Clinical pharmacological innovation in the treatment of depression.

Standard antidepressants have limitations, driving the search for new drugs. Rapid-acting antidepressants, such as those based on ketamine, show promise for treatment-resistant depression. This review documents newly approved and emerging medicines for major depressive disorder, evaluating their efficacy, tolerability, and safety. Many new drugs rely on glutamatergic mechanisms, including mGlu2/3 receptor antagonists, AMPA receptor potentiators, and novel NMDA receptor modulators. Companies are also developing novel psychedelic drugs, though the necessity of psychedelic activity remains unclear. Gaps persist in matching patients to specific treatments and in developing medicines to prevent MDD or its progression.

Study at a glance

Abstract

Deficiencies in standard of care antidepressants are driving novel drug discovery. A new age of antidepressant medications has emerged with the introduction of rapid-acting antidepressants with efficacy in treatment-resistant patients. The newly approved medicines and those in clinical development for major depressive disorder (MDD) are documented in this scoping review of newly approved and emerging antidepressants. Compounds are evaluated for clinical efficacy, tolerability, and safety and compared to those of standard of care medicines. A new age of antidepressant discovery relies heavily on glutamatergic mechanisms. New medicines based upon the model of ketamine have been delivered and are in clinical development. Rapid onset and the ability to impact treatment-resistant depression, raises the question of the best first-line medicines for patients. Drugs with improvements in tolerability are being investigated (e.g. mGlu2/3 receptor antagonists, AMPA receptor potentiators, and novel NMDA receptor modulators). Multiple companies are working toward the identification of novel psychedelic drugs where the requirement for psychedelic activity is not fully known. Gaps still exist - methods for matching patients with specific medicines are needed, and medicines for the prevention of MDD and its disease progression need research attention.