Innovative approaches for the development of antidepressant drugs: current and future strategies
by
Schechter LE, Ring RH, Beyer CE, Hughes ZA,
Khawaja X, Malberg JE, Rosenzweig-Lipson S.
Discovery Neuroscience, Wyeth Research,
CN 8000, Princeton, New Jersey 08543.
NeuroRx. 2005 Oct;2(4):590-611.

ABSTRACT

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), alpha-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.

CRH
NMDA
SSRIs
NARIs
RIMAs
1990s
Antisense
Agomelatine
Comparisons
Neurotrophins
New anxiolytics
GABA-ergic drugs
New antidepressants
Antidepressants 2006
Neurokinins/substance P
SNaRIs, NaSSAs, and NaRIs
CFR-1 antagonists: antalarmin
Beyond the monoamine hypothesis
An historical analysis of the creation of the concept of an antidepressant

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