Associate editor: T.A. Branchek
Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application

https://doi.org/10.1016/j.pharmthera.2005.11.006Get rights and content

Abstract

Major depression is a debilitating and recurrent disorder with a substantial lifetime risk and a high social cost. Depressed patients generally display co-morbid symptoms, and depression frequently accompanies other serious disorders. Currently available drugs display limited efficacy and a pronounced delay to onset of action, and all provoke distressing side effects. Cloning of the human genome has fuelled expectations that symptomatic treatment may soon become more rapid and effective, and that depressive states may ultimately be “prevented” or “cured”. In pursuing these objectives, in particular for genome-derived, non-monoaminergic targets, “specificity” of drug actions is often emphasized. That is, priority is afforded to agents that interact exclusively with a single site hypothesized as critically involved in the pathogenesis and/or control of depression. Certain highly selective drugs may prove effective, and they remain indispensable in the experimental (and clinical) evaluation of the significance of novel mechanisms. However, by analogy to other multifactorial disorders, “multi-target” agents may be better adapted to the improved treatment of depressive states. Support for this contention is garnered from a broad palette of observations, ranging from mechanisms of action of adjunctive drug combinations and electroconvulsive therapy to “network theory” analysis of the etiology and management of depressive states. The review also outlines opportunities to be exploited, and challenges to be addressed, in the discovery and characterization of drugs recognizing multiple targets. Finally, a diversity of multi-target strategies is proposed for the more efficacious and rapid control of core and co-morbid symptoms of depression, together with improved tolerance relative to currently available agents.

Section snippets

Depression as a heterogeneous and multifactorial disorder

Major (unipolar) depression is a serious and highly prevalent disorder that is triggered by a complex interplay of genetic, developmental, and environmental factors. Its most characteristic (and diagnostic) symptoms are depressed mood (sadness) and an almost complete and enduring inability to experience pleasure (melancholy or anhedonia) (Table 1). Depressive states are also characterized by a constellation of other essentially psychological symptoms, ranging from poor concentration to

Three crucial and interrelated issues

In the search for novel antidepressant agents, several fundamental and interrelated themes must be addressed: (1) the impact of sequencing the human genome (Venter et al., 2001, Guttmacher & Collins, 2002, Roses, 2002a, Searls, 2003, Bartfai, 2004, International Human Genome Sequencing Consortium, 2004, Claverie, 2005); (2) the role of monoaminergic versus non-monoaminergic mechanisms in the pathogenesis and management of depression (Bosker et al., 2004, Millan, 2004, Pacher & Kecskemeti, 2004b

The genome as a source of novel targets

In the genome-driven pursuit of novel antidepressants–and, in general, other classes of therapeutic agent–the previous decade or so has witnessed a clear predilection for “selective” drugs. This pre-occupation partially reflects simplistic assumptions concerning the utility of the human genome as a starting point for target identification and drug discovery (Fig. 2) (Sections 2.2 and 15). For a fuller understanding of arguments supporting the use of multi-target antidepressants, it is

Clinically available antidepressants all act via monoaminergic mechanisms

Although the precise nature of the deficit(s) remains under discussion, there is compelling evidence that monoaminergic transmission is perturbed in depressive states (Caldecott-Hazard et al., 1991a, Caldecott-Hazard et al., 1991b, Maes & Meltzer, 1995, Chaouloff et al., 1999, Millan et al., 2000c, Elhwuegi, 2004, Morilak & Frazer, 2004). Accordingly, all clinically available antidepressants elicit a broad-based enhancement in extracellular levels of monoamines, and precursor depletion studies

The aims of augmentation treatment

Despite optimization of dose-regimes and switches to other antidepressants, certain patients cannot tolerate, or fail to respond to, standard agents (Prudic et al., 1996, Nelson, 1998, Nelson, 2003, Klein et al., 2004). Alternative strategies must therefore be envisaged (Fava, 2003, Klein et al., 2004). One option is a non-drug intervention, such as ECT (Section 6.2). (Prudic et al., 1996, Kinney et al., 2000, Blier, 2003, Husain et al., 2004). Alternatively, adjunctive psychotherapy

“Somatic” strategies for the treatment of depression

It is interesting to evoke “alternative” strategies for the treatment of depression that do not involve drug treatment and that, as outlined below, act via a diversity of cerebral mechanisms. For certain interventions, such as cognitive–behavioral therapy (psychotherapy) (Thase & Friedman, 1998, Hensley et al., 2004, O'Reardon et al., 2004, Pampallona et al., 2004, Scott & Watkins, 2004, Hollon et al., 2005, Paykel et al., 2005b) and light therapy for seasonal (and others forms of) depression (

“The atypical”, multireceptorial antipsychotic, clozapine

There is nothing radical in advocating multi-target agents for the improved treatment of depression. By analogy, schizophrenia–a complex and heterogeneous disorder that reflects the dysfunction of numerous transmitters–is most appropriately treated by “multi-target” antipsychotics (Kuperberg et al., 2002, Miyamoto et al., 2003, Dean & Scarr, 2004, Roth et al., 2004b, Stahl & Grady, 2004). The most familiar example is the “atypical” agent, clozapine. In contrast to haloperidol and other

Diffuse neural circuits control mood and are implicated in depressive states

Mimicking other critical physiological functions, mood is controlled by a hierarchy of highly redundant and heterogeneous homeostatic mechanisms (Mayberg et al., 1999, Berthoud, 2002, George et al., 2002a, Millan, 2003, Murphy et al., 2003a, Searls, 2003, Jandacek and Woods, 2004, Seminowicz et al., 2004, Bennett & Hacker, 2005, Fox et al., 2005b, Morgane et al., 2005, Yuste et al., 2005). Accordingly, a diversity of endogenous modulators has been implicated in the response (loosely termed

Increasing the efficiency of re-uptake inhibition

This discussion of multi-target strategies for enhancing antidepressant efficacy commences with those agents that directly regulate extracellular levels of monoamines by modulating their re-uptake. Such mechanisms are not restricted to conventional 5-HT, NA, and DA transporters in that they encompass several, less familiar and accessory re-uptake sites informally referred to as “uptake2”. This section 9.1 also evokes a distinctive class of antidepressant that acts at 2 complementary sites on a

Combined monoaminergic and non-monoaminergic antidepressants

Section 9 summarized several approaches whereby the antidepressant properties of 5-HT and/or NA re-uptake inhibitors may be reinforced by “adding on” activities at other monoaminergic sites. Despite the potentially challenging chemistry (Section 13), one may conceive of analogous strategies whereby monoamine re-uptake inhibition could be combined with actions at non-monoaminergic targets. Several promising and representative examples are discussed below.

Trace amines and their novel “TA” receptors

Trace amines are both synthesized in the

Need for improved control of co-morbid symptoms

As stressed in the Introduction (Section 1.6), depressed subjects almost invariably reveal a disruption of sleep patterns and they frequently display a desynchronization of circadian rhythms. Decreased libido, anxiety, and cognitive symptoms are also common, a significant sub-population of patients presents with obesity and attendant metabolic disturbances, whereas still others complain of physical discomfort and even frank pain—often gastrointestinal. In this regard, it is unfortunate that the

Masking side effects with a multi-target profile

One legitimate justification for prioritizing selective agents is the desire to avoid undesirable side effects mediated by sites other than those transducing clinical efficacy (Section 3.3) (Mir & Taylor, 1997, Vida & Looper, 1998). However, focused multi-target agents may also possess improved dose margins between beneficial and unwanted actions. In the simplest case, assuming that 2 complementary components of activity underlie therapeutic activity (exerted additively or synergistically), the

Expanded scope for the discovery of novel antidepressants

The initial anthropocentric assumption that the human genome would reveal a virtually infinite repertoire of novel targets has evaporated with estimations that the number of protein-coding genes (∼ 25–30,000) is far lower than originally anticipated (Hopkins & Groom, 2002, Kubinyi, 2003, International Human Genome Sequencing Consortium, 2004, Xing et al., 2004, Claverie, 2005). Further, despite extensive (and tissue-specific) alternative splicing, post-transcriptional mRNA editing and other

The characterization of multi-target versus selective antidepressants: opportunities and challenges

“All antidepressants are multi-target, but some are more multi-target than others,” (with apologies to George Orwell)

.

Network approaches to understanding the brain and central nervous system disorders: “systems” biology

No more than an alphabet of nucleic or amino acids does a dictionary of gene or protein sequences provide a satisfactory basis for understanding the function and dysfunction of the human brain, nor a directory for selecting targets for novel therapeutic agents. Furthermore, although knowledge of the human genome and proteome will facilitate mapping of the cellular organization of GPCRs, kinases, transporters, and other important proteins, static “wiring diagrams” are only a starting point for

A systematic search for multi-target agents: a new tendency in central nervous system drug discovery?

The title of this Section 16.1 refers to a recent tendency of re-equilibrating drug research and discovery programs to embrace both selective and multi-target strategies (Sections 7.5 and 13.4). Indeed, since the inception of this review in mid-2004, an unprecedented (and unanticipated) spate of articles has appeared that, from a variety of viewpoints, counterbalances the genome-driven focus on selective agents in emphasizing the importance of multi-target (viz., “multi-component,

Acknowledgments

The author would like to express his thanks to M. Soubeyran for unflagging secretarial assistance; Sir James Black for insightful comments and exchanges; J-M Rivet for skillful preparation of graphics; G. Lavielle for expert consultations on Chemistry; A. Gobert and A. Dekeyne for invaluable logistical support; L. Maiofiss for collaborative work on multivariate analyses; and R. Gannon for advice on circadian rhythms. He also thanks A. Grant and J. Barber (Aske's) for awaking his interest in

References (3730)

  • L.F. Agnati et al.

    Intercellular communication in the brain: wiring versus volume transmission

    Neuroscience

    (1995)
  • L.F. Agnati et al.

    How receptor mosaics decode transmitter signals. Possible relevance of cooperativity

    Trends Biochem Sci

    (2005)
  • J. Akiyoshi et al.

    Effects of antidepressants on intracellular Ca2+ mobilization in CHO cells transfected with the human 5-HT2C receptor

    Biol Psychiatry

    (1996)
  • H.C. Akunne et al.

    Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant

    Neuropharmacology

    (2001)
  • A. Albinsson et al.

    Preclinical pharmacology of FG5893: a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors

    Eur J Pharmacol

    (1994)
  • A. Albinsson et al.

    Involvement of the 5-HT2 receptor in the 5-HT receptor-mediated stimulation of prolactin release

    Eur J Pharmacol

    (1994)
  • M. Aldana

    Boolean dynamics of networks with scale-free topology

    Physica D

    (2003)
  • G.S. Alexopoulos

    Frontostriatal and limbic dysfunction in late-life depression

    Am J Geriatr Psychiatry

    (2002)
  • G.S. Alexopoulos et al.

    Executive dysfunction and the course of geriatric depression

    Biol Psychiatry

    (2005)
  • E. Alm et al.

    Biological networks

    Curr Opin Struct Biol

    (2003)
  • G. Alonso et al.

    Immunocytochemical localization of the sigma(1) receptor in the adult rat central nervous system

    Neuroscience

    (2000)
  • C.A. Altar et al.

    Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain

    Biol Psychiatry

    (2003)
  • M. Altieri et al.

    Expression analysis of brain-derived neurotrophic factor (BDNF) mRNA isoforms after chronic and acute antidepressant treatment

    Brain Res

    (2004)
  • I. Amado-Boccara et al.

    Effects of antidepressants on co7gnitive functions: a review

    Neurosci Biobehav Rev

    (1995)
  • J. Amat et al.

    Microinjection of urocortin 2 into the dorsal raphe nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala

    Neuroscience

    (2004)
  • R. Amici et al.

    A serotonergic (5-HT2) receptor mechanism in the laterodorsal tegmental nucleus participates in regulating the pattern of rapid-eye-movement sleep occurrence in the rat

    Brain Res

    (2004)
  • J. Amsterdam et al.

    Fluoxetine efficacy in menopausal women with and without estrogen replacement

    J Affect Disord

    (1999)
  • F. Amtage et al.

    Characterization of nicotinic receptors inducing noradrenaline release and absence of nicotinic autoreceptors in human neocortex

    Brain Res Bull

    (2004)
  • A. Anand et al.

    Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder

    Biol Psychiatry

    (1999)
  • J.M. Andersen et al.

    Effects of scopolamine and d-cycloserine on non-spatial reference memory in rats

    Behav Brain Res

    (2002)
  • I.M. Anderson

    Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability

    J Affect Disord

    (2000)
  • G. Andersson et al.

    Effects of FG 5893, a new compound with 5-HT1A receptor agonistic and 5-HT2 receptor antagonistic properties, on male rat sexual behavior

    Eur J Pharmacol

    (1994)
  • J.I. Andrés et al.

    Synthesis of 3α,4-dihydro-3H-[1]benzopyrano[4,3-c)isoxazoles, displaying combined 5-HT uptake inhibiting and alpha2-adrenoceptor antagonistic activities: a novel series of potential antidepressants

    Bioorg Med Chem Lett

    (2003)
  • I. Angel et al.

    Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties

    Eur J Pharmacol

    (1993)
  • I.A. Antonijevic et al.

    Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men

    Neuropharmacology

    (2000)
  • T.A. Abdu et al.

    Coronary risk in growth hormone deficient hypopituitary adults: increased predicted risk is due largely to lipid profile abnormalities

    Clin Endocrinol

    (2001)
  • M. Abellan et al.

    Dual control of dorsal raphe serotonergic neurons by GABAB receptors. Electrophysiological and microdialysis studies

    Synapse

    (2000)
  • W. Abi-Saab et al.

    Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients: support for serotonin-2 receptor modulation of schizophrenia symptoms

    Psychopharmacology

    (2002)
  • M.A. Abou-Gharbia et al.

    Synthesis and SAR of adatanserin: novel adamantyl aryl-and heteroarylpiperazines with dual serotonin 5-HT1A and 5-HT2 activity as potential anxiolytic and antidepressant agents

    J Med Chem

    (1999)
  • J.S. Abramowitz

    Treatment of obsessive–compulsive disorder in patients who have comorbid major depression

    J Clin Psychol

    (2004)
  • D.M. Abrous et al.

    Adult neurogenesis: from precursors to network and physiology

    Physiol Rev

    (2005)
  • A. Adamantidis et al.

    Disrupting the melanin-concentrating hormone receptor1 in mice leads to cognitive deficits and alterations of NMDA receptor function

    Eur J Neurosci

    (2005)
  • A. Adell

    Antidepressant properties of substance P antagonists: relationship to monoaminergic mechanisms?

    Curr Drug Targets CNS Neurol Disord

    (2004)
  • C.H. Adler et al.

    Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease

    Mov Disord

    (2003)
  • O. Agid et al.

    Algorithm-based treatment of major depression in an outpatient clinic: clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation

    Int J Neuropsychopharmacol

    (2003)
  • A. Agmo et al.

    GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat

    Psychopharmacology

    (1997)
  • L.F. Agnati et al.

    Existence and theoretical aspects of homomeric and heteromeric dopamine receptor complexes and their relevance for neurological diseases

    Neuromol Med

    (2005)
  • Y. Ago et al.

    Sulpiride in combination with fluvoxamine increases in vivo dopamine release selectively in rat prefrontal cortex

    Neuropsychopharmacology

    (2005)
  • G. Aguilera et al.

    Regulation of vasopressin V1b receptors in the anterior pituitary gland of the rat

    Exp Physiol

    (2000)
  • S. Ahlenius et al.

    Synergistic actions of the 5-HT1A receptor antagonist WAY-100635 and citalopram on male rat ejaculatory behavior

    Eur J Pharmacol

    (1998)
  • Cited by (480)

    View all citing articles on Scopus
    View full text