Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs Mark J. Millan Psychopharmacology Department, Institut du Recherches Servier, Centre de Recherches de Croissy, Paris, France Summary: The past decade of efforts to find improved treat- mechanism with a nonmonoaminergic component of activity is ment for major depression has been dominated by genome- an attractive strategy. For example, agomelatine (a melatonin driven programs of rational drug discovery directed toward agonist/5-HT2C antagonist) has clinically proven activity in highly selective ligands for nonmonoaminergic agents. Selec- major depression. Dual neurokinin1 antagonists/5-HT reuptake tive drugs may prove beneficial for specific symptoms, for inhibitors (SRIs) and melanocortin4 antagonists/SRIs should certain patient subpopulations, or both. However, network anal- display advantages over their selective counterparts, and hista- yses of the brain and its dysfunction suggest that agents with mine H3 antagonists/SRIs, GABAB antagonists/SRIs, glutama- multiple and complementary modes of action are more likely to tergic/SRIs, and cholinergic agents/SRIs may counter the com- show broad-based efficacy against core and comorbid symp- promised cognitive function of depression. Finally, drugs that toms of depression. Strategies for improved multitarget exploi- suppress 5-HT reuptake and blunt hypothalamo–pituitary–adre- tation of monoaminergic mechanisms include triple inhibitors nocorticotrophic axis overdrive, or that act at intracellular pro- of dopamine, serotonin (5-HT) and noradrenaline reuptake, and teins such as GSK-3␤, may abrogate the negative effects of drugs interfering with feedback actions of monoamines at in- chronic stress on mood and neuronal integrity. This review hibitory 5-HT1A, 5-HT1B and possibly 5-HT5A and 5-HT7 re- discusses the discovery and development of dual- and triple- ceptors. Specific subsets of postsynaptic 5-HT receptors medi- acting antidepressants, focusing on novel concepts and new ating antidepressant actions are under study (e.g., 5-HT4 and drugs disclosed over the last 2 to 3 years. Key Words: Anti- 5-HT6). Association of a clinically characterized antidepressant depressant, multitarget, network, stress, HPA axis, CRF. FROM HIGHLY SELECTIVE AGENTS TO depression.2–8 There is a need for improved control not MULTITARGET ANTIDEPRESSANTS just of affective deficits, but also of other symptoms, such as insomnia, circadian desynchronization, sexual Major depression is a common, heterogeneous, and dysfunction, cognitive impairment, and pain. Moreover, often incapacitating disorder triggered by a complex pat- depression shows high comorbidity with other serious tern of genetic, epigenetic, developmental, and environ- CNS disorders (Table 1).3,7 mental factors.1 Although commonly used antidepres- All currently available antidepressants harness mono- sants, such as the selective serotonin (5-HT) reuptake aminergic mechanisms. The past decade has witnessed a inhibitor (SSRI) fluoxetine, are often effective, full effi- genome-driven focus on the rational discovery of highly cacy is only apparent after several weeks; and many selective drugs acting at innovative, nonmonoaminergic patients only partially respond, and some remain refrac- targets (FIG. 1).3–9 Along with genetically modified mice tory. Accordingly, considerable efforts are invested in the search for better drugs (and other, nonpharmaco- as animal models, such agents are vital in the experimen- therapeutic approaches) for more effective treatment of tal and therapeutic exploration of novel drug targets and hypotheses. In addition, selective antidepressants may prove helpful against particular symptoms and in discrete subpopulations of patients who have specific patholo- gies.1,3 Nonetheless, agents that interact with several Address correspondence and reprint requests to: Mark J. Millan, IDR Servier, Psychopharmacology Dept., 125 chemin de Ronde, 78290 complementary targets or with distributed cerebral net- Croissy-sur-Seine, Paris, France. E-mail: [email protected]. works (or with both) offer greater hope for the broad- Vol. 6, 53–77, January 2009 © The American Society for Experimental NeuroTherapeutics, Inc. 53 54 M. J. MILLAN Table 1. Symptoms and CNS Disorders Frequently Comorbid with Major Depression Symptom Motor Decreased Retardation Depressed Cognitive Sleep Circadian Sexual Psychosis or Disorder Mood Anxiety Perturbation* Quality Disruption Dysfunction or Mania Pain Excitation Major depression ϩϩϩ ϩϩ ϩϩ ϩϩ ϩϩ ϩ ϩ ϩ ϩϩ Anxiety disorders ϩϩ ϩϩϩ ϩϩ ϩϩ ϩ ϩ Ϫ ϩ ϩϩ Bipolar disorder ϩϩ ϩ ϩϩ ϩϩ ϩϩ ϩ ϩϩϩ† Ϫϩ OCD ϩϩϩ‡ ϩϩ ϩ ϩ ϩ ϩ Ϫ ϩ Schizophrenia ϩ ϩ ϩϩ ϩ ϩ ϩ ϩϩϩ ϩ ϩϩ Parkinson’s ϩϩ ϩ ϩϩ ϩϩ ϩ ϩϩ ϩ ϩϩ ϩϩϩ Alzheimer’s ϩ ϩ ϩϩϩ ϩϩ ϩϩ NR ϩϩ Ϫ ϩϩ Epilepsy ϩ ϩ ϩϩ ϩϩ ϩ ϩ Ϫ ϩ Ϫ Stroke ϩϩ ϩ ϩϩϩ ϩ ϩ ϩ ϩ ϩϩ ϩϩ Chronic pain ϩϩ ϩϩ ϩ ϩϩ ϩ ϩϩ ϩ ϩϩϩ ϩϩ OCD ϭ obsessive compulsive disorder; NR ϭ not usually relevant; ϩϩϩ ϭ cardinal; ϩϩ ϭ prominent; ϩϭwell recognized; Ϫϭnot characteristic. *Cognitive perturbation is a complex construct, with patterns of disruption differing markedly among disorders. †Mania. ‡Cause? Or consequence? Or both? based and efficacious treatment of both cardinal and Second, agents that have complementary components comorbid symptoms of depression.3,7,10–16 of action have a greater chance of controlling both the The present author has, elsewhere, comprehensively mood deficits of depression and other symptoms reflect- discussed conceptual bases underpinning multitarget an- ing contrasting pathophysiological substrates, such as tidepressants, and reviewed a broad range of mechanisms mnemonic deficits, desynchronization, and pain.1,3 implicated in the pathogenesis and potentially im- Third, coadministration of various classes of adjunc- 3 proved control of affective disorders. The present tive agent, from lithium to atypical antipsychotics to review outlines the principal advances of the last few thyroxine, reinforces the efficacy of SSRIs.3,18–22 This is years, focusing on the discovery and development of clearly not equivalent to an increase in dose: improved drugs that have dual and triple mechanisms of antide- efficacy reflects engagement of mechanisms complemen- pressant activity. tary to 5-HT reuptake inhibition—not just more of the same, but something different on top. THE SEARCH FOR DUAL- AND TRIPLE- Fourth, prototypical drugs for the treatment of other ACTING ANTIDEPRESSANTS: RATIONALE major psychiatric and neurological disorders act via a Numerous arguments support the contention that mul- diversity of neuronal mechanisms distributed across titarget mechanisms may be more effective and better many cerebral regions (Table 2). Similarly, pharmaco- tolerated than their highly selective counterparts in the logical, somatic, and psychological approaches for re- management of CNS disorders (see elsewhere in this lieving depression are unlikely to act via any common issue). Several lines of evidence specifically substantiate unitary mechanism. interest in dual- and triple-acting antidepressants. Fifth, in line with this assertion, sleep deprivation First, there is no single cause of major depression. (rapidly effective) and electroconvulsive therapy (active Rather, a vast array of interacting genes, epigenetic in- in many drug-refractory patients), as well as deep brain fluences, developmental events, and environmental influ- stimulation, transcranial magnetic stimulation, and vagal ences collectively (and often synergistically) compro- nerve stimulation (although data are less extensive), en- 3,6,7,23 mise mood and trigger affective disorders.1 Despite gage a broad array of molecular substrates and, as contemporary notions of endophenotype (i.e., gene-re- suggested by imaging studies, extensive cerebral circuits lated dysfunction specific to an individual), genetic (Table 3).23–27 The same holds for psychological ap- screening, and individual medicine,1,17 treatment strate- proaches such as cognitive-behavioral therapy, which gies with a broad influence on corticolimbic circuits likewise affect overarching cerebral networks rather than implicated in depression are more likely than highly any single circumscribed brain region.28–30 This is a far selective agents to be effective in significant patient cry, then, from a highly selective drug targeting a single numbers. protein (Table 3). Ideally, one should identify the key Neurotherapeutics, Vol. 6, No. 1, 2009 MULTITARGET AGENTS IN MAJOR DEPRESSION 55 FIG. 1. Nonmonoaminergic mechanisms for treatment of major depression under clinical investigation with selective drugs. Numbers in Roman numerals refer to the highest phase of clinical development attained to date. Certain mechanisms are being evaluated for other indications, such as AMPA receptor facilitators, PDE-4 inhibitors, and nicotinic modulators for Alzheimer’s disease. There is still no proof that selective drugs acting via such nonmonoaminergic mechanisms can robustly treat depression. Antag ϭ antagonist; CRF ϭ corticotrophin releasing factor; GR ϭ glucocorticoid receptor; MCH ϭ melanin concentrating hormone; NK ϭ neurokinin; PAM ϭ positive allosteric modulator; PDE ϭ phosphodiesterase; V ϭ vasopressin. mechanisms of such treatments and transform them into from stimulation of 5-HT2C sites (discussed later in this more accessible multitarget agents—although this is un- article). likely to prove simple. In the search for dual-acting,