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/
Source: PubMed


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
    • "Brain areas, such as the prefrontal cortex and the amygdala, and the dopaminergic and serotonergic activities are involved in the judgement of ambiguous stimuli (Berridge, 2007;Schultz, 1997) and in the fear response (D'Angio et al., 1988;Davis et al., 1994). The animal's affective state or mood may modulate some or all activities of these brain areas (Mendl et al., 2009;Ruhé et al., 2007). For example, in mice studies, high brain dopamine levels have been associated with positive affective state (Ashby et al., 1999;Burgdorf and Panksepp, 2006), while the absence of D4Rs, a dopamine receptor, has been related to increased avoidance behaviour to novel stimuli (Dulawa et al., 1999;Falzone et al., 2002). "
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    ABSTRACT: Cognitive bias (CB) has been recently proposed as a tool to study emotions by assessing the cognitive function through behaviour observation. It is based on the premise that subjects in a negative affective state perform more negative judgements about ambiguous stimuli than subjects in positive affective state. This study aimed at investigating if halothane genotype (homozygous Hal-free, NN vs. heterozygous Hal carrier, Nn) and gender (gilts, G vs. entire males, EM) affect the CB in pigs. Moreover, the results of the CB test (CBT) were compared with the results of a novel object test (NOT) in order to assess the influence of fear in the decision taken by pigs during the CBT. The results of both tests were contrasted with the concentration of brain neurotransmitters in four different brain areas in order to analyse the involvement of the dopaminergic and serotonergic pathways on the pigs' affective state and fear. A total of 48 pigs, in terms of 12Hal-free gilts (NNG), 12Hal carrier gilts (NnG), and 12Hal-free entire males (NNEM) and 12Hal carrier entire males (NnEM) were put on the CBT at the age of 20 weeks and on the NOT four days later. After two days, pigs were slaughtered and four brain structures (amygdala, prefrontal cortex, hippocampus and hypothalamus) were dissected for the analysis of brain neurotransmitters. The CBT and NOT results did not show any effect of the genotype and gender or their interaction on pigs' emotional response (p > 0.10). However, the CBT correlated positively with the NOT (r = 0.49; p = 0.0005), with pigs classified with a negative CB tending to be more fearful in front of the novel object than those with a positive CB (p = 0.05). Moreover, the pigs that took longer to get in contact with the novel object in the NOT also had lower (p = 0.013) concentration of dopamine in the prefrontal cortex and increased DOPAC/dopamine ratio in the hypothalamus (p = 0.003). These results suggest that fear level plays an important role in the decision taken by the pig dealing with ambiguous stimuli.
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    • "For example, in monoamine depletion studies, acute tryptophan depletion was associated with a mood decrease in remitted drug-free patients with MDD. Also, 5-HT or norepinephrine and dopamine depletion slightly lowered mood in healthy controls with a family history of MDD (Ruhe et al., 2007). Consistent with post-mortem and preclinical studies, human positron emission tomography (PET) studies examining the serotonin receptors 1A, 2A, 1B, or transporter in vivo mostly provide support for serotonergic dysfunction in MDD (Savitz et al., 2013). "
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    ABSTRACT: Abstract The monoamine hypothesis of depression posits that an imbalance in monoaminergic neurotransmission is causally related to the clinical features of depression. Antidepressants influencing serotonin mainly aim at raising serotonin concentrations, thereby increasing serotonergic transmission at the level of the synapse, for example by inhibiting the serotonin transporter. However, the serotonin system is multifaceted. Different serotonin receptor subtypes turn the serotonergic system into a complex neurochemical arrangement that influences diverse neurotransmitters in various brain regions. Classical antidepressants as well as other psychopharmacological agents have various crucial effects on serotonin receptors. We aim at providing a clinically useful characterization of serotonin receptor subtypes in the treatment of depression. Clarifying the mode of action and the interplay of serotonin receptors with pharmacological agents should help antidepressant mechanisms and typical side effects to be better understood. Against this background, we feature the novel antidepressants vortioxetine, vilazodone and milnacipran/levomilnacipran with regard to their serotonin receptor targets such as the 5-HT1A, 5-HT3 and 5-HT7 which may account for their specific effects on certain symptoms of depression (e.g. cognition and anxiety) as well as a characteristic side-effect profile.
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    • "It has long been known that dysfunction of ascending serotonergic pathways is crucially implicated in psychiatric disorders, such as panic, depression, and suicide. Several lines of evidence support this viewpoint, including that (1) low levels of serotonin (5- hydroxytriptophan; 5-HT) metabolites were found in depressed suicides [9], (2) depletion of 5-HT in volunteers triggers relapse of depressive episodes [10], (3) affective disorders appear to be linked to changes in the activity of serotonin transporter (SERT) [11], and (4) treatment with 5-HT reuptake inhibitors mitigates depressive symptoms, at least in a subpopulation of patients [12]. In addition, in depressed patients a number of structural defects were observed in the dorsal raphe nucleus (DRN), the brainstem region which provides the majority of cortical serotonergic fibers. "
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