Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, low-tryptophan diet followed the next morning by a 16-amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=psych&articleId=495012&pdfFileName=archpsyc_47_5_002.pdf

Serotonin Function and the Mechanism of Antidepressant Action: Reversal of Antidepressant-Induced Remission by Rapid Depletion of Plasma Tryptophan

In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs.

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications.

Abnormalities in the hypothalamic-pituitary-adrenal axis (HPA) have been the most consistently demonstrated biological markers in depressive illness. Numerous other neuroendocrine disturbances have also been described, including blunted clonidine-induced growth hormone release and blunted fenfluramine-induced prolactin release. These disturbances are generally interpreted in terms of monoaminergic receptor dysfunction. The theory presented here suggests that chronic stress which activates the HPA will in certain susceptible people produce changes in central monoamines. The high level of glucocorticoid receptors on such central neurons is postulated as mediating the alterations. Thus monoamine abnormalities, rather than being a core aetiological feature of depression, are seen as secondary to HPA overdrive.

Glucocorticoids and the genesis of depressive illness. A psychobiological model.

Objective: To investigate the effects of tryptophan depletion in untreated depressed patients. Rapid dietary depletion of the precursor of serotonin synthesis, tryptophan, causes a transient return of depression in 67% of patients who have had a therapeutic antidepressant response. Method: Forty-three untreated depressed patients underwent tryptophan depletion in a double-blind, placebocontrolled cross-over study. After testing, they received open sequential antidepressant treatment. Results: Mood did not change when tryptophan was depleted but did change on the day after the depletion test. Relative to the control test, 37% of the patients had 10-point or greaterdecreasein Hamilton Depression Rating Scale (Ham-D) score, while 23% had a 10-point or greaterincreasein Ham-D score on the day after the tryptophan depletion test. Change in mood was correlated to treatment response after testing. Patients whose condition worsened proved to be highly refractory to treatment while those who showed improvment were more likely to respond. Conclusions: That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin.

Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients.

Affective cognition and its disruption in mood disorders.

• The increases in plasma levels of prolactin (PRL) and growth hormone (GH) following intravenous administration of the 5-hydroxytryptamine precursor tryptophan (100 mg/kg) were assessed in 30 depressed patients and 30 control subjects. In depressed patients who lost less than 10 lb, PRL responses were significantly reduced compared with controls. In contrast, the PRL responses of patients with weight loss exceeding 10 lb were significantly greater than those of either controls or the other depressed patients. Growth hormone responses to tryptophan were significantly decreased in patients who lost less than 10 lb. Prolactin, but not GH, responses correlated significantly with the postdexamethasone plasma cortisol concentration; however, an apparent relationship between GH and PRL responses and suicidal behavior was probably due to the common factor of weight loss. The results suggest that depressed patients have different types of abnormal 5-hydroxytryptamine—mediated neuroendocrine responses that correlate with the presence or absence of severe weight loss and cortisol hypersecretion. Further investigations are needed to establish if these abnormalities are central to the depressive disorder or have implications for treatment response.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=PSYCH&articleId=494162&pdfFileName=archpsyc_44_11_008.pdf

Eileen M. Charig

Papers

Neuroendocrine Responses to Intravenous Tryptophan in Major Depression