WPA Bulletin WPA Bulletin on Depression Vol No A publication

WPA Bulletin WPA Bulletin on Depression Vol. 12 - No. 36, 2008 A publication of the World Psychiatric Association S Depression and circadian rhythms N T Editorial D. Moussaoui P1 E Depression and Circadian Rhythms M.A. Crocq P2 T Biological Rhythms and Depression: Treatment Opportunities C O N A. Wirz-Justice P5 WORLD PSYCHIATRY ASSOCIATION WPA EXECUTIVE COMMITTEE President: Juan E. Mezzich (USA) President-Elect: Mario Maj (Italy) Secretary General: John Cox (UK) Secretary for Finance: Sam Tyano (Israel) Secretary for Meetings: Pedro Ruiz (USA) Secretary for Education: Allan Tasman (USA) Secretary for Publications: Helen Herrman (Australia) Secretary for Sections: Miguel R. Jorge (Brazil) WPA BULLETIN ON DEPRESSION EDITORIAL COMMITTEE Jorge Alberto Costa e Silva - Brazil Parameshvara Deva - Malaysia Cornelius Katona - UK Juan José Lopez-Ibor - Spain Mario Maj - Italy Roger Montenegro - Argentina Driss Moussaoui (Scientific Director) - Morocco Ahmed Okasha - Egypt WPA COUNCIL Norman Sartorius - Switzerland Ernst Peter Berner, George Christodoulou, Jorge Alberto SECRETARIAT: Stéphanie Champemond Costa e Silva, Felice Lieh-Mak, Pierre Pichot, Norman WPA ZONE REPRESENTATIVES Servier International - 192 avenue Charles de Gaulle Enrique Camarena (Mexico), Edgard Belfort (Venezuela), Sartorius, Fini M. Schulsinger, Costas Stefanis, Roger 95578 Neuilly-sur-Seine - France Montenegro, Ahmed Okasha, Juan-José López-Ibor. Julio Arboleda-Florez (Canada), Michelle Riba (USA), Tel: 33 1 55 72 44 82 Fax: 33 1 5 72 38 11 Roger Montenegro (Argentina), Michel Botbol (France), Marianne Kastrup (Denmark), Levent Küey (Turkey), Dusica Lecic-Tosevski (Serbia and Montenegro), Tarek Okasha (Egypt), Charles Baddoura (Lebanon), Oye Gureje (Nigeria), Fred Kigozi (Uganda), Haroon Rashid Chaudhry (Pakistan), J. K. Trivedi (India), Naotaka Shinfuku (Japan), Bruce Singh (Australia). The WPA Bulletin on Depression is supported by an unrestricted grant from Servier WPA Bulletin on Depression. Vol. 13 - N° 36, 2008 E d i t o r i a l hythms are one of the most fundamental aspects of life not just in the animal and plant worlds, but also for humans. The day-night cycle was crucial from the earliest times, and cavemen were only able to gather food or hunt during the daytime. The rhythm of the seasons also had a profound effect on agriculture, with growers forced to follow the seasonal cycle to raise crops. Like his forebears, modern man is also dependent on the rhythm of time, but now he is tied to the beating of the clock. Time in human societies and its rate of passage are becoming increasingly rapid. Plane journeys, the Internet, mobile phones, and satellite television have all shrunk geographical distances and shortened time, occasionally eliminating them altogether. It is not surprising that psychiatric illnesses, and depression in particular, should in their turn be subject to disruptions in temporal rhythms. R In every human being there is part of the brain that acts as a clock, orchestrating physical and mental activity in order to ensure successful adaptation to the prevailing environment. This structure, known as the suprachiasmatic nucleus (SCN), controls endocrine systems and manages body temperature, blood pressure, levels of wakefulness, and sleep patterns. The SCN is located in the anterior base of the hypothalamus and comprises around 20 000 neurons (compared with 100 billion neurons for the entire brain). It oversees the rhythms of each cell in the human body. Isolated SCN neurons have a cyclical rhythm of approximately 24 hours. The molecular and genetic aspects of this remarkable property have been elucidated over the last decade. Some 14 genes and the proteins they produce govern this 24-hour rhythm via a feedback control system. The clock protein blocks its own production within the nucleus by means of mRNA. This action ends with enzymatic degradation of protein after a period of approximately 24 hours, allowing resumption of production of mRNA and of the protein in cyclical fashion. The SCN receives information via the optic chiasm concerning light conditions and then synchronizes with the lighting, with night-time equating to a number of biological changes in the brain: melatonin production by the pineal gland, reduced noradrenergic tone of the locus ceruleus, increased serotoninergic tone, a marked decrease in production of plasma cortisol, and a slow increase in levels of plasma growth hormone. The latter reaches a peak at 1 or 2 o’clock in the morning, at which time plasma cortisol concentrations are lowest. This is due to the body’s need to repair damage caused during daytime by the growth hormone, resulting in the need for inactivation of cortisol, the hormone responsible for activity and combativeness. The chief problem of depression is deregulation of the body’s hormonal rhythms and sleep patterns, with ceaseless production of high levels of plasma cortisol. This has a negative impact on sleep, which is frequently disrupted and of poor quality due to excessive functioning of the activity hormone when the body requires rest. This phenomenon partly accounts for such symptoms as fatigue and sluggishness. In addition, production of high concentrations of plasma cortisol day and night has a toxic effect on the brain, leading to a significant decrease in numbers of synapses per neuron, reduced dendritic branching, and finally atrophy of the hippocampus, resulting in the cognitive disturbances characteristic of depression. This process explains how depression may be viewed as a disease of disrupted rhythms and why this topic was selected for the present issue of the WPA Bulletin on Depression. We thus received papers from Anna Wirtz-Justice, who has devoted and continues to devote her research efforts to the links between psychiatric disease and time (chronopsychiatry), and from M-A Crocq, whose main interest is in genetics in psychiatry and links between sleep and mental dysfunction. A deeper understanding of the role of cycles and rhythm in depression will allow practitioners to provide patients with better advice on healthy lifestyles through consideration of the tempo at which they live their lives. Driss MOUSSAOUI Ibn Rushd University Psychiatric Center, Casablanca, Morocco psych@menara.ma 1 WPA Bulletin on Depression. Vol. 13 - N° 36, 2008 Depression and Circadian Rhythms Introduction: Depression and rhythms Rhythms play a major role in the classification, phenomenology, treatment, and etiology of mood disorders. The environment we live in is intrinsically rhythmic: the most obvious rhythms are circadian and circannual. The term circadian (from the Latin ‘circa’ about, and ‘dies’ day) designates physiological activity that occurs approximately every 24 hours. Though the term did not appear in scientific usage before the 1950s, the 24-hour day and night cycle, caused by the earth’s rotation around the sun, predates the appearance of man on earth. Light, our main zeitgeber, dictates when we should toil and rest, and when food is available. Like all living creatures, we came to develop biological clocks to adjust to this cyclical environment. In addition to circadian rhythms, another prominent rhythm in our environment is circannual, or in more simple terms the year’s seasons, which have also long been recognized as a determinant of mood. that time that depression was conceptualized as a recurrent illness. The French psychiatrist Jean-Pierre Falret described la folie circulaire (circular madness) in 1853, characterized by the succession of depression and mania. However, Falret failed to recognize the whole spectrum of bipolar illness and to gather all its subtypes into a single diagnostic entity. For instance, Falret distinguished a separate category, named “folie intermittente,” for cases showing 1- to 4-week intervals (which we would diagnose as rapid cycling today). Our current diagnostic concepts are based on the work of Emil Kraepelin (1856–1926) who defined manic-depressive illness. In Kraepelin’s conception, most mood disorders were a biological illness, and recurrent by nature. This periodic recurrence of mood disorder was a most intriguing feature, and several explanations were offered. For instance, Theodor Meynert (1833–1892), a professor of psychiatry in Vienna, Austria, and a teacher of Sigmund Freud between 1883 and 1886, postulated that the succession of depression and mania might be caused by cycles of constriction and dilation of cortical frontal blood vessels; frontal vascular dilation and the resulting frontal hyperemia caused mania, whereas frontal vessel constriction would cause depression. Clinicians wondered whether manic-depressive cycles had a natural period. Before the advent of mood-regulating medications, it was possible to follow up large series of patients over several years. It seems that the course of illness evolved towards an average of one episode per year in many patients. Kraepelin, after studying 406 patients, concluded that the disease showed a tendency later on to run its course more quickly (ie, intervals shortened and the duration of attacks increased). Kraepelin’s initial case series was later reanalyzed by Eliot Slater Marc-Antoine Crocq, M.D. Centre Hospitalier, 68250 Rouffach, France ma.crocq@ch-rouffach.fr (1904–1983). Slater showed that Kraepelin's findings were biased by a mathematical artifact (patients with an accelerating illness course tended to be overrepresented in Kraepelin's calculations). Slater confirmed that the course of the illness tended to accelerate, but not as fast as initially reported by Kraepelin. He also found that the highest peak of mood episodes occurred around May and June, with a second peak in September; that individual patients showed a tendency to fall ill in the same season of the year; and that each patient had his own mean interval, his own rhythm, and his own tendency to fall ill after a distinct time. This acceleration of the illness course was reinterpreted by modern authors, such as Robert M. Post in the early 1980s, with the “kindling” hypothesis. According to this hypothesis, the first depressive episodes are hard to trigger and necessitate a significant amount of external stressors, whereas subsequent episodes occur with increasing facility. The higher the number of previous episodes, the greater is the probability of a new episode occurring. Rhythms and the diagnostic classification of mood disorders One of the most striking clinical features of mood disorders is the periodicity of their recurrence. Most individuals who present a depressive episode will show a recurrence in the subsequent years. This periodicity, and more specifically the recurrence and polarity of episodes, are key criteria in the diagnostic classification of mood disorders in both the DSM-IV-TR (Diagnostic and Statistical Manual, American Psychiatric Association) and the ICD10 (International Classification of Diseases, World Health Organization). Modern diagnostic entities in psychiatry emerged at the end of the 19th century. It was at Rhythms and the phenomenology of mood disorders Depressive mood fluctuates in the course of a day. This is particularly pronounced when depression is more severe. In the DSM-IV-TR, melancholic features include early morning awakening (2 hours earlier than usual) and a worsening of the mood in the morning. Disturbances of normal clinical and biological circadian rhythms are a core feature of depression. The suprachiasmatic nuclei (SCN) modulate biological, physiological, and behavioral parameters that follow circadian rhythms, such as central body temperature, blood pressure, cortisol secretion, the immune response, motor activity, and cognitive 2 performance. Moreover, the SCN control sleep-wake rhythms, ie, the sleep phase and daytime alertness of individuals. Without exception, all of these circadian rhythms appear to be disrupted in depressed patients. This has been shown both for easily measurable physiological rhythms, such as body temperature or cardiac frequency, and for hormonal rhythms (melatonin, growth hormone, prolactin, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes). Blunted amplitude of many rhythms appears to be the main chronobiological abnormality in depression. In other words, rhythms are flattened. One of the most extensively investigated rhythms in depression is cortisol secretion. In normal controls, cortisolemia is maximal (zenith) around 8 A.M., and minimal (nadir) around midnight. Depressed patients show hypercortisolemia, a flattened circadian curve, reduced duration of the nocturnal quiescent period, and earlier or elevated nadir (higher evening cortisol). The flattening of cortisol rhythm has been shown to be particularly pronounced in patients with psychotic major depression (Keller et al., 2006). Hypercortisolemia is accompanied by resistance to cortisol suppression by dexamethasone. It was hoped in the early 1980s that the dexamethasone suppression test (DST) would find clinical use in psychiatry to diagnose depression. However, the sensitivity and specificity of the DST are not high as initially thought. In fact, the sensitivity of the DST (rate of a positive outcome, or nonsuppression of cortisol) in major depression is modest (about 40%-50%) but is higher (about 60%-70%) in very severe, especially psychotic, affective disorders, including major depression with psychotic as well as melancholic features. The disturbances of the sleep-wake cycle, another key circadian function, are traditional symptoms of depression. Clinically, patients report poor sleep quality. Table 1 lists the main abnormalities of sleep architecture in depressed patients. Polysomnographic studies indicated that the shortening of REM sleep latency (period of time between sleep onset and REM onset) might be a diagnostic marker of depression. How- ever, reduction in REM sleep latency has also been reported in other psychiatric disorders. Interestingly, depression is “turned off” by therapeutic sleep deprivation and “turned on” by recovery sleep, which introduces us to the next section, discussing the therapeutic and etiological importance of rhythms in depression. Rhythms and the etiology of mood disorders Many types of rhythm manipulation have been shown to have an effect on mood, either negative or positive. Even healthy persons feel the cognitive and emotional effects of jet lag or of transition from standard to daylight saving time. It is known that sleep deprivation or shifts in the timing of sleep affect mood states. An interesting therapeutic intervention is the stabilization of social rhythms to prevent relapse in bipolar illness. Changes in social rhythms can cause relapse in bipolar illness. For instance, Kadri et al (2000) showed that 45% of bipolar patients relapsed during the month of Ramadan; these relapses were not related to plasma concentration of lithium and most of the relapses were manic (71.4 %). Conversely, Ellen Frank has shown that stabilization of social routines can prevent relapse. Thus, bipolar patients should be encouraged to get out of bed, have breakfast, and have their first social contact, etc., at a constant time. This indicates that social rhythms can interact with biological rhythms. Some subtypes of mood disorders seem to be clearly induced by modifications of rhythms. One example is seasonal depression (also known as winter depression), which seems to be etiologically linked to circannual rhythms. Robert Burton wrote as early as 1621 in his famous treatise on the “Anatomy of Melancholy” that “of the seasons of the year, the autumn is most melancholy.” Table 2 lists a few key facts about seasonal depression. Individual chronotypes, or the morningness–eveningness dimension, might be associated with the vulnerability to seasonal depression, as shown by a study carried out by Natale et al in college students (Psychiatry Research, 2005). Specifically, it seems that eveningness might predispose to increased seasonality of mood. Eveningness is associated with later bedtime and waking-up time, greater morning sleepiness, and ease of returning to sleep in the early morning. This dimension can be measured with the questionnaire of Horne and Östberg (1976). Female-specific mood disorders offer other examples of disorders with a clear chronobi- Increase in sleep onset latency Increase in intra-sleep and early morning awakening Shortening of REM latency Decrease in delta sleep (loss of sleep stages 3 & 4) Table I. Disturbances of sleep architecture in depression Seasonal depression was described by Rosenthal et al., 1984 Seasonal pattern can be specified in DSM-IV-TR (not in ICD-10) Mood sags notably in November Onset might occur when light variation is the fastest (ie, at the autumn equinox, about 22–23 September) Prevalence increases with higher latitudes Younger persons are at higher risk Women comprise 60% to 90% of patients The early morning decrease in plasma melatonin is delayed by about 2 hours (Terman, 1987). Light therapy acts by inducing phase advance For treatment, morning light is more effective than evening light Table 2. Key facts about seasonal depression. 3 WPA Bulletin on Depression. Vol. 13 - N° 36, 2008 ological basis. The first example is premenstrual syndrome (the correct diagnostic term was “late luteal phase dysphoric disorder” in DSM-III-R, and was changed to “premenstrual dysphoric disorder” in DSM-IV). Other examples are pregnancy and postpartum depression. Finally, mood changes are also associated with menopause. It has been hypothesized that female-specifAuthors K. Mishima et al., Am J Med Genet. 2005;1:101-104 ic mood disorders might be triggered by gonadal steroid changes that disrupt normal amplitude and phase relationships between circadian rhythms, and thereby elicit mood disturbances in vulnerable women. It is not known whether some individuals are more vulnerable to disruption of blunting of circadian rhythms. Do some individuals require stronger external zeitgebers to synchronize their internal rhythms? We are just beginResults 421 Japanese subjects. Evening preference and delayed sleep onset in 3111 C/C homozygotes (n=12) 410 normal adults. C allele associated with 10- to 44-minute delay in preferred timing for activity or sleep episodes No association with evening preference ning to explore the genetics of circadian rhythms. Human circadian rhythms originate in the SCN. Several genes expressed in the SCN have been identified in recent years. So far, the gene that has been the most extensively studied in mood disorders is the CLOCK gene (Circadian Locomotor Output Cycles Kaput), which encodes proteins regulating the persistence and length of the circadian cycle. As shown in Table 3, recent genetic association studies with a polymorphism in the human CLOCK gene suggest that it might play a role in circadian preference and the symptomatic expression of bipolar illness. However, these results await replication in more studies. D. Katzenberg et al., Sleep. 1998;21:569-76 Conclusion As outlined in this article, rhythms, cycles, and periodicity are the essence of mood disorders. One is tempted to speculate that the disruption and blunting of circadian rhythms are reflected in the patient’s subjective perception that the flow of time is blocked, and in his painful experience that life is static. Shakespeare found beautiful words to express this in the famous soliloquy of Macbeth, in response to the news of his wife’s death: “Tomorrow, and tomorrow, and tomorrow, Creeps in this petty pace from day to day, To the last syllable of recorded time” (Act 5, Scene 5, lines 18-20). D.L. Robilliard et al., J Sleep Res. 2002;11:305-12 U. Bailer et al., European Neuropsychopharmacology. 2005;15:51-55 No association with affective disorders (unipolar depression and bipolar patients, n=102; 103 controls) C/C homozygosity is associated with a larger number of previous depressive or manic episodes in bipolar individuals Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression F. Benedetti et al., Am J Med Genet. 2003;123:23-26 Francesco Benedetti et al., American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2007;5:631-635 Table 3. Association studies with the 3111 T/C human CLOCK Gene Polymorphism (3’ flanking region) FURTHER READING Dialogues in Clinical Neuroscience. Issue 38, The Core of Depression. 2008 (in press). Available online at: www.dialogues-cns.org. Frank E. Interpersonal and social rhythm therapy: a means of improving depression and preventing relapse in bipolar disorder. J Clin Psychol. 2007;63:463-473. Kadri N, Mouchtaq N, Hakkou F, Moussaoui D. Relapses in bipolar patients: changes in social rhythm? Int J Neuropsychopharmacol. 2000;3:45-49. Keller J, Flores B, Gomez RG, Solvason HB, Kenna H, Williams GH, Schatzberg AF. Cortisol circadian rhythm alterations in psychotic major depression. Biol Psychiatry. 2006;60:275-281. 4 Biological Rhythms and Depression: Treatment Opportunities Introduction n all cultures, altered biological rhythms have been recognized as an essential characteristic of major depression. Diurnal variation of mood, early morning awakening, and sleep disturbances belong to the core symptoms, and depressive phases often follow a regular periodicity. Bipolar patients, in particular rapid cyclers, undergo remarkably precise switches between clinical states. In temperate latitudes, seasonal affective disorder (SAD) is linked to decreasing light availability in autumn and winter. Circadian (24-hour) rhythms not only underlie mood disorders, but, importantly, manipulations of rhythms or sleep can treat them. Sleep deprivation has long been established as the most rapid antidepressant known—about 60% of patients improve on the next day. Light is the treatment of choice for SAD. A much broader range of applications for light is developing, in particular, in nonseasonal major depression. These biologically based, nonpharmaceutic treatments, which are fastacting, inexpensive, and with few side effects, fulfill the requirements to become—alone or combined—part of standard antidepressant treatment in both industrialized and developing countries. Anna Wirz-Justice Centre for Chronobiology Psychiatric University Clinics Basel, Switzerland e-mail: anna.wirz-justice@unibas.ch I circadian rhythms. The genetic program is slightly different from 24 hours (in humans usually longer) and thus the internal clock requires regular synchronization to the external 24-hour day by so-called “zeitgebers” or entraining agents. The major zeitgeber for the SCN is light. The SCN contain the highest serotonin concentrations in the brain, through input from the raphe nuclei. The SCN drive the rhythm of nighttime melatonin synthesis in the pineal gland as well as receiving feedback about the amount of circulating melatonin via melatonin receptors in the SCN. This concept of light and melatonin as major zeitgebers synchronizing the biological clock is important when we consider how they can be used as therapeutic agents. Other known zeitgebers are social signals (see E Frank, this issue), meals, and exercise— which provide the daily structure well known to psychiatrists as important, but now conceptualized in terms of their ability to synchronize and stabilize rhythmic behavior. Sleep is regulated by interactions between the circadian pacemaker in the SCN and a homeostatic process (described by sleep pressure rising during wakefulness and being dissipated during sleep). This “two-process model” explains many aspects of sleep-wake cycle physiology. It has also been used to help understand possible abnormalities in mood disorders. Depressive patients might have a poor buildup of sleep pressure. Perhaps the short-term improvement after a night’s sleep deprivation is related to sleep pressure rising to normal levels only after 40 hours of wakefulness (but then inducing relapse by dropping to former low values following a recovery night’s sleep). If light can improve mood—this effect could occur through its zeitgeber ability to synchronize rhythms (shifting phase), or to increase the amplitude of the circadian signal leading to higher day-to-day stability. Another direct effect of light is on brain serotonin turnover—the more light received, the higher the levels of this neurotransmitter known to be involved in the affective state. Without going into the serious body of clinical research that has investigated mechanisms and efficacy of sleep deprivation in its various forms or light therapy in many different psychiatric and sleep disorders (see ‘Further reading’ for reviews), this paper will focus on practical applications. Wake therapy Although many thousands of patients all over the world have improved with sleep deprivation, it has not really caught on as a first-line treatment for major—particularly melancholic—depression. It may be the paradox of recommending the opposite of what is expected—to take sleep away from someone who has sleep problems is not very convincing. That is why in recent years we have changed the name to wake therapy—instead of robbing a depressed patient of her wished-for sleep, we give her more wakefulness as a cure! Over the years, modifications of total sleep deprivation have been developed—partial sleep deprivation in the second half of the night appears to work just as well. Thus, the patient can go to bed early, have a few hours of deep sleep, and wake up at 01:00 or 02:00 and stay up for the rest of the night. In the “phase advance” treatment, sleep is not deprived but shifted to 5-6 hours earlier than usual for a few days until improvement occurs. The important factor for improvement in this procedure is not the loss of sleep itself but being awake in the second half of the night (the circadian minimum where mood is at its lowest). The main reason, however, why sleep deprivation has remained a curious phenomenon Circadian rhythms and sleep regulation Life on this rotating planet is subject to a predictable 24-hour rhythm of day alternating with night, and daylength changing with the seasons. All species have evolved to adapt to the solar light-dark cycle with appropriate timing of behavior and physiology. This timing has become internalized: a complex genetic clockwork located in the suprachiasmatic nuclei (SCN) generates all 5 WPA Bulletin on Depression. Vol. 13 - N° 36, 2008 and not a mainline treatment, is that the majority of patients relapse after recovery sleep. Why invest staff and patient effort in wake therapy if the improvement is only transient? On the one hand, the rapid improvement and rapid relapse has made sleep deprivation an ideal research tool to better understand factors underlying mood switches. But for everyday practice, the focus has been to find techniques to maintain the improvement obtained so rapidly. One of the most cited unmet needs in the psychopharmacology of depression is the slow latency of response to current medications. The idea that wake therapy can meet this need by switching patients out of depression within hours, not weeks, makes it attractive to look for combinations with other methods to prevent relapse. In Milan, a group of psychiatrists have been using (repeated) wake therapy for more than a decade to treat hospitalized bipolar and unipolar depressed patients. Successful maintenance of response has been found in patients when treated with lithium, with selective serotonin reuptake inhibitors, and light therapy. They find no enhanced switch rate into (hypo)mania. An example is presented in Case #1. complete amelioration of the depressive syndrome leading to perceived euthymia in the early morning. The first recovery sleep was followed by a partial but definite depressive syndromal relapse. The second wake therapy led again to perceived euthymia, without relapse after recovery sleep; the benefit was sustained after the third wake therapy. Euthymia persisted during the following days, and the patient was discharged. Plasma lithium levels were kept high for six months, and then reduced to a target level of 0.75 mEq/L. Nine years later, the patient is still euthymic. She still takes lithium, which also prevents the moderate seasonal mood fluctuations which recurred over her lifetime. Her brother, who suffered from severe bipolar disorder, also showed a good response to wake therapy for depression and dark therapy for mania. (F. Benedetti, personal communication) trists understand this application but are not aware of further developments over the last decade. In particular, light therapy has been applied in many other psychiatric disorders, from bulimia to the sleep-wake cycle disturbances of Alzheimer's dementia and antepartum depression. Double-blind placebo-controlled studies have shown that light therapy combined with a selective serotonin reuptake inhibitor leads to more rapid (within a week) and more profound (by ca. 30%) improvement in patients with nonseasonal major depression, suggesting an advantage of using combined light and drug. Although environmental light supplementation seems an obvious approach for treating winter depression, it has not yet been widely used for nonseasonal depression. If one considers the social withdrawal in major depression, then a secondary consequence might be less exposure to outdoor light (indoor light is not bright enough to have any clinical effect). Many doctors from tropical countries have asked—somewhat skeptically—why should we use light treatment in our country which has so much sunshine? Yet it would be interesting to measure how much bright light depressed patients in such climates actually get. Since sunny countries are often also hot, people escape the heat and remain inside, away from the sunshine. When outdoors, they wear sunglasses. I would predict that all over the world, independent of climate and latitude, depressed patients probably hide from the light. Odd as it may seem (especially for tropical countries), we recommend that the doctor order a 30-minute walk outside every day in the early morning for depressed patients. This could be considered a “natural” and, moreover, free therapeutic option, but requires regularity to be efficacious. In contrast, “dark therapy” (keeping patients in longer-than-usual nights) may treat mania as fast as neuroleptics, and even stop rapid cycling. Two examples from Siberia (Case #2) and New York (Case #3) illustrate the new applications. The best timing of light in bipolar patients appears to be different from the early morning light recommended for SAD. The case study #2 here corroborates find- Light therapy Case #1: Light therapy was specifically developed as a zeitgeber treatment for SAD patients, who become depressed as the days shorten and spontaneously remit during the longer days in spring and summer. The efficacy of light is greatest in the early morning, but patients also improve at other times of day, suggesting that light acts both to shift rhythms earlier in the morning (zeitgeber action) and as an antidepressant “drug” (without a time dependency). The most effective time of day for beginning morning light treatment for SAD patients can be individually prescribed according to their circadian rhythm type, by means of an online morningnesseveningness questionnaire (see Auto-MEQ on www.cet.org). This nonprofit site has been established to provide practical information for doctors and patients on all aspects of light therapy, and is being expanded through translation into a number of languages. Light is now clearly established as the treatment of choice for SAD, and many psychia- Bipolar depression and wake therapy A 51-year-old woman with difficultto-treat bipolar disorder type I was hospitalized in the San Raffaele Clinic in Milan during a depressive episode that had lasted eight months. All medication was stopped, except lithium, which was increased. After five mood episodes and three forced hospitalizations in two years, with so many disappointing therapeutic failures, the patient and her relatives had very low expectations of psychiatry in general and the chronotherapeutic approach in particular. She underwent three consecutive cycles of total sleep deprivation, each followed by a recovery night sleep. However, after the first wake therapy she experienced rapid and 6 ings in a recently published series of bipolar patients who showed mixed states with morning light and improvement with afternoon light. Case #3 Treatment-resistant chronic depression and light therapy A 24-year-old single woman in New York with a lifetime history of dysthymia and a history of anorexia and social phobia, suffered from chronic major depression for the last 6 years. She had been unresponsive to multiple drug trials. Treatment with the monoamine oxidase inhibitor tranylcypromine 100 mg induced a full complement of early, middle, and late insomnia. Light therapy at 07:15 for 30 min promptly coalesced sleep (23:30-07:00) and within 3 weeks the patient showed complete remission and was discharged. She continued with light + tranylcypromine at home, but was not compliant with light treatment. Whenever she stopped using the light she would experience relapse within 2 days. On resumption of the light, she would feel improvement within 2 days and complete remission in 4 days. Although light alone might have maintained her improvement, with such a serious chronic depression it is difficult for psychiatrists to withdraw the drug and rely on light monotherapy. (M Terman, with permission) controlled preparations of melatonin will soon be recognized by regulatory agencies. Melatonin itself is not an antidepressant, but improving and stabilizing sleep is an important part of antidepressant therapies. Case #2: Bipolar depression and light therapy A bipolar patient in Novosibirsk had experienced her first depressed / hypomania phases at age 22. Depression episodes significantly outnumbered and were longer than hypomania episodes. There was a rapid (within a day) switch from depression to hypomania (which lasted less than 1 month). Depression was characterized by atypical features, but anxiety often prevailed in affect. Although not reaching the criteria for SAD, she entered a light treatment trial at age 29 out of interest. After morning light (08:00-10:00, 2500 lux for 2 hours for a week), she experienced clear activation, better mood, but anxiety, irritability, and a feeling of dissatisfaction appeared to increase. The negative effect was brief, but with repeated daily light exposures it became more prominent. When switched to afternoon light (16:0018:00), she felt better than after morning light, with no mixed states. From 1991 the patient has had her own light box at home and regularly uses light therapy on her own for 15-20 minutes in the afternoon. (K. Danilenko and A. Putilov, personal communication) Chronotherapeutics for major depression Chronotherapeutic options are summarized in the Table below and can be added on to antidepressant “treatment as usual”. Implication for clinical practice (SAD and nonseasonal depression, unipolar and bipolar disorder, chronic and therapy-resistant, adjuvant to medication) Wake therapy (a whole night’s sleep deprivation, or partial sleep deprivation in the second half of the night) is the most rapid antidepressant known Repeated wake therapy (followed by recovery sleep) to promote maintained response Phase advance of the sleep-wake cycle to maintain the sleep deprivation response Morning timed light therapy to maintain the sleep deprivation response Dark therapy (to stop rapid cycling, mania) Melatonin (for sleep disturbances in depression) Melatonin (in the evening) to enhance phase advances with light (in the morning) Light therapy is the treatment of choice for winter depression (SAD), which is most prevalent at temperate latitudes Light therapy for nonseasonal depression with or without medication Melatonin Melatonin, exogenously administered, also acts as a zeitgeber to synchronize circadian rhythms and sleep (for example, in blind persons). It induces sleepiness by causing vasodilatation of hands and feet and hence heat loss, with a consequent decline in core body temperature, which facilitates a rapid sleep onset. Melatonin has few minor effects on sleep itself (as measured in the EEG), and thus is a sleeppromoting agent rather than a direct hypnotic in the classical sense. Very low doses suffice ( ~ 1 mg) and rarely have any side effects been documented. We hope that well-researched pharmaceutical quality- An even more striking application of light therapy for nonseasonal depression is in adjunctive treatment for chronic or treatment-resistant depression, as exemplified in Case #3. More trials of these combinations are required to establish a solid evidence base, but given the lack of side effects, the ease of application, and the often rapid improvement that had not been attained with antidepressant drugs alone, adding light therapy seems to be widely indicated. 7 WPA Bulletin on Depression. Vol. 13 - N° 36, 2008 Implementation of this strategy in clinical practice will be provided by a new manual in preparation (Benedetti F, Terman M, Wirz-Justice A. Psychiatric Chronotherapeutics: A Treatment Manual). Treatments can be combined in a flexible manner step by step according to the patient’s response, as exemplified below: 1. all patients can use light therapy. Treatment of 10 000 lux for 30 min is begun at the time allocated by the patient’s MEQ chronotype. This timing of light remains fixed throughout a trial of at least two weeks. Depending on response, dosage can be increased by lengthening the duration of light therapy by 15 min every few days. 2. for patients who are willing to try wake therapy, a single night’s sleep deprivation is carried out, with light treatment in the morning at the calculated optimum, continuing as in 1. 3. for the “complete chronotherapeutic package”, a single night’s sleep deprivation is accompanied by light therapy as in 2. On the recovery night after sleep deprivation, the patient goes to bed five hours earlier than usual and wakes up five hours earlier than usual (“phase advance” therapy). On night two, sleep is shifted to three hours earlier than usual, and, on night three and thereafter, sleep is maintained one hour earlier than usual. Close monitoring of the patient’s state can help decide which chronotherapeutic should be tried next. The full combination of repeated sleep deprivation and/or phase advance may be required only for treatment-resistant patients. Both wake and light therapy can be considered to fulfill the World Psychiatric Association’s requirements for globally applicable, low-cost, rapidly effective antidepressants. 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. More information about the neurosciences? Go to www.servier.com Depression: a new approach to the pathophysiology of depression, treating depression beyond symptoms, new insights into brain neuroplasticity - Video Assessment scales in depression to download WPA Bulletin on Depression, an educational program of the World Psychiatric Association, published since 1993 and distributed all over the world DCNS Dialogues in Clinical Neurosciences, an interface between clinical neuropsychiatry and neurosciences by providing state-of-the art information and original insights into relevant clinical, biological, and therapeutic aspects How to get published? All you need to know to publish in psychiatry! Meetings XIV WPA World Congress Prague, Czech Republic. September 19-25, 2008 Contact: www.wpa-prague2008.cz www.servier.com www.wpanet.org Section Publications/Other WPA Publications/WPA Educational Programs SI/DTC - 08 ST 015 BA