Melatonin Analog May Have Role in Treating Major Depression

Fran Lowry

May 20, 2011

May 20, 2011 — Novel melatonin analogs — traditionally used to regulate circadian rhythms and improve disrupted sleep patterns — may also be effective in the treatment of major depression, Australian researchers say.

In particular, the melatonin analog agomelatine may represent an important new addition to the current array of medications to treat major depression because it provides similar levels of antidepressant activity as some other common antidepressants, with fewer adverse effects, according to a study published online first May 18 in The Lancet.

Agomelatine is not yet approved by the Food and Drug Administration (FDA) in the United States but is on the market in Europe and Australia.

"Melatonin analogues provide a new and efficacious mechanism for producing notable phase shifts in human beings," study authors Ian B. Hickie, MD, from the University of Sydney, Camperdown, Australia, and Naomi L. Rogers, PhD, from Central Queensland University, Mackay, Australia, write.

"Although these drugs have been mainly studied for sleep disorders, they also have the potential to be used as primary or adjunctive drugs across a wider range of neuropsychiatric disorders characterized by persistent circadian disturbance."

Agomelatine, which also binds 5-HT2c receptors, shows antidepressant effects, has a favorable adverse effect and safety profile, and has the potential to restore circadian function between depressive episodes. With these attributes, the study authors write, "Agomelatine may occupy a unique place in the management of some patients with severe depression and other major mood disorders."

Improves Mood and Sleep

In an interview with Medscape Medical News, Dr. Rogers noted that agomelatine acts by having a direct antidepressant effect through binding to melatonin receptors and blocking serotonin receptors.

Dr. Naomi L. Rogers

"It also improves circadian disruption and sleep-wake disturbance, which in turn leads to improved mood symptoms as well as improvements in sleep-wake behavior," she said.

There is clear evidence for strong links between circadian disturbance and some of the most characteristic symptoms of clinical depression, including delayed sleep onset, nonrestful sleep, early-morning wakening, daytime fatigue, and blunting or reversal of the normal morning peaks in subjective energy, mood, and alertness.

"Many of the traditional antidepressant treatments are effective in alleviating the mood and depressive symptoms but other symptoms, such as sleep disturbance, remain. These other symptoms can have a significant impact on quality of life, daily functioning, and also have other health impacts," Dr. Rogers said.

"There is evidence that improving sleep-wake patterns and circadian rhythms improves mood symptoms, and that disturbances to the circadian and sleep-wake systems may worsen mood symptoms. In patients with depression there is evidence that sleep disturbance often occurs prior to the first onset of depressive symptoms and may also be a marker for relapse of symptoms in many patients," she added.

The melatonin analogues bind to the same receptor sites in the brain but with different affinities, Dr. Rogers said.

Equivalent Efficacy, Fewer Adverse Effects

The study authors compared melatonin, ramelteon, tasimelteon, PD-6735, and agomelatine and found agomelatine to be the analogue with the most potential for the treatment of major depression.

They report that in the short term agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline. They also report that in the longer term fewer patients taking agomelatine relapse (23.9%) than those receiving placebo (50.0%).

Because agomelatine does not raise serotonin levels, it has less potential for the gastrointestinal, sexual, and metabolic adverse effects that are often seen with other antidepressant drugs, they write.

Medscape Medical News invited Josepha Cheong, MD, professor of psychiatry at the University of Florida in Gainesville, to comment on the research.

"The paper is important because we know that circadian rhythms and sleep-wake patterns are integral to our understanding of affective disorders. In depression, where sleep disturbance is one of the cardinal symptoms, melatonin-based therapies represent a really interesting and novel approach," Dr. Cheong said.

A definite plus for the melatonin analogues is their relative lack of gastrointestinal adverse effects, she added.

"Sleep is integral to well-being, so it only makes sense that if you correct the sleep disorder that is associated with the affective disorder, whether it is anxiety, depression, or mania, that people will feel better, so I think that intuitively, it makes sense, but we’ve got to be very careful until it is FDA approved," Dr. Cheong said. "But we need more classes of antidepressants. I definitely think this is very exciting."

Dr. Hickie reports financial relationships with Wyeth, Eli Lily, Servier, Pfizer, and AstraZeneca. He is also supported by a National Health and Medical Research Council Australian Medical Research Fellowship and a participant in a family practice –based audit of sleep disturbance and major depression, supported by Servier, the manufacturers of agomelatine. Dr. Rogers reports that she has received grant support from Vanda Pharmaceuticals, Servier, Pfizer, and Cephalon and has received honoraria for lectures from Pfizer, CSL Biotherapies, and Servier. She has also received an unrestricted educational grant from Servier. Dr. Cheong has disclosed no relevant financial relationships.

Lancet. Published online May 18, 2011. Abstract

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