Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signalling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan.

Serotonin: modulator of a drive to withdraw.

Serotonin is a fundamental neuromodulator in both vertebrate and invertebrate nervous systems, with a suspected role in many human mental disorders. Yet, because of the complexity of serotonergic function, researchers have been unable to agree on a general theory. One function suggested for serotonin systems is the avoidance of threat. We propose and review evidence for an alternative hypothesis, that a phylogenetically primitive of function of serotonin is to oppose the activating neuromodulators (particularly noradrenalin and dopamine). The functional effect of this opposition can be seen as applying a drive to withdraw from dangerous, aversive or high stimulation environments. Proposing that serotonin is involved in a drive to withdraw and seek contentment, instead of a drive to avoid, may be compatible with several lines of evidence on serotonin function and may facilitate a better understanding of serotonergic neuromodulation in human psychopathology.

Irritability rather than depression during interferon treatment is linked to increased tryptophan catabolism.

OBJECTIVE: Treatment with recombinant interferon is associated with high rates of psychiatric comorbidity. We investigated the relation between catabolism of the essential amino acid tryptophan, being rate-limiting of peripheral and cerebral serotonin formation, and psychiatric symptoms in patients undergoing combination treatment with interferon-alpha and ribavirin. PATIENTS AND METHODS: Eighteen patients with viral hepatitis C who received interferon were included. A psychiatrist screened patients before and while on interferon-alpha treatment for 2 months, using a structured diagnostic interview. Fasting plasma tryptophan and platelet serotonin levels were measured at each visit. RESULTS: At baseline no evident psychopathology was observed. After 2 months of interferon treatment, 10 patients experienced increased irritability. No other structural psychopathology was observed. Decreased plasma tryptophan level correlated with the presence of irritability (p = .047). Platelet serotonin levels were found to be decreased during treatment (p = .002). CONCLUSIONS: Aggressive impulse dysregulation is highly prevalent in patients receiving interferon treatment. This is associated with decreased plasma tryptophan levels which may lead to attenuated peripheral and central serotonergic neurotransmission.

Patients with carcinoid syndrome exhibit symptoms of aggressive impulse dysregulation.

OBJECTIVE: Carcinoid tumors can produce excessive amounts of biogenic amines, notably serotonin. We assessed psychiatric symptoms in carcinoid patients and peripheral metabolism of tryptophan, the precursor of serotonin. METHODS: Twenty consecutive patients with carcinoid syndrome underwent a structured psychiatric interview applying DSM-IV (Diagnostical Statistical Manual) criteria. Tumor activity was measured by determination of 24-hour urine excretion of 5-hydroxyindoleacetic acid (5-HIAA) and platelet serotonin levels. Plasma tryptophan levels were measured and compared with sex- and age-matched references. RESULTS: Fifteen patients (75%) fulfilled diagnostic DSM-IV criteria for a disorder of impulse control. Tryptophan plasma levels were lower in patients compared with controls (p =.031) and were correlated negatively with urinary 5-HIAA excretion (p =.001). CONCLUSIONS: Impulse control disorders are prevalent in patients with carcinoid syndrome. The serotonin production by the tumor possibly decreases the tryptophan pool in the cerebrospinal fluid, which is the essential substrate for the production of brain serotonin as a pivotal neurotransmitter.

Tryptophan as a link between psychopathology and somatic states.

OBJECTIVE: Several somatic illnesses are associated with psychiatric comorbidity. Evidence is provided that availability of the essential amino acid tryptophan, which is the precursor of serotonin, may cause this phenomenon. METHODS: We performed a database search to find relevant articles published between 1966 and 2002. For our search strategy, we combined several diseases from the categories hormonal, gastrointestinal, and inflammatory with the search terms "tryptophan" and "serotonin." RESULTS: The catabolism of tryptophan is stimulated under the influence of stress, hormones and inflammation by the induction of the enzymes tryptophan pyrrolase (in the liver) and IDO (ubiquitous). Because of the reduction in blood levels of tryptophan under these circumstances the formation of cerebral serotonin is decreased. CONCLUSIONS: It is argued that the coupling of peripheral tryptophan levels and cerebral serotonin levels has physiological significance. The clinical implications and therapeutic consequences of changes in tryptophan and consequently serotonin metabolism are discussed.

Influence of antipsychotic agents on neurological soft signs and dyskinesia in first episode psychosis.

First episode psychosis patients treated with atypical antipsychotics had significantly fewer signs of dyskinesia than patients treated with classical antipsychotics, but there were no significant differences regarding the total number of neurological soft signs (NSS). This suggests that the type of antipsychotic medication does not influence NSS, but that atypical antipsychotics are associated with less dyskinesia in the early stages of treatment.