title: Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.
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.
authors.affiliation: Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada. Electronic address: pandrews@mcmaster.ca.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Andrews
authors.affiliation: Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Aadil
authors.initials: A
authors.lastname: Bharwani
authors.affiliation: Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Kyuwon R
authors.initials: KR
authors.lastname: Lee
authors.affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Orange, CA, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Fox
authors.affiliation: 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.
authors.forename: J Anderson
authors.initials: JA
authors.lastname: Thomson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Analysis; Depression; Distraction; Energy regulation; Hippocampus; Hypothalamus; Learning; Plasticity; Prefrontal cortex; Serotonin; Working memory