Have Effective Antidepressants Finally Arrived? Developments in Major Depressive Disorder Therapy.

After decades of limited progress in treating major depressive disorder (MDD), especially for patients unresponsive to standard antidepressants, the serendipitous discovery of ketamine's antidepressant effects has renewed optimism. This has spurred development of related drugs like S-ketamine and oral NMDA antagonists showing promise in late-stage trials. An extended-release combination of bupropion (105 mg) and dextromethorphan (45 mg) reduced MADRS total scores in recipients. Neurosteroids such as brexanolone and zuranolone represent another class, modulating GABA neurotransmission, a pathway long used for insomnia and anxiety. Psychedelic drugs, after nearly 50 years of legal restrictions, are also being investigated, with psilocybin under study for treatment-resistant depression.

Study at a glance

Abstract

Among the greatest unmet needs in major depressive disorder (MDD) is a lack of effective pharmacotherapies for patients who do not respond to first- and second-line antidepressant medications. After decades of muted progress, optimism regarding the future of MDD therapy rose after scientists serendipitously uncovered the antidepressant effects of ketamine. The discovery of ketamine's antidepressant effects inspired the search for related newer medications, such as S-ketamine. Orally administered NMDA antagonists have also demonstrated considerable promise in recently concluded, late-stage clinical trials. Researchers evaluating an extended-release combination of bupropion (105 mg) and dextromethorphan (45 mg) found that recipients experienced a decline in MADRS total score. Neurosteroids, such as brexanolone and zuranolone, appear to represent another class of antidepressants. These drugs appear to modulate GABA neurotransmission, which has long been known to be a pathway for drugs that are used to treat insomnia and anxiety. After nearly 50 years of legal injunctions against their use, psychedelic drugs have attracted interest among researchers seeking alternative antidepressants. Psilocybin, derived from mushrooms, remains under investigation for its benefits in treatment-resistant depression.