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