Previous studies have suggested that the N-methyl-d-aspartate (NMDA) glutamate receptor complex is implicated in the pathophysiology of several neuropsychiatric disorders. Especially the glycine coagonist site of this receptor has been proposed as a therapeutic target. It has been hypothesized that the NMDA receptor and the serotonergic system, which function is compromised in affective disorders, are functionally coupled. Furthermore, several studies suggest that peripheral levels of amino acids are associated with psychotic symptomatology. We therefore measured plasma levels of glutamate, glycine, tryptophan and the tryptophan ratio in 20 bipolar-I patients during the manic phase and at remission of symptomatology. Data were compared to a matched group of healthy controls and a group of euthymic bipolar-I patients. During the manic phase, a significant increase of both glutamate and glycine was found, that persisted at remission. Tryptophan and the tryptophan ratio were decreased in manic patients. Subsequent analysis showed that changes in glutamate, tryptophan and tryptophan ratio could be attributed to the use of anticonvulsants. The increased glycine, however, was not related to the use of mood stabilizers. Although the exact relationship between peripheral measures of amino acids, e.g., glycine is not fully clear, the results of this study suggest an involvement of glycine and/or its coagonist site of the NMDA receptor in a manic relapse of patients with a bipolar-I disorder.