Depression: From Psychopathology to Pharmacotherapy

J. F. Cryan, B. E. Leonard

• Verlag: S. Karger
• Jahr: 2010
• ISBN:
  9783805596060
• Thema: Medicine
• Thema: Psychiatry & Mental Health

Despite the availability of antidepressants for over 40 years, a substantial proportion of depressed patients do not respond adequately to treatment. Failure to respond effectively to treatment contributes to physical ill-health and psychiatric morbidity, often resulting in premature death of the depressed patient. The purpose of this volume is to consider the possible reasons for the limitations of the currently available antidepressants, to examine the advances in our understanding of the psychopathology of depression and how such knowledge may assist in the discovery of new methods of treatment. Leading international experts in this field discuss the possible underlying reasons for depression and limitations of current antidepressants. Opportunities for novel therapeutic approaches to dysfunctional circadian rhythms and mood disorders as well as current status and future perspectives for optimizing antidepressant management of depression are reviewed. This publication illustrates the breadth of the latest research and is valuable reading for psychiatrists, neuroscientists and pharmacologists.

Experimental Models of Depression and the Mechanisms of Action of Antidepressants

Cryan JF, Leonard BE (eds): Depression: From Psychopathology to Pharmacotherapy.
Mod Trends Pharmacopsychiatry. Basel, Karger, 2010, vol 27, pp 199–223

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Neurotrophic Factors and Antidepressant Action: Recent Advances

Olivia F. O'Leary^a · Eero Castrén^b

^aSchool of Pharmacy, University College Cork, Cork, Ireland; ^bNeuroscience Centre, University of Helsinki, Helsinki, Finland

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Abstract

It is now commonly accepted that neuronal plasticity plays a central role in depression and antidepressant drug action. Accumulating evidence from studies in both humans and animals suggests that depression is associated with alterations in the cellular architecture of specific brain regions that are important for the regulation of mood. Moreover, many of these changes are attenuated or reversed by chronic antidepressant treatment. Since neurotrophic factors regulate many features of neuronal plasticity including the proliferation and structure of neurons, there is a rapidly growing interest in determining whether growth factor signalling might contribute to the pathophysiology and treatment of depression. Several families of neurotrophic factors are found in the adult brain including the neurotrophins, fibroblast growth factors, insulin-like growth factors, transforming growth factors, neuropoietic cytokines as well as various other growth factors such as vascular endothelial growth factor. Of all the neurotrophic factors, brain-derived neurotrophic factor (BDNF) has been the most intensively investigated in the depression and antidepressant research field, and there is convincing supporting evidence of a role for BDNF in the pathophysiology and treatment of depression. Additional evidence suggests that other neurotrophic factors, such as fibroblast growth factor, vascular endothelial growth factor and insulin-like growth factor 1, might also contribute to the mechanism of antidepressant drug action, although more exhaustive investigations are required. The present chapter reviews both human and animal studies investigating the roles of neurotrophic factors in the pathophysiology and treatment of depression.

Copyright © 2010 S. Karger AG, Basel

Over the last decade, it has become clear that neuronal plasticity plays a central role in depression and antidepressant drug action. Antidepressant treatments increase the expression of several neurotrophic factors that are important regulators of neuronal growth and survival as well as various facets of neuronal plasticity including neurogenesis and synapse formation [1-5]. Post-mortem and neuroimaging studies suggest that depression is associated with reduced volumes of specific brain regions that are important for the regulation of mood, including the hippocampus and prefrontal cortex [6]. Parallel studies in animals demonstrate that chronic stress, which is a precipitating factor for depression, can induce atrophy in both of these brain regions and can also result in functional behavioural changes that are reminiscent of clinical depression [7]. Moreover, antidepressant treatments can attenuate the hippocampal volume loss observed in depression as well as the stress-induced changes in both animal behaviour and the cellular architecture of the hippocampus [7, 8]. Taken together, there is unmistakable evidence that alterations in neuronal structure and function (i.e. neuronal plasticity) are fundamental components of the mechanism of antidepressant drug action.

Table 1. Neurotrophic factors which are thought to play a role in the pathophysiology and treatment of depression

Neurotrophins Nerve growth factor (NGF) Brain-derived neurotrophic factor (BDNF) Neurotrophin 3 (NT-3) Neurotrophin 4/5 (NT-4/5)

Fibroblast growth factors (FGF)

Insulin-like growth factors (IGF)

Vascular endothelial growth factor (VEGF)

Transforming growth factors Transforming growth factor β’ Glial cell-line-derived neurotrophic factor (GDNF) Neurturin Persephin Artemin

Neuropoietic cytokines Leukaemia inhibitory factor (LIF) Ciliary neurotrophic factor (CNTF)

Since neurotrophic factors regulate many features of neuronal plasticity, there has been a rapidly growing interest in determining whether growth factor signalling might contribute to the pathophysiology and treatment of depression. Neurotrophic factors were initially identified as proteins that are required for neuronal survival and differentiation during development [9, 10]. However, many of these factors are also actively expressed during adulthood and can be found in tissues other than the brain [10]. Neurotrophic factors can be classified into several different families including the neurotrophins, fibroblast growth factors (FGFs), insulin-like growth factors (IGF), transforming growth factors, neuropoietic cytokines as well as various other growth factors including vascular endothelial growth factor (VEGF) (table 1). Of all the neurotrophic factors, brain-derived neurotrophic factor (BDNF) has been the most intensively in the depression and antidepressant research field. Nevertheless, in the present chapter, we also outline how the other neurotrophic factors might contribute to the mechanism of antidepressant drug action.

Neurotrophins: Brain-Derived Neurotrophic Factor, Nerve Growth Factor, Neurotrophin 3 and Neurotrophin 4/5

Brain-Derived Neurotrophic Factor

BDNF was initially described as a secreted protein that supports the survival of a subset of peripheral neurons during development [10]. However, it is now recognised that BDNF is an important mediator of several activity-dependent plasticity processes both in the adult and developing brain [3]. The function of BDNF is mediated through 2 different receptors, TrkB and p75^NTR. Binding of mature BDNF to TrkB is thought to mediate most of the plasticity-enhancing effects of BDNF, while binding of its precursor protein, Pro-BDNF, to p75^NTR has been linked to apoptosis and synaptic depression [11]. In this way, BDNF-mediated signalling pathways can regulate dynamic neuronal networks by creating and maintaining active neuronal connections which are appropriate for information processing, while eliminating the inactive connections which mediate random noise. For this reason, the role of BDNF in depression and antidepressant action has been intensively investigated.

Clinical Evidence for a Role of BDNF in Depression and Antidepressant Drug Action

Several studies including 2 meta-analyses have demonstrated that serum BDNF levels are reduced in depressed patients [12–16]. Moreover, serum BDNF levels are normalised in patients that successfully respond to antidepressant treatments including chemical antidepressants, electroconvulsive therapy, sleep deprivation therapy and repetitive transcranial magnetic stimulation [14, 15, 17–21]. Even though several negative findings have also been reported, meta-analysis studies strongly suggest that serum BDNF levels are reduced in depression and are increased by antidepressant treatments [15, 16]. Although serum levels of BDNF are clearly altered by antidepressant treatments, it is currently unclear whether such changes reflect BDNF levels in the brain. However, post-mortem studies have reported that BDNF protein levels are increased in specific areas of the hippocampus of medicated depressed patients [22].

The role of BDNF in the pathophysiology and treatment of depression has also been investigated using genetic association studies. A number of studies have investigated whether the common Val66Met polymorphism as well as other single nucleotide polymorphisms (SNPs) in the bdnf gene are associated with risk for depression or the efficacy of antidepressants. Generally, these studies report a lack of association of bdnf SNPs with both the clinical response to antidepressants and the risk for depression [23–28]. Given the limited number of studies investigating the contribution of bdnf gene variants to the antidepressant response, it is clear that significantly more clinical research is warranted before any firm conclusions can be drawn.

Chronic Stress in Animals Decreases BDNF Expression in the Hippocampus in an Antidepressant-Reversible Manner

Exposing animals to chronic stress induces both cellular changes in the hippocampus and alterations in behaviour that are reminiscent of depression. It has been consistently reported that exposure to different types of chronic stress decreases mRNA levels of BDNF in the hippocampus of both the rat and the mouse [29–34]. These stress-induced reductions in BDNF mRNA levels have been observed in most subregions of the hippocampus including the dentate gyrus, CA1 and CA3 areas [35, 36]. Moreover, this effect can be reversed or prevented by various classes of antidepressant drugs including monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, serotonin-nor-epinephrine reuptake inhibitors, as well as other antidepressant treatments including buproprion, electroconvulsive shock (ECS), subconvulsive electrical stimulation and voluntary exercise [29, 30, 33, 35–38]. Similarly, both pharmacological and genetic animal models of physiological responses to stress, such as chronic corticosterone treatment or antisense-induced downregulation of the glucocorticoid receptor, reduce mRNA levels of BDNF in the hippoca...