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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

Article in Neuroscience&BiobehavioralReviews·February2015

DOI:10.1016/j.neubiorev.2015.01.018

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Neuroscience and Biobehavioral Reviews 51 (2015) 164–188

Neuroscience and Biobehavioral Reviews 51 (2015) 164–188 Contents lists available at ScienceDirect Neuroscience and

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journal homepage: www.elsevier.com/locate/neubiorev

journal homepage: www.elsevier.com/locate/neubiorev Review Is serotonin an upper or a downer? The evolution of

Review

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

and its role in depression and the antidepressant response Paul W. Andrews a , ∗ ,

Paul W. Andrews a, , Aadil Bharwani a , Kyuwon R. Lee a , Molly Fox b , J. Anderson Thomson Jr. c,d

a Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada

b Department of Psychiatry and Human Behavior, University of California Irvine, Orange, CA, USA

c Counseling and Psychological Services, University of Virginia Student Health, Charlottesville, VA, USA

d Institute of Law, Psychiatry, and Public Policy, University of Virginia, Charlottesville, VA, USA

a r t i c

l e

i n f o

Article history:

Received 4 September 2013 Received in revised form 8 January 2015 Accepted 15 January 2015 Available online 24 January 2015

Keywords:

Analysis

Depression

Serotonin

Energy regulation

Learning

Plasticity

Working memory

Distraction

Hippocampus

Prefrontal cortex

Hypothalamus

a b s t r a c t

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 mul- tiple 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. © 2015 Elsevier Ltd. All rights reserved.

Contents

1. Introduction

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165

2. Serotonin is elevated in multiple depressive phenotypes

 

168

2.1.

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2.1.1. Polymorphism

in the SERT

gene

 

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2.1.2. 5-HIAA levels

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vein

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2.1.3. Tryptophan depletion increases DRN activity in depressed patients taking ADMs

 

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2.1.4. Increased preference for carbohydrates in

 

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2.1.5. Tianeptine

 

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170

2.1.6. Anxiety

 

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170

Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); DA, dopamine; NE, norepinephrine; ADM, antidepressant medication; SSRIs, selective serotonin reuptake inhibitors; SERT, serotonin transporter; 5-HIAA, 5-hydroxyindoleacetic acid; PFC, prefrontal cortex; mPFCv, ventral part of the rodent medial prefrontal cortex; DLPFC, dorsolateral prefrontal cortex; VLPFC, ventrolateral prefrontal cortex; DRN, dorsal raphe nucleus; PET, positron emission tomography; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; NET, norepinephrine transporter; DAT, dopamine transporter.

Corresponding author. Tel.: +1 905 525 9140x20820; fax: +1 9055296225. E-mail address: pandrews@mcmaster.ca (P.W. Andrews).

http://dx.doi.org/10.1016/j.neubiorev.2015.01.018

0149-7634/© 2015 Elsevier Ltd. All rights reserved.

P.W. Andrews et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 164–188

165

2.2.

In non-human

animal

models

 

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170

2.2.1. Stressor

models

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2.2.2. Genetic models

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2.2.3. Lesion

models

 

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2.3.

Summary.

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3. energy regulation function of the serotonergic system

The

 

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3.1.

Overview of the serotonergic system

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171

3.2.

The

evolution of serotonin in mitochondria

 

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3.3.

The

mitochondrial functions of

 

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3.4.

What is the function of

the serotonergic system?

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3.4.1. Serotonin and

energy

regulation

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3.4.2. The homeostatic equilibrium level of serotonin transmission is increased in situations requiring a rebalancing of

 
 

metabolically

expensive

processes

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173

4. homeostatic response to SSRIs and symptom reduction

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4.1.

Acute SSRI

treatment disrupts energy homeostasis

 

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4.2.

The

brain’s

compensatory responses to SSRI treatment

 

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4.3.

The

mechanisms

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reduction

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175

4.4.

Symptom reduction is a temporary overshoot of the homeostatic equilibrium

 

176

4.5.

The effects

of SSRIs during recalibration of serotonin transmission

 

176

5. What is serotonin

doing

in

melancholia?

 

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