Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response

Andrews, Paul W.; Bharwani, Aadil; Lee, Kyuwon R.; Fox, Molly; Thomson, J. Anderson

doi:10.1016/j.neubiorev.2015.01.018

Cited by 224 publications

(189 citation statements)

References 407 publications

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“…All commonly prescribed ADs target one or more monoamines (serotonin, norepinephrine, and dopamine), which are ancient, phylogenetically conserved molecules that are homeostatically regulated by complex systems with multiple components [27,28,29]. These monoamine systems are functionally integrated in many biological processes.…”

Section: Introductionmentioning

confidence: 99%

“…However, most of the body's serotonin is synthesized in the gut where it spills into the bloodstream, is distributed throughout the body [29], and is taken up by platelet cells and tissues by the serotonin transporter [30,31], which is widely expressed [32,33,34,35]. Serotonin evolved in mitochondria [27], and, in many cell types, cellular uptake of serotonin depends on mitochondrial activity [36,37,38,39,40], which suggests serotonin supports many biological processes. Indeed, serotonin regulates growth, development, reproduction, neuronal activity, digestion, immune function, thermoregulation, tissue repair, maintenance, electrolyte balance, mitochondrial function, and the storage, mobilization and distribution of energetic resources [3,27,41].…”

Section: Introductionmentioning

confidence: 99%

“…Serotonin evolved in mitochondria [27], and, in many cell types, cellular uptake of serotonin depends on mitochondrial activity [36,37,38,39,40], which suggests serotonin supports many biological processes. Indeed, serotonin regulates growth, development, reproduction, neuronal activity, digestion, immune function, thermoregulation, tissue repair, maintenance, electrolyte balance, mitochondrial function, and the storage, mobilization and distribution of energetic resources [3,27,41]. By blocking the transporter in the brain and periphery, selective serotonin reuptake inhibitors (SSRIs), which are the most widely prescribed ADs, could potentially degrade many adaptive processes [3,42].…”

Section: Introductionmentioning

confidence: 99%

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The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

Maslej

Bolker²,

Russell³

et al. 2017

Psychother Psychosom

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Background: Antidepressants (ADs) are commonly prescribed medications, but their long-term health effects are debated. ADs disrupt multiple adaptive processes regulated by evolutionarily ancient biochemicals, potentially increasing mortality. However, many ADs also have anticlotting properties that can be efficacious in treating cardiovascular disease. We conducted a meta-analysis assessing the effects of ADs on all-cause mortality and cardiovascular events in general-population and cardiovascular-patient samples. Methods: Two reviewers independently assessed articles from PubMed, EMBASE, and Google Scholar for AD-related mortality controlling for depression and other comorbidities. From these articles, we extracted information about cardiovascular events, cardiovascular risk status, and AD class. We conducted mixed-effect meta-analyses testing sample type and AD class as moderators of all-cause mortality and new cardiovascular events. Results: Seventeen studies met our search criteria. Sample type consistently moderated health risks. In general-population samples, AD use increased the risks of mortality (HR = 1.33, 95% CI: 1.14-1.55) and new cardiovascular events (HR = 1.14, 95% CI: 1.08-1.21). In cardiovascular patients, AD use did not significantly affect risks. AD class also moderated mortality, but the serotonin reuptake inhibitors were not significantly different from tricyclic ADs (TCAs) (HR = 1.10, 95% CI: 0.93-1.31, p = 0.27). Only “other ADs” were differentiable from TCAs (HR = 1.35, 95% CI: 1.08-1.69). Mortality risk estimates increased when we analyzed the subset of studies controlling for premedication depression, suggesting the absence of confounding by indication. Conclusions: The results support the hypothesis that ADs are harmful in the general population but less harmful in cardiovascular patients.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

Maslej

Bolker²,

Russell³

et al. 2017

Psychother Psychosom

Self Cite

View full text Add to dashboard Cite

show abstract

“…In vivo and in vitro methods have been used to image receptor binding in brain to examine the anatomical distribution of serotonergic receptors in suicide and nonfatal suicide behavior [12][13][14], and how regional brain binding patterns differ from psychiatrically normal individuals. The consensus that there is a serotonin system abnormality is a lot stronger than which brain areas are involved and the direction of the difference in binding [15][16][17][18] and explanations for discrepancies include heterogeneity of the patient population, small group sizes, small effect sizes and variability in outcome measures due to demographic variables including sex and age in live cases and also postmortem interval and brain pH in in vitro studies.…”

Section: H]8-oh-dpat Binding To 5-ht1a Receptorsmentioning

confidence: 99%

Disconnect Between Brainstem Serotonin Neurons And Prefrontal Cortex Serotonin Receptors In Suicide

Underwood¹,

Arango²

2018

Acta Psychopathol

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Serotonin neurotransmission is widely reported as reduced in suicide attempt and completion. Evidence suggests reduced serotonin innervation of the prefrontal cortex and homeostatic upregulation of postsynaptic 5-HT 1A and perhaps 5-HT 2A receptors in suicide. However, in the brainstem, we have previously found more tryptophan hydroxylase serotonin biosynthetic enzyme and more serotonin in suicide decedents suggesting serotonergic hyperfunction, but also more autoreceptor binding that could result in reduced neuronal firing. We sought evidence of a disconnect between the brainstem and prefrontal cortex examining the serotonin transporter (SERT) and 5-HT 1A receptor in the dorsal and median raphe nucleus and SERT, 5-HT 1A and 5-HT 2A receptor binding in prefrontal cortex and in anterior cingulate cortex postmortem.Suicide decedents (n=11) and controls (n=18) died suddenly minimizing agonal effects and had a postmortem interval ≤ 24 hour. Autoradiography was performed in right hemisphere coronal sections at a pre-genual level and in transverse sections through the brainstem.In controls, there were correlations between DRN and MRN SERT and 5-HT 2A receptor binding throughout prefrontal cortex, and between DRN and MRN 5-HT 1A receptor binding and medial and ventral prefrontal cortex. In suicide decedents there were no such relationships.The absence of correlations between brainstem source serotonergic neuron function and receptors on target neurons in prefrontal cortex in suicides suggests a disconnect that may contribute to suicide neuropathology.

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“…SSRIs reduce energy metabolism by increasing extracellular serotonin, which is restored by compensatory mechanisms. That is the reason why depressive patients suffer worsening depressive symptoms during the first weeks of the treatment with SSRIs [26].…”

Section: Major Depression: Signalling Mechanisms Of Different Neurotrmentioning

confidence: 99%

Additional Antidepressant Pharmacotherapies According to a Neural Network

Werner¹,

Coveñas²

2016

Brain Disord Ther

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Major depression, a frequent psychiatric disease, is associated with neurotransmitter alterations in the midbrain, hypothalamus and hippocampus. Deficiency of postsynaptic excitatory neurotransmitters such as dopamine, noradrenaline and serotonin and a surplus of presynaptic inhibitory neurotransmitters such as GABA and glutamate (mainly a postsynaptic excitatory and partly a presynaptic inhibitory neurotransmitter), can be found in the involved brain regions. However, neuropeptide alterations (galanin, neuropeptide Y, substance P) also play an important role in its pathogenesis. A neural network is described, including the alterations of neuroactive substances at specific subreceptors. Currently, major depression is treated with monoamine reuptake inhibitors. An additional therapeutic option could be the administration of antagonists of presynaptic inhibitory neurotransmitters or the administration of agonists/antagonists of neuropeptides.

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Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response

Cited by 224 publications

References 407 publications

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

Disconnect Between Brainstem Serotonin Neurons And Prefrontal Cortex Serotonin Receptors In Suicide

Additional Antidepressant Pharmacotherapies According to a Neural Network

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