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

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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). The most effective time of ered a “natural” and, moreover, free thera- stopped, except lithium, which was day for beginning morning light treatment peutic option, but requires regularity to be increased. After five mood episodes for SAD patients can be individually pre- efficacious. and three forced hospitalizations in scribed according to their circadian rhythm two years, with so many disap- type, by means of an online morningness- In contrast, “dark therapy” (keeping pointing therapeutic failures, the eveningness questionnaire (see Auto-MEQ patients in longer-than-usual nights) may patient and her relatives had very on www.cet.org). This nonprofit site has treat mania as fast as neuroleptics, and even low expectations psychiatry in gen- been established to provide practical infor- stop rapid cycling. eral and the chronotherapeutic mation for doctors and patients on all approach in particular. She under- aspects of light therapy, and is being Two examples from Siberia (Case #2) and went three consecutive cycles of expanded through translation into a num- New York (Case #3) illustrate the new appli- total sleep deprivation, each fol- ber of languages. cations. The best timing of light in bipolar lowed by a recovery night sleep. patients appears to be different from the However, after the first wake ther- Light is now clearly established as the treat- early morning light recommended for SAD. apy she experienced rapid and ment of choice for SAD, and many psychia- The case study #2 here corroborates find-

6 ings in a recently published series of bipolar controlled preparations of melatonin will patients who showed mixed states with Case #3 soon be recognized by regulatory agen- morning light and improvement with after- Treatment-resistant chronic cies. Melatonin itself is not an antidepres- noon light. depression and light therapy sant, but improving and stabilizing sleep is an important part of antidepressant thera- A 24-year-old single woman in pies. Case #2: New York with a lifetime history Bipolar depression and light of dysthymia and a history of Chronotherapeutics for therapy anorexia and social phobia, suf- major depression fered from chronic major depres- A bipolar patient in Novosibirsk had sion for the last 6 years. She had Chronotherapeutic options are summarized experienced her first depressed / been unresponsive to multiple in the Table below and can be added on to hypomania phases at age 22. drug trials. Treatment with the antidepressant “treatment as usual”. Depression episodes significantly monoamine oxidase inhibitor outnumbered and were longer than tranylcypromine 100 mg induced hypomania episodes. There was a a full complement of early, mid- Implication for clinical practice rapid (within a day) switch from dle, and late insomnia. Light ther- depression to hypomania (which apy at 07:15 for 30 min promptly (SAD and nonseasonal depression, lasted less than 1 month). Depres- coalesced sleep (23:30-07:00) and unipolar and bipolar disorder, chronic sion was characterized by atypical within 3 weeks the patient and therapy-resistant, adjuvant to med- features, but anxiety often pre- showed complete remission and ication) vailed in affect. Although not reach- was discharged. She continued ing the criteria for SAD, she entered with light + tranylcypromine at Wake therapy (a whole night’s sleep a light treatment trial at age 29 out home, but was not compliant with deprivation, or partial sleep depriva- of interest. After morning light light treatment. Whenever she tion in the second half of the night) is (08:00-10:00, 2500 lux for 2 hours stopped using the light she would the most rapid antidepressant known for a week), she experienced clear experience relapse within 2 days. activation, better mood, but anxi- On resumption of the light, she Repeated wake therapy (followed by ety, irritability, and a feeling of dis- would feel improvement within 2 recovery sleep) to promote main- satisfaction appeared to increase. days and complete remission in 4 tained response The negative effect was brief, but days. Although light alone might with repeated daily light exposures have maintained her improve- Phase advance of the sleep-wake cycle it became more prominent. When ment, with such a serious chronic to maintain the sleep deprivation switched to afternoon light (16:00- depression it is difficult for psy- response 18:00), she felt better than after chiatrists to withdraw the drug morning light, with no mixed and rely on light monotherapy. (M Morning timed light therapy to main- states. From 1991 the patient has Terman, with permission) tain the sleep deprivation response had her own light box at home and regularly uses light therapy on her Dark therapy (to stop rapid cycling, own for 15-20 minutes in the after- Melatonin mania) noon. (K. Danilenko and A. Putilov, personal communication) Melatonin, exogenously administered, also Melatonin (for sleep disturbances in acts as a zeitgeber to synchronize circadi- depression) an rhythms and sleep (for example, in An even more striking application of light blind persons). It induces sleepiness by Melatonin (in the evening) to enhance therapy for nonseasonal depression is in causing vasodilatation of hands and feet phase advances with light (in the adjunctive treatment for chronic or treat- and hence heat loss, with a consequent morning) ment-resistant depression, as exemplified decline in core body temperature, which in Case #3. More trials of these combina- facilitates a rapid sleep onset. Melatonin Light therapy is the treatment of tions are required to establish a solid evi- has few minor effects on sleep itself (as choice for winter depression (SAD), dence base, but given the lack of side measured in the EEG), and thus is a sleep- which is most prevalent at temperate effects, the ease of application, and the promoting agent rather than a direct hyp- latitudes often rapid improvement that had not notic in the classical sense. Very low doses been attained with antidepressant drugs suffice ( ~ 1 mg) and rarely have any side Light therapy for nonseasonal depres- alone, adding light therapy seems to be effects been documented. We hope that sion with or without medication widely indicated. well-researched pharmaceutical quality-

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Implementation of this strategy in clinical 2. for patients who are willing to try wake Close monitoring of the patient’s state can practice will be provided by a new manual therapy, a single night’s sleep depriva- help decide which chronotherapeutic in preparation (Benedetti F, Terman M, tion is carried out, with light treatment should be tried next. The full combination Wirz-Justice A. Psychiatric Chronotherapeu- in the morning at the calculated opti- of repeated sleep deprivation and/or phase tics: A Treatment Manual). Treatments can mum, continuing as in 1. advance may be required only for treat- be combined in a flexible manner step by 3. for the “complete chronotherapeutic ment-resistant patients. step according to the patient’s response, as package”, a single night’s sleep depriva- exemplified below: tion is accompanied by light therapy as Both wake and light therapy can be consid- 1. all patients can use light therapy. Treat- in 2. On the recovery night after sleep ered to fulfill the World Psychiatric Associa- ment of 10 000 lux for 30 min is begun deprivation, the patient goes to bed five tion’s requirements for globally applicable, at the time allocated by the patient’s hours earlier than usual and wakes up low-cost, rapidly effective antidepressants. MEQ chronotype. This timing of light five hours earlier than usual (“phase remains fixed throughout a trial of at advance” therapy). On night two, sleep least two weeks. Depending on is shifted to three hours earlier than response, dosage can be increased by usual, and, on night three and there- lengthening the duration of light thera- after, sleep is maintained one hour ear- py by 15 min every few days. lier than usual.

FURTHER READING Benedetti F, Barbini B, Colombo C, Smeraldi E. Chronotherapeutics in a psychiatric ward. Sleep Med Rev. 2007;11:509-522. Lam RW. Seasonal Affective Disorder and Beyond. Light Treatment for SAD and Non-SAD Conditions. Washington DC: American Psychiatric Press; 1998. Sit D, Wisner KL, Hanusa BH, Stull S, Terman M. Light therapy for bipolar disorder: a case series in women. Bipolar Disord. 2007;9:918-927. Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr. 2005;10:647-663. Terman M. Evolving applications of light therapy. Sleep Med Rev. 2007;11:497-507. Wirz-Justice A, Van den Hoofdakker RH. Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry. 1999;46:445-453.