Is Serotonin An Upper Or A Downer? The Evolution Of The Serotonergic System And Its Role In Depressi

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Neurosci Biobehav Rev. 2015 Apr;51:164-88. doi: 10.1016/j.neubiorev.2015.01.018. Epub 2015 Jan 24.
Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.
Andrews PW1, Bharwani A2, Lee KR2, Fox M3, Thomson JA Jr4.
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Abstract
The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.

Copyright © 2015 Elsevier Ltd. All rights reserved.

KEYWORDS:
Analysis; Depression; Distraction; Energy regulation; Hippocampus; Hypothalamus; Learning; Plasticity; Prefrontal cortex; Serotonin; Working memory

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

 

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New England Journal of Medicine review on Major Depression, stated:

“…numerous studies of norepinephrine and serotonin metabolites in plasma, urine, and cerebrospinal fluid as well as postmortem studies of the brains of patients with depression, have yet to identify the purported deficiency reliably.”

The data has poked holes in the theory and even the field of psychiatry itself is putting down it’s sword. One of my favorite essays by Lacasse and Leo has compiled sentiments from influential thinkers in the field – mind you, these are conventional clinicians and researchers in mainstream practice – who have broken rank, casting doubt on what psychiatry has to offer around antidepressants:

From: Depression: It’s Not Your Serotonin