Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry 12: 331-359

Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Molecular Psychiatry (Impact Factor: 14.5). 04/2007; 12(4):331-59. DOI: 10.1038/
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Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). Monoamine depletion studies investigate the direct effects of monoamines on mood. Acute tryptophan depletion (ATD) or para-chlorophenylalanine (PCPA) deplete 5-HT, acute phenylalanine/tyrosine depletion (APTD) or alpha-methyl-para-tyrosine (AMPT) deplete NE/DA. Available depletion studies found conflicting results in heterogeneous populations: healthy controls, patients with previous MDD in remission and patients suffering from MDD. The decrease in mood after 5-HT and NE/DA depletion in humans is reviewed and quantified. Systematic search of MEDLINE and EMBASE (1966-October 2006) and cross-references was carried out. Randomized studies applying ATD, PCPA, APTD or AMPT vs control depletion were included. Pooling of results by meta-analyses was stratified for studied population and design of the study (within or between subjects). Seventy-three ATD, 2 PCPA, 10 APTD and 8 AMPT studies were identified of which 45 ATD and 8 APTD studies could be meta-analyzed. 5-HT or NE/DA depletion did not decrease mood in healthy controls. 5-HT or NE/DA depletion slightly lowered mood in healthy controls with a family history of MDD. In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants. In conclusion, monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed.

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Available from: Henricus G Ruhé, Jan 22, 2014
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    • "In studies examining the effects of tryptophan depletion on mood and depression, results have been consistent (Ruhé, Mason, & Schene, 2007). For example, in a meta-analysis of studies from 1966 through 2006, tryptophan depletion showed decreased mood states in participants with major depressive disorders, with a family history of depressive disorders, or with major depressive disorders in remission (Ruhé et al., 2007). However, there was no effect on the mood of healthy participants who were subjected to tryptophan depletion. "
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    ABSTRACT: Using a randomized crossover study design, 25 healthy young adults were examined for differences in anxiety, depression, and mood after consuming a high tryptophan and a low tryptophan diet for 4days each. There was a 2week washout between the diets. A within-subjects analysis of the participants' mood indicated significantly (p<.01) more positive affect scores after consuming a high tryptophan diet as compared to a low tryptophan diet. Negative affect differences between the diets were not statistically significant (p>.05). Also, consuming more dietary tryptophan resulted in (p<.05) less depressive symptoms and decreased anxiety. Copyright © 2014 Elsevier Inc. All rights reserved.
    Archives of Psychiatric Nursing 12/2014; 29(2). DOI:10.1016/j.apnu.2014.11.008 · 0.85 Impact Factor
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    • "The effect of ATD on mood depends on the features of the subjects (Moore et al. 2000; Young and Leyton 2002). Normally, healthy men show no effect, but healthy men with a family history of depression show a modest lowering of mood, as do healthy women in some but not all studies (Ruhe et al. 2007). Patients newly recovered from depression and still being treated with a specific serotonin reuptake inhibitor often show a more substantial response suggestive of transiently reinstated depressive symptoms. "
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    ABSTRACT: Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood. This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women. In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n = 13) and nonuser controls (n = 17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task. The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n = 7), relative to controls (n = 9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users. The group sizes were small, when males and females were considered separately. Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.
    Psychopharmacology 10/2014; 231:707-716. DOI:10.1007/s00213-013-3287-2 · 3.88 Impact Factor
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    • "Significantly, depletion of neither 5HT nor NA has major effects on mood in people who are not depressed or at high risk for depression (Ruhé et al., 2007). Similarly, neither manipulation produces a depressive phenotype in control animals that have not been subjected to animal models of depression and treated with antidepressant drugs (Cryan et al., 2004; Lucki and O'Leary, 2004; Yalcin et al., 2008). "
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    ABSTRACT: The first half of this paper briefly reviews the evidence that (i) stress precipitates depression by damaging the hippocampus, leading to changes in the activity of a distributed neural system involving, inter alia, the amygdala, the ventromedial and dorsolateral prefrontal cortex, the lateral habenula and ascending monoamine pathways, and (ii) antidepressants work by repairing the damaged hippocampus, thus restoring the normal balance of activity within that circuitry. In the second half of the paper we review the evidence that heightened vulnerability to depression, either because of a clinical history of depression or because of the presence of genetic, personality or developmental risk factors, also confers resistance to antidepressant drug treatment. Thus, although antidepressants provide an efficient means of reversing the neurotoxic effects of stress, they are much less effective in conditions where vulnerability to depression is elevated and the role of stress in precipitating depression is correspondingly lower. Consequently, the issue of vulnerability should feature much more prominently in antidepressant research. Most of the current animal models of depression are based on the induction of a depressive-like phenotype by stress, and pay scant attention to vulnerability. As antidepressants are relatively ineffective in vulnerable individuals, this in turn implies a need for the development of different clinical and preclinical methodologies, and a shift of focus away from the current preoccupation with the hippocampus as a target for antidepressant action in vulnerable patients.
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