Innovative approaches for the development of antidepressant drugs: Current and future strategies

Abstract

Summary: Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2C , ␣-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT 2C , 5-HT 6 ) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

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“…The poor affinities of the compounds for serotonin, norepinephrine, and dopamine transporters, relative to σ receptors, thus increased the likelihood that the observed antidepressant-like effects were mediated through σ receptors. Among the other binding sites that were studied (opioid, NMDA, 5-HT 2 , D 2 receptors), all were potential targets or modulators of antidepressant drugs (Jutkiewicz, 2006;Nestler and Carlezon, 2005;Schechter et al, 2005). Thus, it was significant that the two novel compounds (UMB23, UMB82) displayed little to no binding to these sites.…”

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