Unterweger, 1989, 1992).

In a more recent study neopterin values, measured in sera of acutely ill schizophrenic patients, were found with the lowest concentrations at the day of admission followed by a significant increase at the end of treatment which consequently led to a significant difference in the comparison between schizophrenic patients and healthy controls (p < 0.03). The increase of neopterin observed in this study does not support the hypothesis of an CMI-activation in acute schizophrenia because neopterin values still remained inside the 95th percentile of age-matched controls. In accordance with our previous investigations (Sperner-Unterweger, 1989, 1992) and with the data published by Dunbar (1992) these results militate against the active involvement of viruses in the etiology of acute schizophrenia since neopterin can be regarded as a sensitive marker of viral infection such presenting with much higher neopterin values then those found in this study (Wachter, 1989). Similarly, the mainly normal neopterin values measured in these acutely ill schizophrenic patients stand in marked contrast to the elevations observed in autoimmune diseases (Wachter, 1989). It is important to note, however, that while CMI does not appear to be activated in these patients, the possibility remains that CMI might have been active earlier in the course of their illness, perhaps causing damage well before schizophrenia was clinically evident. Although in this study lowest neopterin values were found in the acute state of the illness followed by a slight increase occuring concomitantly with a continous stabilization of psychopathology it seems rather unlikely that antipsychotic medication could be responsible for this development because neither our group nor Dubar (1992) found an influence of medication on neopterin levels (Sperner-Unterweger, 1989, 1992).

Besides measuring neopterin, tryptophan and kynurenine concentrations were also evaluated in serum of the acutely ill schizophrenic patients. The kynurenine data of this investigation showed the same development as neopterin with lowest values on day 0 followed by a significant increase during treatment without presenting remarkable elevations which would be expected in the state of immune stimulation due to an acceleration of the kynurenine pathway metabolism (Heyes, 1992).

By interpreting the tryptophan data one has to keep in mind that tryptophan is substrate for two enzymic pathways: (1) tryptophan-5- hydroxylase converts tryptophan to 5-hydroxy-tryptophan to finally form the neurotransmitter 5-hydroxy-tryptamine (serotonin), (2) tryptophan pyrrolase and indoleamine (2,3)-dioxygenase (IDO) respectively, catalyse the degradation of tryptophan via the kynurenine pathway. The activity of tryptophan-5-hydroxylase as well as degradation of trytophan by IDO are both directly and indirectly associated with immune activation. IFN-gamma, released during states of cellular immune activation, will activate GTP-cyclohydrolase I in various cells, the key enzyme for the biosynthesis of pteridines. In most cells this will lead to increased formation of 5, 6, 7, 8-tetrahydrobiopterin and initiate the formation of serotonin if tryptophan 5-hydroxylase is present (Fuchs, 1991). By contrast, in human monocytes/macrophages large amounts of neopterin are formed instead of tetrahydrobiopterin (Fuchs et al, 1988; Werner, 1989). Our data presenting rather unchanged tryptophan levels during the observation periode do not support an acute state of CMI activation. Small fluctuations of tryptophan levels are probably due to changes in nutrition, assuming that some acutely ill schizophrenic patients do not eat regularly as long as they are outpatients; with admission to hospital they get regular meals containing sufficient amounts of essential aminoacids like tryptophan. The low kynurenine levels in patients at study entry would support the view of decreased endogenous levels of IFN-gamma.

Another study dealing with T-cell-subsets in schizophrenia showed highest values of total T-lymphocytes (CD3+) and T-helper cells (CD4+) in the acute state of schizophrenic psychosis, whereas remitted patients showed normal values. In contrast, NK-cells were found with lowest counts in acutely ill patients followed by normalization in remission of psychosis. Summarizing the results of these studies dealing with the cell mediated immune system in schizophrenia, the hypothesis of an immune dysfunction in the acute state of the illness is supported by low or subnormal neopterin, low kynurenine, low NK- cells, elevated CD3+ and CD4+ cells. These observations could be due to an inbalance of the TH-1 and TH-2 immunity (subclassification of T-helper-cells) (Parker, 1993). Decreased or low neopterin point to low or decreased production of IFN-gamma in schizophrenia. TH-1 and TH- 2 derived cytokines negatively regulate the production of each other (Romagnani, 1994). This data would support the concept of a diminished TH-1 type immune response probably due to an activated TH-2 type immune response. The changed balance of these T-helper subtypes would be typical for a chronic infection. However, serological studies will be needet to confirm this assumptions.