Enhanced selective serotonin re-uptake inhibitors as antidepressants: 2004 – 2006

Abstract

Depression is a major psychiatric disorder. It affects millions of people worldwide and inflicts tremendous economic burden on societies. The advent of selective serotonin re-uptake inhibitors as antidepressants has been a revolutionary advance in the treatment of depression and related disorders. However, selective serotonin re-uptake inhibitors are also associated with several undesirable properties, such as delayed onset of action, low response rate and side effects. The present search for a newer generation of antidepressants is focused on overcoming these issues. The patent literature covered in this review, during 2004 – 2006, illustrates several strategies employed by the pharmaceutical industry in the development of enhanced serotonin re-uptake inhibitors. Encouraged by the success of venlafaxine and duloxetine, several companies have pursued dual-acting serotonin and noradrenaline re-uptake inhibitors as drug candidates for depression treatment. Molecules with combined serotonin re-uptake inhibitor and 5-HT autoreceptor (5-HT_1A and/or 5-HT_1B) antagonist properties are being developed. In particular, recent research suggests that serotonin 5-HT_1B antagonists alone or combined with selective serotonin re-uptake inhibitors might hold unique promise as efficacious antidepressants. Finally, efforts are underway to formulate new drug candidates with both serotonin re-uptake inhibitor and neurokinin 1 (NK₁) antagonist activities. Despite mixed results from clinical trials with several NK₁ antagonists, effective therapeutic agents for depression may still emerge from compounds with combined serotonin reuptake inhibitor/NK₁ antagonist properties.

Keywords::

• antidepressant
• depression
• 5-HT_1A
• 5-HT_1B
• NK₁ antagonist
• noradrenaline re-uptake inhibitor
• neurokinin receptor
• substance P
• selective serotonin re-uptake inhibitor
• serotonin transporter