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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.

Author information

1
Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada. Electronic address: pandrews@mcmaster.ca.
2
Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
3
Department of Psychiatry and Human Behavior, University of California Irvine, Orange, CA, USA.
4
Counseling and Psychological Services, University of Virginia Student Health, Charlottesville, VA, USA; Institute of Law, Psychiatry, and Public Policy, University of Virginia, Charlottesville, VA, USA.

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.

KEYWORDS:

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

PMID:
25625874
DOI:
10.1016/j.neubiorev.2015.01.018
[Indexed for MEDLINE]
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