Durk Fekkes

The Effects of High-Dose and Low-Dose Tryptophan Depletion on Mood and Cognitive Functions of Remitted Depressed Patients.

It has frequently been demonstrated that acute tryptophan depletion (ATD) induces a transient depressed mood in some patients who are in remission from depression. However, the effects of ATD on cognitive processes in remitted depressed patients have not been investigated. The aim of the present study was to investigate the effects of different extents of depletion on mood and cognitive tasks involving neutral and emotional stimuli. Twenty patients in remission or in partial remission from depression received ATD in a double-blind, crossover design. Mood was assessed at both sessions before, at +6.5 h and +24 h afterdepletion. Cognitive assessment in both sessions started at +4.75 h, and also before and after the whole procedure. The ATD mixtures induced the expected reductions of plasma tryptophan levels. High-dose ATD induced a depressive response in a subsample of patients and impaired theprocessing of positive information independent of mood change. Attention for neutral stimuli (Stroop interference) improved in a dose-dependent manner. ATD may affect mood and cognition via different pathways: one implicated in mood regulation and the processing ofemotional information, and one for the processing of neutral information. The first pathway may be more important for discriminating vulnerability to impaired serotonin function. The comparison of the effects of high-dose and low-dose ATD is useful for those studies aiming to investigate the relationships among 5-HT, mood and cognition.

Abnormal amino acid metabolism in patients with early stage Alzheimer dementia

Summary. Plasma levels of several amino acids were studied in 14 patients with early stage probable Alzheimers disease (AD) and 17 age-matched controls. In the AD patients a possible relationship between amino acid levels and behavioural symptomatology was also investigated. We found significantly reduced levels of tryptophan and methionine in plasma samples from the AD patients compared to the control subjects. Moreover, plasma tyrosine/large neutral amino acids (LNAA) ratio and the ratio of plasma taurine and the product of the plasma levels of methionine and serine (TSM-ratio) were significantly increased in the AD patients in comparison with the controls. However, no difference was found in plasma tryptophan/LNAA ratio and in homocysteine levels between both groups. Concerning the behavioural symptomatology no significant correlation was found between the Reisberg Behave AD scale and plasma amino acid levels or ratios. The reported findings suggest that abnormal amino acid metabolism is present in the early stages of AD. We hypothesize that this abnormality could play a role in the pathogenesis of behavioural changes occurring in later stages of AD.

Atypical antipsychotics and the relevance of glutamate and serotonin

In the present study, including 66 schizophrenic patients and 73 healthy controls, the effect of atypical antipsychotic treatment over a period of 14 weeks on psychotic symptoms and plasma levels of glutamate and monoaminergic metabolites was investigated. Treatment induced a modest reduction of psychotic symptoms in 42% of the patients (response criterion: Brief Psychiatric Rating Scale [BPRS] decrease >/=40%). Poor response was associated with severity of psychopathology, age and duration of disease. Glutamate at baseline was significantly higher in patients as compared to controls (p<0.01). During treatment, a significant further increase of glutamate, not related to response, was observed. Glutamate levels correlated significantly with negative symptom scores at baseline and weeks 3, 6 and 14 (p<0.05). At baseline, serotonin (5-HT) in plasma and 5-HT in platelets were significantly lower in the poor responders as compared to controls (p<0.05) and increased significantly during treatment (p<0.05). In the responders, treatment coincided with a decrease of 5-HT parameters. No differences in plasma levels of HVA, 5-HIAA and their ratio were observed between controls and response groups. The results of this study suggest an effect of atypical antipsychotics on glutamatergic neurotransmission and an association between lower pretreatment peripheral 5-HT parameters and response.

Bipolar mania and plasma amino acids: Increased levels of glycine

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.

Amino acids in schizophrenia: evidence for lower tryptophan availability during treatment with atypical antipsychotics?

Summary.Amino acids play a role in neurotransmitter availability in the central nervous system, in that e.g. the synthesis of brain serotonin depends on the concentration of its precursor tryptophan. Disturbances in amino acid metabolism have been implicated in the pathophysiology of schizophrenia.In the present study the effect of a 14 week treatment with atypical antipsychotics on the plasma levels of amino acids was investigated in patients with schizophrenia and compared to normal controls.Non-responders (≤20% decrease in BPRS at endpoint) demonstrated lower baseline values of methionine as compared to good responders (≥50% decrease in BPRS at endpoint; p<.05) and controls (p<.01). The ratio between tryptophan and the other large neutral amino acids (Trp/LNAA ratio) in poor-responders (<40%) decreased during treatment as compared to responders (≥40%; p<.05).It is concluded that poor or non-response to atypical antipsychotics may be associated with an impaired synthesis of serotonin in the central nervous system.

Effect of light therapy on biopterin, neopterin and tryptophan in patients with seasonal affective disorder

The serotonergic system is believed to play a key role in the pathophysiology of seasonal affective disorder (SAD). Tetrahydrobiopterin is an essential cofactor in the hydroxylation of tryptophan and, therefore, in the synthesis of serotonin, while neopterin is known as a marker of cell-mediated immune activity. The present study was designed to measure levels of biopterin, neopterin and tryptophan in plasma of 19 depressed patients with a history of SAD, before and after light therapy as well as in a control group. In the group of patients a significantly lower plasma biopterin and tryptophan level and a higher neopterin level was demonstrated. After light therapy, the level of biopterin increased to that of the controls but lowered again in summer. Neopterin concentrations remained on the same level after light therapy, whereas tryptophan levels increased slightly after light therapy and reached normal values in summer. It is concluded that the vulnerability for a depressive episode is enhanced by lowered levels of biopterin that, however, in SAD becomes symptomatically manifest in the presence of increased immune activity at the same time.

Schizophrenia-associated neural growth factors in peripheral blood. A review

In this paper we review the findings on neural growth factors in the peripheral blood of schizophrenia patients. The studies we review provide evidence for the fact that in schizophrenia the levels of growth factors in peripheral blood are disturbed. The most robust results (7 studies) are reported for S100B protein, which seems to be elevated in acute psychosis and in patients with predominant negative symptoms. We conclude that there are aberrant levels of growth factors in peripheral blood in schizophrenia patients, probably most notably in patients with negative symptoms. Large-scale longitudinal multivariate studies, investigating the levels of several growth factors at the same time might give insight in etiological processes and identify clinically useful subsets of patients within the heterogeneous schizophrenia sample.