The monoamine hypothesis of depression has been the cornerstone of antidepressant treatment for several decades.52 However, many questions remain unanswered as to the underlying pathophysiology of affective disorders and if monoamines themselves are responsible for regulating unipolar and bipolar depressives states. It is clear, as stated earlier, that the etiology of depression and bipolar disorder is still unknown. Arguably, however, the clinical and preclinical data supporting the monoamine hypothesis are beyond question. With this in mind, the fact remains that the clinical response is delayed several weeks following administration of monoaminergic antidepressant agents, suggesting that other mechanisms may well be involved in the efficacy of these agents. It has long been suggested that alterations in gene expression may be a contributing factor for the delayed clinical response, thereby resulting in changes in signal transduction mechanisms (Figure 1).35>44'53 Several purported mechanisms may account for the delay in the clinical response: (1) receptor downregulation; (2) other components of cellular signaling that are regulated by cyclic AMP, which are prominent transcription factors in the brain (phosphorylated cAMP response element-binding protein, CREB); and (3) factors controlling cellular plasticity such as brain-derived neurotrophic factor (BDNF).
At present, the number one challenge is to develop novel antidepressants with greater efficacy and rapid onset of action. To this end, several pharmaceutical companies continue to bet on the tried and tested monoamine reuptake inhibitors approach, the latest entrant in the US depression market being duloxetine (47). This was launched in 2004, and is reported to have a faster onset of action and efficacy in treating the physical pain associated with depression. Escitalopram, the active enantiomer of citalopram, was launched in 2003 and is marketed as having a faster onset of action and lower rates of discontinuation. This perceived low-risk (risk aversive) approach has resulted in several other mixed-monoaminergic reuptake inhibitors, which are currently under development (Phase II/III), including: desvenlafaxine (48), a metabolite of venlafaxine (see Section 6.03.5.2.4); GW353162 (49), a metabolite of bupropion; GW372475, SEP-225289, ORG 4420 (50), DOV 216,303 (51), DOV 21,947, and DOV 102,677.
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