Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application

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.

Catechol-O-methyltransferase (COMT) polymorphisms predict treatment response in electroconvulsive therapy

“…There is a possibility that those patients with depression having less dopaminergic activity in prefrontal cortex (due to highactive COMT enzyme) may respond better to ECT, which in turn increases dopaminergic activity. 2,10 However, studies of this topic are far from conclusive and further studies are needed to confirm these results. Our result is in line with Szegedi et al 11 who reported that COMT high (Val)-allele carriers responded better to treatment with mirtazapine in major depression.…”

“…1,2 However, the mechanism of the action of ECT is unknown. Several lines of evidence suggest that dopaminergic actions in the prefrontal cortex may be involved.…”

“…Several lines of evidence suggest that dopaminergic actions in the prefrontal cortex may be involved. [2][3][4][5][6][7][8] Catechol-O-methyltransferase (COMT) is a major enzyme in dopamine metabolism in the prefrontal cortex. A common functional polymorphism at codon 158 in the gene coding for COMT (COMT Val158Met) results in substantial effects, with Met (low-activity) allele homozygosity leading to a three-to fourfold reduction in enzymatic activity compared with the Val (highactivity) allele homozygosity.…”

Stimulation of the β3-Adrenoceptor as a Novel Treatment Strategy for Anxiety and Depressive Disorders

“…Studies in humans and animals have shown a relationship between alterations in noradrenergic (NA) brain system function and behaviors associated with depression and anxiety (Ressler and Nemeroff, 2000;Millan, 2006). For example, the b 1 and b 2 adrenoceptors are known to participate in stress-related behavioral changes (Gorman and Dunn, 1993;Gurguis et al, 1999;Cecchi et al, 2002) and to mediate the effects of antidepressant treatment (Hancock and Marsh, 1985;Stahl et al, 1987;Manier et al, 1989;Holoubek et al, 2004).…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…Accordingly, considerable efforts are invested in the search for better drugs (and other, nonpharmacotherapeutic approaches) for more effective treatment of depression. [2][3][4][5][6][7][8] There is a need for improved control not just of affective deficits, but also of other symptoms, such as insomnia, circadian desynchronization, sexual dysfunction, cognitive impairment, and pain. Moreover, depression shows high comorbidity with other serious CNS disorders (Table 1).…”