The Second Psychopharmacology Revolution

The field of psychopharmacology was born during the 15 years between 1955 and 1970. Now, nearly 60 years later, the field of psychiatry may be at the beginning of a second psychopharmacology revolution.

During the first psychopharmacology revolution, antipsychotics, antidepressants, and antianxiety agents were discovered. At the same time, lithium was shown to be effective in treating bipolar disorder. These medications provided psychiatrists with treatments to help patients hospitalized in asylums as well as outpatients suffering from milder symptoms.

Initial antidepressants included two categories of medications: tricyclic antidepressants and monoamine oxidase inhibitors. Both are still available. These drugs influence either norepinephrine or serotonin (or both neurotransmitters) in the brain. Four to eight weeks of treatment are often required before the effects of these antidepressants become evident.

In the late 1980s, other groups of antidepressants such as SSRIs (selective serotonin reuptake inhibitors) and SNRIs (selective norepinephrine reuptake inhibitors) were introduced. These drugs also influence either serotonin or norepinephrine and require 4-6 weeks to work. Although the side effects of SSRIs and SNRIs are different from those associated with tricyclic antidepressants and monoamine oxidase inhibitors, they work in ways that are quite similar to the older drugs. Although they did not represent major leaps forward, they became preferred treatments based on ease-of-use and side effect profiles.

The field of psychiatry may now be entering a second psychopharmacology revolution. Over the past 20 years, ketamine, a medication already approved as an anesthetic, has been found to have rapid and substantial antidepressant effects when administered intravenously at lower-than-anesthetic doses. Ketamine’s antidepressant effects occur within hours and can last up to a week or more following a single infusion. New ketamine-like medications are under investigation. In March 2019, the FDA approved one such drug, esketamine, as a nasal spray for the treatment of treatment-resistant depression in adults. In addition to working much more rapidly than older antidepressants (hours to days instead of weeks), the ketamine-like agents influence a different transmitter system, glutamate. Glutamate is the most common excitatory neurotransmitter in the brain, and it works very differently than either serotonin or norepinephrine.

A second major new advance in psychopharmacology involves a group of drugs called neurosteroids (or neuroactive steroids). The structure and function of neurosteroids are very different than either the older antidepressants or ketamine. A neurosteroid called allopregnanolone (also known as brexanolone), administered as a 60-hour intravenous infusion was approved by the FDA in March 2019 for the treatment of severe postpartum depression. The results of a study of an oral neuroactive steroid (called SAGE-217) with properties similar to allopregnanolone were recently published in the New England Journal of Medicine. This study demonstrated that SAGE-217 leads to rapid improvement for both men and women suffering from major depression. This work must be replicated in larger studies before the FDA will consider the drug for approval as an antidepressant; however, it has already had a successful late-stage clinical trial for postpartum depression. SAGE-217 influences the most common inhibitory brain neurotransmitter, GABA (gamma-aminobutyric acid). Interestingly, glutamate (influenced by ketamine) directly stimulates the electrical activity of certain nerve cells while GABA (influenced by allopregnanolone-type drugs) directly inhibits the electrical activity of certain nerve cells.

The ketamine-based drugs and the neurosteroid-based drugs are revolutionary in terms of the rapidity of their antidepressant effects and their mechanisms of action. Other medications with truly different mechanisms are also in the early stages of investigation. It is possible that the 15 years between 2015 and 2030 will be as remarkable in terms of psychopharmacology as the 1955-1970 era.

This column was written by Eugene Rubin, MD, Ph.D., and Charles Zorumski, MD.

NOTE: In full disclosure, one of the authors (CZ) studies the cellular mechanisms of neuroactive steroids and ketamine, the classes of molecules described in this post. He is a co-author of the SAGE-217 paper recently published in the New England Journal of Medicine. He is also a member of the Scientific Advisory Board of Sage Therapeutics and a shareholder in the company. SAGE-217 is being developed by Sage Therapeutics, and Sage Therapeutics funded the clinical studies of brexanolone and SAGE-217.