Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 15, Number 14, 2009

Contents

New Antidepressant Drugs: Beyond Monoaminergic Mechanisms
Executive Editors: F. López-Muñoz and C. Álamo


Editorial: Pp. 1559-1562


Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today Pp. 1563-1586
F. López-Muñoz and C. Alamo
[Abstract] [Purchase Article] [PMID: 19442174 PubMed - indexed for MEDLINE]


CRF Receptors as a Potential Target in the Development of Novel Pharmacotherapies for Depression Pp. 1587-1594
G.R. Valdez
[Abstract] [Purchase Article] [PMID: 19442172 PubMed - indexed for MEDLINE]


Targeting Glutamatergic Signaling for the Development of Novel Therapeutics for Mood Disorders Pp. 1595-1611
R. Machado-Vieira, G. Salvadore, L.A. Ibrahim, N. Diaz-Granados and C.A. Zarate Jr.
[Abstract] [Purchase Article] [PMID: 19442176 PubMed - indexed for MEDLINE]


Opiates as Antidepressants Pp. 1612-1622
E. Berrocoso, P. Sánchez-Blázquez, J. Garzón and J.A. Micó
[Abstract] [Purchase Article] [PMID: 19442177 PubMed - indexed for MEDLINE]


Endocannabinoids in the Treatment of Mood Disorders: Evidence from Animal Models Pp. 1623-1646
F.R. Bambico, A. Duranti, A. Tontini, G. Tarzia and G. Gobbi
[Abstract] [Purchase Article] [PMID: 19442178 PubMed - indexed for MEDLINE]


Tachykinin Receptors as Therapeutic Targets in Stress-Related Disorders Pp. 1647-1674
K. Ebner, S.B. Sartori and N. Singewald
[Abstract] [Purchase Article] [PMID: 19442179 PubMed - indexed for MEDLINE]


Melatonin Receptor Agonist Agomelatine: A New Drug for Treating Unipolar Depression Pp. 1675-1682
M. Bourin and C. Prica
[Abstract] [Purchase Article] [PMID: 19442180 PubMed - indexed for MEDLINE]


New Approaches to Antidepressant Drug Design: Cytokine Regulated Pathways Pp. 1683-1687
A. Nishida, T. Miyaoka, T. Inagaki and J. Horiguchi
[Abstract] [Purchase Article] [PMID: 19442181 PubMed - indexed for MEDLINE]


Cyclic AMP-Specific Phosphodiesterase-4 as a Target for the Development of Antidepressant Drugs Pp. 1688-1698
H-T. Zhang
[Abstract] [Purchase Article] [PMID: 19442182 PubMed - indexed for MEDLINE]


Antidepressants, β-Arrestins and GRKs: From Regulation of Signal Desensitization to Intracellular Multifunctional Adaptor Functions Pp. 1699-1708
M. Golan, G. Schreiber and S. Avissar
[Abstract] [Purchase Article] [PMID: 19442183 PubMed - indexed for MEDLINE]




Abstracts


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Editorial: New Antidepressant Drugs: Beyond Monoaminergic Mechanisms

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 López-Muñoz and Cecilio Álamo, University of Alcalá, 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].

Currently, there is considerable scientific data, from both animal and human experimentation, supporting the participation of non-monoaminergic mechanisms in the physiopathology of depression; attempts to find antidepressants that initiate their effects through non-monoaminergic mechanisms are intense, though satisfactory results have yet to be obtained. There are various reasons for this, the first being that the experimental models developed for the study of antidepressants that act on serotonergic or noradrenergic functionalism may not be capable of detecting other mechanisms. Furthermore, there is no non-aminergic antidepressant in the clinical field that can validate these experimental methods. And finally, basic research –above all clinical research–, which must include large numbers of patients, together with high response rates obtained with placebo (particularly in short studies), means that the development of these drugs is an extremely expensive undertaking. All in all, it is not surprising that the focus has up to now been on the “more predictable” research with monoaminergic antidepressants [8].

However, in the last 15 years or so it would seem that a change has been coming about. One of the landmarks in this sense is the advent of agomelatine (S-20098), a molecule synthesized in 1991 by Adir & Co., a subsidiary of Laboratoires Servier. Agomelatine is the first antidepressant with proven clinical efficacy that approaches the treatment of depression from a pharmacological perspective other than that of the other drugs employed up to now. The primary mechanism of this agent is its agonistic action on MT₁ and MT₂ melatonin receptors [7]. In the present special issue, Michel Bourin and Corina Prica (University of Nantes, France) discuss the preclinical and clinical studies with this agent, stressing how agomelatine has opened up the spectrum of treatment for unipolar depression “beyond monoamines” [9].

In any case, the relationship between therapeutic effect and the increase in monoamine rate in the synaptic cleft brought about by antidepressants is so robust that some authors consider it equivalent to nothing more than a switch that triggers adaptive mechanisms responsible for the clinical effect of these drugs. This could explain the delay in onset of the therapeutic effect so characteristic of antidepressants. It is not illogical, therefore, to think that the increase in synaptic concentrations of serotonin (5-HT) and/or noradrenaline (NA) produces in the central nervous system (CNS) secondary biochemical changes (β-adrenergic and 5-HT₂ receptors down-regulation; desensitization of D₂ and α₂-presynaptic autoreceptors) or tertiary changes (desensitization of the adenylatocyclase system coupled to the β-adrenergic receptors), which would offset the biochemical anomalies responsible for depressive disorders [10].

The role of G proteins (GP) in the modulation of receptor signals has aroused considerable interest in the last few years. This is due to the fact that these proteins constitute the initial post-receptor step in the most important intracellular transduction pathways. Antidepressants, in long-term administration, are capable of modifying the functioning of different elements of these GPs, which suggests that in depression there may be some disorder in the superfamily of GPs coupled to receptors, and that antidepressants would act by modifying –supposedly towards “normality”– this dysfunction of GPs. Therefore, it has been argued that a therapeutic objective in dealing with affective disorders may involve the action of drugs on GPs [10]. In this special issue, Moran Golan, Gabriel Schreiber and Sofia Avissar (Ben Gurion University of Neguev, Israel) discuss the possibility of developing antidepressant medications targeting GRKs (G protein-coupled receptor kinases) and β-arrestin responsible for the internalization and desensitization of G proteins coupled to receptors [11]. Moreover, the role of β-arrestin has increased considerably in the wake of its proven involvement in the mitogen-activated protein kinase (MAPK) cascade and its capacity to interact with regulators of transcription factors. It would seem that a new antidepressant therapeutic target has been established with the discovery of the broad role of β-arrestin.

Furthermore, researchers have for many years been exploring the possibility of imitating the cascade of intracellular effects produced after prolonged administration of antidepressants. In such conditions, we can observe an increase in levels of cAMP, which is reflected in an increase in the expression of CREB (cAMP response element-binding) and BDNF (brain-derived neurotrophic factor), elements that appear to play a crucial role in antidepressant efficacy. Levels of cAMP have been successfully increased through blocking of its metabolization by inhibition of phosphodiesterase (PDE). In fact, rolipram, a non-selective PDE4 inhibitor, shows antidepressant activity, though its clinical utility is greatly affected by its enormous capacity to produce nausea and vomiting [8]. The excellent review by Han-Ting Zhang (West Virginia University Health Sciences Center, United States) in this issue reports on the substantial progress made in the identification of roles of PDE4D splice variants in mediating antidepressant activity, that can help to avoid the nausea and vomiting characteristic of these inhibitors [12]. Moreover, research has developed mixed inhibitors of PDE4 and PDE7 or PDE4 and serotonin reuptake with antidepressant potential and minimal adverse effects.

The discovery, around 20 years ago, of the role of corticotropin-releasing hormone (CRH) in the control of the reactions of the hypothalamic-pituitary-adrenal axis (HPA) and other CNS areas to stress has revolutionized our knowledge of the neurobiology of depression and has opened up interesting therapeutic perspectives. Hyperactivity of the HPA axis has been described in depressive patients, together with reduced control of negative feedback of glucocorticoids. CRH appears to act not only as a releasing factor of adrenocorticotropic hormone (ACTH), but also as a neurotransmitter that mediates emotional, cognitive and behavioural reactions [10]. Despite the fact that the molecular bases of this functional disorder of the HPA axis have not been fully clarified, numerous clinical studies have suggested that the functional normalization of this axis may be a necessary step for stabilization of the remission of depressive symptoms. In the light of these antecedents, Glenn R. Valdez (Grand Valley State University, United States) explores the role of corticotropin-releasing factor (CRF) receptor subtypes and CRF receptor specific ligand and their role in psychiatric conditions influenced by stress, proposing the system controlled by CRF as a potential target, with its advantages and disadvantages, for the treatment of depression [13].

The hypothesis of the participation of cytokines in depression emerges from the observation that the treatment of diverse pathologies with some of them, such as interferons, interleukin-1, interleukin-2, and tumour necrosis factor-α (TNF-α), can produce a series of symptoms similar to those detected in depression (anhedonia, reduced social interaction, fatigue, etc.). Moreover, certain cytokines can be regulated by stress, and there are reports of alterations of the immunological system in depressive disorders (e.g., high levels of interleukin-6). In contrast, treatment with fluoxetine has normalized levels of this cytokine [7]. These and other data, thoroughly discussed in the work by Akida Nishida, Tsuyshi Miyaoka, Takuji Inagaki and Jun Horiguchi (Shimane University School of Medicine, Japan), have permitted the search for antidepressants that employ as therapeutic target the pathways used by cytokines [14]. It is possible that in future at least some types of depression could be treated with new drugs with anti-inflammatory and antidepressant properties.

In the line of seeking agents that can act through mechanisms different from the classic ones, ample evidence now exists that glutamate homeostasis and neurotransmission are disrupted in MDD in humans. For example, clinical studies suggest that N-methyl-D-aspartate (NMDA) receptor antagonists may produce robust antidepressant effects within hours, and which are probably due to changes in synaptic activity rather than morphological changes. On the other hand, diverse antidepressants, be they tricyclic agents, MAOIs or SSRIs, administered over a long period, antagonize the glycine locus of the NMDA receptor in cortical membranes. Moreover, various modulators of the NMDA receptor complex imitate the effects of antidepressants in several predictive pre-clinical models of antidepressant action and provoke a hyporegulation of cortical β-adrenergic receptors. Similarly, there is dysregulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors in depression, and AMPA receptor agonists act as antidepressant agents, perhaps by inducing BDNF expression. Metabotropic glutamate receptors which regulate glutamate neuronal transmission can inhibit neurogenesis and antagonists to these receptors also exhibit antidepressant-like properties in behavioural assays by acting downstream of AMPA receptors [7,15]. These and other aspects, such as rapidity of antidepressive response or their possible utility in conditions comorbid with depression, related to glutamatergic transmission, are developed by Rodrigo Machado-Vieira, Giacomo Salvadore, Lobna A. Ibrahim, Nancy Diaz-Granados, and Carlos A. Zarate, from NIMH-NIH (Bethesda, United States), in this issue [16].

Substance P, a neurokinin that acts on NK-1 receptors, has aroused enormous interest in psychiatry due to its identification in the circuits related to fear and anxiety, circumstances involving the release of neurokinin, together with its location alongside serotonin and noradrenaline. On the other hand, the administration of agonists of substance P results in characteristic defensive reactions, such as escape attempts, behavioural reactions, cardiovascular activation and increased discharge from the locus coeruleus, related to responses to stress [8]. In contrast, antagonists of these receptors appear to exhibit experimental anxiolytic and antidepressant properties. The initial excitement aroused by MK-869, an NK-1 antagonist, with antidepressant efficacy in humans similar to that of paroxetine, fell off in the wake of later studies in phases II and III, in which there was observed a high response to placebo; in turn, interest in developing these antagonists waned [8,10]. Even so, and as discussed in this special issue by Karl Ebner, Simone B. Sartori and Nicolas Singewald (Leopold-Franzens University of Innsbruck, Austria), there are still antidepressant therapeutic options for antagonists of other receptors (NK-2), as well as for different conditions that involve stress [17]. Likewise, as these authors point out, the profile of neurokinin anatagonists could be useful as complements to antidepressants, be it by increasing their effects, decreasing the delay in their action onset or reducing their adverse side effects.

Transmission by endocannabinoids in the CNS is a topic that is attracting more and more interest from the therapeutic point of view. In this regard, the manipulation of CB-1 receptors, the principal target of endocannabinoids, presents potent effects on behaviour induced by stress and anxiety in rodents. It is not surprising that some ligands of this receptor, or substances that increase its endogenous ligands, may have antidepressant properties. However, the results so far are inconsistent [8]. Francis Rodriguez-Bambico, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, and Gabriella Gobbi (McGill University, Canada, and University of Urbino Carlo Bo, Italy), in their contribution to this special issue, describe the experimental bases for a possible use of endocannabinoids as antidepressants, highlighting their capacity (as is the case of other antidepressants) for boosting noradrenergic and serotoninergic mechanisms, at the same time as favouring hippocampal neurogenesis, via pathways distinct from those used by conventional drugs [18]. Nevertheless, the clinical use of endocannabinoids, as the authors point out, would require the clarification of some doubts, not least those concerning their peripheral effects.

Some authors have also involved the opioid system in depression and in their consideration of the action mechanism of antidepressants. This view is based fundamentally on the classic observation that some opiate agents may have certain antidepressant power. Indeed, some authors have requested the approval of the partial agonist buprenorphine in the treatment of resistant depressions. But moreover, it is known that electroconvulsive therapy (ECT) increases plasmatic levels of β-endorphin, and that the administration of amitryptiline increases the concentration of leu-enkephalin in the hypothalamus and spinal cord. Also, research has detected an increase in the density of opioid receptors of the μ type, in both the frontal cortex and caudate nucleus of suicide victims, a density which decreases where there is long-term administration of antidepressants [10]. As pointed out by Esther Berrocoso, Pilar Sánchez-Blázquez, Javier Garzón and Juan A. Micó (University of Cádiz, and Cajal Institute – CSIC, Spain), there is considerable preclinical data that involves endogenous opioid peptides and their receptors as candidates in the quest for new antidepressants [19]. Moreover, mu-opioid and delta-opioid activation and/or kappa-opioid blockade produce antidepressant-like effects in a number of preclinical assays, suggesting that these may be other pharmacological targets for treating depression in humans. Likewise, research has shown the existence of common steps in the opiate and NMDA transduction pathways, which also supports the hypothesis of the possible antidepressant effect of opioids. The contributions by these authors suggest that in the future it will be possible to obtain antidepressants which act via opioid mechanisms, without the problems of addiction they present.

Finally, it should be stressed that many different research groups have considered a whole range of neurotransmission and neuromodulation systems as possible therapeutic targets for depression. All such contributions are of great importance, since the problem facing us probably has no single key, and it is the research effort as a whole that will finally help to unlock the “Pandora’s Box” constituted by disorders of the mind and their treatment. In the meantime, we should try to make progress in the use of the existing therapeutic arsenal, with a view to helping our patients endure their illness. Even so, we must look to the future for the improvement of antidepressant treatment, and that means considering some of the neurobiological alternatives presented in this special issue.

References

[1] World Health Organization. Depression. Available at: www.who.int/mediacentre.http://www.who.int/mental_health/
management/depression/definition/en/. [Accessed on Jan 7, 2009].

[2] ESEMeD/MHEDEA 2000. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand 2004; 420: 21-27.

[3] Martín-Águeda B, López-Muñoz F, Rubio G, García-García P, Silva A, Álamo C. Current situation of depression healthcare in Spain: results of a psychiatrists’ survey. Eur J Psychiat 2006; 20: 211-223.

[4] López-Muñoz F, Álamo C, Guerra JA, Rubio G. Twenty-four years of scientific publications on selective serotonin reuptake inhibitors (SSRI): A bibliometric approach. In: Shirley AC Ed, Focus on serotonin uptake inhibitor research. New Cork: Nova Science Publishers, Inc. 2006; 191-219.

[5] López-Muñoz F, Alamo C. Monoaminergic neurotransmission: The history of the discovery of antidepressants from 1950s until today. Curr Pharm Des 2009; 15(14): 1563-1586.

[6] Álamo C, López-Muñoz F, Armada MJ. Agomelatina: un nuevo enfoque farmacológico en el tratamiento de la depresión con traducción clínica. Psiq Biol 2008; 15: 125-139.

[7] Álamo C, López-Muñoz F, Martín B, Cuenca E. Biología de la depresión y del tratamiento antidepresivo: mirando al futuro. In: Pichot P Ed, Diagnóstico diferencial y racionalización del tratamiento psicofarmacológico. Madrid: Aula Médica 2001; 87-124.

[8] Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006; 7: 137-151.

[9] Bourin M, Prica C. Melatonin receptor agonist agomelatine: A new drug for treating unipolar depression. Curr Pharm Des 2009; 15(14): 1675-1682.

[10] Álamo C, Cuenca E, López-Muñoz F. Avances en psicofarmacología y perspectivas de futuro. In: Avendaño MC, Tamargo J Eds, Nuevos avances en Medicamentos, Monografía XV. Madrid: Real Academia Nacional de Farmacia (Instituto de España) 2004; 351-431.

[11] Golan M, Schreiber G, Avissar S. Antidepressants, β-arrestins and GRKs: From regulation of signal desensitization to intracellular multifunctional adaptor functions. Curr Pharm Des 2009; 15(14): 1699-1708.

[12] Zhang HT. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des 2009; 15(14): 1688-1698.

[13] Valdez GR. CRF receptors as a potential target in the development of novel pharmacotherapies for depression. Curr Pharm Des 2009; 15(14): 1587-1594.

[14] Nishida A, Miyaoka T, Inagaki T, Horiguchi J. New approaches to antidepressant drug design: Cytokine-regulated pathways. Curr Pharm Des 2009; 15(14): 1683-1687.

[15] Thakker-Varia S, Alder J. Neuropeptides in depression: Role of VGF. Behav Brain Res 2009; 197: 262-278.

[16] Machado-Vieira R, Salvadore G, Ibrahim LA, Díaz-Granados N, Zarate CA. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 2009; 15(14): 1595-1611.

[17] Ebner K, Sartori SB, Singewald N. Tachykinin receptors as therapeutic targets in stresss-related disorders. Curr Pharm Des 2009; 15(14): 1647-1674.

[18] Rodríguez-Bambico F, Duranti A, Tontini A, Tarzia G, Gobbi G. Endocannabinoids in the treatment of mood disorders: Evidence from animal models. Curr Pharm Des 2009; 15(14): 1623-1646.

[19] Berrocoso E, Sánchez-Blázquez P, Garzón J, Micó JA. Opiates as antidepressants. Curr Pharm Des 2009; 15(14): 1612-1622.


Cecilio Álamo and Francisco López-Muñoz
Department of Pharmacology
University of Alcalá
Ctra. Madrid-Barcelona, Km 33,600
28871 Alcalá de Henares, Madrid
Spain
Tel: (34) 917248210
Fax: (34) 917248205
E-mail: cecilioalamo@hotmail.com


[Back to top] [Purchase Article] [PMID: 19442174 PubMed - indexed for MEDLINE]
Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today
F. López-Muñoz and C. Alamo

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.


[Back to top] [Purchase Article] [PMID: 19442175 PubMed - indexed for MEDLINE]
CRF Receptors as a Potential Target in the Development of Novel Pharmacotherapies for Depression
G.R. Valdez

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.


[Back to top] [Purchase Article] [PMID: 19442176 PubMed - indexed for MEDLINE]
Targeting Glutamatergic Signaling for the Development of Novel Therapeutics for Mood Disorders
R. Machado-Vieira, G. Salvadore, L.A. Ibrahim, N. Diaz-Granados and C.A. Zarate Jr.

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.


[Back to top] [Purchase Article] [PMID: 19442177 PubMed - indexed for MEDLINE]
Opiates as Antidepressants
E. Berrocoso, P. Sánchez-Blázquez, J. Garzón and J.A. Micó

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 co-expressed 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.


[Back to top] [Purchase Article] [PMID: 19442178 PubMed - indexed for MEDLINE]
Endocannabinoids in the Treatment of Mood Disorders: Evidence from Animal Models
F.R. Bambico, A. Duranti, A. Tontini, G. Tarzia and G. Gobbi

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-HT_1A 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.


[Back to top] [Purchase Article] [PMID: 19442179 PubMed - indexed for MEDLINE]
Tachykinin Receptors as Therapeutic Targets in Stress-Related Disorders
K. Ebner, S.B. Sartori and N. Singewald

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.


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Melatonin Receptor Agonist Agomelatine: A New Drug for Treating Unipolar Depression
M. Bourin and C. Prica

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-HT_2C 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.


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New Approaches to Antidepressant Drug Design: Cytokine Regulated Pathways
A. Nishida, T. Miyaoka, T. Inagaki and J. Horiguchi

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.


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Cyclic AMP-Specific Phosphodiesterase-4 as a Target for the Development of Antidepressant Drugs
H-T. Zhang

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.


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Antidepressants, β-Arrestins and GRKs: From Regulation of Signal Desensitization to Intracellular Multifunctional Adaptor Functions
M. Golan, G. Schreiber and S. Avissars

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 associate with 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 ontranscription factors and cofactorsin which β-arrestins mediateregulation 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.