Recent insights into antidepressant therapy: Distinct pathways and potential common mechanisms in the treatment of depressive syndromes

Highlights

• BDNF, p11 and Homer1a mediate the action of various antidepressant measures.

• BNDF, p11 and Homer1a interacting with each other form a molecular network.

• this network leads to facilitation of AMPA receptor signaling and plasticity.

• AMPA receptors might be a central mediator of antidepressant effects.

Abstract

There is an urgent, unmet clinical need for faster and more efficient antidepressant drugs with higher response rates. In animal models of depression it was shown in the last few years that inhibition of three signaling molecules (BDNF, p11 and Homer1a) prevents efficacy of antidepressant therapy. These data not only show the crucial role of these factors for the treatment of depression, but may also point towards a better understanding of the molecular changes responsible for successful antidepressant therapy. Reviewing the literature concerning BNDF, p11 and Homer1a we here describe a molecular network in which these molecules interact with each other finally leading to facilitation of AMPA receptor signaling and plasticity, corroborating the current idea of AMPA receptors being a promising drug target in depression.

Introduction

Major depression is estimated to affect more than 300 million people worldwide and is associated with high individual suffering, increased risk of suicide and an enormous economic burden for the society (Eaton et al., 2008; Mrazek et al., 2014). Depressive symptoms are most likely the final common pathway of a multitude of different pathological processes triggered in the brain by stressful events (acute, chronic or early-life stress) or immunological and psychological challenge through a somatic disease. Hypotheses on the neurobiology of depression include alterations in various mechanisms such as e.g. neuroplasticity, neurogenesis and neuroimmunological regulation, the relative impact of which may depend on the specific individual disposition. Furthermore, there is an important effect of psychosocial factors, such as the living conditions, on the efficacy of antidepressant medication (Branchi, 2011; Chiarotti et al., 2017). Other factors such as early changes in emotional and social processing induced by neuropsychological factors may also modify the efficacy of antidepressant treatment (Harmer et al., 2017). It has even be argued that depression is not an illness in the classical meaning, but rather a condition formed by a network of related but independent symptoms, the dynamics of which may vary with particular contextual influences and should thus be analyzed by network analysis techniques (Bosboom and Cramer, 2013; Fried et al., 2015). While research on alterations by antidepressant therapy in serotonergic and noradrenergic neurotransmission has dominated the field for years, newer targets have been described in the last few years. These include e.g. FK506 binding protein (FKBP) 51, a co-chaperone regulating the glucocorticoid receptor, which was found important in the pathogenesis and treatment of stress-related disorders such as depression (Fries et al., 2017; Zannas et al., 2016). Equally important for the regulation of stress-dependent behavior are the corticotropin-releasing factor (CRF) gene and the central expression of CRF receptor protein in determining an individual’s risk of developing depression (Waters et al., 2015). Potentially involved in the pathophysiology of depression is also the P2RX7 gene polymorphism rs2230912, a polymorphism of the gene for the P2 × 7 receptor which regulates the activity of ion channels in the neuronal membrane. The reliability of these latter findings is, however, controversial (Feng et al., 2014; Czamara et al., 2017). Very recent results have demonstrated a role for voltage activated Ca²⁺ channels in the treatment of depression. Selective serotonin reuptake inhibitors (SSRIs) directly inhibit these channels; resulting in an inhibition of stress-induced facilitated long-term depression (LTD) and depressive behavior even in the absence of the serotonin transporter in SERT-KO mice (Normann et al., 2017).

The goal of the present publication is not to compare and discuss all these various pathophysiological possibilities and mechanisms of antidepressant therapy, but rather to find biochemical actions that are common to various different treatments and may therefore provide clues to final mechanisms shared by various types of depressive syndromes and their treatment. Thus, not only classical antidepressant drugs, but also ketamine, electroconvulsive therapy (ECT) and sleep deprivation (SD) have been shown to increase brain levels of i) brain derived neurotrophic factor (BDNF) (Bjorkholm and Monteggia, 2016) ii) p11 (Svenningsson et al., 2013) and iii) Homer1a (Serchov et al., 2016). In the following article we will briefly present the basic characteristics of each of these different targets of treatment, discuss the pertinent potential mechanisms of action and finally examine how these targets might interact in successful antidepressant therapy.