Realizing the Promise of Chronotherapy

In 2014, Thomas Insel, MD, then Director of the U.S. National Institute of Mental Health, wrote that “ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades.” Particularly because ketamine — an anesthetic and club drug popularly known as Super K — “reduces depression within six hours, with effects that are equal to or greater than the effects of six weeks of treatment with other antidepressant medications.” Following Insel’s pronouncement, ketamine took off: dozens of studies were conducted, and hundreds of ketamine clinics opened nationwide.  Similarly, within the past few years, psychedelic drugs including psilocybin have been  undergoing a renaissance, in no small part because they rapidly relieve depressive symptoms and have a unique mechanism of action.

In contrast, other recent studies of another antidepressant treatment with a unique mechanism of action and early and rapid onset have led to little if any hoopla. For example: our November 2020 Journal of Affective Disorders paper suggesting that triple chronotherapy can relieve depression symptoms in less than a week. Triple chronotherapy consists of one night of sleep deprivation (“wake night”); recovery sleep starting in the afternoon (far earlier than habitually), followed by several days with sleep beginning a few hours later each night; and daily morning exposure to bright light delivered through a broad-spectrum light box. Alas, we got little if any press.

Led by Dr. Jonathan W. Stewart, at the New York State Psychiatric Institute in Columbia University’s Depression Evaluation Service, our research team enrolled 44 adult outpatients with unipolar depressive disorders. Study participants were randomly assigned to receive either triple chronotherapy or a comparison condition: morning bright light exposure while wearing amber goggles (which filter out all blue and adjacent green wavelengths) and assigned sleep times, but no wake night. We found evidence of rapid onset of action: depression went into remission within a week for 25% of active treatment patients compared to 6.7% of the comparison treatment patients.

However large this group difference appeared, on a statistical basis this didn’t differ significantly in our small sample, so our findings must be viewed mostly as suggestive. Depression scores on the Hamilton Depression Rating Scale did significantly improve within one week, and there were no major side effects, such as manic reactions. Seventy-three percent of subjects were able to complete the 6-week protocol. We are now completing analysis of data to determine whether the one-week gains are maintained at six-week follow-up, and are discussing ways to improve the treatment protocol.

What our findings do clearly show is that triple chronotherapy is feasible in an outpatient setting, and that it is not terribly difficult to implement. Participants were able to follow the study procedures at home, including staying awake an entire night, rather than requiring in-person supervision by research staff in hospital. Patients reported that they liked using the light boxes and optimizing their sleep times — so this was not an unpleasant treatment approach.

We would now proceed to a larger confirmatory study enrolling 100 or more subjects, which would likely provide statistically significant results, but are limited by a lack of funding. Chronotherapy remains something of an orphan treatment, without significant support from NIMH or other federal agencies, philanthropy, or device manufacturers. Despite mounting evidence for its effectiveness in seasonal affective disorder, bipolar depression, and major depression, there is no rush of funding for new studies or treatment centers. (An impressive exception is the current multicenter trial of triple chronotherapy for perinatal depression, under the supervision of Katherine Sharkey MD of Brown University.)

The lack of broader funding is a shame, because there are innumerable questions to study. Our goals (along with other chronotherapy research groups) are to further explore this new methodology, and to make it widely available. But first, researchers need to answer basic questions: Does it work? And for whom? Also, how does it work? What is the optimal design of chronotherapy to get the best results? And finally, what is the best way to disseminate the treatment to people who could benefit?

Why is there so little support for chronotherapy research, especially since it doesn’t require administration of risky, potentially addictive drugs? Is it because chronotherapy is viewed within the range of “complementary” treatments? Or because chronotherapy lacks significant patentability, other than for device patents to light box manufacturers, while research-standard light boxes are readily available for under two hundred dollars?

Whatever the reason, the paucity of full-scale clinical trials is a shame, since chronotherapy holds such promise. If you look at the literature, you’ll see that most studies are still small, under-powered, and underfunded. There is enough evidence by now to support doing them right.


David Hellerstein is a Professor of Clinical Psychiatry at Columbia University Medical Center, and a Research Psychiatrist at the New York State Psychiatric Institute. He conducts research on novel treatments of mood disorders including medications, psychotherapies and complementary modalities. He is currently studying psilocybin (street name, “magic mushrooms”) for the treatment of depression and other disorders. His most recent book is Heal Your Brain: How the New Neuroscience Can Help You Go from Better to Well.