Review article
News and ReviewsAre neuropeptides relevant for the mechanism of action of SSRIs?
Highlights
•
Until now mechanism of action of SSRIs has not been elucidated exactly. •
Some neuropeptides are involved in the neurobiology of stress-related mood diseases. •
Interaction of some neuropeptides with serotonergic system has been evidenced. •
Influence of SSRIs on six neuropeptide systems has been presented. •
Changes in neuropeptides may be relevant to therapeutic and side effects of SSRIs.
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are drugs of first choice in the therapy of moderate to severe depression and anxiety disorders. Their primary mechanism of action is via influence of the serotonergic (5-HT) system, but a growing amount of data provides evidence for other non-monoaminergic players in SSRI effects. It is assumed that neuropeptides, which play a role as neuromodulators in the CNS, are involved in their mechanism of action. In this review we focus on six neuropeptides: corticotropin-releasing factor – CRF, galanin – GAL, oxytocin – OT, vasopressin – AVP, neuropeptide Y – NPY, and orexins – OXs. First, information about their roles in depression and anxiety disorders are presented. Then, findings describing their interactions with the 5-HT system are summarized. These data provide background for analysis of the results of published preclinical and clinical studies related to SSRI effects on the neuropeptide systems. We also report findings showing how modulation of neuropeptide transmission influences behavioral and neurochemical effects of SSRIs. Finally, future research necessary for enriching our knowledge of SSRI mechanisms of action is proposed. Recognition of new molecular targets for antidepressants will have a significant effect on the development of novel therapeutic strategies for mood-related disorders.
Keywords
SSRIs
;
Neuropeptides
;
Depressive disorders
;
Anxiety disorders
;
Animal studies
;
Clinical research
Introduction
Selective serotonin reuptake inhibitors (SSRIs) are broadly applied drugs. They are the drugs of first choice in treating moderate to severe depression, not only because of therapeutic efficacy but also because of their superior tolerability and safety compared to other antidepressants, such as tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). When used chronically for six to twelve months they reduce risk of relapse. However, they are imperfect drugs as, among patients with depression, given standard doses of SSRIs, a relatively high rate of non-responders have been reported. They also induce side effects, especially in the initial period of therapy. These undesirable effects are more frequent with some drugs, including apathetic recoveries, gastrointestinal disturbances (nausea, vomiting, diarrhea), weight gain, sexual dysfunction, anxiety, restlessness that resembles akathisia, psychomotor retardation, sleep disturbances and metabolic impairments (dysglycemia, dyslipidemia) (Baldessarini, 2006; Reid and Barbui, 2010; Hieronymus et al., 2016; Chávez-Castillo et al., 2018). SSRIs are frequently prescribed for the long-term treatment of anxiety disorders: generalized anxiety disorders, phobias, obsessive-anxiety compulsive disorders, posttraumatic stress disorders and panic disorders (Baldessarini, 2006; Reid and Barbui, 2010; Hieronymus et al., 2016). These comprise the primary anxiety disorders according to the American Psychiatric Association DSM-V (American Psychiatric Association, 2013). Today, depressive and anxiety disorders are considered a critical health problem. The World Health Organization (WHO) has reported a significant increase in the number of people living with depression-related illnesses. It is estimated that 15–25% of people in Western communities may experience at least one episode of major depression (WHO, 2012). As WHO describes, between 1990 and 2013 the number of people suffering from depression/anxiety increased by nearly 50% (from 416 million to 615 million) (WHO, 2016). Epidemiological data indicate that one third of the world's population suffers from anxiety disorders (Bandelow and Michaelis, 2015).
There are six commercially available SSRIs: fluoxetine, fluvoxamine, citalopram, escitalopram, paroxetine and sertraline (Baldessarini, 2006). Although they clearly share the same primary mechanism of action, they have no identical secondary pharmacologic characteristics (Sanchez et al., 2014). Their primary mechanism of action is thought to occur via their modulation of monoaminergic, mainly serotoninergic (5-HT), transmission in which somatodendritic 5-HT1A autoreceptors play an essential role in 5-HT self-regulation.
After short-term administration, these drugs act as inhibitors of serotonin transporter (5-HTT, also known as SERT) and induce a modest extracellular increase in 5-HT associated with attenuation of neuronal 5-HT synthesis and release in response to activation of somatodendritic 5-HT1A autoreceptors. Eventually, following multiple SSRI administrations, which are required to achieve a therapeutic effect, progressive neuroadaptative changes develop. 5-HT-induced desensitization of raphe 5-HT1A autoreceptors resulted in increased 5-HT release, followed by desensitization of postsynaptic 5-HT receptors (Artigas, 2013). However, several critical arguments were raised against the monoamine theory of depression, revealing its weaknesses (Krishnan and Nestler, 2008), and, consequently, suggesting that the mechanism of action of antidepressants is more complex. In fact, several non-monoaminergic explanations for antidepressive drug effects relating to SSRIs have been proposed. Preclinical and clinical studies have demonstrated anti-inflammatory and anti-neuroinflammatory effects of SSRIs (Kubera et al., 2011; Tynan et al., 2012), pro-neurogenic and neurotrophic properties of SSRIs (Mahar et al., 2014) and an ability of SSRIs to modulate glutamatergic neurotransmission (Freudenberg et al., 2015). Moreover, interconnected roles of 5-HT, neutrophins and the immune system in depression and antidepressant therapy have been shown (Haase and Brown, 2015).
Additionally, this review of the leading hypotheses on the action of SSRIs has been extended to include findings related to the influence of SSRIs on neuropeptides. In the central nervous system (CNS), neuropeptides are the most highly expressed neuromodulators. The relevance of neuropeptide systems to the neurobiology of stress-related mood disorders has been previously summarized in several systematic reviews (Binder and Nemeroff, 2010; Morales-Medina et al., 2010; Catena-Dell'Osso et al., 2013; Kormos and Gaszner, 2013). As substances involved in the mechanisms of resilience and vulnerability to stress (Charney, 2004), neuropeptides are important for the successful development of stress adaptations, which are critical players in anxiety and in depressive illnesses (Leonard and Myint, 2009; Schatzberg and Nemeroff, 2010). Moreover, some neuropeptides have been shown to impact an animal's metabolic status, which in turn greatly influences mood and motivation (Kishi and Elmquist, 2005).
In this review we focus on six neuropeptides: corticotropin-releasing factor (CRF), galanin (GAL), oxytocin (OT), vasopressin (AVP), neuropeptide Y (NPY) and orexins (OXs). First, we summarize the most salient findings from preclinical studies concerning neuropeptide changes in animal models of depressive/anxiety disorders and we present data on neuropeptide changes in patients suffering from these mood disturbances. Then, information regarding interactions between neuropeptides and the 5-HT system is described, followed by the presentation of current data regarding the role of neuropeptides in SSRI effects. Finally, we discuss how particular neuropeptides effect the mechanism of action of SSRIs, as demonstrated by preclinical and clinical studies.
Section snippets
The role of neuropeptides in anxiety and depressive disorders
Neuropeptides are short amino-acid chains that differ from classic neuromediators with regard to their biosynthesis, storage and release mechanisms (Reiner, 1991). They are primarily synthesized by neurons, exhibiting a wide spectrum of secretory functions and acting via specific G protein-coupled metabotropic receptors (GPCRs) (Ögren et al., 2010). Here, we present a short characterization of six neuropeptides in order to highlight important findings relating to their contribution to the
Interaction between neuropeptides and the serotonergic system
Anatomical and functional interaction between serotonergic and neuropeptide systems support the idea that neuropeptides partially mediate the pharmacological effects of SSRIs.
Influence of SSRI on the neuropeptide transmission
To date, preclinical and clinical data indicate that SSRIs affect neuropeptide systems (Schloss and Henn, 2004). These data suggest that potential relationships exist between neuropeptide signaling and antidepressant effects, which may additionally have implications relating to drug influence on mood, anxiety, neurohormone axes and control of feeding. Several studies have been conducted to evaluate the influence of SSRIs on neuropeptide systems (Table 2, Table 3).
Concluding remarks
Findings from well-designed studies world-wide indicate that the mechanism of action of antidepressant drugs, including SSRIs, is complex. Based primarily on preclinical study results, it is thought that the pharmacological effects of SSRIs are partially mediated by neuropeptides.
In this paper we focused on well-known neuropeptides, CRF, OT, AVP, NPY, and the more recently discovered molecules, GAL and the OXs. The most important results related to neuropeptide effects and neuropeptide
Acknowledgements
Funding: This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
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