23rd ECNP Press conference on impact of circadian rhythms on human brain

February 17, 2016

Melatonin is a hormone secreted by the pineal gland only at night, and is suppressed by light. Cued by darkness, melatonin is especially important for the onset of sleep, but is also involved in many other systems - cardiovascular, immune, endocrine, and metabolic. If rhythms are out of sync, as in depression, then melatonin rhythms also occur at the wrong time thus accentuating the sleep disturbance. Exogenously administered, melatonin acts as a zeitgeber to synchronise circadian rhythms. In addition, its thermoregulatory action is important to induce a rapid onset of sleep, though it is not a sedative agent per se.

Wake therapy (a single night's sleep deprivation) is the most rapid antidepressant available today: approximately 60% of patients, independent of diagnostic subtype, respond with marked improvement within hours. A single night's sleep deprivation induces similar brain changes as many weeks of antidepressant drugs (Benedetti and Smeraldi, 2009). Relapse after recovery sleep can be prevented by daily light therapy, concomitant administration of antidepressants (SSRIs), lithium (for bipolar patients), or a short phase advance of sleep over 3 days. Combinations of these interventions show great promise (Wirz-Justice et al., 2005, 2009).

Despite the growing evidence for the efficacy of the available chronotherapeutic methods, it is surprising how limited the use of these treatments still is. Given the rapid action of chronotherapeutics, lack of side effects, and easy combination possibilities, how can sleep physicians and psychiatrists be educated about their use? Perhaps it is the patients that need to be educated, who are much more interested in non-pharmaceutic approaches? Obviously, treatments that are not patentable do not make profits for industry, thus denying the commercial marketing model used for drugs. Because they do not go through official clinical trial registration at federal regulatory agencies, chronotherapeutic treatments are not on the list for insurance reimbursement. On account of their simplicity, chronotherapeutics contrast with high-tech medicine, and for this reason are often not taken seriously.

Clinical implications

In clinical practice there is still rather widespread ignorance about circadian sleep disturbances and chronotherapeutics in spite of the significant evidence base. How can wider dissemination of chronotherapeutics be achieved?

First, enterprising doctors should try them out. Only with first-hand experience does the reality of efficacy and response emerge.

Second, the techniques should be taught in medical school and during residency - since it is the younger generation that is most open to change and use of cogent alternatives to medication. The nonprofit, multilingual patients' website www.cet and clinicians' website www.chronotherapeutics of the Center for Environmental Therapeutics (CET) illustrate some first attempts to meet this Phase 3 educational challenge.

Third, through its societies, the field of chronotherapeutics needs to advocate recognition for reimbursement.

In the treatment of affective disorders, chronotherapeutics offer a new synthesis of non-pharmacologic interventions designed to accelerate remission in patients with depression and bipolar disorder. Combining chronotherapeutics with concomitant or follow-up medication shows great promise.

Given the urgent need for new strategies to treat patients with residual depressive symptoms, clinical trials of wake therapy and/or adjuvant light therapy, coupled with follow-up studies of long-term recurrence, are of high priority.


Circadian dysfunction can have drastic consequences on brain functions. Increasing evidence suggests that disrupted temporal organisation impairs behaviour, cognition, and affect (Benca et al., 2009).

Disruption of circadian clock genes impairs sleep-wake cycle and behavioural rhythms, which may be implicated in mental disorders. Several different psychiatric disorders, including depression, bipolar disorder, seasonal affective disorder (SAD), schizophrenia, and borderline-related disorders are commonly associated with abnormalities in circadian rhythms.

In particular, biological clocks play a major role in the pathophysiology of affective disorders. Synchronising impaired circadian rhythms, improving sleep, or paradoxically staying awake most of the night can be extremely helpful to treat patients with depression and bipolar disorder.

Chronotherapeutic combinations of light and wake therapy achieve fast results and, by reducing residual symptoms, also minimise relapse over many months. In addition, chronotherapeutics seem to be a major facilitator of drug response, and, in combination with antidepressants, a promising method to stabilise patients over the long term.

Researchers are working on extending our knowledge concerning pharmaceutical and non-pharmaceutical ways to alter circadian rhythms. Recent discoveries of molecular clocks responsible for the generation of circadian rhythms provide novel insights into temporal disruption, offering new therapeutic avenues for the treatment of affective disorders.

Source: European College of Neuropsychopharmacology