Current Pharmaceutical Design - Volume 15, Issue 14, 2009

Depression constitutes one of the most prevalent psychiatric disorders in our society. According to the World Health Organization (WHO), some 121 million people are currently suffering from depression, with an annual prevalence of 5.8% for men and 9.5% for women [1]. However, these figures may vary according to the population studied and the criteria or diagnostic instruments used. A recent study carried out in 6 European countries found that prevalence over the life course was 12.8% in the case of major depression and 14% for any depressive disorder (9.5% in men and 18.2% in women) [2]. Depression is the leading cause of disability as measured by Years Lived with Disability (YLDs), and was the fourth greatest contributor to the global burden of disease in 2000. By the year 2020, depression is projected to reach second place in the ranking of Disability Adjusted Life Years (DALYs) calculated for all ages and both sexes. Today, depression is already the second cause of DALYs in the age category 15-44 years for the two sexes combined [3]. With respect to the treatment of depression, the introduction by serendipity of iproniazid, the first monoamine oxidase inhibitor (MAOI), and imipramine, pioneer of tricyclic antidepressants, in the 1950s (“the psychopharmacological revolution decade”) substantially modified the conceptualization of the therapeutic approach, contributing to a reduction in the suffering of patients who previously went untreated, or were treated with archaic and dangerous biological therapies, often in conditions of institutionalization [4]. Moreover, these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypothesis of depressive disorders: “the monoamine hypothesis of depression”. As we have shown in our review (Francisco Lopez-Munoz and Cecilio Alamo, University of Alcala, Spain) [5], in the last 50 years the monoamine hypothesis has been the pharmacological target for the treatment of depression. The introduction of the so-called atypical, heterocyclic or “second generation” antidepressants (maprotiline, nomifensine, trazodone, mianserine, among others) in the 1970s, and the development and clinical introduction of the third generation of antidepressants, represented by selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, citalopram and paroxetine, in the late 1980s, once again revolutionized therapy for depression. Furthermore, they opened the way for new families of antidepressants: norepinephrine reuptake inhibitors (NARI), reboxetine, or dual-acting serotonin norepinephrine reuptake inhibitors (SNRI), venlafaxine and more recently duloxetine. Nevertheless, all of them, including the presynaptic receptor antagonist mirtazapine, continue to employ the same action mechanism as the classic drugs, that is, the modulation of monoaminergic neurotransmission at a synaptic level [6]. Given that all the antidepressants initiate their effect with a monoaminergic increase at the synaptic cleft, this may condition their action onset, generally more than 3-4 weeks, as well influencing their lack of effectiveness in approximately 30% of patients with major depressive disorder (MDD). In this regard, recent advances involving the new agents has been based not so much on important distinctions from the point of view of therapeutic effectiveness (in some it is not even as high as for the classic drugs), as on a different profiles of adverse side effects and the greater confidence they inspire on the part of general practitioners [3]. Nevertheless, in spite of these advantages, problems in the treatment of depressive patients have not been solved completely, and there is still considerable need for safer, faster-acting and more effective agents that go beyond the “solely monoaminergic” perspective [7].

The 1950s saw the clinical introduction of the first two specifically antidepressant drugs: iproniazid, a monoamine- oxidase inhibitor that had been used in the treatment of tuberculosis, and imipramine, the first drug in the tricyclic antidepressant family. Iproniazid and imipramine made two fundamental contributions to the development of psychiatry: one of a social-health nature, consisting in an authentic change in the psychiatric care of depressive patients; and the other of a purely pharmacological nature, since these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypotheses of depressive disorders. The clinical introduction of fluoxetine, a selective serotonin reuptake inhibitor, in the late 1980s, once again revolutionized therapy for depression, opening the way for new families of antidepressants. The present work reviews, from a historical perspective, the entire process that led to the discovery of these drugs, as well as their contribution to the development of the neuroscientific disciplines. However, all of these antidepressants, like the rest of those currently available for clinical practice, share the same action mechanism, which involves the modulation of monoaminergic neurotransmission at a synaptic level, so that the future of antidepressant therapy would seem to revolve around the search for extraneuronal non-aminergic mechanisms or mechanisms that modulate the intraneuronal biochemical pathways.

Depression is a highly prevalent form of mental illness. This condition is often considered a stress-related disorder because some form of stressful life event frequently triggers depressive symptoms. Corticotropin-releasing factor (CRF) is a 41 amino acid neuropeptide involved in mediating neuroendocrine, autonomic and behavioral responses to environmental demands, and has long been considered one of the body's major regulators of the stress response. Results from clinical studies suggest that normal functioning of the CRF system is altered in patients diagnosed with depression. Two genes encoding distinct G-protein coupled CRF receptors have been identified, the CRF1 receptor and CRF2 receptor. Originally, the belief was that activation of the CRF system would lead to increases in the stress response. Recent characterization of the CRF receptor subtypes and CRF receptor specific ligands, however, suggests that there may be a differential regulation of stress within this system and that imbalances in receptor activation could lead to the development of stress-related psychiatric disorders. Preclinical models show evidence for increased CRF1 receptor activity in the regulation of depressive-like behaviors, and a number of nonpeptide CRF1 receptor antagonists have recently been developed as potential antidepressant medications. Although, the role of CRF2 receptors remains unclear in depression, preclinical evidence suggests that under activation of this receptor may be involved in the regulation of increased depression-like behavior in animals. The present article will review the role of CRF receptors and CRF-related ligands in depression and proposes targeting the CRF system as a potential pharmacotherapy for depressive disorders.

There have been no recent advances in drug development for mood disorders in terms of identifying drug targets that are mechanistically distinct from existing ones. As a result, existing antidepressants are based on decades-old notions of which targets are relevant to the mechanisms of antidepressant action. Low rates of remission, a delay of onset of therapeutic effects, continual residual depressive symptoms, relapses, and poor quality of life are unfortunately common in patients with mood disorders. Offering alternative options is requisite in order to reduce the individual and societal burden of these diseases. The glutamatergic system is a promising area of research in mood disorders, and likely to offer new possibilities in therapeutics. There is increasing evidence that mood disorders are associated with impairments in neuroplasticity and cellular resilience, and alterations of the glutamatergic system are known to play a major role in cellular plasticity and resilience. Existing antidepressants and mood stabilizers have prominent effects on the glutamate system, and modulating glutamatergic ionotropic or metabotropic receptors results in antidepressant-like properties in animal models. Several glutamatergic modulators targeting various glutamate components are currently being studied in the treatment of mood disorders, including release inhibitors of glutamate, N-methyl-D-aspartate (NMDA) antagonists, alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) throughput enhancers, and glutamate transporter enhancers. This paper reviews the currently available knowledge regarding the role of the glutamatergic system in the etiopathogenesis of mood disorders and putative glutamate modulators.

The pathophysiology of mood disorders involves several genetic and social predisposing factors, as well as a dysregulated response to a chronic stressor, i.e. chronic pain. Our present view that depression involves a dysfunction of the monoaminergic system is a result of important clinical and preclinical observations over the past 40 years. In fact, current pharmacological treatment for depression is based on the use of drugs that act mainly by enhancing brain serotonin and noradrenaline neurotransmission by the blockade of the active reuptake mechanism for these neurotransmitters. However, a substantial number of patients do not respond adequately to antidepressant drugs. In view of this, there is an intense search to identify novel targets (receptors) for antidepressant therapy. Opioid peptides and their receptors are potential candidates for the development of novel antidepressant treatment. In this context, endogenous opioid peptides are coexpressed in brain areas known to play a major role in affective disorders and in the action of antidepressant drugs. The actions of endogenous opioids and opiates are mediated by three receptor subtypes (μ, δ and κ), which are coupled to different intracellular effector systems. Also, antidepressants which increase the availability of noradrenaline and serotonin through the inhibition of the reuptake of both monoamines lead to the enhancement of the opioid pathway. Tricyclic antidepressants show an analgesic effect in neuropathic and inflammatory pain that is blocked by the opioid antagonist naloxone. A compilation of the most significant studies will illustrate the actual and potential value of the opioid system for clinical research and drug development.

Among all mental disorders, major depression has the highest rate of prevalence and incidence of morbidity. Currently available antidepressant therapies have limited efficacies; consequently, research on new drugs for the treatment of mood disorders has become increasingly critical. Recent preclinical evidences that cannabinoid agonists and endocannabinoid enhancers, such as the fatty acid amide hydrolase (FAAH) inhibitors, can impact mood regulation have opened a new line of research in antidepressant drug discovery. However, the neurobiological mechanisms linking the endocannabinoid system with the pathophysiology of mood disorders and antidepressant action remain unclarified. In this review, we have presented an update on preclinical data indicating the antidepressant potential of cannabinoid agonists and endocannabinoid enhancers in comparison to standard antidepressants. Data obtained from CB1 knockout (CB1-/-) and FAAH knockout (FAAH-/-) mice have also been examined within this context. We have illustrated how the various classes of antidepressants exert their therapeutic action. In particular, all antidepressants increase the neurotransmission of serotonin after long-term treatment, enhance the tonic activity of hippocampal 5-HT1A receptors, promote neurogenesis, and modulate (decrease or increase) the firing activity of noradrenergic neurons. Interestingly, cannabinoid agonists and endocannabinoid enhancers increase serotonin and noradrenergic neuronal firing activity, increase serotonin release in the hippocampus, as well as promote neurogenesis. Since cannabinoid-derived drugs potentiate monoaminergic neurotransmission and hippocampal neurogenesis through distinct pathways compared to classical antidepressants, they may represent an alternative drug class in the pharmacotherapy of mood and other neuropsychiatric disorders.

The first report demonstrating the therapeutic efficacy of an orally applied neurokinin-1 (NK1) receptor antagonist in depression was published 10 years ago. Although there were difficulties to reproduce this particular finding, a huge amount of data has been published since this time, supporting the potential therapeutic value of various tachykinin ligands as promising novel tools for the management of stress-related disorders including anxiety disorders, schizophrenia and depression. The present review summarizes evidence derived from anatomical, neurochemical, pharmacological and behavioral studies demonstrating the localization of tachykinin neuropeptides including substance P (SP), neurokinin A, neurokinin B and their receptors (NK1, NK2, NK3) in brain areas known to be implicated in stress-mechanisms, mood/anxiety regulation and emotion-processing; their role as neurotransmitters and/or neuromodulators within these structures and their interactions with other neurotransmitter systems including dopamine, noradrenaline and serotonin (5- hydroxytryptamine, 5-HT). Finally, there is clear functional evidence from animal and human studies that interference with tachykinin transmission can modulate emotional behavior. Based on these findings and on evidence of upregulated tachykinin transmission in individuals suffering from stress-related disorders, several diverse tachykinin receptor antagonists, as well as compounds with combined antagonist profile have been developed and are currently under clinical investigation revealing evidence for anxiolytic, antidepressant and antipsychotic efficacy, seemingly characterized by a low side effect profile. However, substantial work remains to be done to clarify the precise mechanism of action of these compounds, as well as the potential of combining them with established and experimental therapies in order to boost efficacy.

Agomelatine markedly differs from other classes of antidepressant drugs: its primary molecular targets in vivo are the melatonin MT1 and MT2 receptors, where it acts as a potent agonist, and the 5-HT2C receptors, where it exerts clear-cut antagonist properties. Agomelatine across a wide range of clinical trials suggests that agomelatine offers an important alternative for the treatment of depression, combining efficacy, even in the most severely depressed patients, with a favorable side-effect profile. It will be of interest to see if agomelatine expands the spectrum of treatment for unipolar depression. It shows efficacy in acute phase and in of maintenance treatment compared to reference antidepressants as paroxetine and venlafaxine.

Monoamine oxidase inhibitor and tricyclic antidepressants have been serendipitously used for the treatment of depression for more than half a century and subsequently found to promote monoaminergic signals in the brain. Antidepressant dugs are still clinically used and industrially designed on the basis of the monoaminergic theory. Recent developments regarding selective monoaminergic uptake inhibitors can further improve the safe and rational treatment for patients with depression. However, monoamine-based antidepressants may cause unfavorable and incomplete remission of a considerable number of patients with depression; therefore, development of new antidepressant drugs based on other mechanisms is required. Meanwhile, there has been an impressive accumulation of knowledge about cytokines that might contribute to the understanding of the pathophysiology of depression. Therefore, this review focuses on the association between depressive disorder and cytokines and discusses the strategies for developing new cytokine-based antidepressant drugs.

Phosphodiesterase-4 (PDE4), one of eleven PDE enzyme families, specifically catalyzes hydrolysis of cyclic AMP (cAMP); it has four subtypes (PDE4A-D) with at least 25 splice variants. PDE4 plays a critical role in the control of intracellular cAMP concentrations. PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain. However, their clinical utility has been hampered by side effects, in particular nausea and emesis. While there is still a long way to go before PDE4 inhibitors with high therapeutic indices are available for treatment of depressive disorders, important advances have been made in the development of PDE4 inhibitors as antidepressants. First, limited, but significant studies point to PDE4D as the major PDE4 subtype responsible for antidepressant- like effects of PDE4 inhibitors, although the role of PDE4A cannot be excluded. Second, PDE4D may contribute to emesis, the major side effect of PDE4 inhibitors. For this reason, identification of roles of PDE4D splice variants in mediating antidepressant activity is particularly important. Recent studies using small interfering RNAs (siRNAs) have demonstrated the feasibility to identify cellular functions of individual PDE4 variants. Third, mixed inhibitors of PDE4 and PDE7 or PDE4 and serotonin reuptake have been developed and may be potential antidepressants with minimized side effects. Finally, relatively selective inhibitors of one or two PDE4 subtypes have been synthesized using structure- and scaffold- based design. This review also discusses the relationship between PDE4 and antidepressant activity based on structures, brain distributions, and pharmacological properties of PDE4 and its isoforms.

G protein-coupled receptors (GPCR) have generated considerable interest in the pharmaceutical industry as drug targets. Theories concerning antidepressant targets of action suggested pre-synaptic monoamine reuptake mechanisms regulating GPCR activities including delayed receptor desensitization and down-regulation. GRKs and β-arrestins translocate to the cell membrane and bind to agonist-occupied receptors. This uncouples these receptors from G proteins and promotes their internalization, leading to desensitization and down-regulation. Thus, GRKs and β-arrestins serve as negative regulators of GPCR signaling. Recently, GPCR have been demonstrated to elicit signals through interaction with β-arrestin as scaffolding proteins, independent of heterotrimeric G-protein coupling. β-arrestins function as scaffold proteins that interact with several cytoplasmic proteins and link GPCR to intracellular signaling pathways such as MAPK cascades. Recent work has also revealed that β-arrestins translocate from the cytoplasm to the nucleus and associatewith transcription cofactors such as p300 and CREB. They also interact with regulators of transcription factors. We review findings concerning effects of antidepressants on GRKs and β-arrestins and the plethora of antidepressants effects on signal transduction elements in which GRKs and β-arrestins serve as signaling scaffold proteins, and on transcription factors and cofactors in which β-arrestins mediate regulation of transcription. The emergence of G-protein-independent signaling pathways, through β-arrestins, changes the way in which GPCR signaling is evaluated, from a cell biological to a pharmaceutical perspective and raises the possibility for the development of pathway specific therapeutics e.g., antidepressant medications targeting GRKs and β-arrestin regulatory and signaling proteins.