Integrating the monoamine, neurotrophin and cytokine hypotheses of depression — A central role for the serotonin transporter?

doi:10.1016/j.pharmthera.2014.10.002

Pharmacology & Therapeutics

Volume 147, March 2015, Pages 1-11

https://doi.org/10.1016/j.pharmthera.2014.10.002 Get rights and content

Abstract

Monoamine, in particular serotonergic neurotransmission has long been recognized as an important factor in the aetiology of depression. The serotonin transporter (SERT) is the primary regulator of serotonin levels in the brain and a key target for widely used antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs). In realising the limitations of current antidepressant therapy, depression research has branched out to encompass other areas such as synaptic plasticity, neurogenesis and brain structural remodelling as factors which influence mood and behaviour. More recently, the immune system has been implicated in the development of depression and various intriguing observations have inspired the cytokine hypothesis of depression. Over the past two decades evidence of in vitro and in vivo regulation of SERT function by pro-inflammatory cytokines as well as by mechanisms of synaptic plasticity has been accumulating, offering a mechanistic link between the monoamine, neurotrophin and cytokine theories of depression. This review will focus firstly on the interconnected roles of serotonin and neurotrophins in depression and antidepressant therapy, secondly on the impact of the immune system on serotonin transporter regulation and neurotrophin signalling and finally we propose a model of reciprocal regulation of serotonin and neurotrophin signalling in the context of inflammation-induced depression.

Introduction

Depression is a common psychological condition affecting up to 15% of the population in industrialised nations and by 2030 is projected by the World Health Organisation to be the leading cause of disease burden globally (Moussavi et al., 2007). Though mood disorders vary greatly in their precise symptom set and comorbidities, depression typically refers to unipolar depression, also known as clinical or major depression. This condition is characterised by several core symptoms including a persistent low mood, anhedonia, feelings of hopelessness, guilt and pessimism as well as cognitive impairment. Patients may also present with other often contradictory symptoms including lethargy, insomnia, social withdrawal and sexual dysfunction among a range of others. Despite advances in the diagnosis, recognition and categorisation of depression the underlying causes of the symptoms are still poorly understood.

One of the early theories attempting to explain the pathogenesis of depression was the monoamine theory which hypothesised that depression may be a result of decreased availability of monoamine neurotransmitters such as serotonin and noradrenaline in the central nervous system (CNS) (Krishnan & Nestler, 2008). The hypothesis is based on the serendipitous discovery that drugs which increase monoamine availability are effective antidepressants. This has led to the development and widespread use of the newer generation of safer, more effective selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors. However, despite some successes in understanding and treating depression from a monoamine centric viewpoint many questions still remain. For example, SSRIs are not effective in treating all patients with depression. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study revealed complete remission in only about one third of patients following first-line treatment with the SSRI citalopram (Trivedi et al., 2006). The same study confirmed the previously observed latency of the antidepressant effect in patients that do respond, recording an average mean time to remission of 6–7 weeks (Trivedi et al., 2006). In conclusion, this and other studies suggest that monoamine transporter blockade is only part of the therapeutic mechanism. Emerging findings regarding the role of synaptic plasticity (Lee & Kim, 2010) and neurogenesis (Eisch & Petrik, 2012) in depression along with the discovery that the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is a fast acting potent antidepressant (Berman et al., 2000), have undermined the dominant position once held by the monoamine hypothesis. However, despite the fact that the monoamine hypothesis as a sole model for the development of depressive disorders now seems dated it is undeniable that monoamine neurotransmission, in particular the action of serotonin, plays an integral role in regulating mood, and conditions that perturb monoamine networks in the brain have significant behavioural consequences. This review aims to discuss the role of the serotonin transporter (SERT), the key target for SSRI antidepressants, in the context of recent developments in depression research, such as the contribution of neuroplasticity and the role of neurotrophins. We will give particular focus to the cytokine hypothesis of depression and explore the functional consequences of cytokine-induced alterations of SERT activity on processes relevant for depression, as well as attempting to integrate the major prevailing theories of depression.

Section snippets

The serotonin transporter and serotonin signalling in depression and antidepressant therapy

Serotonin or 5-hydroxytryptamine (5-HT) is a simple monoamine synthesised from tryptophan and is found in a wide variety of organisms. In mammals it is distributed throughout the body with approximately 90% of 5-HT produced in the periphery by enterochromaffin cells in the gastrointestinal tract (Berger et al., 2009). Most of the remaining 5-HT is produced in the serotonergic neurons of the raphe nuclei and although these cells are restricted to a relatively small area of the brain, their

Cytokines hypothesis of depression

Over the past two decades the links between the immune system and the CNS have become ever more apparent. The brain is no longer considered an immune privileged organ, it is now recognised that the brain has a working, highly regulated immune system, comprised of both humoral and cellular immune factors (Eyre and Baune, 2012, Ransohoff and Brown, 2012), all of which are engaged in bi-directional communication with the immune system in the periphery (Maier, 2003). Immune system challenge and

Model of inflammation triggered perturbation of serotonin-BDNF homeostasis

As outlined above, the past few years have seen a growing body of evidence regarding the regulation of CNS SERT function by peripheral and central immune system activation. However, taken in isolation, these observations of cytokine-induced alterations of SERT activity go little further toward understanding the pathogenesis of depression than the early monoamine hypothesis. A greater understanding of the molecular, cellular and structural consequences of alterations in SERT function by the

Future directions

While the model we proposed here is consistent with published findings, the finer details of the molecular mechanisms of SERT activity regulation by BDNF and how these relate to alterations observed in inflammatory conditions, including microglia activation are largely unknown. While several studies have demonstrated that BDNF enhances SERT activity (Daws et al., 2007, Benmansour et al., 2008, Guiard et al., 2008), the signalling pathways involved remain obscure. Presumably BDNF acts through

Conflict of interest

The authors declare there are no conflicts of interest.

Acknowledgment

EB is funded by the MolCellBiol PhD Programme, under the Programme for Research in Third-Level Institutions, co-funded under the European Regional Development Fund.