Recent insights into antidepressant therapy: Distinct pathways and potential common mechanisms in the treatment of depressive syndromes
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.
Section snippets
The role of brain derived neurotrophic factor (BDNF) in antidepressant therapy
BDNF is one of the best studied neuronal growth factors with an important role in adult neurogenesis, neuronal maturation and synaptic plasticity. It has been implicated in several neuropsychiatric diseases including e.g. schizophrenia and autism, but its major role is believed to be in depression treatment. Since this function of BDNF has been comprehensively reviewed recently (Bjorkholm and Monteggia, 2016) we will limit our discussion to some selected aspects pertinent to our question of
The function of p11 in depression and its regulation by antidepressants
P11 (also known as S100A10) is a member of the S100 gene family that acts as an adaptor protein and is critically involved in amplification of serotonergic signaling and the regulation of gene transcription (Svenningsson et al., 2013). P11 is downregulated in depressed humans and in a mouse model of depression and increased by electroconvulsive therapy or chronic administration of antidepressants including SSRIs. P11 mediates the antidepressant effects of BDNF and ketamine (Park et al., 2016;
The role of Homer1a as a universal mediator of pharmacological and non-pharmacological treatments of depression
The long homer scaffolding proteins such as Homer1 are proteins in the postsynaptic density (PSD) bridging metabotropic glutamate receptors such as mGluR1 and mGluR5 with many proteins involved in Ca2+ signaling, which have been implicated in the pathophysiology of mood disorders. The long Homer forms contain at their carboxy-terminal a coiled-coil (CC) structure followed by leucine zipper motifs that mediate Homer–Homer oligomerization and facilitate glutamate-mediated excitatory signaling (
The crosstalk between BDNF, p11 and Homer1a in antidepressant therapy
We have shortly summarized in the preceding subsections various novel mechanisms presently considered as essential in the treatment of depression. This consideration is based on the findings that blocking only one of the discussed signaling molecules (BDNF, p11, Homer1a) prevented the efficacy of antidepressant therapy in mice. This suggests that these signaling molecules are part of a molecular network which is required for antidepressant therapy.
There is evidence that BDNF regulates levels of
The role of glutamatergic AMPA receptors signaling as final mechanism mediating the antidepressant effect of BDNF, p11 and Homer1a
Since the unexpected discovery of ketamine as rapid antidepressant drug in 2000 (Berman et al., 2000) the potential role of the glutamate signaling in depression has been a major topic in psychiatric research. In particular glutamate-related genes appear associated with the risk for mood disorders, suicide, and treatment response in humans (de Souza et al., 2017). Ketamine acts as a NMDA receptor channel blocker and a number of clinical trials have confirmed its property as antidepressant
Facilitated AMPA receptor signaling and synaptic plasticity
As discussed above, alterations in BDNF, p11 and Homer1a evoked by various different antidepressant measures converge in a modulation of AMPA receptor signaling which affects long-term synaptic plasticity. There are two forms of functional plasticity regulating the strength of synaptic transmission in response to neuronal activity: long-term potentiation (LTP) increases, whereas long-term depression (LTD) decreases, synaptic transmission for hours in brain slices or even for weeks and months in
The role of muscarinic acetylcholine receptors
The potential importance of the glutamate signaling system for antidepressant therapy is also corroborated by data obtained with the nonselective (M1 – M5) muscarinic acetylcholine receptor antagonist scopolamine. Janowsky’s laboratory (Gillin et al., 1991) showed a pronounced and rapid antidepressant effect of scopolamine, which was reproduced in several publications (Drevets et al., 2013; Furey and Drevets, 2006; Jaffe et al., 2013). Recent analysis of the mechanism of action of scopolamine
The role of the brain region
An important factor in considering the impact of the various mechanisms discussed above is the brain region in which the effects are observed. The neural circuits implicated in mood disorders appear to form an extended network including the medial prefrontal cortex (including also the anterior cingulate cortex, especially its pre- and sub-genual parts) as well as limbic, striatal, thalamic and basal forebrain structures (Price and Drevets, 2012). Region-specific effects appear to play an
Potential role of BDNF, p11 and Homer1a in the etiology of depression
Depression is caused by stressful events (acute, chronic or early-life stress) or immunological and psychological challenge through a somatic disease and various genetic factors may increase the risk for the development of depression. Are BDNF, p11 and Homer1a affected by depression-causing circumstances and are genetic variations known in the genes of these factors that might increase the risk for depression?
Despite the clear role for BDNF for the treatment of depression its potential role in
Conclusions
Recent findings from independent research approaches have contributed to our understanding of depression beyond disturbances in serotonergic and/or noradrenergic neurotransmission, which had dominated the field for decades. We have argued in the preceding chapters that three targets (BDNF, p11, homer1a) identified as important in the action of various antidepressant measures, share a common final outcome, i.e. the modulation of AMPA receptor signaling, which is now believed to be a central
Author contributions
Idea, conceptualization and first draft: D.v.C., Writing, Review and Editing: T.S., C.N., K.B., D.v.C.
Acknowledgment
The experimental studies of the authors underlying part of this article were funded by grants from the German Research Council (DFG) (CA 115/5-4) to D.v.C and K.B., (BI 668/2-2 and BI 668/5-1) to K.B., (SE 2666/2-1) to T.S., the European Union FP7 program “MoodInflame’’ to D.v.C. and the German Ministry for Research and Education (BMBF) grant e:bio – Modul I –ReelinSys (Project B: 031 6174A) to K.B.
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