Biological Rhythms and Depression: Treatment Opportunities
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Biological Rhythms and Anna Wirz-Justice Centre for Chronobiology Depression: Treatment Psychiatric University Clinics Basel, Switzerland Opportunities e-mail: [email protected] Introduction circadian rhythms. The genetic program is higher day-to-day stability. Another direct slightly different from 24 hours (in humans effect of light is on brain serotonin n all cultures, altered bio- usually longer) and thus the internal clock turnover—the more light received, the high- logical rhythms have been requires regular synchronization to the exter- er the levels of this neurotransmitter known recognized as an essential nal 24-hour day by so-called “zeitgebers” or to be involved in the affective state. Without I characteristic of major entraining agents. The major zeitgeber for going into the serious body of clinical depression. Diurnal variation of mood, the SCN is light. The SCN contain the high- research that has investigated mechanisms early morning awakening, and sleep dis- est serotonin concentrations in the brain, and efficacy of sleep deprivation in its various turbances belong to the core symptoms, through input from the raphe nuclei. The forms or light therapy in many different psy- and depressive phases often follow a regu- SCN drive the rhythm of nighttime mela- chiatric and sleep disorders (see ‘Further lar periodicity. Bipolar patients, in particu- tonin synthesis in the pineal gland as well as reading’ for reviews), this paper will focus on lar rapid cyclers, undergo remarkably pre- receiving feedback about the amount of cir- practical applications. cise switches between clinical states. In culating melatonin via melatonin receptors temperate latitudes, seasonal affective dis- in the SCN. Wake therapy order (SAD) is linked to decreasing light availability in autumn and winter. Circadi- This concept of light and melatonin as major Although many thousands of patients all an (24-hour) rhythms not only underlie zeitgebers synchronizing the biological clock over the world have improved with sleep mood disorders, but, importantly, manip- is important when we consider how they deprivation, it has not really caught on as a ulations of rhythms or sleep can treat can be used as therapeutic agents. Other first-line treatment for major—particularly them. Sleep deprivation has long been known zeitgebers are social signals (see E melancholic—depression. It may be the established as the most rapid antidepres- Frank, this issue), meals, and exercise— paradox of recommending the opposite of sant known—about 60% of patients which provide the daily structure well known what is expected—to take sleep away from improve on the next day. Light is the treat- to psychiatrists as important, but now con- someone who has sleep problems is not ment of choice for SAD. A much broader ceptualized in terms of their ability to syn- very convincing. That is why in recent years range of applications for light is develop- chronize and stabilize rhythmic behavior. we have changed the name to wake thera- ing, in particular, in nonseasonal major py—instead of robbing a depressed patient depression. These biologically based, non- Sleep is regulated by interactions between of her wished-for sleep, we give her more pharmaceutic treatments, which are fast- the circadian pacemaker in the SCN and a wakefulness as a cure! Over the years, mod- acting, inexpensive, and with few side homeostatic process (described by sleep ifications of total sleep deprivation have effects, fulfill the requirements to pressure rising during wakefulness and being been developed—partial sleep deprivation become—alone or combined—part of dissipated during sleep). This “two-process in the second half of the night appears to standard antidepressant treatment in both model” explains many aspects of sleep-wake work just as well. Thus, the patient can go industrialized and developing countries. cycle physiology. It has also been used to to bed early, have a few hours of deep sleep, help understand possible abnormalities in and wake up at 01:00 or 02:00 and stay up Circadian rhythms and mood disorders. Depressive patients might for the rest of the night. In the “phase sleep regulation have a poor buildup of sleep pressure. Per- advance” treatment, sleep is not deprived haps the short-term improvement after a but shifted to 5-6 hours earlier than usual for Life on this rotating planet is subject to a pre- night’s sleep deprivation is related to sleep a few days until improvement occurs. The dictable 24-hour rhythm of day alternating pressure rising to normal levels only after 40 important factor for improvement in this with night, and daylength changing with hours of wakefulness (but then inducing procedure is not the loss of sleep itself but the seasons. All species have evolved to relapse by dropping to former low values fol- being awake in the second half of the night adapt to the solar light-dark cycle with lowing a recovery night’s sleep). If light can (the circadian minimum where mood is at appropriate timing of behavior and physiol- improve mood—this effect could occur its lowest). ogy. This timing has become internalized: a through its zeitgeber ability to synchronize complex genetic clockwork located in the rhythms (shifting phase), or to increase the The main reason, however, why sleep depri- suprachiasmatic nuclei (SCN) generates all amplitude of the circadian signal leading to vation has remained a curious phenomenon 5 WPA Bulletin on Depression. Vol. 13 - N° 36, 2008 and not a mainline treatment, is that the complete amelioration of the trists understand this application but are not majority of patients relapse after recovery depressive syndrome leading to aware of further developments over the last sleep. Why invest staff and patient effort in perceived euthymia in the early decade. In particular, light therapy has been wake therapy if the improvement is only morning. The first recovery sleep applied in many other psychiatric disorders, transient? On the one hand, the rapid was followed by a partial but defi- from bulimia to the sleep-wake cycle distur- improvement and rapid relapse has made nite depressive syndromal relapse. bances of Alzheimer's dementia and sleep deprivation an ideal research tool to The second wake therapy led again antepartum depression. Double-blind place- better understand factors underlying mood to perceived euthymia, without bo-controlled studies have shown that light switches. But for everyday practice, the relapse after recovery sleep; the therapy combined with a selective serotonin focus has been to find techniques to main- benefit was sustained after the reuptake inhibitor leads to more rapid (with- tain the improvement obtained so rapidly. third wake therapy. Euthymia per- in a week) and more profound (by ca. 30%) One of the most cited unmet needs in the sisted during the following days, improvement in patients with nonseasonal psychopharmacology of depression is the and the patient was discharged. major depression, suggesting an advantage slow latency of response to current medica- Plasma lithium levels were kept of using combined light and drug. tions. The idea that wake therapy can meet high for six months, and then this need by switching patients out of reduced to a target level of 0.75 Although environmental light supplemen- depression within hours, not weeks, makes mEq/L. Nine years later, the patient tation seems an obvious approach for treat- it attractive to look for combinations with is still euthymic. She still takes lithi- ing winter depression, it has not yet been other methods to prevent relapse. In Milan, um, which also prevents the mod- widely used for nonseasonal depression. If a group of psychiatrists have been using erate seasonal mood fluctuations one considers the social withdrawal in major (repeated) wake therapy for more than a which recurred over her lifetime. depression, then a secondary consequence decade to treat hospitalized bipolar and Her brother, who suffered from might be less exposure to outdoor light unipolar depressed patients. Successful severe bipolar disorder, also (indoor light is not bright enough to have maintenance of response has been found in showed a good response to wake any clinical effect). Many doctors from trop- patients when treated with lithium, with therapy for depression and dark ical countries have asked—somewhat skep- selective serotonin reuptake inhibitors, and therapy for mania. (F. Benedetti, tically—why should we use light treatment light therapy. They find no enhanced switch personal communication) in our country which has so much sun- rate into (hypo)mania. An example is pre- shine? Yet it would be interesting to mea- sented in Case #1. sure how much bright light depressed Light therapy patients in such climates actually get. Since sunny countries are often also hot, people Light therapy was specifically developed as escape the heat and remain inside, away Case #1: a zeitgeber treatment for SAD patients, who from the sunshine. When outdoors, they Bipolar depression and wake become depressed as the days shorten and wear sunglasses. I would predict that all therapy spontaneously remit during the longer days over the world, independent of climate and in spring and summer. The efficacy of light latitude, depressed patients probably hide A 51-year-old woman with difficult- is greatest in the early morning, but patients from the light. Odd as it may seem (espe- to-treat bipolar disorder type I was also improve at other times of day, suggest- cially for tropical countries), we recommend hospitalized in the San Raffaele ing that light acts both to shift rhythms ear- that the doctor order a 30-minute walk out- Clinic in Milan during a depressive lier in the morning (zeitgeber action) and as side every day in the early morning for episode that had lasted eight an antidepressant “drug” (without a time depressed patients. This could be consid- months. All medication was dependency).