Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1

Major depressive disorder (MDD) is a chronic, recurring and potentially life-threatening mental illness. Current treatments are inadequate - many depression medications, although safe and effective, generally have a slow onset of clinical benefit and around half of the MDD patients do not show full remission with optimized treatment. Therefore, there is still a need for the development of faster-acting and more effective medication for MDD. Recent studies have demonstrated that the TREK-1 protein, one of the 17 members of the two-pore domain K+ (K2P) potassium channel family, is inhibited by the antidepressant fluoxetine. Deletion of TREK-1 in mice caused a substantially reduced elevation of corticosterone levels under stress, and produced behaviour similar to that of naive animals treated with fluoxetine in various behavioural tests. These findings suggested that the blocker of the TREK-1 channel might potentially be a new type of antidepressant. Sipatrigine (BW619C89), a neuroprotective agent, has been found to be a potent antagonist of TREK-1. Its related compound, lamotrigine, has been approved for the treatment of bipolar depression and is used to supplement antidepressant medication in patients with treatment-resistant depression. Furthermore, in addition to its antagonistic effect on TREK-1, sipatrigine is also a glutamate release inhibitor. Excessive glutamatergic neurotransmission is associated with depressive-like behaviours and inhibiting glutamate neurotransmission may be implicated in antidepressant therapeutic mechanisms. From the above findings of the effects of sipatrigine on TREK-1 and glutamate neurotransmission, it is hypothesised that sipatrigine could have potential therapeutic effects for MDD or bipolar depression. Further evaluation of its antidepressant therapeutic and toxic effects in animal models is needed before clinical application. (c) 2007 Elsevier Ltd. All rights reserved.