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
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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.
    Journal of Psychopharmacology 10/2015; DOI:10.1177/0269881115609072 · 3.59 Impact Factor
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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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    ABSTRACT: Mood disorders and major depression are frequently comorbid with epilepsy. While the nature of this comorbidity is not fully understood, multiple lines of evidence suggest that changes in serotonin (5-HT) neurotransmission may be an underlying mechanism. In this study, we tested the hypothesis that chronic epilepsy in rats can be associated with loss of 5-HT neurons in the dorsal raphe (DR) nuclear complex, the main source of 5-HT projections to the cerebral cortex, which would help to explain respective behavioral deficits. Epilepsy was induced using the kainate model of status epilepticus in adult Wistar rats. After a 3-month recovery period, all kainate-treated rats that had experienced status epilepticus showed spontaneous seizures and reduced sucrose preference (anhedonia), a core symptom of depression. No changes in the forced swim test were detected. The total numbers of 5-HT immunoreactive cells were estimated in all DR subdivisions of control and epileptic rats. Interestingly, epilepsy-related loss of 5-HT neurons (approximately 35%) was observed only in the interfascicular part of the DR complex, which is known to innervate brain regions involved in depression. These findings support the notion that mental health impairments observed in epilepsy may be related to loss of a specific population of the DR 5-HT neurons projecting to limbic brain areas.
    Behavioural brain research 10/2015; 297. DOI:10.1016/j.bbr.2015.10.010 · 3.03 Impact Factor
    • "Interestingly, there is an accumulation of suggestive evidence that the same neurochemical systems that underlie the effects of AMPH—which is a potent releaser of dopamine (DA), norepinephrine (NE), and to a lesser extent, serotonin (5-HT) (Rothman et al. 2001)—par- tially mediate the above components of emotional functioning . For example, all three of these monoamine neurotransmitters are likely to be involved in variations in positive mood (Ruhé et al. 2007). Additionally, anhedonia and low positive affect have been linked with decreased DA function in particular (Wise 1982) and are putatively pathognomonically specific to depression and distinct from anxiety (Watson et al. 1988a; Clark and Watson 1991). "
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    ABSTRACT: Background: Previous research on emotional correlates of individual differences in subjective responses to D-amphetamine has focused on relatively broad personality traits. Yet, emotional functioning is best characterized by several narrow subcomponents, each of which may contribute uniquely to amphetamine response. Here, we examine several specific subdomains of emotional functioning in relation to acute amphetamine response. Method: At a baseline session, healthy stimulant-naive volunteers (N = 97) completed measures of several subdomains of baseline trait emotional functioning and then completed two counterbalanced experimental sessions during which they received a single oral dose of 20 mg D-amphetamine or placebo. Acute subjective drug response measures were completed at repeated intervals before and after drug administration. Data from subjective measures that were significantly modulated by amphetamine were reduced using principal component analysis (amphetamine or placebo) into three higher-order factors of "positive mood," "arousal," and "drug high." Amphetamine did not significantly alter any "negative" subjective states. Separate multiple regression analyses were conducted regressing these three drug factors on baseline trait emotional functioning scales. Results: The combined set of trait emotional functioning indicators accounted for approximately 22 % of the variance in acute amphetamine-induced positive mood changes. Greater anticipatory pleasure and greater anxious distress each uniquely predicted greater amphetamine-induced positive mood. Trait emotional functioning did not significantly predict amphetamine-induced changes in arousal or drug high. Discussion: Emotional traits appear to moderate drug-induced positive mood but not other dimensions of amphetamine effects. Different facets of emotional functioning may differentially modulate amphetamine's subjective effect profile.
    Psychopharmacology 10/2015; 156. DOI:10.1007/s00213-015-4091-y · 3.88 Impact Factor
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