The July 2017 cover of Time magazine carried a sobering message: “Depression afflicts 300 million people. One-third don’t respond to treatment.” Indeed, the numbers are staggering. In the United States alone, depression each year affects nearly 7% of adults and 13% of adolescents. This common and complex disorder can interfere with the ability to function, think, act, participate, respond, work, sleep, learn, engage and socialize. It can bring about feelings of sadness, emptiness, hopelessness, worthlessness, irritability and guilt. Left untreated, depression also can lead to catastrophic outcomes and has been a major factor in the alarming 25% increase in the nation’s suicide rate between 1999 and 2014.

It has been more than 30 years since the antidepressant Prozac came on the scene, ushering in a new generation of psycho-pharmaceuticals called selective serotonin reuptake inhibitors—SSRIs—that have enabled millions of people to regain control over their moods and their lives. While the medicine chest of antidepressants has continued to grow and new approaches to psychotherapies and other treatments have evolved since then, there has been no similar kind of game-changing breakthrough to help those who have not responded to available treatments. There is, however, some interesting—and promising—work on the horizon.

In this issue of Proto, we look at “New Tools for Depression,” which examines a wave of innovative treatments directed at easing the impact of this pervasive, debilitating health condition. Perhaps of greatest interest right now is ketamine, a short-acting anesthetic that has shown stunning success in stopping major depression—and suicidal thoughts. While ketamine has some significant drawbacks, including its potential for diversion for abuse or hallucinatory effects at high doses, its overarching benefits have led several major pharmaceutical companies to explore it as a foundation on which to design what could become a totally new category of antidepressants. Beyond ketamine, hope also lies in several clever nondrug interventions, such as simply raising the body’s temperature or using innovative and more intense forms of cognitive behavioral therapy.

The Massachusetts General Hospital Department of Psychiatry, like other major psychiatric research programs around the world, continues to explore many avenues that could lead to better, faster and safer treatments to ease the burden of depression. We may not know today what the next transformative treatment will be, but one thing is clear: It can’t come soon enough for the millions who continue to struggle with the devastating effects of depression.