22015Mar

Chronotherapy for Depression: Rapid, Large, Stable Effect

A chronotherapeutic intervention combining sleep deprivation (wake therapy), bright-light therapy, and sleep scheduling may have lasting benefits for some patients with major depression, follow-up data from a randomized, controlled trial suggest.

“This is the first study to show adjunct short-term wake therapy and long-term bright light therapy as an effective and feasible method to attain and maintain remission. Patients continued to improve in the follow-up phase and obtained very high remission rates,” report Klaus Martiny MD, PhD, from Psychiatric Centre Copenhagen, in Denmark.

The study was published online February 17 in Acta Psychiatrica Scandinavica.

Immediate, Large, Stable Effect

The study involved 75 patients with major depression and lasted for 29 weeks. During a 1-week run-in phase, all patients received duloxetine (Cymbalta, Eli Lilly and Company) (60 mg daily). This was followed by a 1-week intervention phase in which all patients were admitted to an open psychiatric ward and were randomly assigned to either the chronotherapeutic intervention (wake group) or to daily exercise.

During the intervention phase, the wake group participated in three total wake therapies interspersed by recovery sleep nights and started daily morning bright-light therapy along with a protocol to stabilize their sleep-wake cycle. Patients in the exercise group exercised for at least 30 minutes each day. All patients were discharged after 1 week.

In the 7-week outpatient continuation phase, wake-therapy patients continued with daily bright-light therapy and sleep time stabilization, and patients in the exercise group continued to exercise. During the next 20 weeks (follow-up phase), patients continued with their assigned regimen but were allowed to increase the dosage of duloxetine or to switch to other antidepressants.

The researchers previously reported that both groups responded to adjunctive treatment, but wake and light therapy produced an “immediate, large, stable and statistically significant better antidepressant effect.”

After 1 week of adjunctive treatment, response was obtained in 41.4% of patients in the wake group vs 12.8% of patients in the exercise group, and remission was achieved in 23.9% vs 5.4%, respectively. At week 9, response was obtained in 71.4% of chronotherapy patients vs 47.3% of exercise patients; remission was achieved in 45.6% and 23.1%, respectively.

The researchers now report that at week 29, the chronotherapeutic intervention maintained “superiority” over exercise, with a statistically significant higher remission rate in the wake- therapy group than in the exercise group (61.9% vs 37.9%; P = .01).

In addition, endpoint scores on the 17-item Hamilton Depression Scale Hamilton Depression Scale (HAM-D17) were statistically lower in the wake group than the exercise group (7.5 vs 10.1; P = .02).

“Fastest Antidepressant Known to Man”

“Response and remission rates were very high at endpoint but could have been inflated by drop-out of patients with persistent depression,” the authors note. During the first 9 weeks of therapy, seven patients dropped out of the wake-therapy group, and four patients dropped out of the exercise group, leaving 64 patients in the study at the 20-week follow-up phase (30 in the wake group and 34 in the exercise group).

During the follow-up phase, six patients dropped out of the wake group because of becoming pregnant, not wanting to use contraception, abuse of alcohol, being lost to follow-up, noncompliance with medication, or worsening of depression. Four patients in the exercise group dropped out because of mania, noncompliance with study procedures, traveling abroad, or worsening of depression.

The researchers note that the dropout rate is within “normal ranges” for studies of serotonin-norepinephrine reuptake inhibitors. However, the dropout rate for the whole 29-week period was somewhat higher in the wake group, “which could signify that the chronotherapeutic regime was difficult for some patients even though they did do better than the patients in the exercise group. This might influence the generalizability of the study,” the researchers say.

“It’s been known for decades that sleep deprivation is the fastest antidepressant known to man for about 40% to 60% of patients with depression,” Philip Gehrman, PhD, CBSM, of the Department of Psychiatry, University of Pennsylvania, Philadelphia, and member of the Penn Sleep Center, noted in an interview withMedscape Medical News.

“The problem is as soon as you go back to sleep, the depression comes back. So people have looked for ways to maintain the antidepressant effect, and the most effective strategies seem to be either starting morning bright-light therapy after sleep deprivation and/or phase advance, moving your schedule earlier,” explained Dr Gehrman, who was not involved in the study.

“There are a fair number of studies now showing that that combination actually works really well for some people and helps sustain the antidepressant effect of sleep deprivation. In the US, I don’t think anyone really does this routinely in clinical practice because no insurance company is going to pay to have people in the lab to do this. There are a couple of groups in Europe who do this more routinely,” Dr Gehrman said.

“It’s a shame it’s not part of more routine clinical care because it does work so well,” he added.

The authors report no relevant financial relationships.

Acta Psychiatr Scand. Published online February 17, 2015. Abstract