Handbook of Clinical Neurology, Vol. 106 (3rd series) Neurobiology of Psychiatric Disorders T.E Schlaepfer and C.B. Nemeroff, Editors # 2012 Elsevier B.V. All rights reserved Chapter 42 Chronotherapeutics (light and wake therapy) as a class of interventions for affective disorders ANNA WIRZ-JUSTICE 1 * AND MICHAEL TERMAN 2 Centre for Chronobiology, Psychiatric Clinics, University of Basel, Switzerland 1 2 College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute and Center for Environmental Therapeutics, New York, NY, USA INTRODUCTION Physicians have associated changes in biological rhythms with mood disorders for centuries. One of the most striking clinical phenomena in affective disorders is their periodicity of recurrence, ranging from seasonal depression to rapidcycling manic-depressive episodes that can be as short as 48 hours. Diurnal variation of mood and early-morning awakening in depression have been incorporated into established diagnostic systems, as has the seasonal pattern modifier defining winter depression (seasonal affective disorder, SAD) (American Psychiatric Association, 1994). A great deal of depression research has documented abnormal circadian rhythms in biochemistry, neuroendocrine function, physiology, and behavior, often linked to changes in affective state: rhythms have been found to be shifted in timing, diminished in amplitude, or of greater day-to-day variability (Wirz-Justice, 1995, 2006; Germain and Kupfer, 2008). Additionally, alterations in the sleep electroencephalogram in depression, although not pathognomonic or specific, display recognizable patterns of disturbance (Benca et al., 1992). Whether these circadian rhythm disturbances are of etiological significance with respect to mood disorders or whether they are a consequence of altered behavior is still unclear. Today we are experiencing a flourishing of circadian biology which has revealed the molecular basis of 24-hour rhythmicity driven by clock genes as well as documenting the importance of adequate daily “zeitgebers” (rhythm phase resetters) to synchronize internal with external time (Albrecht, 2002; Hastings and Herzog, 2004). We now have the appropriate methods to investigate the specificity of circadian rhythm changes in affective disorders. We also have important nonpharmaceutical treatments that are more rapid in action than conventional antidepressants. Not only are daily and seasonal rhythms disturbed in major depression, but the converse is true – manipulating rhythms can resolve the symptoms, even to remission. Over 35 years ago, an apparently paradoxical behavioral treatment of major depression was first scientifically studied. The clinical finding that sleep deprivation rapidly improved severe depression the morning after a night spent awake has been replicated in thousands of cases (reviewed by Wirz-Justice and van den Hoofdakker, 1999). Timing the sleep deprivation to the second half of the night, with equivalent effects, suggests a circadian component in this response as well. Over 25 years ago, winter depression was “rediscovered”: seasonal mood disorder was conceptualized in terms of the role of day length in seasonal hibernation and reproduction in animals (Rosenthal et al., 1984). The idea of administering light therapeutically by simulating a summer day was an obvious next step. Light therapy emerged as the first successful treatment in psychiatry based on neurobiological principles. Surprisingly, however, further research showed light therapy also useful for patients without SAD: it has great promise for disorders that include the sleep–wake cycle disturbances in Alzheimer’s dementia, bulimia nervosa, premenstrual dysphoric disorder, depression during pregnancy, adult attention-deficit/hyperactivity disorder, and, importantly, nonseasonal major depression (Lam, 1998; Terman and Terman, 2005, 2010; Terman, 2007; Wirz-Justice et al., 2009a). *Correspondence to: Dr. Anna Wirz-Justice, Centre for Chronobiology, Psychiatric Clinics, University of Basel, Wilhelm Klein Strasse 27, CH-4012 Basel, Switzerland. Tel: 41 61 325 5473, Fax: 41 61 325 5556, E-mail: anna.wirz-justice@unibas.ch 698 A. WIRZ-JUSTICE AND M. TERMAN What is chronotherapeutics? Chronotherapeutics can be defined as basic research in chronobiology translated into valid treatments. The term is broad, and the treatments subsumed under this heading are not limited to affective disorders. Here, our focus will be on treatments for depression that have undergone controlled randomized clinical trials (light therapy) or have been so widely studied over decades that clinical demonstrations of efficacy are compelling (sleep deprivation). This chapter summarizes the current state of the art of chronotherapeutics, based on the consensus report of a committee convened by the International Society for Affective Disorders (ISAD) (Wirz-Justice et al., 2005). This has been followed up by the publication of a manual providing treatment guidelines for clinical practice (Wirz-Justice et al., 2009a), and a non-profit website Center for Environmental Therapeutics, www.cet.org. Why chronotherapeutics? Chronotherapeutics provides an untapped potential for unmet needs in the treatment of depression. The onset of action of antidepressants is still not rapid enough, a proportion of patients do not respond, and others have residual symptoms that portend relapse. We do not yet have the next generation of antidepressants that adequately address these issues. Strategies promoting adjuvant therapy are on the increase, whether a combination with other medications such as pindolol or thyroid hormone, or a combination with psychological interventions such as cognitive-behavioral therapy. Thus, it is appropriate to address the use of the nonpharmaceutical, biologically based therapies of sleep deprivation and light therapy not only as potentially powerful adjuvants, but also as antidepressants in their own right (Wirz-Justice et al., 2004, 2005, 2009a). NEUROBIOLOGICAL UNDERPINNINGS Sleep and mood are very closely linked. Given that sleep disturbances are characteristic of major depression, a brief overview of the principles underlying chronobiology and sleep regulation may help the clinician understand the why and wherefore of these apparently paradoxical or unusual treatment paradigms. The circadian system The biological clock resides in the suprachiasmatic nucleus (SCN), a master pacemaker that regulates circadian rhythms in brain and body (Challet, 2007). Photic information from the retina reaches the SCN via a direct projection, the retinohypothalamic tract, and via an indirect projection originating in the intergeniculate leaflet. In addition, the SCN receives serotonergic input from the raphe nuclei, which may modulate the response of the SCN to light and are thought to be involved in the phase-resetting effects of nonphotic stimuli (Challet, 2007). The classical cone and rod photoreceptors participate in light transduction, but the major transducer of nonvisual circadian photic input to the SCN appears to be the photopigment melanopsin in retinal ganglion cells, which is highly sensitive to blue wavelength light (Hankins et al., 2008). Nocturnal synthesis of the pineal hormone melatonin is driven by the SCN and melatonin itself feeds back on melatonin receptors in the SCN. In this respect, exogenous administration of melatonin can act as a zeitgeber. Even though the SCN is the so-called master clock, circadian oscillators are found in every organ and, indeed, in every cell (Balsalobre, 2002). Moreover, each organ has its own appropriate zeitgeber. For example, light is the major zeitgeber for the SCN, but it does not affect clocks in the liver; the zeitgeber for the latter is food – which in turn cannot synchronize the SCN (Stokkan et al., 2001). This complex temporal organization helps in understanding the ease with which internal desynchronization can occur between different clocks in body and brain, and external desynchronization between the timing of body rhythms with respect to the day–night cycle (e.g., with shift work or crossing time zones). This misalignment has profound effects on mood, sleep, and health. Genetic vulnerabilty and stress influence circadian rhythms and sleep timing, leading to the symptoms characteristic of affective disorders. Circadian regulation interacts with, and is determined by, neurotransmitter function; for example, the highest concentrations of central nervous system (CNS) serotonin are in the SCN (Challet, 2007). CNS serotonin turnover undergoes marked circadian and seasonal rhythmicity and is rapidly stimulated by light exposure (Lambert et al., 2002). The important role of light as circadian rhythm phase resetter can thereby be linked to the established role of serotonin in mood disorders. Conversely, direct serotonergic manipulation by a selective serotonin reuptake inhibitor can also reset the clock (Sprouse et al., 2006). Sleep regulation The most accepted model of sleep regulation considers the timing and architecture of sleep to be a consequence of interactions between a homeostatic process of rising sleep pressure dependent on the duration of prior wakefulness, that is dissipated during the sleep period (process S), and an independent circadian clock (process C) (Daan et al., 1984) (Fig. 42.1). This model helps conceptualize possible abnormalities in depression. A deficit in process S would be manifested in a slower build-up of sleep pressure during wakefulness CHRONOTHERAPEUTICS (LIGHT AND WAKE THERAPY) AS A CLASS OF INTERVENTIONS Healthy control Depressed patient DAY 1 DAY 2 sleep deprivation sleep 699 is also probably programmed in certain sleep genes (Franken and Tafti, 2003). Since the timing of sleep appears to be important for mood, these genetic factors may be relevant to a chronobiological vulnerability for depression, in that wrong or poor alignment of internal phase with the external world increases susceptibility to depressive mood swings. sleep The usefulness of models to understand chronobiological treatments 0 8 24 16 32 40 Elapsed Time Awake Homeostatic Process S phase relationship between C & S Circadian Process C amplitude Zeitgebers e.g. light phase 24 8 16 24 8 16 24 Time of Day Fig. 42.1. Schematic representation of the two-process model of sleep regulation over 2 days. The homeostatic process S represents the increase in sleep pressure with elapsed time awake, and its dissipation during sleep. The circadian process C follows time of day and is characterized by its endogenous period, phase, and amplitude. The primary zeitgeber, light, acts on C, not S. The thin dotted lines represent changes that might be found in depressed patients. (Fig. 42.1, upper panel, dotted line). A full night’s sleep deprivation would raise it nearer to normal values – at least for the next day. A deficit in process C could be manifested in lowered amplitude (many rhythms measured in depressed patients are blunted), and/or earlier or later phase (Fig. 42.1, lower panel, dotted line). Zeitgebers such as light act directly on process C and not on process S (Daan et al., 1984). The two-process model of sleep regulation is also useful to understand how chronobiological treatments differ in their mode of action, by targeting either the sleep homeostat or the circadian system. Manipulations of the sleep–wake cycle, whether of duration (total or partial sleep deprivation) or timing (partial sleep deprivation, phase advance), have profound and rapid effects on depressed mood in 60% of all diagnostic subgroups of affective disorders (Wirz-Justice and van den Hoofdakker, 1999). The therapeutic effect of sleep deprivation is postulated to be linked to an increase of homeostatic sleep pressure (Wirz-Justice, 1995, 2006). However, a phase advance of sleep alone, without sleep deprivation, also improves mood, which suggests an important role for the circadian system (Wehr et al., 1979). It works both ways, since shifting phase relationships between processes C and S can cause, in vulnerable individuals, mood decreases (when rhythms are shifted later) or improvements (when shifted earlier) (Wirz-Justice, 1995, 2006). A dramatic example is the greater incidence of depressive episodes when landing after a westward flight or manic episodes after flying east (Jauhar and Weller, 1982). Light therapy was originally developed as a zeitgeber treatment for SAD patients, who become depressed as the days shorten (with delayed sunrise) and spontaneously remit during the longer days in spring and summer (Partonen and Pandi-Perumal, 2010). Bright light has three major effects on the circadian system: it increases amplitude and shifts phase (depending on the time of application), thereby modifying phase relationships between the internal clock and sleep (Wirz-Justice, 2006). Any of these effects might alone suffice for mood elevation (as well as modifying serotoninergic function; Lambert et al., 2002). Sleep timing and mood The importance of stable entrainment Individual preference in timing of the sleep–wake cycle (the so-called chronotype, ranging from early birds or “larks” to late-night “owls”) (Roenneberg et al., 2003) is partially determined by clock genes. This characteristic is independent of individual sleep duration (long versus short sleepers) (Roenneberg et al., 2003), which What, then, is important in the connection of circadian rhythms with depression (Wirz-Justice et al., 2009b)? Stable internal and external phase relationships (i.e., the timing between core body rhythms such as melatonin and temperature as well as the timing of sleep with respect to the day–night cycle) seem to be crucial for 700 A. WIRZ-JUSTICE AND M. TERMAN Mood VAS score Table 42.1 Chronotherapeutics in major depression 6 worse 5 sleep advance 4 fixed sleep 24 4 8 12 16 20 24 4 8 Time of day (h) Fig. 42.2. The circadian rhythm of mood as measured in healthy young men half-hourly over 26 hours under controlled conditions. Sleep had slowly been shifted 2 hours earlier in the sleep-advance group compared with the control fixed-sleep group, but the circadian rhythm of melatonin in both groups remained similar. We postulate that the sudden drop in mood that lasted the entire night resulted from this slight difference in phase relationships. VAS, visual analog scale. (Redrawn from Wirz-Justice, 2008, with permission; original data in Danilenko et al., 2003.) a stable, euthymic mood state. Any misalignment brings with it the propensity for mood fluctuation, particularly in vulnerable individuals. However, the precise neurobiological mechanisms by which altered circadian phase relationships lead to altered mood state remain unknown. We have an experimental example of how a slight shift in sleep timing can modify mood state even in healthy subjects. In this controlled study, carried out in near darkness, sleep timing was either slowly advanced by 20 minutes per day over 6 days or kept constant (Danilenko et al., 2003). Sleep was shifted 2 hours earlier but the melatonin rhythm remained near its original phase. This slight misalignment was associated with a sudden drop in nighttime mood (Fig. 42.2). Chronobiological concepts emphasize the important role of zeitgebers to stabilize phase. Light and melatonin are the strongest zeitgebers, but dark (and rest) periods, regularity of social schedules, and meal times also play a role. The justification for resynchronizing disturbed phase relationships between the clock and sleep is the resulting improvement in mood (Wirz-Justice et al., 2009b). ZEITGEBERS AS THERAPY The physiological principles and clinical indications we have discussed above provide the background for applying chronotherapeutics to major depression. A summary of these treatments and their applications is given in Table 42.1. Chronotherapeutics in major depression Light therapy (for seasonal affective disorder, nonseasonal depression) Light therapy as adjuvant to selective serotonin reuptake inhibitors (nonseasonal depression, chronic depression, therapy-resistant depression) Total sleep deprivation (wake therapy) or partial (in the second half of the night) phase advance of the sleep– wake cycle; combinations thereof with antidepressants, lithium, pindolol, light therapy, phase advance (for major depression) Dark or rest therapy (to stop rapid cycling between mania and depression) Dark therapy (for mania) Melatonin (for sleep disturbances in depression, enhancing circadian phase advances with light) Light therapy Light therapy can be considered the most successful clinical application of circadian rhythm concepts to date. Light therapy has attained consensus as the treatment of choice for SAD (Partonen and Pandi-Perumal, 2010). Beyond the additional demonstrations that the method is also effective as monotherapy for nonseasonal depression, two research groups have demonstrated in doubleblind placebo-controlled studies that light therapy combined with selective serotonin reuptake inhibitors leads to more rapid improvement (within a week) with significantly fewer residual symptoms (Benedetti et al., 2003; Martiny, 2004) (Fig. 42.3). Exploratory clinical work indicates that the advantage of combined approaches is not limited to this category of antidepressants. Dark therapy Single case studies of rapidly cycling bipolars have shown that extending darkness (or rest, or sleep) immediately stops the recurring pattern, a rather astonishing result in these therapy-resistant patients (Wehr et al., 1998; Wirz-Justice et al., 1999). Further support for the relevance of these findings is that extended darkness (not rest, and not sleep) in bipolar patients can reduce manic symptoms as rapidly as the conventional antipsychotics generally used (Barbini et al., 2005). A similar result can be achieved more easily by using eyeglasses that specifically filter out the circadian-sensitive blue wavelengths. A pilot study of these amber-coloured glasses showed improvement in half of the bipolar patients studied with sleep-onset insomnia (Phelps, 2008). CHRONOTHERAPEUTICS (LIGHT AND WAKE THERAPY) AS A CLASS OF INTERVENTIONS Zung Depression Score Benedetti et al, 2003 60 placebo and citalopram (N=12) 55 50 green light and citalopram (N=18) 45 0 1 A 2 3 Week # 4 Martiny, 2004 HAMD-17 score 25 20 dim red light and sertraline (N=54) 15 10 bright white light and sertraline (N=48) 0 B 1 2 3 week # 4 5 Fig. 42.3. Two randomized controlled studies of adjuvant light in patients with nonseasonal major depression showed a significantly more rapid improvement and greater symptom reduction over the clinical trial than with medication and placebo. The upper panel (A) (redrawn from Figure 2, Benedetti et al., 2003) compares depressive patients treated with citalopram (40 mg) and additional morning green light (400 lux, 30 min/day) or citalopram and a placebo (deactivated negative ion generator). The lower panel (B) (drawn from Table 6, Martiny, 2004) compares depressive patients treated with sertraline and adjuvant morning bright white light (10 000 lux, 1 hour/day) or sertraline and dim red light (50 lux, 30 min/day). HAMD-17, Hamilton Rating Scale for Depression17 items. Melatonin Melatonin, exogenously administered, acts as a zeitgeber to synchronize circadian rhythms and sleep (for example, in blind persons) (Arendt, 2003). Melatonin induces sleepiness directly via thermoregulatory changes – the “warm-feet effect” (Kräuchi et al., 1999). The soporific action of increased distal body temperature coupled with reduced core body temperature points to the usefulness of melatonin for a variety of 701 sleep disorders. The few studies administering melatonin to depressed patients have found improvements in sleep, but not mood (deVries and Peeters, 1997; Dolberg et al., 1998). The first novel antidepressant using chronobiological principles is the melatonin agonist agomelatine. Given in the evening, its zeitgeber action is identical to the mother compound in that it advances circadian phase and its vasodilatatory effect promotes sleep (Kräuchi et al., 1997). The antidepressant properties appear to be related to its serotonergic antagonist component (Millan et al., 2003). Although not yet formally investigated (but already successfully used clinically), evening melatonin combined with morning light appears to potentiate circadian rhythm phase advances, thereby expediting and enhancing the antidepressant effect (see case study in Terman and Terman, 2010). As such, melatonin is not being applied as a direct soporific or hypnotic. Wake therapy (sleep deprivation) The slow response to most antidepressants is the biggest problem for psychiatrists and their patients. In remarkable contrast is the improvement within hours of staying awake all night. Response to a single wake therapy session occurs in approximately 60% of patients with major depression, across all diagnostic subgroups (Wu and Bunney, 1990; Leibenluft and Wehr, 1992; Wirz-Justice and van den Hoofdakker, 1999; Berger et al., 2003). However, because relapse usually follows recovery sleep (or even short daytime naps), this treatment has not caught on except in German-speaking countries where it was first described. It has taken a new generation of researchers to be inventive, and after attaining fast response with one or more nights of wake therapy, adding various treatments to hold that response (see below). Phase advance of the sleep–wake cycle A crucial experiment that shifted the timing of the sleepwake cycle 6 hours earlier demonstrated that being awake during the second half of the night was critical for antidepressant response rather than the sleep deprivation per se. The improvement occurred more slowly (over 3 days) than the acute single total sleep deprivation, but lasted longer (3 weeks) (Wehr et al., 1979). The analogy with jet lag supported the idea that it was important to realign abnormal internal phase relationships. Although difficult to carry out the procedure on an inpatient unit, it was theoretically important, and led to further studies comparing phase advance with phase delay following a single total sleep deprivation (Riemann et al., 1999). Shorter and more practical versions of sleep phase advance therapy have now been implemented (Voderholzer et al., 2003; Moscovici and 702 A. WIRZ-JUSTICE AND M. TERMAN Kotler, 2009; Wu et al., 2009). In particular, following a total night’s sleep deprivation there is little difficulty in asking a tired but no longer depressed patient to go to bed at 5 or 6 p.m. The sleep period is then shifted to 7 or 8 p.m. on the second night, and 9–10 p.m. (or habitual sleep time) on the third night. This 3-day phase advance provides an extra chronotherapeutic option that may potentiate the other treatments. Wake therapy and combinations Several combination strategies have been used to maintain the rapid response after wake therapy. The antidepressant response can be successfully sustained with lithium salts (Szuba et al., 1994; Benedetti et al., 1999; Colombo et al., 2000), the 5-HT1a-antagonist pindolol (Smeraldi et al., 1999), morning light therapy (Neumeister et al., 1996; Colombo et al., 2000), and sleep phase advance therapy (Riemann et al., 1999; Benedetti et al., 2001a; Voderholzer et al., 2003). Recent promising studies have used such combinations to expedite improvement (Martiny et al., 2011; Moscovici and Kotler, 2009; Wu et al., 2009). Table 42.2 Timing of morning light therapy* based on MEQ score MEQ score 16–18 19–22 23–26 27–30 31–34 35–38 39–41 42–45 46–49 50–53 54–57 58–61 62–65 66–68 69–72 73–76 77–80 81–84 Begin light at 08:45 08:30 08:15 08:00 07:45 07:30 07:15 07:00 06:45 06:30 06:15 06:00 05:45 05:30 05:15 05:00 04:45 04:30 *Start of 10 000 lux, 30-minute session, approximately 8.5 hours after estimated melatonin onset. MEQ, Morningness–Eveningness Questionnaire. LIGHT THERAPY: TREATMENT GUIDELINES A treatise on the methodology of light therapy has been published and is recommended to readers (Terman and Terman, 2005; www.cnsspectrums.com). Our detailed treatment manual has been published (Wirz-Justice et al., 2009). Here, we summarize the main conclusions of these guidelines. Timing of light therapy sessions Timing of morning light appears to be important in SAD patients (the greater the phase advance, the better the response; Terman et al., 2001), and preliminary evidence suggests that this careful timing is also important for nonseasonal major depression (F Benedetti, personal communication). Optimum timing of light treatment is related to internal body clock time and not to external time. A reasonable estimate of internal body clock time without directly measuring the melatonin cycle is an individual’s chronotype, as assessed by the HorneÖstberg Morningness–Eveningness Questionnaire (MEQ) score (Appendix). An algorithm for timing light treatment based on the MEQ score has been developed (Table 42.2). An online, automated version of the MEQ (www.cet.org) returns the MEQ score and recommends treatment time to the respondent (Terman et al., 2002), and patients can complete this exercise and print out results in preparation for the psychiatric consultation session. Downloads are also available in Chinese, Danish, Dutch, English, French, German, Hungarian, Italian, Japanese, Polish, Portuguese, Rumanian, Russian, and Spanish, with information about calculating the MEQ score and thus determining recommended timing of light therapy (Table 42.2). Response assessment and monitoring An extended version of the Hamilton Depression Scale (SIGH-ADS, www.cet.org) (Williams and Terman, 2003) provides a structured interview covering both melancholic and atypical symptoms. Light therapy is typically self-administered at home, which can reduce compliance (obviously, sitting in front of a light box involves more time and effort than taking a pill). Given that timing is important to maximize the therapeutic effect, compliance by outpatients can be problematic. Hypersomnic patients can initially be scheduled at the time of habitual awakening and then edged earlier across days toward the target interval. Clinical experience suggests that most such patients could not sustain the earlier awakening without the use of light. CHRONOTHERAPEUTICS (LIGHT AND WAKE THERAPY) AS A CLASS OF INTERVENTIONS Apparatus The second generation of bright light boxes has a number of important improvements over early models: they are smaller, portable, with raised and downward-tilted placement of the radiating surface, a diffusion screen with nearly complete ultraviolet filtering, and high-output white fluorescent lamps with ballasts that eliminate flicker, yielding maximum illuminance of approximately 10 000 lux at 30–33 cm distance. This configuration, with direction of gaze downward toward the table surface, provides nonglare illumination suitable for reading, and is generally well tolerated. Critical design features have not yet been specified or regulated, but miniature lighting devices and blue-enhanced lamps are not recommended. Suggested criteria are listed on the nonprofit Center for Environmental Therapeutics website, www.cet.org. An example of such a lamp is shown in Fig. 42.4. Ocular safety There is no obvious acute light-induced pathology or longer-term sequela following even years of light therapy (Gallin et al., 1995). New patients should have had an eye exam within the past year. There are no Side-effects Adverse events are rare; emergent sleep disturbances are usually related to timing and can be rapidly adjusted (late-evening light can lead to initial insomnia, and earlymorning light to premature awakening). Infrequent side-effects are hypomania, mild visual complaints, irritability, headache, and nausea, which usually subside within a few days of treatment or with dose decreases. Light therapy for whom? SEASONAL Flicker-Free UV Filtered Tilt Adjustable Glare-Free Height Adjustable Ample Screen Area Fig. 42.4. A portable, light-weight light treatment apparatus that fulfills important safety and comfort criteria, and has been shown to be antidepressant in controlled clinical trials (Terman and Terman, 2006; www.cet.org). 703 definite contraindications for bright light treatment other than for the retinopathies, and awareness of putative interactions with photosensitizing medications in the ultraviolet or visible ranges of the spectrum. At present, we recommend maintaining broadspectrum white illumination, but filtering wavelengths lower than 450 nm to minimal levels, considering the potential blue light hazard (www.mdsupport.org). Even though the circadian photoreceptor system has been found to be most sensitive in this short-wavelength range, there are no long-term safety or efficacy studies to allow narrow-band blue-light devices to be recommended at present. AFFECTIVE DISORDER Light is the treatment of choice for winter depression. Over the last 25 years a large number of controlled studies have yielded overwhelming consensus for the rapid efficacy of bright light for SAD. Recent reviews and guidelines provide further details of ongoing and developing applications (Lam, 1998; Even et al., 2007; Terman and Terman, 2005, 2010; Westrin and Lam, 2007; Partonen and Pandi-Perumal, 2010). SUBSYNDROMAL SEASONAL AFFECTIVE DISORDER The phenomenology of subsyndromal SAD (the winter blues) is similar to that of SAD, except that patients do not meet criteria for major depression (Kasper et al., 1989b). However, the presence and severity of atypical neurovegetative symptoms, including food cravings and difficulty awakening, can be similar to those in SAD, as can fatigability. Subsyndromal SAD has far higher prevalence than SAD itself (Terman, 1988; Kasper et al., 1989b). Clinical trials have demonstrated significant improvement with light therapy (Kasper et al., 1989a). Optimum light scheduling and dose appear to be similar for subsyndromal SAD and SAD. Importantly, the lower severity of depressed mood in subsyndromal SAD does not imply that a lower dose of light will be sufficient to relieve symptoms. A. WIRZ-JUSTICE AND M. TERMAN 704 BULIMIA NERVOSA A number of studies indicate that morning bright light improves mood as well as controlling bulimic symptoms, whether or not patients have comorbid SAD (Lam, 1998). PREMENSTRUAL DYSPHORIC DISORDER, ANTEPARTUM MAJOR DEPRESSION Preliminary investigations suggest that light therapy is a viable option for the treatment of premenstrual dysphoric disorder and major depression during pregnancy (Lam, 1998; Epperson et al., 2004). A recent doubleblind, randomized, placebo-controlled study of antepartum depression supports the use of light therapy (Wirz-Justice et al., 2011). This offers a safe somatic treatment alternative to antidepressant drugs, whether or not the woman has a history of seasonality. NONSEASONAL MAJOR DEPRESSION Beyond its established application for SAD, light therapy for nonseasonal depression appears both safe and effective. Kripke (1998) compared several controlled trials in terms of the relative benefit of light versus various placebo controls, and in as little as 1 week the results fell within the range of classic antidepressant drug studies of 4–16 weeks. Few of the early light studies in nonseasonal depression were of sufficient duration to compare with other treatments. Systematic reviews generally support efficacy of light treatment (Tuunainen et al., 2004; Golden et al., 2005; Even et al., 2007). Light treatment in patients with chronic major depression achieved a surprising remission rate of 50% compared with a placebo (low-density negative air ionization) (Goel et al., 2005). The early light therapy studies in geriatric depression showed only partial success. Light therapy has been used to alleviate disruptive and cognitive symptoms of senile dementia, though a summary review of the studies did not find the evidence convincing (Forbes et al., 2009). More research is required, particularly long-term studies, since these serious disturbances cannot be easily controlled within a week or two. The first major double-blind controlled study (Riemersma-van der Lek et al., 2008) following demented patients over 3.5 years with light therapy and/or melatonin indicated an effect size equivalent or better than with conventional anticholinesterase inhibitors. COMBINATION CHRONOTHERAPEUTICS Bright light augmentation of antidepressant drug treatment Several investigators have combined light with drugs and found accelerated improvement relative to drugs alone (Levitt et al., 1991; Beauchemin and Hays, 1997), and the method has already seen widespread use with European inpatients (Benedetti et al., 2003). A large Danish outpatient trial for patients with nonseasonal depression on sertraline treatment (n ¼ 102) found that remission rate and speed of improvement were greater under the active light condition (10 000 lux, 60 minutes) than placebo (50 lux, 30 minutes) (Martiny, 2004) (see Fig. 42.3). Withdrawal of light resulted in relapse (similar to findings with withdrawal of antidepressants; Martiny et al., 2006). Even chronically depressed patients, whose illness had lasted at least 2 years, responded to adjunct light therapy, a finding of great clinical importance (Goel et al., 2005). A large study of patients with SAD (n ¼ 282) found that the relapse occurring after light had been stopped could be prevented by citalopram (Martiny et al., 2004). Wake and light therapy combined with antidepressant drugs In an expanded protocol, patients with nonseasonal depression received light therapy, medications, and a single session of late-night wake therapy at the start of treatment, with marked improvement in 1 day and benefit over a dim light control within 1 week (Neumeister et al., 1996). In Italy, this model has been extended for general inpatient use, following treatment studies of nonseasonal major depression (in conjunction with citalopram; Benedetti et al., 2003) and bipolar disorder (in conjunction with lithium; Colombo et al., 2000) that showed large benefits attributable to morning light therapy. One controlled study yielded a remission rate of 43% in a group for whom standard antidepressants and psychotherapy had been inadequate (Loving et al., 2002). The successful completion of large-scale trials in Europe strongly supports the implementation of adjunctive light and wake therapy for treatment of nonseasonal major depressive disorder, with the prospect of reduced duration of hospitalization (Wirz-Justice et al., 2005). Combined wake and light therapy improved the acute response in patients with bipolar I disorder treated with antidepressants and lithium salts: 44% of drug-resistant patients responded, and 70% with no previous history of drug resistance improved (Benedetti et al., 2005). Importantly, a 9-month follow-up showed that 57% of nonresistant responders (but only 17% of drug-resistant responders) remained euthymic. This is the first study documenting long-term remission rates that are influenced by chronotherapeutics. A second study of treatment-resistant patients combined antidepressants with a week-long protocol of wake therapy, phase advance, and light, also with acute and long-term potentiation of “treatment as usual” (Wu et al., 2009). A third long-term study compared CHRONOTHERAPEUTICS (LIGHT AND WAKE THERAPY) AS A CLASS OF INTERVENTIONS duloxetine and a daily individual exercise program with duloxetine combined with wake therapy, light therapy, and guidance on sleep hygiene. Over the first 9 weeks of the trial, the chronotherapeutic intervention induced a rapid and sustained response superior to the response seen in the exercise group (Martiny et al., 2011). Newer exploratory nonpharmaceutical treatments DAWN SIMULATION One drawback of bright light therapy is the required daily time commitment. By contrast, dawn simulation is presented during the last period of the patient’s sleep episode, with a relatively dim signal gradually rising over 90 minutes or longer from about 0.001 lux (near starlight) to approximately 300 lux (attenuated sunrise). As with bright light therapy, there is an antidepressant response and normalization of hypersomnic and abnormal sleep patterns (Terman et al., 1989; Avery et al., 1993, 1994, 2001). A large controlled study compared 3 weeks’ treatment with bright light (10000 lux, 30 minutes) upon habitual wake-up time, dawn simulation (250 lux maximum, beginning 90 minutes before habitual wake-up time), or a brief light pulse (250 lux beginning 13 minutes before habitual wake-up time, for total dose equivalence in lux minutes with the dawn) (Terman and Terman, 2006). All three lighting conditions were equally superior to the placebo condition. The effectiveness of dawn simulation may depend on the presentation of diffuse, broad-field illumination that reaches the sleeper in varying postures. Such efficacy has not been demonstrated for commercial alarm clock lamps, which have small, directional fields. NEGATIVE CHRONOTHERAPEUTIC GUIDELINES In order to provide practical guidelines for clinicians to carry out chronotherapeutics, a treatment manual has been written under the auspices of the Center for Environmental Therapeutics (www.cet.org; Wirz-Justice et al., 2009a). Chronotherapeutic combinations are flexible and should be implemented step by step according to the patient’s response (or nonresponse). Concomitant antidepressants as required are included to provide treatment as usual. Chronotherapeutic options begin with light for outpatients or inpatients who cannot sustain wake therapy. A second step is light combined with a single night’s sleep deprivation. A third step includes a 3day phase advance. The full combination of light, three-times wake therapy, and 3-day sleep phase advance will not be necessary or feasible in all cases. Operationally, the options can be tied to a decision tree based on the patient’s current state at a series of evaluation points. Examples of such treatment options are presented as a day-by-day strategy to follow while closely monitoring response (Fig. 42.5). 1. AIR IONIZATION Negative air ionization presents a new therapeutic modality, whose routes of biological reception and nervous system response are still unknown. The air circulation outdoors varies greatly in negative ion content (higher in humid, vegetated environments and at the seashore; lower in urban environments and heated or airconditioned interiors). A controlled trial for treatment of SAD (Terman et al., 1998) found a greater reduction in depression ratings after 2 weeks of 30 minutes of high-density ion exposure sessions every morning than after low-density ion exposure (inactive placebo control). In the dawn simulation study described above, two additional groups received high- or low-density negative air ionization for 90 minutes before habitual wakeup time, with timing matched to the dawn condition (Terman and Terman, 2006). After 3 weeks of 705 treatment, the therapeutic effect of high-density ions was similar that of bright light or dawn simulation, but far exceeded improvement under low-density ions. 2. 3. Light therapy alone. The timing of light therapy at the circadian optimum for phase advances by morning light is derived from the 19-item MEQ (Appendix). The patient goes to bed at his or her habitual time, which will vary by about 6 hours across cases. If a complete response to light does not emerge within 3 days, the duration of exposure is gradually increased from 30 to 60 minutes. The first example (Fig. 42.5A) is for an 8-hour sleeper with MEQ score of 58 (intermediate chronotype), for whom Table 42.2 specifies light administration at 6 a.m., an hour earlier than habitual rise time. Bedtime is concomitantly shifted 1 hour earlier. Light therapy alone is for patients who refuse sleep deprivation (or clinicians who think it is too drastic). Improvement can be rapid, but satisfactory outcome often takes several weeks. If the situation permits, a single night of wake therapy initiates the chronotherapeutic regimen, followed by stabilizing light therapy at the circadian optimum, as above (Fig. 42.5B). The patient remains awake for 36 hours before beginning sleep 1 hour earlier than on the habitual schedule. If depression has not remitted, the single night of wake therapy is followed by a 3-day sleep phase advance concomitant with light therapy at the circadian optimum (Fig. 42.5C). The patient begins by going to bed 5 hours earlier than on the habitual 706 A. WIRZ-JUSTICE AND M. TERMAN Sleep allowed, normal room light if awake. Light therapy (10,000 lux) LIGHT THERAPY AT CIRCADIAN OPTIMUM HOUR DAY 17 18 Evaluation 1–2 2–3 Light 30 min 3–4 4–5 5–6 6–7 Light 45 min 7–8 8–9 9–10 10–11 Light 60 min 11–12 12–13 13–14 14–15 15–16 A 17 18 SINGLE NIGHT AWAKE + LIGHT THERAPY HOUR 18 DAY 17 Evaluation 1–2 2–3 Wake, Light 30 min 3–4 Light 30 min 4–5 5–6 6–7 Light 45 min 7–8 8–9 9–10 10–11 Light 60 min 11–12 12–13 13–14 14–15 15–16 B 17 18 19 20 21 22 23 24 01 02 03 04 05 06 07 19 20 21 22 23 24 01 02 03 04 05 06 07 19 20 21 22 23 24 01 02 03 04 05 06 07 19 20 21 22 23 24 01 02 03 04 05 06 07 23 24 01 02 03 04 05 06 07 SINGLE NIGHT AWAKE + LIGHT THERAPY + SLEEP PHASE ADVANCE HOUR 18 19 20 21 22 DAY 17 Evaluation 1–2 2–3 Wake, Light 30 min 3–4 Sleep -4 h, Light 30 min 4–5 Sleep -2 h, Light 30 min 5–6 Light 30 min 6–7 Light 45 min 7–8 8–9 9–10 10–11 Light 60 min 11–12 12–13 13–14 14–15 15–16 C Fig. 42.5. Examples of chronotherapeutic schemata from the step-by-step decision tree for adjuvant chronotherapeutics. All patients continue ongoing medication or initiate antidepressant treatment before beginning the sequence. The timing of light therapy is derived from the patient’s chronotype score and referenced to habitual sleep time. Example A uses gradually increasing light “dosage” for outpatients or inpatients who cannot sustain wake therapy. Example B combines light with a single night’s wake therapy. Example C adds a 3-day sleep phase advance. (Reproduced from Wirz-Justice et al., 2009a, with permission from S Karger, Basel.) schedule, assisted by a short-acting hypnotic if sleep does not come easily after 32 hours of wakefulness. The patient is awakened for the second half of the night, 4 hours preceding morning light therapy. If the patient has responded at this point, sleep onset is delayed in 2-hour steps over the next two nights until it reaches the target bedtime, 1 hour earlier than on the habitual schedule. An elaborated decision tree continues to follow the developing clinical response. If the depression remits after one night of wake therapy, we continue with light alone. Otherwise, we begin the sleep phase advance. If the depression remits, we complete the sleep phase advance over 3 days. If the depression continues, we proceed to give a second wake therapy, and, if necessary, a third (with sleep recovery nights in between). CHRONOTHERAPEUTICS (LIGHT AND WAKE THERAPY) AS A CLASS OF INTERVENTIONS These are current examples of practice in several inpatient units (Benedetti et al., 2007), with growing acceptance by once-skeptical psychiatrists. In particular, New York Presbyterian Hospital has administered light therapy on an inpatient unit for treatment-resistant patients who undergo multiple electroconvulsive therapy (ECT), with some success. We do not suggest that light therapy should replace ECT, but the encouraging results imply a remarkable and important role for this simple treatment even in serious, chronic major depression. CONCLUSION: CHRONOTHERAPEUTICS AS A PRIMARY TREATMENT Wake and light therapy are safe, with a minimal sideeffect profile. They do not interact negatively with ongoing medication (barring photosensitivity in the visible range, e.g., with first-generation neuroleptics). An important economic aspect is that they may also reduce duration of hospitalization. In a general psychiatric hospital setting, the combination of wake therapy (three sessions over a week) with antidepressants as usual resulted in discharge 3 days earlier than with drug treatment alone (Benedetti et al., 2005). Remarkable retrospective analyses have revealed a similar 3-day advantage for patients exposed to more natural light in sunny hospital rooms than those staying in dimmer rooms (Beauchemin and Hays, 1996; Benedetti et al., 2001b). The accumulated data on light therapy for SAD and nonseasonal depression support its broader application in psychiatric clinical practice, whether or not as 707 monotherapy. Clinicians should consider adjunctive light therapy when the response to antidepressants is delayed or incomplete. Emerging data suggest that light therapy be used as a first-line treatment given together with the chosen antidepressant, and, if possible, 1–3 nights of wake therapy to trigger a rapid clinical response. We have initiated a privacy-protected website forum for clinicians to discuss this emerging field (www.chronothe rapeutics.org). In summary, circadian rhythm and sleep research has led to a set of nonpharmaceutical therapies for depression suitable for everyday practice (Wirz-Justice et al., 2004, 2005, 2009a). The use of the term “wake therapy” instead of “sleep deprivation” has become more common and is recommended for clinical use, since it emphasizes to the patient that we are not taking away sleep (which is anyway disturbed) but rather providing an active treatment through prolonged wakefulness. ACKNOWLEDGMENT US National Institute of Mental Health Grant MH42931 supported the research of MT. DISCLOSURES Michael Terman is president and Anna Wirz-Justice is on the scientific advisory board of the 501 (c)(3) nonprofit educational and research agency, Center for Environmental Therapeutics, 337 West 20th Street, Suite 4M, New York, NY. 708 A. WIRZ-JUSTICE AND M. TERMAN Appendix Morningness–Eveningness Questionnaire SELF-ASSESSMENT VERSION (MEQ-SA)1 Name: _______________ Date: ____________ For each question, please select the answer that best describes you by circling the point value that best indicates how you have felt in recent weeks. 1. Approximately what time would you get up if you were entirely free to plan your day? [5] 5:00 AM–6:30 AM (05:00—06:30 h) [4] 6:30 AM–7:45 AM (06:30—07:45 h) [3] 7:45 AM–9:45 AM (07:45—09:45 h) [2] 9:45 AM–11:00 AM (09:45—11:00 h) [1] 11:00 AM–12 noon (11:00—12:00 h) 2. Approximately what time would you go to bed if you were entirely free to plan your evening? [5] 8:00 PM–9:00 PM (20:00—21:00 h) [4] 9:00 PM–10:15 PM (21:00—22:15 h) [3] 10:15 PM–12:30 AM (22:15—00:30 h) [2] 12:30 AM–1:45 AM (00:30—01:45 h) [1] 1:45 AM–3:00 AM (01:45—03:00 h) 3. If you usually have to get up at a specific time in the morning, how much do you depend on an alarm clock? [4] Not at all [3] Slightly [2] Somewhat [1] Very much 4. How easy do you find it to get up in the morning (when you are not awakened unexpectedly)? [1] Very difficult [2] Somewhat difficult [3] Fairly easy [4] Very easy 5. How alert do you feel during the first half hour after you wake up in the morning? [1] Not at all alert [2] Slightly alert 1 6. 7. 8. 9. 10. [3] Fairly alert [4] Very alert How hungry do you feel during the first half hour after you wake up? [1] Not at all hungry [2] Slightly hungry [3] Fairly hungry [4] Very hungry During the first half hour after you wake up in the morning, how do you feel? [1] Very tired [2] Fairly tired [3] Fairly refreshed [4] Very refreshed If you had no commitments the next day, what time would you go to bed compared to your usual bedtime? [4] Seldom or never later [3] Less than 1 hour later [2] 1–2 hours later [1] More than 2 hours later You have decided to do physical exercise. A friend suggests that you do this for one hour twice a week, and the best time for him is between 7 and 8 AM (07—08 h). Bearing in mind nothing but your own internal “clock,” how do you think you would perform? [4] Would be in good form [3] Would be in reasonable form [2] Would find it difficult [1] Would find it very difficult At approximately what time in the evening do you feel tired, and, as a result, in need of sleep? [5] 8:00 PM–9:00 PM (20:00—21:00 h) [4] 9:00 PM–10:15 PM (21:00—22:15 h) [3] 10:15 PM–12:45 AM (22:15—00:45 h) [2] 12:45 AM–2:00 AM (00:45—02:00 h) [1] 2:00 AM–3:00 AM (02:00—03:00 h) Some stem questions and item choices have been rephrased from the original instrument (Horne and Östberg, 1976) to conform with spoken American English. Discrete item choices have been substituted for continuous graphic scales. Prepared by Terman M, Rifkin JB, Jacobs J, White TM (2001), New York State Psychiatric Institute, 1051 Riverside Drive, Unit 50, New York, NY 10032. January 2008 version. Supported by National Institute of Health Grant MH42931. See also: automated English version (AutoMEQ) at www.cet.org. Horne JA and Östberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. International Journal of Chronobiology 1976: 4, 97–100. CHRONOTHERAPEUTICS (LIGHT AND WAKE THERAPY) AS A CLASS OF INTERVENTIONS 11. You want to be at your peak performance for a test that you know is going to be mentally exhausting and will last two hours. You are entirely free to plan your day. Considering only your “internal clock,” which one of the four testing times would you choose? [6] 8 AM–10 AM (08—10 h) [4] 11 AM–1 PM (11—13 h) [2] 3 PM–5 PM (15—17 h) [0] 7 PM–9 PM (19—21 h) 12. If you got into bed at 11 PM (23 h), how tired would you be? [0] Not at all tired [2] A little tired [3] Fairly tired [5] Very tired 13. For some reason you have gone to bed several hours later than usual, but there is no need to get up at any particular time the next morning. Which one of the following are you most likely to do? [4] Will wake up at usual time, but will not fall back asleep [3] Will wake up at usual time and will doze thereafter [2] Will wake up at usual time, but will fall asleep again [1] Will not wake up until later than usual 14. One night you have to remain awake between 4–6 AM (04—06 h) in order to carry out a night watch. You have no time commitments the next day. Which one of the alternatives would suit you best? [1] Would not go to bed until the watch is over [2] Would take a nap before and sleep after [3] Would take a good sleep before and nap after [4] Would sleep only before the watch 15. You have two hours of hard physical work. You are entirely free to plan your day. Considering only your internal “clock,” which of the following times would you choose? [4] 8 AM–10 AM (08—10 h) [3] 11 AM–1 PM (11—13 h) [2] 3 PM–5 PM (15—17 h) [1] 7 PM–9 PM (19—21 h) 16. You have decided to do physical exercise. A friend suggests that you do this for one hour twice a week. The best time for her is between 10 and 11 PM (22—23 h). Bearing in mind only your internal “clock,” how well do you think you would perform? [1] Would be in good form [2] Would be in reasonable form [3] Would find it difficult [4] Would find it very difficult 709 17. Suppose you can choose your own work hours. Assume that you work a five-hour day (including breaks), your job is interesting, and you are paid based on your performance. At approximately what time would you choose to begin? [5] 5 hours starting between 4 and 8 AM (04—08 h) [4] 5 hours starting between 8 and 9 AM (08—09 h) [3] 5 hours starting between 9 AM and 2 PM (09—14 h) [2] 5 hours starting between 2 and 5 PM (14—17 h) [1] 5 hours starting between 5 PM and 4 AM (17—04 h) 18. At approximately what time of day do you usually feel your best? [5] 5–8 AM (05—08 h) [4] 8–10 AM (08—10 h) [3] 10 AM–5 PM (10—17 h) [2] 5–10 PM (17—22 h) [1] 10 PM–5 AM (22—05 h) 19. One hears about “morning types” and “evening types.” Which one of these types do you consider yourself to be? [6] Definitely a morning type [4] Rather more a morning type than an evening type [2] Rather more an evening type than a morning type [1] Definitely an evening type _____ Total points for all 19 questions INTERPRETING AND USING YOUR MORNINGNESS^EVENINGNESS SCORE This questionnaire has 19 questions, each with a number of points. First, add up the points you circled and enter your total morningness–eveningness score here: Scores can range from 16 to 86. Scores of 41 and below indicate “evening types.” Scores of 59 and above indicate “morning types.” Scores between 42 and 58 indicate “intermediate types.” 16–30 31–41 42–58 59–69 70–86 definite evening moderate evening intermediate moderate morning definite morning Occasionally a person has trouble with the questionnaire. For example, some of the questions are difficult to answer if you have been on a shift work schedule, if you don’t work, or if your bedtime is unusually late. 710 Score Sleep onset Wake-up A. WIRZ-JUSTICE AND M. TERMAN 16–30 31–41 42–58 59–69 70–86 2:00–3:00 AM (02:00—03:00 h) 10:00–11:30 AM (10:00—11:30 h) 12:45–2:00 AM (00:45—02:00 h) 8:30–10:00 AM (08:30—10:00 h) 10:45 PM–12:45 AM (22:45—00:45 h) 6:30–8:30 AM (06:30—08:30 h) 9:30–10:45 PM (21:30—22:45 h) 5:00–6:30 AM (05:00—06:30 h) 9:00–9:30 PM (21:00—21:30 h) 4:00–5:00 AM (04:00—05:00 h) Your answers may be influenced by an illness or medications you may be taking. If you are not confident about your answers, you should also not be confident about the advice that follows. One way to check this is to ask whether your morningness–eveningness score approximately matches the sleep onset and wake-up times listed in the table above. If your usual sleep onset is earlier than 9:00 PM (21:00 h) or later than 3:00 AM (03:00 h), or your wakeup is earlier than 4:00 AM (04:00 h) or later than 11:30 AM (11:30 h), you should seek the advice of a light therapy clinician in order to proceed effectively with treatment. We use the morningness–eveningness score to improve the antidepressant effect of light therapy. Although most people experience good antidepressant response to light therapy when they take a regular morning session using a 10 000 lux white light device (see www. cet.org for recommendations) for 30 minutes, often this will not give the best possible response. If your internal clock is shifted relative to external time (as indirectly measured by your morningness–eveningness score), the timing of light therapy needs to be adjusted. The table below shows the recommended start time for light therapy for a wide range of morningness–eveningness scores. If your score falls beyond this range (either very low or very high), you should seek the advice of a light therapy clinician in order to proceed effectively with treatment. Morningness–Eveningness Score 23–26 27–30 31–34 35–38 39–41 42–45 46–49 50–53 54–57 58–61 62–65 66–68 69–72 73–76 Start time for light therapy 8:15 AM 8:00 AM 7:45 AM 7:30 AM 7:15 AM 7:00 AM 6:45 AM 6:30 AM 6:15 AM 6:00 AM 5:45 AM 5:30 AM 5:15 AM 5:00 AM If you usually sleep longer than 7 hours per night, you will need to wake up somewhat earlier than normal to achieve the effect – but you should feel better for doing that. Some people compensate by going to bed earlier, while others feel fine with shorter sleep. If you usually sleep less than 7 hours per night you will be able to maintain your current wake-up time. If you find yourself automatically waking up more than 30 minutes before your session start time, you should try moving the session later. Avoid taking sessions earlier than recommended, but if you happen to oversleep your alarm clock, it is better to take the session late than to skip it. Our recommended light schedule for evening types – say, 8:00 AM (08:00 h) for a morningness–eveningness score of 30 – may make it difficult to get to work on time, yet taking the light earlier may not be helpful. Once you have noted improvement at the recommended hour, however, you can begin inching the light therapy session earlier by 15 minutes per day, enabling your internal clock to synchronize with your desired sleep– wake cycle and work schedule. The personalized advice we give you here is based on a large clinical trial of patients with seasonal affective disorder (SAD) at Columbia University Medical Center in New York. Patients who took the light too late in the morning experienced only half the improvement of those who took it approximately at the times indicated. These guidelines are not only for SAD, but are also helpful in treatment of nonseasonal depression, for reducing insomnia at bedtime, and for reducing the urge to oversleep in the morning. Our advice serves only as a general guideline for new users of light therapy. There are many individual factors that might call for a different schedule or dose (intensity, duration) of light. Any person with clinical depression should proceed with light therapy only under clinical guidance. Reference: Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectrums 2005; 10: 647– 663. (Downloadable at www.cet.org) Copyright # 2008, Center for Environmental Therapeutics, www.cet.org. All rights reserved. This material may be copied without permission only for personal use. Use or distribution by commercial parties is prohibited. CHRONOTHERAPEUTICS (LIGHT AND WAKE THERAPY) AS A CLASS OF INTERVENTIONS REFERENCES Albrecht U (2002). 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