One strategy focuses on the use of N-methyl-D-aspartate glutamate-receptor antagonists providing the promise of rapid antidepressant action,127 including clinically significant effects from one dose that were sustained for up to 1 week.128 Another study129 has suggested the use of repeated dose intravenous ketamine for the acute treatment of treatment-resistant depression. Although the effect of glutamate on depression is promising, this has not necessarily been the case for other novel pharmacological mechanisms. The failures of CRF1 antagonist compounds and substance-P antagonists have continually been noted. Another advance is the introduction of agomelatine —a melatonin (MT1 and MT2) agonist and a 5-HT2C-receptor antagonist. Agomelatine has shown a generally favourable tolerability and efficacy, therefore providing a promising alternative for patients who do not respond to existing pharmacotherapies, or who cannot tolerate their side-effects.130 Placebo-controlled research provides evidence for the effectiveness of agomelatine as both an acute and a continuation treatment for major depression.131–133