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Research Groups and Topics
| Terman Group | Wirz-Justice Group |
| Oren Group | Benedetti Group |
| Literature Survey | 2007 Collection on Chronobiology and Psychiatry |
Terman Group
A naturalistic pattern of dawn simulation (93 min, 0.001-250 lux) delivered to sleeping patients with winter depression has clinical efficacy sirnilar to postawakening bright light therapy. The authors tested the circadian phase- shifting capacity of the dawn signal in a placebo-controlled, randomized 3-week field trial using 4 photic or nonphotic comparators: 30-min, 10,000-1ux bright light therapy; a 13-min, 250-1ux light pulse at the end of sleep; and high- and low-density negative air ionization timed to match the darnrn. Bright light and dawn treatments both produced average phase advances of -30 min, while the pulse and ion exposure had minimal effect. The authors conclude that very dim, incremental levels of light at the end of the night, with a dominant red component through eyelid filtering, facilitate circadian thyth* phase advances, possibly in conjunction with room light after awakening.
Addressing seasonal affective disorder. Journal of Employee Assistance. 2007;37:10-11.
Employers are naturally concerned about reduced work productivity in workers who suffer SAD or the winter doldrums. Intervention by employee assistance programs, and light treatment on the workplace, however, pose sensitive problems of confidentiality and the reluctance of workers to reveal depression to supervisors and colleagues. In this article, Dr. Terman outlines an effective fix-it strategy based on CET's offerings.
BACKGROUND: This clinical trial assessed two novel nonpharmaceutical treatments for
winter depression, naturalistic dawn simulation and high-density negative air
ionization, delivered during the final hours of sleep.
METHODS: Patients were 99 adults (77 women, 22 men) with winter seasonal pattern of
Major Depressive Disorder (94 cases) and Bipolar II Disorder (5 cases). Five parallel
groups received: (a) dawn simulation (0.0003-250 lux in the pattern of 5 May at 45 ºN
latitude); (b) a dawn light pulse (13 min, 250 lux, with illuminant dose of 3.25 x 103
lux•min matched to the simulated dawn); (c) post-awakening bright light (30 min, 10,000
lux); (d) negative air ionization at high flow rate (93 min, 4.5 x 1014 ions/sec); or
(e) ionization at low flow rate (93 min, 1.7 x 1011 ions/sec). Symptoms were assessed
over 3 weeks using the Structured Interview Guide for the Hamilton Depression Rating
Scale – Seasonal Affective Disorder Version.
RESULTS: Posttreatment improvement was: bright light, 57.1%; dawn simulation, 49.5%;
dawn pulse, 42.7%; high-density ions, 47.9%; and low-density ions, 22.7% (significantly
lower than the others). Contrary to hypothesis, analysis of variance failed to find
superiority of dawn simulation to the dawn pulse or bright light. However, the dawn
pulse led to a pattern of residual or exacerbated depressive symptoms similar to that
seen in low-density ion nonresponders.
CONCLUSIONS: Naturalistic dawn simulation and high-density ionization are active
antidepressants that do not require effort of post-awakening bright light therapy.
They can be considered candidate alternatives to bright light or medication.
BACKGROUND: This randomized controlled trial investigates the efficacy of two non-pharmacologic treatments, bright light and high-density negative air ions for non-seasonal chronic depression. Both methods have shown clinical success for seasonal affective disorder (SAD). METHOD: Patients were 24 (75%) women and 8 (25%) men, ages 22-65 years (mean age ± S.D., 43.7 ± 12.4 years), with Major Depressive Disorder, Single Episode (DSM-IV code, 296.2), Chronic (episode duration > or = 2 years). Patients were entered throughout the year and randomly assigned to exposure to bright light (10 000 lux, n = 10), or high-density (4.5 x 1014 ions/s flow rate, n = 12) or low-density (1.7 x 1011 ions/s, n = 10, placebo control) negative air ions. Home treatment sessions occurred for 1 h upon awakening for 5 weeks. Blinded raters assessed symptom severity weekly with the Structured Interview Guide for the Hamilton Depression Rating Scale--Seasonal Affective Disorder (SIGH-SAD) version. Evening saliva samples were obtained before and after treatment for ascertainment of circadian melatonin rhythm phase. RESULTS: SIGH-SAD score improvement was 53.7% for bright light and 51.1% for high-density ions v. 170% for low-density ions. Remission rates were 50%, 50% and 0% respectively. The presence or severity of atypical symptoms did not predict response to either treatment modality, nor were phase advances to light associated with positive response. CONCLUSIONS: Both bright light and negative air ions are effective for treatment of chronic depression. Remission rates are similar to those for SAD, but without a seasonal dependency or apparent mediation by circadian rhythm phase shifts. Combination treatment with antidepressant drugs may further enhance clinical response.
The susceptibility of the circadian system to selective phase shifting by timed light exposure has broad implications for the treatment of sleep-phase and depressive disorders. Light therapies have been devised that can normalize the patterns of delayed sleep phase syndrome (through circadian phase advances) and advanced sleep phase syndrome (through circadian phase delays). Doctors and patients need to become cognizant of the daily intervals when light exposure—and darkness—can facilitate or hamper adjustment. The primary intervals lie at the edges of the “subjective night,” which coincide with the tails of the nocturnal melatonin cycle, but they can be inferred clinically through a chronotype questionnaire. The lighting schedule may have to be continually adjusted as the subjective night shifts gradually in the desired direction. The treatment strategy for seasonal and nonseasonal depressive disorders is similar. In winter depression, the magnitude of phase advances correlates with the degree of mood improvement, and the optimum timing of light therapy must be specified relative to circadian rather than solar time. Apart from its use as a monotherapy, light therapy in both outpatient and inpatient trials indicates that light therapy accelerates remission of nonseasonal depression in conjunction with medication. Exploratory applications for treatment of antepartum and premenstrual depression, bulimia nervosa, sleep disruption of senile dementia, and shift work and jet lag disturbance are considered. The chapter provides the clinician with guidelines for selecting lighting apparatus based on safety, efficacy, and comfort factors; summarizes adverse effects of light overdose; and offers a straightforward protocol for selecting treatment time of day.
Chronotherapeutics (light and wake therapy) in affective disorders. Psychol Med. 2005;35:939-44.
The Committee on Chronotherapeutics, delegated by the International Society for Affective Disorders (ISAD), makes the following recommendations after reviewing the evidence as of November 2004. (1) Wake therapy is the most rapid antidepressant available today: approximately 60% of patients, independent of diagnostic subtype, respond with marked improvement within hours. Treatment can be a single or repeated sleep deprivation, total (all night) or partial (second half of the night). Relapse can be prevented by daily light therapy, concomitant administration of SSRIs, lithium (for bipolar patients), or a short phase advance of sleep over 3 days following a single night of wake therapy. Combinations of these interventions show great promise. (2) Light therapy is effective for major depression--not only for the seasonal subtype. As an adjuvant to conventional antidepressants in unipolar patients, or lithium in bipolar patients, morning light hastens and potentiates the antidepressant response. Light therapy shows benefit even for patients with chronic depression of 2 years or more, outperforming their weak response to drugs. This method provides a viable alternative for patients who refuse, resist or cannot tolerate medication, or for whom drugs may be contraindicated, as in antepartum depression. (3) Given the urgent need for new strategies to treat patients with residual depressive symptoms, clinical trials of wake therapy and/or adjuvant light therapy, coupled with follow-up studies of long-term recurrence, are a high priority.
Bright light therapy for seasonal affective disorder (SAD) has been investigated and applied for over 20 years. Physicians and clinicians are increasingly confident that bright light therapy is a potent, specifically active, nonpharmaceutical treatment modality. Indeed, the domain of light treatment is moving beyond SAD, to nonseasonal depression (unipolar and bipolar), seasonal flare-ups of bulimia nervosa, circadian sleep phase disorders, and more. Light therapy is simple to deliver to outpatients and inpatients alike, although the optimum dosing of light and treatment time of day requires individual adjustment. The side-effect profile is favorable in comparison with medications, although the clinician must remain vigilant about emergent hypomania and autonomic hyperactivation, especially during the first few days of treatment. Importantly, light therapy provides a compatible adjunct to antidepressant medication, which can result in accelerated improvement and fewer residual symptoms.
BACKGROUND: Bright light therapy was shown to be a promising treatment for
depression during pregnancy in a recent open-label study. In an extension of this
work, we report findings from a double-blind placebo-controlled pilot study.
METHOD:Ten pregnant women with DSM-IV major depressive disorder were randomly
assigned from April 2000 to January 2002 to a 5-week clinical trial with either a
7000 lux (active) or 500 lux (placebo) light box. At the end of the randomized
controlled trial, subjects had the option of continuing in a 5-week extension phase.
The Structured Interview Guide for the Hamilton Depression Scale-Seasonal Affective
Disorder Version was administered to assess changes in clinical status. Salivary
melatonin was used to index circadian rhythm phase for comparison with
antidepressant results.
RESULTS:Although there was a small mean group advantage of active treatment
throughout the randomized controlled trial, it was not statistically significant.
However, in the longer 10-week trial, the presence of active versus placebo light
produced a clear treatment effect (p =.001) with an effect size (0.43) similar to
that seen in antidepressant drug trials. Successful treatment with bright light was
associated with phase advances of the melatonin rhythm.
CONCLUSION:These findings provide additional evidence for an active effect
of bright light therapy for antepartum depression and underscore the need for an
expanded randomized clinical trial.
Brightening Depression. Science, 303: 467-468.
Scale scores on the Tridimensional Personality Questionnaire (TPQ)-novelty seeking (NS), harm avoidance (HA), and reward dependence (RD)-can predict response to antidepressants. This study examined 89 patients with Bipolar Disorder (I, II) or Major Depressive Disorder, both with recurrent winter seasonal pattern. The TPQ was administered while the patients were depressed, following 10-14 days of bright light therapy (30 min, 10,000 lux) and after spontaneous springtime remission. The Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) assessed the severity of depression. At baseline, there were no significant differences between diagnostic subgroups or responders and non-responders on the TPQ or SIGH-SAD scales, though baseline RD scores were significantly higher in women than men. Furthermore, neither severity of depression nor magnitude of post-treatment clinical improvement was significantly correlated with baseline TPQ scores. Only HA scores decreased after treatment, with responders showing the greatest effect. HA scores also decreased from the baseline to springtime assessments for the group as a whole, with no difference between responders and non-responders. This is the first study to demonstrate that HA is state- rather than trait-dependent in seasonal affective disorder. The TPQ dimensions of temperament do not predict response to light therapy.
Patients with seasonal affective disorder (SAD) may vary in symptoms of their depressed winter mood state, as we showed previously for nondepressed (manic, hypomanic, hyperthymic, euthymic) springtime states [Goel et al., 1999]. Identification of such differences during depression may be useful in predicting differences in treatment efficacy or analyzing the pathogenesis of the disorder. In a cross-sectional analysis, we determined whether 165 patients with Bipolar Disorder (I, II) or Major Depressive Disorder (MDD), both with seasonal pattern, showed different symptom profiles while depressed. Assessment was by the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD), which includes a set of items for atypical symptoms. We identified subgroup differences in SAD based on categories specified for nonseasonal depression, using multivariate analysis of variance and discriminant analysis. Patients with Bipolar Disorder (I and II) were more depressed (had higher SIGH-SAD scores) and showed more psychomotor agitation and social withdrawal than those with MDD. Bipolar I patients had more psychomotor retardation, late insomnia, and social withdrawal than bipolar II patients. Men showed more obsessions/compulsions and suicidality than women, while women showed more weight gain and early insomnia. Whites showed more guilt and fatigability than blacks, while blacks showed more hypochondriasis and social withdrawal. Darker-eyed patients were significantly more depressed and fatigued than blue-eyed patients. Single and divorced or separated patients showed more hypochondriasis and diurnal variation than married patients. Employed patients showed more atypical symptoms than unemployed patients, although most of the subgroup distinctions lay on the Hamilton Scale. These results comprise a set of biological and sociocultural factors-including race, gender, and marital and employment status-which contribute to depressive symptomatology in SAD. Significant mood and sociocultural factors, in contrast to biological factors of gender and eye color, were similar to those reported for nonseasonal depression. Lightly pigmented eyes, in particular, may serve to enhance photic input during winter and allay depressive symptoms in vulnerable populations.
Internal night. Arch Gen Psychiatry. 2001;58:1115-6.
BACKGROUND: We investigated a possible mechanism of action for the antidepressant response to light-phase advances of the circadian clock-by measuring the onset of melatonin secretion before and after light treatment in the morning or evening. METHODS: Plasma melatonin was sampled in 42 patients with seasonal affective disorder, in the evening or overnight while depressed and after 10 to 14 days of light therapy (10 000 lux for 30 minutes) when symptoms were reassessed. RESULTS: Morning light produced phase advances of the melatonin rhythm, while evening light produced delays, the magnitude depending on the interval between melatonin onset and light exposure, or circadian time (morning, 7.5 to 11 hours; evening, 1.5 to 3 hours). Delays were larger the later the evening light (r = 0.40), while advances were larger the earlier the morning light (r = 0.50). Although depression ratings were similar with light at either time of day, response to morning light increased with the size of phase advances up to 2.7 hours (r = 0.44) regardless of baseline phase position, while there was no such correlation for evening light. In an expanded sample (N = 80) with the sleep midpoint used as a reference anchor for circadian time, early morning light exposure was superior to late morning and to evening exposure. CONCLUSION: The antidepressant effect of light is potentiated by early-morning administration in circadian time, optimally about 8.5 hours after melatonin onset or 2.5 hours after the sleep midpoint.
BACKGROUND: Retinal sensitivity may play a role in the pathogenesis of seasonal affective disorder (SAD) and response to light therapy. METHODS: Using a dark adaptation procedure, SAD patients and normal control subjects were tested in the winter and summer, with patients retested after light treatment. The eyes were preadapted to bright light followed by 30 min in darkness, during which subjects detected a dim signal titrated around the detection threshold. Photopic (cone-mediated) and scotopic (rod-mediated) components of the data were identified by nonlinear exponential curve fits to successive threshold estimates. RESULTS: Patients (n = 24) showed significantly lower cone and rod thresholds in the summer than winter, while control subjects (n = 12) showed a similar trend. Relative to the control subjects, however, patients were supersensitive in winter (lower cone final threshold, faster rod recovery). Clinical responders to morning light showed a small summer-like increase in cone sensitivity, whereas nonresponders became subsensitive. In comparison to darker-eyed patients, blue-eyed patients showed a larger summertime increase in cone sensitivity and a similar trend after response to morning light. CONCLUSIONS: Heightened retinal sensitivity with increased light exposure, and supersensitivity of patients relative to control subjects in winter, may play roles in the pathogenesis of winter depression and the action of therapeutic light.
BACKGROUND: Bright light therapy has been established for treatment of winter depression, or seasonal affective disorder (SAD). Analysis of side effects most often have focused on a narrow set of suspected symptoms, based on clinical observation (e.g., headache, eyestrain, nausea, insomnia, and hyperactivity). This study broadens the purview to a set of 88 physical and subjective symptoms that might emerge, remit, or remain unchanged relative to baseline, thus reducing bias toward assessment of presumed side effects. METHOD: Eighty-three patients with SAD (DSM-III-R criteria for mood disorders with seasonal pattern [winter type] and National Institute of Mental Health criteria for SAD) received bright light therapy at 10,000 lux for 30 minutes daily in the morning or evening for 10 to 14 days. They completed a questionnaire (Systematic Assessment for Treatment Emergent Effects), rating symptom severity before and after treatment. Results were compared for morning or evening treatment and for responders and nonresponders. RESULTS: Several side effects emerged--mostly mildly--including jumpiness/jitteriness (8.8%), headache (8.4%), and nausea (15.9%), mirroring findings of past studies with a less inclusive scope. In most cases, remission rate equalled or exceeded emergence rate. Several nondepressive symptoms also showed large improvement, including poor vision and skin rash/itch/irritation. Being overactive/excited/elated showed greater emergence under morning light and greater remission under evening light. Emergence of nausea was greater than remission in responders. CONCLUSION: The dominant effect of light treatment was improvement in bothersome s ymptoms. Although patients should be advised of side effects and guided in dose manipulations to reduce them, attention also should be drawn to the substantial benefit-to-risk ratio. Improvement of symptoms outside the depressive cluster, seen in both responders and nonresponders, may point to new therapeutic uses of light therapy.
Two structured interviews, the Hypomania Interview Guide (Including Hyperthymia), for Seasonal Affective Disorder (HIGH-SAD) and its successor, the Hypomania Interview Guide (Including Hyperthymia), Retrospective Assessment Version (HIGH-R), were validated for the assessment of nondepressed spring/summer mood states in patients with DSM-III-R or DSM-IV diagnoses of Recurrent Bipolar disorder (I, II or NOS) or Recurrent Major Depressive Disorder (MDD; unipolar), both with Seasonal Pattern, and in normal control subjects (HIGH-SAD only). The instruments retrospectively rate the frequency and severity of DSM diagnostic criterion features as well as several non-DSM features. Both instruments had high internal consistency. Normal controls had lower total scores than unipolar patients, who had lower scores than bipolar patients. Total score classified 85-91% of patients with seasonal affective disorder (SAD) into the correct unipolar or bipolar group. For boundary mood cases, small subsets of features provided better classification accuracy. Based on total score, MDD patients were divided into three subgroups: euthymes (normal mood), hyperthymes (slightly elevated mood), and high-hyperthymes (scores overlapping with hypomania). With the exception of sharpened thinking, DSM items dominated patient classifications. Distinct clusters of "positive" (pleasant, agreeable) or "negative" (impairing) features described the mood states. The HIGH-R and HIGH-SAD are useful for discriminating and classifying hypomania and mania in bipolar patients, and euthymia and hyperthymia in unipolar patients.
This study aimed to determine symptom patterns in patients with chronic fatigue syndrome (CFS), in summer and winter. Comparison data for patients with seasonal affective disorder (SAD) were used to evaluate seasonal variation in mood and behavior, atypical neurovegetative symptoms characteristic of SAD, and somatic symptoms characteristic of CFS. Rating scale questionnaires were mailed to patients previously diagnosed with CFS. Instruments included the Personal Inventory for Depression and SAD (PIDS) and the Systematic Assessment for Treatment Emergent Effects (SAFTEE), which catalogs the current severity of a wide range of somatic, behavioral, and affective symptoms. Data sets from 110 CFS patients matched across seasons were entered into the analysis. Symptoms that conform with the Centers for Disease Control and Prevention (CDC) case definition of CFS were rated as moderate to very severe during the winter months by varying proportions of patients (from 43% for lymph node pain or enlargement, to 79% for muscle, joint, or bone pain). Fatigue was reported by 92%. Prominent affective symptoms included irritability (55%), depressed mood (52%), and anxiety (51%). Retrospective monthly ratings of mood, social activity, energy, sleep duration, amount eaten, and weight change showed a coherent pattern of winter worsening. Of patients with consistent summer and winter ratings (n = 73), 37% showed high global seasonality scores (GSS) > or = 10. About half this group reported symptoms indicative of major depressive disorder, which was strongly associated with high seasonality. Hierarchical cluster analysis of wintertime symptoms revealed 2 distinct clinical profiles among CFS patients: (a) those with high seasonality, for whom depressed mood clustered with atypical neurovegetative symptoms of hypersomnia and hyperphagia, as is seen in SAD; and (b) those with low seasonality, who showed a primary clustering of classic CFS symptoms (fatigue, aches, cognitive disturbance), with depressed mood most closely associated with irritability, insomnia, and anxiety. It appears that a subgroup of patients with CFS shows seasonal variation in symptoms resembling those of SAD, with winter exacerbation. Light therapy may provide patients with CFS an effective treatment alternative or adjunct to antidepressant drugs.
BACKGROUND: Artificial bright light presents a promising nonpharmacological treatment for seasonal affective disorder. Past studies, however, have lacked adequate placebo controls or sufficient power to detect group differences. The importance of time of day of treatment--specifically, morning light superiority--has remained controversial. METHODS: This study used a morning x evening light crossover design balanced by parallel-group controls, in addition to a nonphotic control, negative air ionization. Subjects with seasonal affective disorder (N = 158) were randomly assigned to 6 groups for 2 consecutive treatment periods, each 10 to 14 days. Light treatment sequences were morning-evening, evening-morning, morning-morning, and evening-evening (10,000 lux, 30 min/d). Ion density was 2.7 x 10(6) (high) or 1.0 x 10(4) (low) ions per cubic centimeter (high-high and low-low sequences, 30 min/d in the morning). RESULTS: Analysis of depression scale percentage change scores showed low-density ion response to be inferior to all other groups, with no other group differences. Response to evening light was reduced when preceded by treatment with morning light, the sole sequence effect. Stringent remission criteria, however, showed significantly higher response to morning than evening light, regardless of treatment sequence. CONCLUSIONS: Bright light and high-density negative air ionization both appear to act as specific antidepressants in patients with seasonal affective disorder. Whether clinical improvement would be further enhanced by their use in combination, or as adjuvants to medication, awaits investigation.
In recent years, bright light treatment of seasonal affective disorder (SAD), recurrent depressions in fall and winter, has been discovered. Newer applications include circadian sleep phase disorder, shift work and jet lag. Apart from creating the visual signal, light can modify retinal structure and physiology. UV and visible light lead to distinct lesions of ocular tissues under certain experimental und naturalistic conditions. In light therapy, a large variety of fixtures is used but the spectral emission of lamps is mostly unknown to the user and clinician leading to the potential hazard of ocular lesions. Therefore, we have analyzed a wide selection of light sources commonly used for treatment. We measured the spectral emission and calculated irradiant doses for several light therapy regimens. Based on these measurements, potential hazards are analyzed, physiological mechanisms of light action are discussed and safety measures for bright light therapy are proposed. They include recommendations for lamps devoid of damaging spectral emissions and standardized therapy fixtures, ophthalmological monitoring of patients with eye diseases and control by optometrists for patients with healthy eyes who are likely to undergo light treatment for extended periods.
OBJECTIVE: The authors' goal was to determine whether the pattern and severity of depressive symptoms predict response to light treatment for seasonal affective disorder. METHOD: Subjects with winter depression (N = 103) were given bright light treatment. Seventy-one were classified as responders, 15 as nonresponders, and 17 as partial responders. Using depression rating scale data and correlational and multivariate analysis, the authors sought predictors of response in baseline symptom and scale scores. RESULTS: Responders were characterized by atypical symptoms, especially hypersomnia, afternoon or evening slump, reverse diurnal variation (evenings worse), and carbohydrate craving. By contrast, nonresponders were characterized mainly by melancholic symptoms, retardation, suicidality, depersonalization, typical diurnal variation (mornings worse), anxiety, early and late insomnia, appetite loss, and guilt. The ratio of atypical to classical symptoms of depression, rather than severity per se, best predicted treatment outcome for the group as a whole. Pretreatment expectations were positively correlated with improvement on the Hamilton Depression Rating Scale but not on a supplementary scale of atypical symptoms. CONCLUSIONS: Light-responsive seasonal affective disorder is distinguished by a dominant atypical symptom profile closely associated with depressed mood. Nonresponders from a clinically distinct group with melancholic features. The patient's symptom profile, therefore, should be considered when diagnosing seasonal affective disorder and selecting treatment.
This study was designed to evaluate the antidepressant effect of negative ions in the ambient air as a potential treatment modality for seasonal affective disorder. Twenty-five subjects with winter depression underwent a double-blind controlled trial of negative ions at two exposure densities, 1 x 10(4) ions/cm3 or 2.7 x 10(6) ions/cm3, using an electronic negative ion generator with wire corona emitters. Home treatments were taken in the early morning for 30 min over 20 days, followed by withdrawals. The severity of depressive symptoms (prominently including the reverse neurovegetative symptoms of hypersomnia, hyperphagia, and fatigability) decreased selectively for the group receiving high-density treatment. Standard depression rating scale assessments were corroborated by clinical impressions. When a remission criterion of 50% or greater reduction in symptom frequency/severity was used, 58% of subjects responded to high-density treatment while 15% responded to low-density treatment (chi 2 = 5.00, df = 1, p = 0.025). There were no side effects attributable to the treatment, and all subjects who responded showed subsequent relapse during withdrawal. Treatment with a high-density negative ionizer appears to act as a specific antidepressant for patients with seasonal affective disorder. The method may be useful as an alternative or supplement to light therapy and medications.
Light treatment for sleep disorders: consensus report. VII. Jet lag. J Biol Rhythms. 1995;10:167-76.
Sleep disturbances are an all-too-familiar symptom of jet lag and a prime source of complaints for transmeridian travelers and flight crews alike. They are the result of a temporary loss of synchrony between an abruptly shifted sleep period, timed in accordance with the new local day-night cycle, and a gradually reentraining circadian system. Scheduled exposure to bright light can, in principle, alleviate the symptoms of jet lag by accelerating circadian reentrainment to new time zones. Laboratory simulations, in which sleep time is advanced by 6 to 8 h and the subjects exposed to bright light for 3 to 4 h during late subjective night on 2 to 4 successive days, have not all been successful. The few field studies conducted to date have had encouraging results, but their applicability to the population at large remains uncertain due to very limited sample sizes. Unresolved issues include optimal times for light exposure on the first as well as on subsequent treatment days, whether a given, fixed, light exposure time is likely to benefit a majority of travelers or whether light treatment should be scheduled instead according to some individual circadian phase marker, and if so, can such a phase marker be found that is both practical and reliable.
Light treatment for sleep disorders: consensus report. VI. Shift work. J Biol Rhythms. 1995;10:157-64.
The unhealthy symptoms and many deleterious consequences of shift work can be explained by a mismatch between the work-sleep schedule and the internal circadian rhythms. This mismatch occurs because the 24-h zeitgebers, such as the natural light-dark cycle, keep the circadian rhythms from phase shifting to align with the night-work, day-sleep schedule. This is a review of studies in which the sleep schedule is shifted several hours, as in shift work, and bright light is used to try to phase shift circadian rhythms. Phase shifts can be produced in laboratory studies, when subjects are kept indoors, and faster phase shifting occurs with appropriately timed bright light than with ordinary indoor (dim) light. Bright light field studies, in which subjects live at home, show that the use of artificial nocturnal bright light combined with enforced daytime dark (sleep) periods can phase shift circadian rhythms despite exposure to the conflicting 24-h zeitgebers. So far, the only studies on the use of bright light for real shift workers have been conducted at National Aeronautics and Space Administration (NASA). In general, the bright light studies support the idea that the control of light and dark can be used to overcome many of the problems of shift work. However, despite ongoing practical applications (such as at NASA), much basic research is still needed.
Light treatment for sleep disorders: consensus report. V. Age-related disturbances. J Biol Rhythms. 1995;10:151-4.
Sleep maintenance insomnia is a major complaint among the elderly. As a result, an inordinate proportion of sleeping pill prescriptions go to individuals over 65 y of age. Because of the substantial problems associated with use of hypnotics in older populations, efforts have been made to develop nondrug treatments for age-related sleep disturbance, including timed exposure to bright light. Such bright light treatments are based on the assumption that age-related sleep disturbance is the consequence of alterations in the usual temporal relationship between body temperature and sleep. Although studies are limited, results strongly suggest that evening bright light exposure is beneficial in alleviating sleep maintenance insomnia in healthy elderly subjects. Less consistent, but generally positive, findings have been reported with regard to bright light treatment of sleep and behavioral disturbance in demented patients. For both groups, it is likely that homeostatic factors also contribute to sleep disturbance, and these may be less influenced by bright light interventions.
Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances. J Biol Rhythms. 1995;10:135-47.
Advanced and delayed sleep phase disorders, and the hypersomnia that can accompany winter depression, have been treated successfully by appropriately timed artificial bright light exposure. Under entrainment to the 24-h day-night cycle, the sleep-wake pattern may assume various phase relationships to the circadian pacemaker, as indexed, for example, by abnormally long or short intervals between the onset of melatonin production or the core body temperature minimum and wake-up time. Advanced and delayed sleep phase syndromes and non-24-h sleep-wake syndrome have been variously ascribed to abnormal intrinsic circadian periodicity, deficiency of the entrainment mechanism, or--most simply--patterns of daily light exposure insufficient for adequate phase resetting. The timing of sleep is influenced by underlying circadian phase, but psychosocial constraints also play a major role. Exposure to light early or late in the subjective night has been used therapeutically to produce corrective phase delays or advances, respectively, in both the sleep pattern and circadian rhythms. Supplemental light exposure in fall and winter can reduce the hypersomnia of winter depression, although the therapeutic effect may be less dependent on timing.
Light treatment for sleep disorders: consensus report. III. Alerting and activating effects. J Biol Rhythms. 1995;10:129-32.
In addition to the well-established phase-shifting properties of timed exposure to bright light, some investigators have reported an acute alerting, or activating, effect of bright light exposure. To the extent that bright light interventions for sleep disturbance may cause subjective and/or central nervous system activation, such a property may adversely affect the efficacy of treatment. Data obtained from patient samples and from healthy subjects generally support the notion that exposure to bright light may be associated with enhanced subjective alertness, and there is limited evidence of objective changes (EEG, skin conductance levels) that are consistent with true physiological arousal. Such activation appears to be quite transient, and there is little evidence to suggest that bright light-induced activation interferes with subsequent sleep onset. Some depressed patients, however, have experienced insomnia and hypomanic activation following bright-light exposure.
PURPOSE: We assessed the potential ocular hazards of bright light therapy for patients with seasonal affective disorder, after both short- and long-term treatment, and identified prospective patients with pre-existing ocular abnormalities. METHODS: Fifty patients with seasonal affective disorder received daily exposure to artificial light in the morning or evening for 30 minutes at an illuminance level of 10,000 lux (irradiant dose, 0.016 J/cm2). Ophthalmologic examinations were performed before and after short-term treatment (two to eight weeks) and after three to six years of use during the fall and winter months. Over the four years of patient intake, the eye examination included subsets of the following tests: visual acuity, intraocular pressure, slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, color vision, visual field, fundus photography, Amsler grid, ocular motility, pupillary reactions, contrast sensitivity, stereopsis, and the macular stress test. RESULTS: No ocular changes were detected after short-term treatment. Long-term treatment (three to six years) of 17 patients, with cumulative exposure durations of 60 to 1,250 hours, also resulted in no ocular abnormalities. CONCLUSIONS: Light therapy yields about 75% clinical remissions. It is effective as an antidepressant and appears safe for the eyes. Current knowledge is insufficient to specify any definite ocular contraindications for bright light therapy, although we recommend that patients with preexisting ocular abnormalities and those using photosensitizing drugs undergo treatment only with periodic ophthalmologic examination.
The visual input stage of the mammalian circadian pacemaking system: I. Is there a clock in the mammalian eye? J Biol Rhythms. 1991;6:5-29.
Threads of evidence from recent experimentation in retinal morphology, neurochemistry, electrophysiology, and visual perception point toward rhythmic ocular processes that may be integral components of circadian entrainment in mammals. Components of retinal cell biology (rod outer-segment disk shedding, inner-segment degradation, melatonin and dopamine synthesis, electrophysiological responses) show self-sustaining circadian oscillations whose phase can be controlled by light-dark cycles. A complete phase response curve in visual sensitivity can be generated from light-pulse-induced phase shifting. Following lesions of the suprachiasmatic nuclei, circadian rhythms of visual detectability and rod outer-segment disk shedding persist, even though behavioral activity becomes arrhythmic. We discuss the converging evidence for an ocular circadian timing system in terms of interactions between rhythmic retinal processes and the central suprachiasmatic pacemaker, and propose that retinal phase shifts to light provide a critical input signal.
The visual input stage of the mammalian circadian pacemaking system: II. The effect of light and drugs on retinal function. J Biol Rhythms. 1991;6:31-48.
Acute light pulses as well as long-term light exposure may not only modulate photoreceptive properties, but also induce reversible or irreversible damage to the retina, depending on exposure conditions. Illuminance levels in laboratory animal colonies and manipulations of lighting regimens in circadian rhythm research can threaten retinal structure and physiology, and may therefore modify zeitgeber input to the central circadian system. Given the opportunity to escape light at any time, the nocturnal rat self-selects a seasonally varying "naturalistic skeleton photoperiod" that protects the eyes from potential damage by nonphysiological light exposures. Both rod rod-segment disk shedding and behavioral circadian phase shifts are elicited by low levels of twilight stimulation. From this vantage point, we hypothesize that certain basic properties of circadian rhythms (e.g., Aschoff's rule and splitting) may reflect modulation of retinal physiology by light. Pharmacological manipulations with or without the addition of lighting strategies have been used to analyze the neurochemistry of circadian timekeeping. Drug modulation of light input at the level of the retina may add to or interact with direct drug modulation of the central circadian pacemaking system.
A high-intensity fluorescent lighting system, tilted downward toward the head, and emitting negligible levels of ultraviolet radiation, was tested under two random crossover protocols in winter-depressed patients: 30-minute sessions at (a) 3,000 lux vs. 10,000 lux in early morning, and (b) morning vs. evening sessions at 10,000 lux. Judgment of clinical remission was based jointly on relative and absolute score improvements on a Structured Interview Guide for the Hamilton Depression Scale--Seasonal Affective Disorder Version (SIGH-SAD) and a set of supplementary atypical-vegetative items. Data are presented for 24 subjects who showed relapse upon withdrawal. An overall remission rate of 75 percent was found for morning light at 10,000 lux. The rates for evening light (25%) and 3,000 lux morning light (19%) were significantly lower. The remission rate for morning light treatment of 10,000 lux for 30 minutes approximately equalled 2,500 lux treatment for 2 hours (data from our earlier studies), suggesting a reciprocity between dosing dimensions of intensity and duration. No pathological changes were revealed by ophthalmological examinations given after 2 to 6 weeks of daily treatment.
Dawn and dusk simulation as a therapeutic intervention. Biol Psychiatry. 1989;25:966-70.
Bright artificial light has been found effective in reducing winter depressive symptoms of Seasonal Affective Disorder, although conclusions about the true magnitude of treatment effect and importance of time of day of light exposure have been limited by methodologic problems. Individual subjects' data from 14 research centers studying 332 patients over 5 years were analyzed with a pooled clustering technique. Overall, 2500-lux intensity light exposure for at least 2 hours daily for 1 week resulted in significantly more remissions--Hamilton Depression Rating Scale (HAM-D) score reduction of 50% or more to a level under 8--when administered in the early morning (53%) than in the evening (38%) or at midday (32%). All three times were significantly more effective than dim light controls (11%). Dual daily exposures (morning-plus-evening light) provided no benefit over morning light alone. In morning-evening crossovers, remission rates were 62% under morning light alone, compared with 28% under evening light alone, with a differential morning-evening response present in 59% of morning responders compared with 10% of evening responders (p less than 0.001). Remission rates with morning light were highest given low severity at baseline (HAM-D score of 10-16: 67% remission), as compared with moderate-to-severe cases (HAM-D score above 16: approximately 40% remission) where no morning-evening differences were found. Firmer conclusions await treatment studies with larger sample sizes and full assessment of atypical vegetative symptoms seen in winter depression but underrepresented in the Hamilton scale. Longer treatment course and greater light intensity may help clarify clinical response despite the impossibility of achieving a conventional blind placebo control.
On the question of mechanism in phototherapy for seasonal affective disorder: considerations of clinical efficacy and epidemiology. J Biol Rhythms. 1988;3:155-72.
A circadian pacemaker for visual sensitivity? Ann N Y Acad Sci. 1985;453:147-61.
Visual signal detectability oscillates as a circadian rhythm, capable of free-running in constant conditions, and entrainment by external lighting schedules. These functions persist after lesioning of the suprachiasmatic nucleus (SCN), implicating a separate pacemaker for visual sensitivity. Its locus, physiology, and mode of interaction with the SCN have yet to be established.
Wirz-Justice Group
The catch-phrase of the decade in government ministries, granting agencies, and plenary sessions at scientific conferences is “translational research,” which seems to have replaced “from bench to bedside” – perhaps because it sounds more impressive. It links research from the basic sciences with clinical investigation, and facilitates the results of clinical trials to be incorporated into clinical practice. In our field of sleep and biological rhythms, we are already doing an enormous amount of translation, yet we scarcely advertise this fact. My first question is, why are we not more energetic in recognising our achievements, to obtain attention from the policy makers?
The Committee on Chronotherapeutics, delegated by the International Society for Affective Disorders (ISAD), makes the following recommendations after reviewing the evidence as of November 2004. (1) Wake therapy is the most rapid antidepressant available today: approximately 60% of patients, independent of diagnostic subtype, respond with marked improvement within hours. Treatment can be a single or repeated sleep deprivation, total (all night) or partial (second half of the night). Relapse can be prevented by daily light therapy, concomitant administration of SSRIs, lithium (for bipolar patients), or a short phase advance of sleep over 3 days following a single night of wake therapy. Combinations of these interventions show great promise. (2) Light therapy is effective for major depression--not only for the seasonal subtype. As an adjuvant to conventional antidepressants in unipolar patients, or lithium in bipolar patients, morning light hastens and potentiates the antidepressant response. Light therapy shows benefit even for patients with chronic depression of 2 years or more, outperforming their weak response to drugs. This method provides a viable alternative for patients who refuse, resist or cannot tolerate medication, or for whom drugs may be contraindicated, as in antepartum depression. (3) Given the urgent need for new strategies to treat patients with residual depressive symptoms, clinical trials of wake therapy and/or adjuvant light therapy, coupled with follow-up studies of long-term recurrence, are a high priority.
Chronobiological strategies may provide an effective means of addressing some of the unmet needs in the treatment of depression, such as shortening the latency of onset of antidepressant action, combating residual symptoms, and preventing relapse in the long term. Light is the treatment of choice for winter depression (or seasonal affective disorder, SAD). Light therapy given as an adjuvant to medication in major nonseasonal depression, as well as in chronic and therapy-resistant depression, speeds up and potentiates clinical response. Light is also efficacious in bipolar depression; in these patients “dark therapy” (long nights) can diminish manic symptoms and stop rapid cycling. Total or partial sleep deprivation in the second half of the night (better known as “wake therapy”) induces marked improvement the following day. This amelioration can be maintained with concomitant treatment with antidepressants, lithium, light therapy, sleep phase advance, or combinations thereof. Careful control of the light-dark cycle and of the timing of mealtimes, activity, and sleep may appear to be old-fashioned methods (“daily structures”) belonging to a long obsolete custodial psychiatry. However, these apparently simple methods gain new validation when reconsidered within the framework of modern chronobiology, since when appropriately timed, application of “zeitgebers” can aid treatment of affective disorders.
Brightening Depression. Science, 303: 467-468.
In healthy young men, administration of a single light pulse (5000 lux for 3 hr) or a single melatonin pill (5 mg) at 20:40 hr under controlled constant routine conditions of <10 lux, yielded a phase delay and a phase advance, respectively, in the circadian marker of dim light melatonin onset 24 hr later. Phase shifts after combining the two interventions were additive. Melatonin suppression is not necessary for a phase shift by light, and melatonin is not a _weak_ Zeitgeber relative to bright light when ambient lighting is strictly controlled.
Human clocks: what can go wrong and how can we right it? In: K.-I. Honma and S. Honma (Eds.), Biological Rhythms, Hokkaido University Press, Sapporo, Vol. 10, 107-124.
We investigated whether low intensity dawn–dusk simulation (DDS), a ‘naturalistic’ form of light therapy designed to embed sleep in its accustomed phase, could improve the disturbed circadian rest–activity cycle, nocturnal sleep and and/or cognitive functions in dementia. A protocol of 3 weeks each of baseline, treatment and follow-up was completed by 13 patients (85 yr old ± 5 yr, MMSE 14 ± 5; n = 9 DDS versus n= 4 ‘placebo’ dim red light) who wore an activity/lux monitor throughout. There were no significant changes in clinical or cognitive status, nor modification of circadian stability or amplitude characteristics of the rest–activity cycle. However, two aspects of sleep responded to DDS but not to dim red light. The main sleep episode was 1:14 h earlier during treatment (p=0.03) compared with before and after DDS. With respect to actimetry-determined sleep variables, the DDS group tended to have shortened ‘sleep latency’, longer ‘sleep duration’, more nocturnal immobility and less nocturnal activity than the dim red group (P<0.01). In parallel, nighttime light exposure tended to be reduced (p=0.07). These promising findings—after only 3 weeks of light treatment in elderly patients with advanced dementia—suggest that the circadian timing system remains functionally responsive even to low intensity DDS light. Increasing zeitgeber strength is an important strategy for improving sleep quality and timing in dementia, and DDS light therapy may provide one of the appropriate means to do so.
Human behavior shows large interindividual variation in temporal organization. Extreme “larks” wake up when extreme “owls” fall asleep. These chronotypes are attributed to differences in the circadian clock, and in animals, the genetic basis of similar phenotypic differences is well established. To better understand the genetic basis of temporal organization in humans, the authors developed a questionnaire to document individual sleep times, self-reported light exposure, and self-assessed chronotype, considering work and free days separately. This report summarizes the results of 500 questionnaires completed in a pilot study. Individual sleep times show large differences between work and free days, except for extreme early types. During the workweek, late chronotypes accumulate considerable sleep debt, for which they compensate on free days by lengthening their sleep by several hours. For all chronotypes, the amount of time spent outdoors in broad daylight significantly affects the timing of sleep: Increased self-reported light exposure advances sleep. The timing of selfselected sleep is multifactorial, including genetic disposition, sleep debt accumulated on workdays, and light exposure. Thus, accurate assessment of genetic chronotypes has to incorporate all of these parameters. The dependence of human chronotype on light, that is, on the amplitude of the light:dark signal, follows the known characteristics of circadian systems in all other experimental organisms. Our results predict that the timing of sleep has changed during industrialization and that a majority of humans are sleep deprived during the workweek. The implications are far ranging concerning learning, memory, vigilance, performance, and quality of life.
Objective: To estimate the prevalence of seasonal affective disorder (SAD) and its subsyndromal form (S-SAD) in Switzerland (47_N). Method: A representative sample from all three language areas of Switzerland (n 1/4 980) were given a structured telephone interview using the extended Seasonal Pattern Assessment Questionnaire (SPAQ+). A smaller, but also representative sample in the city of Basel filled in the SPAQ+ form as well as undergoing a structured diagnostic interview. Results: In this Swiss sample, 2.2% of the population presented with symptom severity of SAD, 8.9% with S-SAD. In Basel, a much higher prevalence of SAD was found. Seasonal problems occurred more often in patients with the Diagnostic and Statistical Manual (DSM)-III diagnosis of major affective disorders than in those with pure anxiety disorders or no psychiatric diagnosis. Conclusion: These estimates for SAD in Switzerland are similar to those found in the Zurich Study, using other methods, and for populations in the UK, with the limitations inherent in retrospective questionnaire studies.
A phase response curve to single bright light pulses in human subjects. Journal of Physiology, 15: 945-952.
The circadian pacemaker is differentially sensitive to the resetting effects of retinal light exposure, depending upon the circadian phase at which the light exposure occurs. Previously reported human phase response curves (PRCs) to single bright light exposures have employed small sample sizes, and were often based on relatively imprecise estimates of circadian phase and phase resetting. In the present study, 21 healthy, entrained subjects underwent pre- and post-stimulus constant routines (CRs) in dim light (approximately 2-7 lx) with maintained wakefulness in a semi-recumbent posture. The 6.7 h bright light exposure stimulus consisted of alternating 6 min fixed gaze (approximately 10 000 lx) and free gaze (approximately 5000-9000 lx) exposures. Light exposures were scheduled across the circadian cycle in different subjects so as to derive a PRC. Plasma melatonin was used to determine the phase of the onset, offset, and midpoint of the melatonin profiles during the CRs. Phase shifts were calculated as the difference in phase between the pre- and post-stimulus CRs. The resultant PRC of the midpoint of the melatonin rhythm revealed a characteristic type 1 PRC with a significant peak-to-trough amplitude of 5.02 h. Phase delays occurred when the light stimulus was centred prior to the critical phase at the core body temperature minimum, phase advances occurred when the light stimulus was centred after the critical phase, and no phase shift occurred at the critical phase. During the subjective day, no prolonged 'dead zone' of photic insensitivity was apparent. Phase shifts derived using the melatonin onsets showed larger magnitudes than those derived from the melatonin offsets. These data provide a comprehensive characterization of the human PRC under highly controlled laboratory conditions.
The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels.The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep ‘facilitator’ in humans and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders.
The effects of a single morning and evening carbohydrate-rich meal for 3 consecutive days on circadian phase of core body temperature (CBT), heart rate, and salivary melatonin rhythms were compared under controlled constant routine conditions. In 10 healthy young men entrained to a natural light-dark cycle with regular sleep timing, CBT and heart rate were significantly elevated for approximately 8 h after the last evening carbohydrate-rich meal (EM), and nocturnal melatonin secretion (as measured by salivary melatonin and urinary 6-sulphatoxymelatonin levels) was reduced, compared to the morning carbohydrate-rich meal (MM) condition. Thus, circadian phase could not be measured until the following day due to this acute masking effect. The day after the last meal intervention, MM showed a significant advanced circadian phase position in CBT (+59+/-12 min) and heart rate (+43+/-18 min) compared to EM. However, dim-light melatonin onset was not significantly changed (+15+/-13 min). The results are discussed with respect to central (light-entrainable) and peripheral (food-entrainable) oscillators. Food may be a zeitgeber in humans for the food-entrainable peripheral oscillators, but melatonin data do not support such a conclusion for the light-entrainable oscillator in the suprachiasmatic nucleus.
People with vasospastic syndrome have cold hands and feet and abnormal vasoconstriction after local cold exposure. Normally there is a circadian rhythm of distal vasodilation, with onset in the early evening, which directly influences ability to fall asleep. We gave a sleep questionnaire to 32 patients with primary vasospastic syndrome and 31 healthy controls. People with vasospasticity had significantly prolonged sleep-onset latency both at onset of night-time sleep and after nocturnal disturbance. This prolonged latency could be associated with impaired capacity for distal vasodilation.
Phase advance after one or three simulated dawns in humans. Chronobiology International, 17: 659-668.
The authors' previous experiments have shown that dawn simulation (at low light intensities) can phase advance the circadian rhythm of melatonin in humans. The aim of this study was to compare the effect of repeated dawn signals on the phase position of circadian rhythms in healthy participants kept under controlled light conditions. Nine men participated in two 9-day laboratory sessions under an LD cycle 17.5:6.5 h, < 30:0 lux, receiving 6 consecutive daily dawn (average illuminance 155 lux) or control light (0.1 lux) signals from 0600 to 0730 h (crossover, random-order design). Two modified constant routine protocols before and after the light stimuli measured salivary melatonin (dim light melatonin onset DLMOn and offset DLMOff) and rectal temperature rhythms (midrange crossing time [MRCT]). Compared with initial values, participants significantly phase delayed after 6 days under control light conditions (at least —42 min DLMOn, —54 min DLMOff, (41 min MRCT) in spite of constant bedtimes. This delay was not observed with dawn signals (+10 min DLMOn, +2 min DLMOff, 0 min MRCT). Given that the endogenous circadian period of the human circadian pacemaker is slightly longer than 24 h, the authors' findings suggest that a naturalistic dawn signal is sufficient to forestall this natural delay drift. They hypothesize that zeitgeber transduction and circadian system response are tuned to the time-rate-of-change of naturalistic twilight signals.
The annual decrease of daylight duration initiates a depressive phase in patients with seasonal affective disorder (SAD), and light therapy treats it. How much bright light exposure in winter and summer these patients actually receive may help understand the pathogenetic factors initiating SAD. Methods: During a week in winter and summer, women with and without SAD kept daily logs of the time spent outdoors, subjective sleep, and self-ratings of mood and alertness. Results: Compared with the winter depressive state, mood, alertness, and sleep of SAD patients improved in summer to control values, but did not correlate with the amount of light exposure. In summer, patients with SAD spent more time outdoors than controls. Limitation: Light logs – in comparison with light monitor measurements – may overestimate light exposure outdoors. Conclusion: Women with SAD do not spend less time outdoors in winter than controls, but spend more time outdoors in summer. Clinical Relevance: Patients with SAD show a high amplitude seasonal difference in outdoor light exposure. The susceptibility to winter depression may arise not from behaviourally-related lack of sufficient light exposure, but an increased vulnerability to the amount of light received. They may require more light than controls to remain euthymic (higher light exposure in summer, light therapy in winter).
Background: Stabilization of rapid-cycling bipolar disorder is extremely difficult. Methods: A refractory bipolar I rapid-cycling patient on valproate was treated with long “nights” (extended sleep in darkness) and daytime light therapy. Results: Rapid cycling immediately stopped on initiation of a 10 hour dark/rest period. This was extended to 14 hours (plus a self-selected 1 hour midday nap) without problems. Depression gradually improved when midday light therapy was added; near-euthymia was attained after light therapy was shifted to the morning. Conclusions: Nonpharmacological chronobiological treatments may be a means to interrupt rapid cycling.
Manipulations of the sleep-wake cycle, whether of duration (total or partial sleep deprivation [SD]) or timing (partial SD, phase advance), have profound and rapid effects on depressed mood in 60% of all diagnostic subgroups of affective disorders. Relapse after recovery sleep is less when patients are receiving medication; it may be prevented by co-administration of lithium, pindolol, serotonergic antidepressants, bright light, or a subsequent phase advance procedure. Diurnal and day-to-day mood variability predict both short-term response to SD and long-term response to antidepressant drug treatment. These mood patterns can be understood in terms of a “two-process model of mood regulation” based on the model well established for sleep regulation: the interaction of circadian and homeostatic processes. The therapeutic effect of SD is postulated to be linked to changes in disturbed circadian- and sleep-wake-dependent phase relationships and concomitant increase of slow-wave-sleep pressure; additionally, SD-induced sleepiness may counteract the hyperarousal state in depression. This model has the advantage of providing a comprehensive theoretical framework and stringent protocols (“constant routine,”,“forced desynchrony”) to dissect out specific disturbances. Many aspects tie in with current serotonergic receptor hypotheses of SD action. A treatment inducing euthymia in severely depressed patients within hours is an important therapeutic option that has come of age for clinical use.
Warm feet promote the rapid onset of sleep. Nature, 401: 36-37.
Why is sleep deprivation an orphan drug? Psychiatry Research, 81: 281-282.
Beginning to see the light. (Invited Commentary) Archives of General Psychiatry, 55: 861-862.
Follow-up study of seasonal affective disorder in Switzerland. Psychopathology, 30: 208-214.
Of 39 diagnosed Seasonal Affective Disorder (SAD) patients who were interviewed 2-5 years after participation in a light therapy trial, 10 continued to have recurrent major depressive episodes in winter, and 17 manifested sub-syndromal SAD (2 patients also had recurrent brief depression, seasonal type). 8 patients had recovered, and 4 had shifted in symptomatology. Thus, over a number of years, the clinical diagnosis changed for the better in 64% of the patients, suggesting that SAD is not a prodromal form of a more chronic major affective disorder, and that light therapy (and perhaps also light-oriented behaviour) reduced the incidence and depth of subsequent depressive episodes. Further evidence for this was the large reduction in use of conventional antidepressant drugs (from 17 to 1) during the follow-up period. Diagnosis of SAD was stable and reliable.
Homeostatic versus circadian effects of melatonin on thermoregulation in humans. Journal of Biological Rhythms, 12: 509-517.
Evidence obtained in animals has suggested a link of the pineal gland and its hormone melatonin with the regulation of core body temperature (CBT). Depending on the species considered, melatonin intervenes in generating seasonal rhythms of daily torpor and hibernation, in heat stress tolerance, and in setting the CBT set point. In humans, the circadian rhythms of melatonin is strictly associated with that of CBT, the nocturnal decline of CBT being inversely related to the rise of melatonin. Whereas there is inconsistent evidence for the suggestion that the decline of CBT may prompt the release of melatonin, conversely, stringent data indicate that melatonin decreases CBT. Administration of melatonin during the day, when it is not normally secreted, decreases CBT by about 0.3 to 0.4 degree C, and suppression of melatonin at night enhances CBT by about the same magnitude. Accordingly, the nocturnal rise of melatonin contributes to the circadian amplitude of CBT. The mechanisms through which melatonin decreases CBT are unclear. It is known that melatonin enhances heat loss, but a reduction of heat production cannot be excluded. Besides actions on peripheral vessels aimed to favor heat loss, it is likely that the effect of melatonin to reduce CBT is exerted mainly in the hypothalamus, where thermoregulatory centers are located. Recent observations have shown that the acute thermoregulatory effects induced by melatonin and bright light are independent of their circadian phase-shifting effects. The effect of melatonin ultimately brings a saving of energy and is reduced in at least two physiological situations: aging and the luteal menstrual phase. In both conditions, melatonin does not exert its CBT-lowering effects. Whereas in older women this effect may represent an age-related alteration, in the luteal phase this modification may represent a mechanism of keeping CBT higher at night to promote a better embryo implantation and survival.
The acute soporific action of daytime melatonin administration: effects on waking EEG power density and alertness. Journal of Biological Rhythms, 12: 636- 643.
Melatonin has been reported to have soporific effects; following daytime administration, it induces sleepiness and reduces sleep onset latency. However, subjective sleepiness is masked by a variety of stimuli and behaviors; thus, it is important to be able to delineate objective psychophysiological sequelae of melatonin administration. Alertness decrements during wakefulness are correlated with augmented theta/alpha power in the waking electroencephalogram (EEG). This has been validated in a constant routine protocol. In a variety of experiments with melatonin administration (5 mg), the authors have shown that the EEG changes can be measured immediately, before any subjective soporific effects are recognized. These increases in theta/alpha power occur when melatonin is administered during the day (1300 or 1800 h) but are less visible when near the endogenous melatonin rise in the evening (2040 h). Importantly, both subjective and objective measures of sleepiness are suppressed when subjects change posture from supine to standing.
'Natural' light treatment of seasonal affective disorder.Journalof Affective Disorders, 37: 109-120.
Patients with seasonal affective disorder (SAD) were treated for 1 week either with a daily 1-h morning walk outdoors (natural light) or low-dose artificial light (0.5 h@2800 lux). The latter treatment (given under double-blind conditions) can be considered mainly placebo and did not improve any of the depression self-ratings, whereas natural light exposure improved all self-ratings. According to the Hamilton depression score, 25% remitted after low-dose artificial light and 50% after the walk. Sleep duration or timing were not crucial for the therapeutic response. The morning walk phase-advanced the onset and/or offset of salivary melatonin secretion, but individual clinical improvement could not be correlated with specific phase-shifts. Morning cortisol was decreased. Low-dose artificial light did not modify melatonin or cortisol patterns. This is the first study to provide evidence for the use of outdoor light exposure as a potential alternative or adjuvant to conventional artificial light therapy in SAD.
Melatonin: nature's soporific? Journal of Sleep Research, 5: 1137-141.
Bright white light does not improve narcoleptic symptoms. Eur Arch Psychiatry Neurol Sci. 238:203-7.
Bright white light (500lx) for 4 h/day was applied to seven narcoleptic patients (age 47-65 years, mean 55 years). The effects of the light on the disturbed sleep-wake cycle in narcoleptics were investigated by the measurement of the following parameters: (1) excessive daytime sleepiness and sustained attention (multiple sleep latency test); (2) rest-activity cycles; (3) self-ratings (mood, anxiety, tiredness); (4) urinary cycles of 6-OH melatonin sulphate and cortisol; (5) sleep EEG. Treatment with bright light showed neither objective nor subjective changes in the clinical symptoms of narcolepsy. While similar "dosage" light applications can phase shift human circadian rhythms and improve depression and hypersomnia in winter depression, it is not an appropriate treatment for narcolepsy.
The non-entrained life of a young gentleman at Oxford. Sleep. 10:57-61.
Sleep logs over 9 months document the delayed sleep phase of a healthy male student at Oxford. The lack of any imperative zeitgebers also permits the rest-activity cycle to exhibit very long (circabidian) days similar to those seen under conditions of temporal isolation. No psychopathology or subjective distress was associated with this unusual rest-activity cycle: It was a preferred life-style.
Seasonality in freerunning circadian rhythms in man. Naturwissenschaften. 71:316-9.
Retrospective analysis of data collected over 15 years in normal subjects isolated from time cures showed seasonal rhythms in the circadian period of the core temperature rhythm, in the amount of sleep (both shorter in spring and longer in autumn), and in the incidence of internal desynchronisation (most often in summer). Women slept longer than men at all times of year.
Sleep, sleep deprivation and depression. A hypothesis derived from a model of sleep regulation. Hum Neurobiol. 1:205-10.
48-hour sleep-wake cycles in manic-depressive illness: naturalistic observations and sleep deprivation experiments. Arch Gen Psychiatry 39:559-65.
Wrist motor activity and sleep were monitored longitudinally in 15 rapidly cycling and 52 nonrapidly cycling manic-depressive patients. The majority of patients experienced one or more consecutive 48-hour sleep-wake cycles (alternate nights with no sleep) when they switched out of depression into mania of hypomania. During a depressive phase, nine rapidly cycling patients were asked to simulate a 48-hour sleep-wake cycle by remaining awake for 40 hours (one night's total sleep deprivation). Eight switched out of depression, and seven were rated as manic or hypomanic; indicating that sleep loss (such as occurs with spontaneous 48-hour sleep-wake cycles) may help to trigger switches from depression to mania. The 48-hour sleep-wake cycles in patients may depend on a mechanism that is normally present in all humans, since normal persons also spontaneously experience near-48 hour sleep-wake cycles in certain experimental conditions.
Phase advance of the circadian sleep-wake cycle as an antidepressant. Science. 206: 710-3.
Sleep in depressed patients resembles sleep in normal subjects whose circadian rhythms of temperature and rapid-eye-movement sleep are phase-advanced (shifted earlier) relative to their sleep schedules. If this analogy is relevant to the pathophysiology of depressive illness, advancing the time of sleep and awakening should temporarily compensate for the abnormal timing of depressed patients' circadian rhythms. Four of seven manic-depressive patients studied longitudinally spontaneously advanced their times of awakening (activity onset) as they emerged from the depressive phase of their illness. In a phase-shift experiment, a depressed manic-depressive woman was twice brought out of depression for 2 weeks by advancing her sleep period so that she went to sleep and arose 6 hours earlier than usual. The antidepressant effect of the procedure was temporary and similar in duration to circadian desynchronization induced by jet lag in healthy subjects. This result supports the hypothesis that abnormalities of sleep patterns in some types of depression are due to abnormal internal phase relationships of circadian rhythms.
Response to sleep deprivation as a predictor of therapeutic results with antidepressant drugs. Am J Psychiatry. 136:1222-3
Oren Group
Circadian phase shifting, alerting, and antidepressant effects of bright light treatment. Clin Sports Med. 2005;24:381-413.
Bright light treatment is the most potent melatonin suppressor and circadian phase shifter and is a safe nonpharmacologic antidepressant for seasonal depression. In addition, bright light treatment may restore performance in conditions of sleep debt and misalignment between peak performance and the athletic event. This article discusses the therapeutic use of bright light treatment, its side effects, and mechanisms of action.
Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings. J Clin Psychiatry. 2004;65:421-425.
BACKGROUND: Bright light therapy was shown to be a promising treatment for depression during pregnancy in a recent open-label study. In an extension of this work, we report findings from a double-blind placebo-controlled pilot study.
METHOD: Ten pregnant women with DSM-IV major depressive disorder were randomly assigned from April 2000 to January 2002 to a 5-week clinical trial with either a 7000 lux (active) or 500 lux (placebo) light box. At the end of the randomized controlled trial, subjects had the option of continuing in a 5-week extension phase. The Structured Interview Guide for the Hamilton Depression Scale-Seasonal Affective Disorder Version was administered to assess changes in clinical status. Salivary melatonin was used to index circadian rhythm phase for comparison with antidepressant results.
RESULTS: Although there was a small mean group advantage of active treatment throughout the randomized controlled trial, it was not statistically significant. However, in the longer 10-week trial, the presence of active versus placebo light produced a clear treatment effect (p =.001) with an effect size (0.43) similar to that seen in antidepressant drug trials. Successful treatment with bright light was associated with phase advances of the melatonin rhythm.
CONCLUSION: These findings provide additional evidence for an active effect of bright light therapy for antepartum depression and underscore the need for an expanded randomized clinical trial.
Brightening Depression. Science, 303: 467-468.
OBJECTIVE: About 5% of pregnant women meet criteria for major depression. No pharmacotherapy is specifically approved for antepartum depression; novel treatment approaches may be welcome. The authors explored the use of morning bright light therapy for antepartum depression. METHOD: An open trial of bright light therapy in an A-B-A design was conducted for 3-5 weeks in 16 pregnant patients with major depression. The Hamilton Depression Rating Scale, Seasonal Affective Disorders Version, was administered to assess changes in mood. A follow-up questionnaire was used to assess outcome after delivery. RESULTS: After 3 weeks of treatment, mean depression ratings improved by 49%. Benefits were seen through 5 weeks of treatment. There was no evidence of adverse effects of light therapy on pregnancy. CONCLUSIONS: These data provide evidence that morning light therapy has an antidepressant effect during pregnancy. A randomized controlled trial is warranted to test this alternative to medication.
Is seasonal affective disorder a disorder of circadian rhythms? CNS Spectr. 2001;6:487-94, 499-501.
Seasonal affective disorder (SAD) is a form of depression that starts in the fall and ends in the spring. This article reviews existing theories about the relationship between circadian rhythms and the disorder. Recent research indicates that as with pharmacologic antidepressants, at least 2-4 weeks are needed to demonstrate the effectiveness of bright-light therapy compared to placebo. The response to such treatment is strongest with precisely timed light exposure: treatment is optimal during the morning hours when the circadian system is susceptible to phase advance. Such clinical improvement is correlated with the magnitude of the phase shift induced. These observations suggest a model of circadian function in SAD and provide important guidelines for its treatment.
Tweaking the human circadian clock with light. Science. 1998;279:333-4.
To determine whether circadian profiles of various plasma hormones are abnormal in patients with winter seasonal affective disorder (SAD), we obtained 24-hour profiles of plasma cortisol, prolactin, and thyrotropin in subsets of a sample of 22 depressed patients with SAD on and off light therapy and in subsets of a sample of 24 normal controls. Cortisol levels did not differ between patients and controls, and levels in patients were not affected by light therapy. Prolactin levels were lower in patients than in controls throughout the day (p < 0.03) but were unaffected by light therapy. Independent of patient vs. control status, prolactin levels were higher in women than in men throughout the day (p < 0.003). Thyrotropin levels were no different in patients and controls, but levels in patients were lower following light therapy (p < 0.05).
The phototherapy light visor: more to it than meets the eye. Am J Psychiatry. 1995;152:1197-202.
OBJECTIVE: The purpose of the study was to ascertain whether phototherapy light visors provide an effective treatment for seasonal affective disorder. Previous studies have demonstrated a moderate response rate but have failed to find any difference in efficacy between light intensities. METHOD: Subjects were randomly assigned to receive, over a 2-week treatment period, 30 minutes of morning phototherapy with a light visor that emitted either a dim (30-lux) red light or a bright (600-lux) white light. Raters were blind to treatment, and patients were unaware of the alternatives. Response was assessed by using the structured 21-item Hamilton Depression Rating Scale, with an eight-item addendum for atypical depressive symptoms. Fifty-seven patients were enrolled across two sites. RESULTS: Patients assigned to the different visors had similar baseline depression scores and similar expectations of outcome. Hamilton depression scale scores declined by 34.6% for subjects given bright white light and by 40.9% for subjects given dim red light. Scores for atypical depressive symptoms fell by 44.1% for patients assigned the bright white light visors and by 49.0% for patients assigned the dim red light visors. Altogether, 39.3% of the patients who received red light and 41.4% of the patients who received bright white light showed a full clinical response. CONCLUSIONS: There were no significant differences in therapeutic response between patients who were treated with red or white light. The results of this study suggest that the phototherapy light visor may function as an elaborate placebo. Alternative explanations, however, are considered.
In a study of the quantitative relationship between ambient light and depression in winter seasonal affective disorder, 13 outpatients and 13 normal comparison subjects each wore a light monitor for 1 week. The patients and normal subjects showed similar light exposure profiles; among the patients, severity of depression was inversely related to photoperiod, and there was a trend toward a correlation between greater severity of depression and later time of onset of morning light exposure. These findings suggest that vulnerability to short photoperiods may be related to depression in winter seasonal affective disorder.
Side effects of light therapy in seasonal affective disorder. Am J Psychiatry. 1993;150:650-2.
The authors report the frequency of side effects of light therapy in 105 patients with seasonal affective disorder treated with three intensities of light. Common symptoms to emerge during treatment were headache (19%), eyestrain (17%), and feeling "wired" (14%). There was no relationship between side effects and intensity of light used.
Predictors of response to phototherapy in seasonal affective disorder. Compr Psychiatry. 1992;33:111-4.
We examined data from 44 women with seasonal affective disorder (SAD) to determine whether any demographic, diagnostic, or symptomatic characteristics would be predictive of a favorable response to phototherapy. Preexistent hypersomnia was particularly associated with lessening of depression after phototherapy. In contrast to a report elsewhere, both "typical" and "atypical" depressive symptoms correlated with improvement after phototherapy.
OBJECTIVE: This study sought to determine whether an equal photon density of green light is superior to red light in treating seasonal affective disorder. METHOD: After recruitment through the media, 20 outpatients with seasonal affective disorder participated in a balanced-order crossover trial of 1 week of green light therapy compared with 1 week of red light therapy. Each treatment consisted of 2 hours of daily light treatment at home in the early morning. Ultraviolet light was excluded from both treatment conditions. The photon densities of the two treatments (2.3 x 1015 photons/sec per cm2) were similar to those used in previous studies of therapy with 2500-lux white light. Fourteen patients completed the study. At least 1 week separated each treatment period to allow time for relapse. Effectiveness of treatment was assessed by analysis of variance of changes in ratings on the Hamilton Rating Scale for Depression. RESULTS: Although patients' expectations of the two treatments were similar, green light induced greater antidepressant effects than red light. A Sequence by Color interaction was also demonstrated. CONCLUSIONS: Green light provides a treatment effect superior to that of red light and similar to that seen in previous studies with white light. These results are consistent with the hypothesis that retinal photoreceptors mediate the antidepressant response in seasonal affective disorder. Identifying optimal wavelengths for light treatment is important in optimizing phototherapy efficacy.
Benedetti Group
Chronotherapeutics in a psychiatric ward. Sleep Med Rev. 2007;11:509-22.
Psychiatric chronotherapeutics is the controlled exposure to environmental stimuli that act on biological rhythms in order to achieve therapeutic effects in the treatment of psychiatric conditions. In recent years some techniques (mainly light therapy and sleep deprivation) have passed the experimental developmental phase and reached the status of powerful and affordable clinical interventions for everyday clinical treatment of depressed patients. These techniques target the same brain neurotransmitter systems and the same brain areas as do antidepressant drugs, and should be administered under careful medical supervision. Their effects are rapid and transient, but can be stabilised by combining techniques among themselves or together with common drug treatments. Antidepressant chronotherapeutics target the broadly defined depressive syndrome, with response and relapse rates similar to those obtained with antidepressant drugs, and good results are obtained even in difficult-to-treat conditions such as bipolar depression. Chronotherapeutics offer a benign alternative to more radical treatments of depression for the treatment of severe depression in psychiatric wards, but with the advantage of rapidity of onset.
Special 2007 Collection on Chronobiology and Psychiatry
Chronobiology and psychiatry. Sleep Med Rev. 11(6):423-7.
Humans show large inter-individual differences in organising their behaviour within the 24-h day—this is most obvious in their preferred timing of sleep and wakefulness. Sleep and wake times show a near-Gaussian distribution in a given population, with extreme early types waking up when extreme late types fall asleep. This distribution is predominantly based on differences in an individuals’ circadian clock. The relationship between the circadian system and different “chronotypes” is formally and genetically well established in experimental studies in organisms ranging from unicells to mammals. To investigate the epidemiology of the human circadian clock, we developed a simple questionnaire (Munich ChronoType Questionnaire, MCTQ) to assess chronotype. So far, more than 55,000 people have completed the MCTQ, which has been validated with respect to the Horne–Østberg morningness–eveningness questionnaire (MEQ), objective measures of activity and rest (sleep-logs and actimetry), and physiological parameters. As a result of this large survey, we established an algorithm which optimises chronotype assessment by incorporating the information on timing of sleep and wakefulness for both work and free days. The timing and duration of sleep are generally independent. However, when the two are analysed separately for work and free days, sleep duration strongly depends on chronotype. In addition, chronotype is both age- and sex-dependent.
Epidemiology of the human circadian clock. Sleep Med Rev. 11(6):429-38.
Humans show large inter-individual differences in organising their behaviour within the 24-h day—this is most obvious in their preferred timing of sleep and wakefulness. Sleep and wake times show a near-Gaussian distribution in a given population, with extreme early types waking up when extreme late types fall asleep. This distribution is predominantly based on differences in an individuals’ circadian clock. The relationship between the circadian system and different “chronotypes” is formally and genetically well established in experimental studies in organisms ranging from unicells to mammals. To investigate the epidemiology of the human circadian clock, we developed a simple questionnaire (Munich ChronoType Questionnaire, MCTQ) to assess chronotype. So far, more than 55,000 people have completed the MCTQ, which has been validated with respect to the Horne–Østberg morningness–eveningness questionnaire (MEQ), objective measures of activity and rest (sleep-logs and actimetry), and physiological parameters. As a result of this large survey, we established an algorithm which optimises chronotype assessment by incorporating the information on timing of sleep and wakefulness for both work and free days. The timing and duration of sleep are generally independent. However, when the two are analysed separately for work and free days, sleep duration strongly depends on chronotype. In addition, chronotype is both age- and sex-dependent.
This article reviews circadian thermoregulation in relation to sleep induction and phase of entrainment in the light of the comprehensive thermophysiological and chronobiological concepts of Jürgen Aschoff. The idea that temperature and sleep are interrelated is based on evolutionary history. Mammalian sleep developed in association with endothermy, and all species, independent of temporal niche, usually sleep during the circadian trough of their core body temperature (CBT) rhythm. The circadian pattern of CBT results from the balance between heat production and heat loss, the latter being relevant for sleep induction. Sleep under entrained conditions is typically initiated on the declining portion of the CBT curve when its rate of change and body heat loss is maximal. Body heat loss before lights off, via selective vasodilatation of distal skin regions, promotes sleepiness and the rapid onset of sleep. This thermophysiological effect represents the cement between the circadian clock and the sleep–wake cycle, and in turn determines phase of entrainment (?) and sleep onset latency (SOL). These interrelationships have been recently studied in a particular subset of the general population, mainly women, who suffer from cold hands and feet (the so-called vasospastic syndrome, VS). Women with VS exhibit not only a lower capacity to lose heat during the daytime but also a prolonged SOL, a disturbed ? of the circadian clock with respect to the sleep–wake cycle and psychologically, a disposition to turn experienced anger inwards. This naturalistic model leads us to a more general conclusion that regulation of distal skin blood flow may have clinical relevance for insomnia, in particular sleep onset insomnia.
Alerting effects of light. Sleep Med Rev. 11(6):453-64.
Light exerts powerful non-visual effects on a wide range of biological functions and behavior. In humans, light is intuitively linked with an alert or wakeful state. Compared to the effects of light on human circadian rhythms, little attention has been paid to its acute alerting action. Here I summarize studies from the past two decades, which have defined and quantified the dose (illuminance levels), exposure duration, timing and wavelength of light needed to evoke alerting responses in humans, as well as their temporal relationship to light-induced changes in endocrinological and electrophysiological sequelae of alertness. Furthermore, neuroanatomical and neurophysiological findings from animal studies elucidating a potential role of light in the regulation of sleep/wake states are discussed. A brief outlook of promising clinical and non-clinical applications of lights’ alerting properties will be given, and its involvement in the design of more effective lighting at home and in the workplace will be considered.
Live to the rhythm, slave to the rhythm. Sleep Med Rev. 11(6):465-484.
Circadian rhythms in health and disease have most often been described in terms of their phases and amplitudes, and how these respond to a single exposure to stimuli denoted as zeitgebers. The present paper argues that it is also important to consider the 24-h regularity in the repeated occurrence of the zeitgebers. The effect of the regularity of stimulation by light, melatonin, physical activity, body temperature, corticosteroids and feeding on synchronization within and between the central circadian clock and peripheral oscillators is discussed. In contrast to the phase shifts that can be recorded acutely after a single zeitgeber pulse, the effects of irregularly versus regularly timed zeitgeber can be studied only in long-term protocols and may develop slowly, which is a possible reason why they have received relatively little attention. Several observations indicate a reciprocal relation between the robustness of the endogenous circadian timing system and its dependency on regularly timed zeitgebers. Especially at old age and in disease, proper functioning of the circadian timing system may become more dependent on regularly timed exposure to zeitgeber stimuli. in such conditions, regularly timed exposure to zeitgeber appears to be highly important for health. After a concise introduction on inputs to the central and peripheral oscillators of the circadian timing system, the paper discusses the responses of the circadian timing system and health to (1) a chronic lack of zeitgeber stimuli; (2) fragmented or quasi-ultradian stimuli and (3) repeated phase shifts in stimuli. Subsequently, the specific relevance to aging is discussed, followed by an overview of the effects of experimentally imposed regularly timed stimuli. Finally, a possible mechanism for the gradually evolving effects of repeated regularly timed stimuli on the circadian timing system is proposed.
This paper presents a clinical review of delayed sleep phase syndrome (DSPS) and non-24-h sleep–wake syndrome (non-24). These syndromes seem to be common and under-recognized in society, not only in the blind, but also typically emerging during adolescence. Both types of syndrome can appear alternatively or intermittently in an individual patient. Psychiatric problems are also common in both syndromes. DSPS and non-24 could share a common circadian rhythm pathology in terms of clinical process and biological evidence. The biological basis is characterized by a longer sleep period, a prolonged interval from the body temperature nadir-to-sleep offset, a relatively advanced temperature rhythm, lower sleep propensity after total sleep deprivation, and higher sensitivity to light than in normal controls. There are multiple lines of evidence suggesting dysfunctions at the behavioral, physiological and genetic levels. Treatment procedures and prevention of the syndromes require further attention using behavioral, environmental, and psychiatric approaches, since an increasing number of patients in modern society suffer from these disorders
Evolving applications of light therapy. Sleep Med Rev. 11(6):497-507.
The psychiatric intervention, light therapy, grew from an intensive 25-year research focus on seasonal affective disorder (SAD). Dosing and timing strategies have been honed to optimize the antidepressant effect, and efficacy relative to placebo has provided the evidence base for widespread implementation. A persistent question has been whether the model system for SAD has wider utility for psychiatric disturbance, even beyond depression. The circadian phase-shifting capacity of timed light exposure is universal, and chronobiological factors are at play across the disease spectrum. Recent promising initiatives extend to light treatment for nonseasonal major depressive disorder and bipolar depression, including drug- and electroconvulsive therapy-resistant cases. With light therapy, patients with antepartum depression may find an alternative to medication during pregnancy. Cognitive improvement under light therapy has been noted in adult attention deficit hyperactivity disorder. Motor function in Parkinson's disease has improved in parallel with the antidepressant effect of light therapy. The rest–activity disturbance of elderly dementia has been partially allayed under light therapy. In a new initiative, three major chronotherapeutic inventions—light therapy, sleep deprivation (wake therapy) and sleep time displacement (sleep phase advance therapy) are being combined to snap hospitalized patients out of deep depression and maintain long-term improvement.
Chronotherapeutics in a psychiatric ward. Sleep Med Rev. 11(6):509-22.
Psychiatric chronotherapeutics is the controlled exposure to environmental stimuli that act on biological rhythms in order to achieve therapeutic effects in the treatment of psychiatric conditions. In recent years some techniques (mainly light therapy and sleep deprivation) have passed the experimental developmental phase and reached the status of powerful and affordable clinical interventions for everyday clinical treatment of depressed patients. These techniques target the same brain neurotransmitter systems and the same brain areas as do antidepressant drugs, and should be administered under careful medical supervision. Their effects are rapid and transient, but can be stabilised by combining techniques among themselves or together with common drug treatments. Antidepressant chronotherapeutics target the broadly defined depressive syndrome, with response and relapse rates similar to those obtained with antidepressant drugs, and good results are obtained even in difficult-to-treat conditions such as bipolar depression. Chronotherapeutics offer a benign alternative to more radical treatments of depression for the treatment of severe depression in psychiatric wards, but with the advantage of rapidity of onset.
Survey
Treatment of winter depression with bright light
| Rosenthal
NE, Sack DA, Gillin JC, et al. Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Archives of General Psychiatry 1984;41:72-80. Seasonal affective disorder (SAD) is a syndrome characterized by recurrent depressions that occur annually at the same time each year. We describe 29 patients with SAD; most of them had a bipolar affective disorder, especially bipolar II, and their depressions were generally characterized by hypersomnia, overeating, and carbohydrate craving and seemed to respond to changes in climate and latitude. Sleep recordings in nine depressed patients confirmed the presence of hypersomnia and showed increased sleep latency and reduced slow-wave (delta) sleep. Preliminary studies in 11 patients suggest that extending the photoperiod with bright artificial light has an antidepressant effect. |
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| Rosenthal
NE, Sack DA, Carpenter CJ, et al. Antidepressant effects of light in seasonal affective disorder. American Journal of Psychiatry 1985;142:163-170. The authors treated winter depression in 13 patients with typical seasonal affective disorder by extending the length of winter days with bright and dim light in the morning and evening in a balanced-order crossover study. Bright light had a marked antidepressant effect, whereas the dim light did not. This response could not be attributed to sleep deprivation. Subsequent pilot studies indicated that bright evening light alone is probably also effective. Several patients were able to maintain the antidepressant response throughout the winter months by continuing daily light treatments. |
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| Wehr
TA, Jacobsen FM, Sack DA, et al. Phototherapy of seasonal affective disorder: Time of day and suppression of melatonin are not critical for antidepressant effects. Archives of General Psychiatry 1986;43:870-875. Seasonal affective disorder is characterized by recurring cycles of fall-winter depression and spring-summer hypomania (or euthymia). In winter, depressed patients with seasonal affective disorder respond to daily treatments with five to six hours of bright artificial light in two to three days. They relapse two to three days after light is withdrawn. In this study carefully controlled experimental conditions were used to determine whether phototherapy acts via a photoperiodic mechanism in which the timing of light is critical for its therapeutic effect. Photoperiodism is a common regulatory mechanism in animal seasonal rhythms and depends for its effect on light-induced changes in the pattern of nocturnal melatonin secretion. The results reported herein of "skeleton photoperiod" experiments indicate that the efficacy of phototherapy may not depend on its timing or its effect on melatonin secretion. |
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| Lewy
AJ, Sack RL, Miller LS, et al. Antidepressant and circadian phase-shifting effects of light. Science 1987;235:352-353. Bright light can suppress nighttime melatonin production in humans, but ordinary indoor light does not have this effect. This finding suggested that bright light may have other chronobiologic effects in humans as well. Eight patients who regularly became depressed in the winter (as day length shortens) significantly improved after 1 week of exposure to bright light in the morning (but not after 1 week of bright light in the evening). The antidepressant response to morning light was accompanied by an advance (shift to an earlier time) in the onset of nighttime melatonin production. These results suggest that timing may be critical for the antidepressant effects of bright light. |
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| Terman
M, Terman JS, Quitkin FM, et al. Light therapy for seasonal affective disorder: a review of efficacy. Neuropsychopharmacology 1989;2:1-22. Bright artificial light has been found effective in reducing winter depressive symptoms of Seasonal Affective Disorder, although conclusions about the true magnitude of treatment effect and importance of time of day of light exposure have been limited by methodologic problems. Individual subjects' data from 14 research centers studying 332 patients over 5 years were analyzed with a pooled clustering technique. Overall, 2500-lux intensity light exposure for at least 2 hours daily for 1 week resulted in significantly more remissions &- Hamilton Depression Rating Scale (HAM-D) score reduction of 50% or more to a level under 8 &- when administered in the early morning (53%) than in the evening (38%) or at midday (32%). All three times were significantly more effective than dim light controls (11%). Dual daily exposures (morning-plus-evening light) provided no benefit over morning light alone. In the morning-evening crossovers, remission rates were 62% under morning light alone, compared with 28% under evening light alone, with a differential morning-evening response present in 59% of morning responders compared with 10% of evening responders (p < 0.001). Remission rates with morning light were highest given low severity at baseline (HAM-D score of 10-16: 67% remission), as compared with moderate-to-severe cases (HAM-D score above 16: approximately 40% remission) where no morning-evening differences were found. Firmer conclusions await treatment studies with larger sample sizes and full assessment of atypical vegetative symptoms seen in winter depression but underrepresented in the Hamilton scale. Longer treatment course and greater light intensity may help clarify clinical response despite the impossibility of achieving a conventional blind placebo control. |
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| Sack
RL, Lewy AJ, White DM, et al. Morning vs. evening light treatment for winter depression: Evidence that the therapeutic effects of light are mediated by circadian phase shifts. Archives of General Psychiatry 1990;47:342-351. Bright light exposure has been found to alleviate the symptoms of recurrent winter depression in many patients. The mechanism of light therapy may involve shifts in the timing (phase) of circadian rhythms. In this study, morning light exposure (which shifts rhythms earlier) was compared with evening light exposure (which shifts rhythms later) in a double-blind, crossover design. The onset of melatonin secretion in the evening was measured under dim light conditions as a marker for circadian timing (phase) before and after each treatment. Eight patients with winter depression and five control subjects were studied. Morning light was found to be significantly better than evening light in reducing depressive symptoms. At baseline, there was a trend for the onset of melatonin production to be later in the patients than in the controls. Morning light shifted the melatonin onset significantly earlier in the patients but not in the controls. Our findings suggest that patients with winter depression have circadian rhythms that are abnormally delayed and that bright light therapy benefits winter depression by providing a corrective advance. |
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| Terman
JS, Terman M, Schlager D, et al. Efficacy of brief, intense light exposure for treatment of winter depression. Psychopharmacology Bulletin 1990;26:3-11. A high-intensity fluorescent lighting system, tilted downward toward the head, and emitting negligible levels of ultraviolet radiation, was tested under two random crossover protocols in winter-depressed patients: 30-minute sessions at a) 3,000 lux vs. 10,000 lux in early morning, and (b) morning vs. evening sessions at 10,000 lux. Judgment of clinical remission was based jointly on relative and absolute score improvements on a Structured Interview Guide for the Hamilton Depression Scale &- Seasonal Affective Disorder Version (SIGH-SAD) which includes a set of supplementary atypical-vegetative items. Data are presented for 24 subjects who showed relapse upon withdrawal. An overall remission rate of 75 percent was found for morning light at 10,000 lux. The rates for evening light (25%) and 3,000 lux morning light (19%) were significantly lower. The remission rate for morning light treatment of 10,000 lux for 30 minutes approximately equaled 2,500 lux treatment for 2 hours (data from our earlier studies), suggesting a reciprocity between dosing dimensions of intensity and duration. No pathological changes were revealed by ophthalmological examinations given after 2 to 6 weeks of daily treatment. |
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| Terman
M, Amira L, Terman JS, et al. Predictors of response and nonresponse to light treatment for winter depression. American Journal of Psychiatry 1996;153(11):1423-1429. OBJECTIVE: The authors' goal was to determine whether the pattern and severity of depressive symptoms predict response to light treatment for seasonal affective disorder. METHOD: Subjects with winter depression (N = 103) were given bright light treatment. Seventy-one were classified as responders, 15 as nonresponders, and 17 as partial responders. Using depression rating scale data and correlational and multivariate analysis, the authors sought predictors of response in baseline symptom and scale scores. RESULTS: Responders were characterized by atypical symptoms, especially hypersomnia,afternoon or evening slump, reverse diurnal variation (evenings worse), and carbohydrate craving. By contrast, nonresponders were characterized mainly by melancholic symptoms, retardation, suicidality, depersonalization, typical diurnal variation (mornings worse), anxiety, early and late insomnia, appetite loss, and guilt. The ratio of atypical to classical symptoms of depression, rather than severity per se, best predicted treatment outcome for the group as a whole. Pretreatment expectations were positively correlated with improvement on the Hamilton Depression Rating Scale but not on a supplementary scale of atypical symptoms. CONCLUSIONS: Light responsive seasonal affective disorder is distinguished by a dominant atypical symptom profile closely associated with depressed mood. Nonresponders from a clinically distinct group with melancholic features. The patient's symptom profile, therefore, should be considered when diagnosing seasonal affective disorder and selecting treatment. |
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| Eastman
CI, Young MA, Fogg LF, et al. Bright light treatment of winter depression, a placebo-controlled trial. Archives of General Psychiatry 1998;55,883-889. Background: Bright light therapy is the recommended treatment for winter seasonal affective disorder (SAD). However, the studies with the best placebo controls have not been able to demonstrate that light treatment has a benefit beyond its placebo effect. Methods: Ninety-six patients with SAD completed the study. Patients were randomly assigned to 1 of 3 treatments for 4 weeks, each 1.5 hours per day: morning light (average start time around 6 AM), evening light (average start about 9 PM), or morning placebo (average start about 6 AM). The bright light (~6000 lux) was produced by light boxes, and the placebos were sham negative-ion generators. Depression ratings using the Structured Interview Guide for the Hamilton Depression Rating Scale, SAD version (SIGH-SAD) were performed weekly. Results: There were no differences among the 3 groups in expectation ratings or mean depression scores after 4 weeks of treatment. However, strict response criteria revealed statistically significant differences; after 3 weeks of treatment morning light produced more of the complete or almost complete remissions than placebo. By 1 criterion (24-item SIGH-SAD score <50% of baseline and =8), 61% of the patients responded to morning light, 50% to evening light, and 32% to placebo after 4 weeks of treatment. Conclusions: Bright light therapy had a specific antidepressant effect beyond its placebo effect, but it took at least 3 weeks for a significant effect to develop. The benefit of light over placebo was in producing more of the full remissions. |
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| Lewy
AJ, Bauer VK, Cutler NL, et al. Morning vs. evening Light treatment of patients with winter depression. Archives of General Psychiatry 1998;55:890-896. Background: According to the phase-shift hypothesis for winter depression, morning light (which causes a circadian phase advance) should be more antidepressant than evening light (which causes a delay). Although no studies have shown evening light to be more antidepressant than morning light, investigations have shown either no difference or morning light to be superior. The present study assesses these light-exposure schedules in both crossover and parallel-group comparisons. Methods: Fifty-one patients and 49 matched controls were studied for 6 weeks. After a prebaseline assessment and a light/dark and sleep/wake adaptation baseline week, subjects were exposed to bright light at either 6 to 8 AM or 7 to 9 AM for 2 weeks. After a week of withdrawal from light treatment, they were crossed over to the other light schedule. Dim-light melatonin onsets were obtained 7 times during the study to assess circadian phase position. Results: Morning light phase-advanced the dim-light melatonin onset and was more antidepressant than evening light, which phase-delayed it. These finding were statistically significant for both crossover and parallel-group comparisons. Dim-light melatonin onsets were generally delayed in the patients compared with the controls. Conclusions: These results should help establish the importance of circadian (morning or evening) time of light exposure in the treatment of winter depression. We recommend that bright-light exposure be scheduled immediately on awakening in the treatment of most patients with seasonal affective disorder. |
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| Terman
M, Terman JS, Ross DC. A controlled trial of timed bright light and negative air ionization for treatment of winter depression. Archives of General Psychiatry. 1998;55:875-882. BACKGROUND: Artificial bright light presents a promising nonpharmacological treatment for seasonal affective disorder. Past studies, however, have lacked adequate placebo controls or sufficient power to detect group differences. The importance of time of day of treatment--specifically, morning light superiority--has remained controversial. METHODS: This study used a morning x evening light crossover design balanced by parallel-group controls, in addition to a nonphotic control, negative air ionization. Subjects with seasonal affective disorder (N = 158) were randomly assigned to 6 groups for 2 consecutive treatment periods, each 10 to 14 days. Light treatment sequences were morning-evening, evening-morning, morning-morning, and evening-evening (10,000 lux, 30 min/d). Ion density was 2.7 x 10^6 (high) or 1.0 x 10^4 (low) ions per cubic centimeter (high-high and low-low sequences, 30 min/d in the morning). RESULTS: Analysis of depression scale percentage change scores showed low-density ion response to be inferior to all other groups, with no other group differences. Response to evening light was reduced when preceded by treatment with morning light, the sole sequence effect. Stringent remission criteria, however, showed significantly higher response to morning than evening light, regardless of treatment sequence. CONCLUSIONS: Bright light and high-density negative air ionization both appear to act as specific antidepressants in patients with seasonal affective disorder. Whether clinical improvement would be further enhanced by their use in combination, or as adjuvants to medication, awaits investigation. |
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| Wirz-Justice
A. Beginning to see the light. Archives of General Psychiatry. 1998;55:861-862. |
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| Golden
RN, Gaynes BN, Ekstrom RD, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. American Journal of Psychiatry. 2005;162:656-662. OBJECTIVE: The purpose of this study was to assess the evidence base for the efficacy of light therapy in treating mood disorders. METHOD: The authors systematically searched PubMed (January 1975 to July 2003) to identify randomized, controlled trials of light therapy for mood disorders that fulfilled predefined criteria. These articles were abstracted, and data were synthesized by disease and intervention category. RESULTS: Only 13% of the studies met the inclusion criteria. Meta-analyses revealed that a significant reduction in depression symptom severity was associated with bright light treatment (eight studies, having an effect size of 0.84 and 95% confidence interval [CI] of 0.60 to 1.08) and dawn simulation in seasonal affective disorder (five studies; effect size=0.73, 95% CI=0.37 to 1.08) and with bright light treatment in nonseasonal depression (three studies; effect size=0.53, 95% CI=0.18 to 0.89). Bright light as an adjunct to antidepressant pharmacotherapy for nonseasonal depression was not effective (five studies; effect size=-0.01, 95% CI=-0.36 to 0.34). CONCLUSIONS: Many reports of the efficacy of light therapy are not based on rigorous study designs. This analysis of randomized, controlled trials suggests that bright light treatment and dawn simulation for seasonal affective disorder and bright light for nonseasonal depression are efficacious, with effect sizes equivalent to those in most antidepressant pharmacotherapy trials. Adopting standard approaches to light therapy's specific issues (e.g., defining parameters of active versus placebo conditions) and incorporating rigorous designs (e.g., adequate group sizes, randomized assignment) are necessary to evaluate light therapy for mood disorders. |
Treatment of nonseasonal depression with bright light, wake therapy, or both
| Wirz-Justice
A, Van den Hoofdakker RH. Sleep deprivation in depression: what do we know, where do we go? Biolological Psychiatry. 1999;46:445-453. Manipulations of the sleep-wake cycle, whether of duration (total or partial sleep deprivation [SD]) or timing (partial SD, phase advance), have profound and rapid effects on depressed mood in 60% of all diagnostic subgroups of affective disorders. Relapse after recovery sleep is less when patients are receiving medication; it may be prevented by co-administration of lithium, pindolol, serotonergic antidepressants, bright light, or a subsequent phase advance procedure. Diurnal and day-to-day mood variability predict both short-term response to SD and long-term response to antidepressant drug treatment. These mood patterns can be understood in terms of a "two-process model of mood regulation" based on the model well established for sleep regulation: the interaction of circadian and homeostatic processes. The therapeutic effect of SD is postulated to be linked to changes in disturbed circadian- and sleep-wake-dependent phase relationships and concomitant increase of slow-wave-sleep pressure; additionally, SD-induced sleepiness may counteract the hyperarousal state in depression. This model has the advantage of providing a comprehensive theoretical framework and stringent protocols ("constant routine," "forced desynchrony") to dissect out specific disturbances. Many aspects tie in with current serotonergic receptor hypotheses of SD action. A treatment inducing euthymia in severely depressed patients within hours is an important therapeutic option that has come of age for clinical use. |
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| Wirz-Justice
A, Terman M, Oren DA, et al. Brightening depression. Science 2004;303:467-469. |
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| Wirz-Justice
A, Benedetti F, Berger M, et al. Chronotherapeutics (light and wake therapy) in affective disorders. Psychological Medicine. 2005;35:939-944. The Committee on Chronotherapeutics, delegated by the International Society for Affective Disorders (ISAD), makes the following recommendations after reviewing the evidence as of November 2004. (1) Wake therapy is the most rapid antidepressant available today: approximately 60% of patients, independent of diagnostic subtype, respond with marked improvement within hours. Treatment can be a single or repeated sleep deprivation, total (all night) or partial (second half of the night). Relapse can be prevented by daily light therapy, concomitant administration of SSRIs, lithium (for bipolar patients), or a short phase advance of sleep over 3 days following a single night of wake therapy. Combinations of these interventions show great promise. (2) Light therapy is effective for major depression--not only for the seasonal subtype. As an adjuvant to conventional antidepressants in unipolar patients, or lithium in bipolar patients, morning light hastens and potentiates the antidepressant response. Light therapy shows benefit even for patients with chronic depression of 2 years or more, outperforming their weak response to drugs. This method provides a viable alternative for patients who refuse, resist or cannot tolerate medication, or for whom drugs may be contraindicated, as in antepartum depression. (3) Given the urgent need for new strategies to treat patients with residual depressive symptoms, clinical trials of wake therapy and/or adjuvant light therapy, coupled with follow-up studies of long-term recurrence, are a high priority. |
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| Tuunainen
A, Kripke DF, Endo T. Light therapy for non-seasonal depression. Cochrane Database Systematic Reviews. 2004;(2):CD004050. BACKGROUND: Efficacy of light therapy for non-seasonal depression has been studied without any consensus on its efficacy. OBJECTIVES: To evaluate clinical effects of bright light therapy in comparison to the inactive placebo treatment for non-seasonal depression. SEARCH STRATEGY: We searched the Depression Anxiety & Neurosis Controlled Trials register (CCDANCTR January 2003), comprising the results of searches of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 -), EMBASE (1980 -), CINAHL (1982 -), LILACS (1982 -), National Research Register, PsycINFO/PsycLIT (1974 -), PSYNDEX (1977 -), and SIGLE (1982 - ) using the group search strategy and the following terms: #30 = phototherapy or ("light therapy" or light-therapy). We also sought trials from conference proceedings and references of included papers, and contacted the first author of each study as well as leading researchers in the field. SELECTION CRITERIA: Randomized controlled trials comparing bright light with inactive placebo treatments for non-seasonal depression. DATA COLLECTION AND ANALYSIS: Data were extracted and quality assessment was made independently by two reviewers. The authors were contacted to obtain additional information. MAIN RESULTS: Twenty studies (49 reports) were included in the review. Most of the studies applied bright light as adjunctive treatment to drug therapy, sleep deprivation, or both. In general, the quality of reporting was poor, and many reviews did not report adverse effects systematically. The treatment response in the bright light group was better than in the control treatment group, but did not reach statistical significance. The result was mainly based on studies of less than 8 days of treatment. The response to bright light was significantly better than to control treatment in high-quality studies (standardized mean difference (SMD) -0.90, 95% confidence interval (CI) -1.50 to -0.31), in studies applying morning light treatment (SMD -0.38, CI -0.62 to -0.14), and in sleep deprivation responders (SMD -1.02, CI -1.60 to -0.45). Hypomania was more common in the bright light group compared to the control treatment group (risk ratio 4.91, CI 1.66 to 14.46, number needed to harm 8, CI 5 to 20).Twenty studies (49 reports) were included in the review. Most of the studies applied bright light as adjunctive treatment to drug therapy, sleep deprivation, or both. Treatment REVIEWERS' CONCLUSIONS: For patients suffering from non-seasonal depression, bright light therapy offers modest though promising antidepressive efficacy, especially when administered during the first week of treatment, in the morning, and as an adjunctive treatment to sleep deprivation responders. Hypomania as a potential adverse effect needs to be considered. Due to limited data and heterogeneity of studies these results need to be interpreted with caution. |
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| Benedetti
F, Colombo C, Pontiggia A, et al. Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. Journal of Clinical Psychiatry. 2003;64:648-653. BACKGROUND: Selective serotonin reuptake inhibitors are effective in approximately 70% of patients with a major depressive episode, but therapeutic changes usually require 2 weeks of administration to become clinically relevant. Adjunct light therapy has been proposed to hasten the effects of drug treatment. The purpose of the present study was to evaluate the effect of morning light therapy or placebo combined with citalopram in the treatment of patients affected by a major depressive episode without psychotic features. METHOD: Thirty inpatients (DSM-IV major depressive disorder [N = 21] and bipolar disorder [N = 9]) were treated with citalopram, 40 mg, and randomized in a 3:2 manner to receive 30 minutes of 400 lux green light treatment in the morning or placebo (exposure to a deactivated negative ion generator) during the first 2 weeks of drug treatment. Timing of light therapy was individually defined to obtain a 2-hour phase advance to morning light. Outcome was measured with the Hamilton Rating Scale for Depression and the Zung Self-Rating Depression Scale every week, and with a Visual Analogue Scale 3 times a day during the first week. RESULTS: All outcome measures showed significantly (p <.05) better mood improvement in light-treated patients, resulting in faster responses to antidepressant treatment. CONCLUSION: The combination of citalopram and light treatment was more effective than citalopram and placebo in the treatment of major depression. With an optimized timing of administration, low-intensity light treatment significantly hastened and potentiated the effect of citalopram, thus providing the clinical psychiatrists with an augmenting strategy that was found effective and devoid of side effects. |
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| Martiny
K. Adjunctive bright light in non-seasonal major depression. Acta Psychiatrica Scandinavica Suppl. 2004;(425):7-28. OBJECTIVE: Bright light treatment is an established treatment for Seasonal Affective Disorder, but in non-seasonal depression research results have been contrasting. METHOD: This study was designed as a 5-week controlled, double-blind, parallel trial in out-patients with a diagnosis (DSM-IV) of non-seasonal major depression, randomized to either active treatment (white light, 10 000 lux, 1 h daily) or placebo treatment (red light, 50 lux, 30 min daily) and concomitant treatment with sertraline in both groups. RESULTS: One hundred and two patients were included in the study. Analyses showed that on all used scales the reduction in depression scores was larger in the bright light group than in the dim light group, and this reached statistical significance on all observer rating scales and on the SCL-90R self-assessment scale. The HAM-D6 was the most sensitive scale to measure improvement at endpoint. CONCLUSION: The study results support the use of bright light as an adjunct treatment to antidepressants in non-seasonal depression. |
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| Goel
N, Terman M, Terman JS, et al. Controlled trial of bright light and negative air ions for chronic depression. Psychological Medicine. 2005;35:945-955. BACKGROUND: This randomized controlled trial investigates the efficacy of two non-pharmacologic treatments, bright light and high-density negative air ions for non-seasonal chronic depression. Both methods have shown clinical success for seasonal affective disorder (SAD). METHOD: Patients were 24 (75%) women and 8 (25%) men, ages 22-65 years (mean age ± S.D., 43.7 ± 12.4 years), with Major Depressive Disorder, Single Episode (DSM-IV code, 296.2), Chronic (episode duration > or = 2 years). Patients were entered throughout the year and randomly assigned to exposure to bright light (10 000 lux, n = 10), or high-density (4.5 x 1014 ions/s flow rate, n = 12) or low-density (1.7 x 1011 ions/s, n = 10, placebo control) negative air ions. Home treatment sessions occurred for 1 h upon awakening for 5 weeks. Blinded raters assessed symptom severity weekly with the Structured Interview Guide for the Hamilton Depression Rating Scale--Seasonal Affective Disorder (SIGH-SAD) version. Evening saliva samples were obtained before and after treatment for ascertainment of circadian melatonin rhythm phase. RESULTS: SIGH-SAD score improvement was 53.7% for bright light and 51.1% for high-density ions v. 170% for low-density ions. Remission rates were 50%, 50% and 0% respectively. The presence or severity of atypical symptoms did not predict response to either treatment modality, nor were phase advances to light associated with positive response. CONCLUSIONS: Both bright light and negative air ions are effective for treatment of chronic depression. Remission rates are similar to those for SAD, but without a seasonal dependency or apparent mediation by circadian rhythm phase shifts. Combination treatment with antidepressant drugs may further enhance clinical response. |
Treatment of winter depression with dawn simulation
| Terman
M, Schlager D, Fairhurst S, et al. Dawn and dusk simulation as a therapeutic intervention. Biological Psychiatry. 1989;25:966-970. |
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| Terman
M and Schlager D. Twilight therapeutics, winter depression, melatonin, and sleep. Sleep and Biological Rhythms, J. Montplaisir and R. Godbout, Eds. New York: Oxford University Press, pp. 113-128. This chapter explores effects of simulated dawn twilight exposures on a group of winter depressives. We ask whether high daylight intensities are necessary to achieve the antidepressant effect if a more naturalistic exposure pattern is provided in the bedroom. Eight subjects in the New York City area were selected with a diagnosis of major affective disorder, depressed, seasonal type, winter pattern by DSM-III-R criteria.While in their depressed state during December through March the subjects were exposed, in 7- to 14-day home trials, to simulated twilight profiles delivered at the bedside. The lighting system included an encased bright fluorescent light source, light attenuation mechanism, microprocessor controller, and photosensor feedback loop. A comprehensive reference-generating algorithm was used to specify the expected momentary level of horizontal illumination of the earth's surface &- from skylight, sunlight, and starlight sources (and, optionally, from moonlight) &- across the 24-hr day at any specified day of year and geographic latitude. The morning light signals consisted of dawn profiles whose latitude, calendar date, and timing varied among the subjects. In all cases, the timing of the twilight signal corresponded to a calendar date well past the onset of natural remission for the subject. The light profiles, determined by the algorithm, progressed to a maximum illuminance approximately 1 min after sunrise, a level maintained until the subject left bed. After 2 weeks of daily dawn twilight exposure, six of the eight subjects showed full remissions of SAD symptoms. Naturalistic dawn exposures, timed to correspond to calendar dates during natural remission, appeared to be effective in alleviating symptoms of winter depression. |
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| Avery
DH, Bolte MA, Dager SR, et al. Dawn simulation treatment of winter depression: a controlled study. American Journal of Psychiatry 1993;150:113-117. OBJECTIVE: This study sought to determine whether dawn simulation was superior to a shorter dimmer "placebo" dawn signal in treating winter depression. METHOD: In a randomized, parallel design, 22 patients with winter depression were treated with either 1 week of a 2-hour dawn simulation peaking at 250 lux or 1 week of a 30-minute dawn simulation peaking at 0.2 lux. The subjects were told that they would receive either a "gradual" dawn or a "rapid" dawn reaching an intensity that would be dimmer than standard bright light treatment. At the end of both the baseline week and the treatment week, subjects were assessed in a blind manner with the Hamilton Rating Scale for Depression. Analysis of covariance was used to compare the two dawn treatments. RESULTS: The 2-hour, 250-lux dawn simulation resulted in Hamilton depression scale scores that were significantly lower than scores after the 30-minute, 0.2-lux dawn simulation. CONCLUSIONS: This study indicates that dawn simulation is an effective treatment for winter depression. |
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| Terman,
M. Light on sleep. Sleep Science: Integrating Basic Research and Clinical Practice, WJ Schwartz, Ed. Basel:Karger;1997,230-251. In this chapter, "the novel therapeutic applications of naturalistic light, soporific at dusk and alerting at dawn, [are evaluated]. Such an approach would have been unimaginable before it was discovered that human rhythms, like those in experimental animals, can be shifted and synchronized by photic stimuli. A good night's sleep may be one unforeseen casualty of our artificially-lit urban lifestyle." -W.J. Schwartz |
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| Avery
DH, Eder DN, Bolte MA, Hellekson CJ, Dunner DL, Vitiello MV, Prinz PN. Dawn simulation and bright light in the treatment of SAD: a controlled study. Biolological Psychiatry. 2001;50:205-216. BACKGROUND: Some small controlled studies have found that dawn simulation is effective in treating seasonal affective disorder (SAD). With a larger sample size and a longer duration of treatment, we compared dawn simulation with bright light therapy and a placebo condition in patients with SAD. METHOD: Medication-free patients with SAD were randomly assigned to one of three conditions: bright light therapy (10,000 lux for 30 min, from 6:00 AM to 6:30 AM), dawn simulation (1.5 hour dawn signal from 4:30 AM to 6:00 AM peaking at 250 lux), and a placebo condition, a dim red light (1.5 hour dawn signal from 4:30 am to 6:00 AM peaking at 0.5 lux.) Over the subsequent 6 weeks, the subjects were blindly rated by a psychiatrist using the Structured Interview Guide for the Hamilton Depression Rating-Seasonal Affective Disorder Version (SIGH-SAD). We modeled the profiles of the remissions (SIGH-SAD < or = 8) and response (> or =50% decrease in SIGH-SAD) to treatment over time using Cox proportional hazards models. RESULTS: The sample consisted of 95 subjects who were randomized to the three conditions: bright light (n = 33), dawn simulation (n = 31) and placebo (n = 31). Dawn simulation was associated with greater remission (p <.05) and response (p <.001) rates compared to the placebo. Bright light did not differ significantly from the placebo. Dawn simulation was associated with greater remission (p <.01) and response (p <.001) rates compared to the bright light therapy. The mean daily hours of sunshine during the week before each visit were associated with a significant increase in likelihood of both remission (p <.001) and response (p <.001). CONCLUSIONS: Dawn simulation was associated with greater remission and response rates compared to the placebo and compared to bright light therapy. The hours of sunshine during the week before each assessment were associated with a positive clinical response. |
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| Terman
M, Terman JS. Controlled trial of naturalistic dawn simulation and negative air ionization for seasonal affective disorder. American Journal of Psychiatry. 2006; in press. Background. This clinical trial assessed two novel nonpharmaceutical treatments for winter depression, naturalistic dawn simulation and high-density negative air ionization, delivered during the final hours of sleep. Methods. Patients were 99 adults (77 women, 22 men) with winter seasonal pattern of Major Depressive Disorder (94 cases) and Bipolar II Disorder (5 cases). Five parallel groups received: (a) dawn simulation (0.0003-250 lux in the pattern of 5 May at 45 ºN latitude); (b) a dawn light pulse (13 min, 250 lux, with illuminant dose of 3.25 x 103 lux•min matched to the simulated dawn); (c) post-awakening bright light (30 min, 10,000 lux); (d) negative air ionization at high flow rate (93 min, 4.5 x 1014 ions/sec); or (e) ionization at low flow rate (93 min, 1.7 x 1011 ions/sec). Symptoms were assessed over 3 weeks using the Structured Interview Guide for the Hamilton Depression Rating Scale – Seasonal Affective Disorder Version. Results. Posttreatment improvement was: bright light, 57.1%; dawn simulation, 49.5%; dawn pulse, 42.7%; high-density ions, 47.9%; and low-density ions, 22.7% (significantly lower than the others). Contrary to hypothesis, analysis of variance failed to find superiority of dawn simulation to the dawn pulse or bright light. However, the dawn pulse led to a pattern of residual or exacerbated depressive symptoms similar to that seen in low-density ion nonresponders. Conclusions. Naturalistic dawn simulation and high-density ionization are active antidepressants that do not require effort of post-awakening bright light therapy. They can be considered candidate alternatives to bright light or medication. |
Treatment of depression with high-density negative air ions
| Terman
M and Terman JS. Treatment of seasonal affective disorder with a high-output negative ionizer. Journal of Alternative and Complementary Medicine 1995;1:87-92. This study was designed to evaluate the antidepressant effect of negative ions in the ambient air as a potential treatment modality for seasonal affective disorder. Twenty-five subjects with winter depression underwent a double-blind controlled trial of negative ions at two exposure densities, 1 x 10(4) ions/cm3 or 2.7 x 10(6) ions/cm3, using an electronic negative ion generator with wire corona emitters. Home treatments were taken in the early morning for 30 min over 20 days, followed by withdrawals. The severity of depressive symptoms (prominently including the reverse neurovegetative symptoms of hypersomnia, hyperphagia, and fatigability) decreased selectively for the group receiving high-density treatment. Standard depression rating scale assessments were corroborated by clinical impressions. When a remission criterion of 50% or greater reduction in symptom frequency/severity was used, 58% of subjects responded to high-density treatment while 15% responded to low-density treatment (chi 2 = 5.00, df = 1, p = 0.025). There were no side effects attributable to the treatment, and all subjects who responded showed subsequent relapse during withdrawal. Treatment with a high-density negative ionizer appears to act as a specific antidepressant for patients with seasonal affective disorder. The method may be useful as an alternative or supplement to light therapy and medications. |
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| Terman
M, Terman JS, Ross DC. A controlled trial of timed bright light and negative air ionization for treatment of winter depression. Archives of General Psychiatry. 1998;55:875-882. BACKGROUND: Artificial bright light presents a promising nonpharmacological treatment for seasonal affective disorder. Past studies, however, have lacked adequate placebo controls or sufficient power to detect group differences. The importance of time of day of treatment--specifically, morning light superiority--has remained controversial. METHODS: This study used a morning x evening light crossover design balanced by parallel-group controls, in addition to a nonphotic control, negative air ionization. Subjects with seasonal affective disorder (N = 158) were randomly assigned to 6 groups for 2 consecutive treatment periods, each 10 to 14 days. Light treatment sequences were morning-evening, evening-morning, morning-morning, and evening-evening (10,000 lux, 30 min/d). Ion density was 2.7 x 10^6 (high) or 1.0 x 10^4 (low) ions per cubic centimeter (high-high and low-low sequences, 30 min/d in the morning). RESULTS: Analysis of depression scale percentage change scores showed low-density ion response to be inferior to all other groups, with no other group differences. Response to evening light was reduced when preceded by treatment with morning light, the sole sequence effect. Stringent remission criteria, however, showed significantly higher response to morning than evening light, regardless of treatment sequence. CONCLUSIONS: Bright light and high-density negative air ionization both appear to act as specific antidepressants in patients with seasonal affective disorder. Whether clinical improvement would be further enhanced by their use in combination, or as adjuvants to medication, awaits investigation. |
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| Terman
M, Terman JS. Controlled trial of naturalistic dawn simulation and negative air ionization for seasonal affective disorder. American Journal of Psychiatry. 2006; in press. Background. This clinical trial assessed two novel nonpharmaceutical treatments for winter depression, naturalistic dawn simulation and high-density negative air ionization, delivered during the final hours of sleep. Methods. Patients were 99 adults (77 women, 22 men) with winter seasonal pattern of Major Depressive Disorder (94 cases) and Bipolar II Disorder (5 cases). Five parallel groups received: (a) dawn simulation (0.0003-250 lux in the pattern of 5 May at 45 ºN latitude); (b) a dawn light pulse (13 min, 250 lux, with illuminant dose of 3.25 x 103 lux•min matched to the simulated dawn); (c) post-awakening bright light (30 min, 10,000 lux); (d) negative air ionization at high flow rate (93 min, 4.5 x 1014 ions/sec); or (e) ionization at low flow rate (93 min, 1.7 x 1011 ions/sec). Symptoms were assessed over 3 weeks using the Structured Interview Guide for the Hamilton Depression Rating Scale – Seasonal Affective Disorder Version. Results. Posttreatment improvement was: bright light, 57.1%; dawn simulation, 49.5%; dawn pulse, 42.7%; high-density ions, 47.9%; and low-density ions, 22.7% (significantly lower than the others). Contrary to hypothesis, analysis of variance failed to find superiority of dawn simulation to the dawn pulse or bright light. However, the dawn pulse led to a pattern of residual or exacerbated depressive symptoms similar to that seen in low-density ion nonresponders. Conclusions. Naturalistic dawn simulation and high-density ionization are active antidepressants that do not require effort of post-awakening bright light therapy. They can be considered candidate alternatives to bright light or medication. |
|
| Goel
N, Terman M, Terman JS, et al. Controlled trial of bright light and negative air ions for chronic depression. Psychological Medicine. 2005;35:945-955. BACKGROUND: This randomized controlled trial investigates the efficacy of two non-pharmacologic treatments, bright light and high-density negative air ions for non-seasonal chronic depression. Both methods have shown clinical success for seasonal affective disorder (SAD). METHOD: Patients were 24 (75%) women and 8 (25%) men, ages 22-65 years (mean age ± S.D., 43.7 ± 12.4 years), with Major Depressive Disorder, Single Episode (DSM-IV code, 296.2), Chronic (episode duration > or = 2 years). Patients were entered throughout the year and randomly assigned to exposure to bright light (10 000 lux, n = 10), or high-density (4.5 x 10^14 ions/s flow rate, n = 12) or low-density (1.7 x 10^11 ions/s, n = 10, placebo control) negative air ions. Home treatment sessions occurred for 1 h upon awakening for 5 weeks. Blinded raters assessed symptom severity weekly with the Structured Interview Guide for the Hamilton Depression Rating Scale--Seasonal Affective Disorder (SIGH-SAD) version. Evening saliva samples were obtained before and after treatment for ascertainment of circadian melatonin rhythm phase. RESULTS: SIGH-SAD score improvement was 53.7% for bright light and 51.1% for high-density ions v. 17% for low-density ions. Remission rates were 50%, 50% and 0% respectively. The presence or severity of atypical symptoms did not predict response to either treatment modality, nor were phase advances to light associated with positive response. CONCLUSIONS: Both bright light and negative air ions are effective for treatment of chronic depression. Remission rates are similar to those for SAD, but without a seasonal dependency or apparent mediation by circadian rhythm phase shifts. Combination treatment with antidepressant drugs may further enhance clinical response. |
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| Goel
Flory R, Ametepe J, Bowers B. A randomized, placebo-controlled trial of bright light and high-density negative air ions for treatment of Seasonal Affective Disorder. Psychiatry Res. 2010;177:101-1088. This study, conducted over the course of 5 years, assessed the antidepressant efficacy of two active treatments, bright white light and high-density negative ions, and the efficacy of two placebo treatments, dim red light and low-density negative ions, for Seasonal Affective Disorder (SAD). In a controlled laboratory setting, 73 women with SAD were exposed to one of the four treatment conditions over 12 consecutive days. Pretreatment expectation ratings did not significantly differ among the four treatment groups; however, expectation scores and treatment benefits were positively related. Over the course of treatment, subjects in all four groups showed significant score decreases on the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version-Self Rating (SIGH-SAD-SR) and on the Beck Depression Inventory (BDI). For raw scale scores, neither main effects of treatment nor interactions between treatment and time were significant. When remission outcome criteria were used, bright white light was significantly more effective than any of the other three treatments, and exposure to high-density negative ions was more effective than either of the two placebo conditions, although the difference was not significant. |
Treatment of sleep disorders (including jet lag and shift work distress) with light
| Eastman
CI, Gazda CJ, Burgess HJ, Crowley SJ, Fogg LF. Advancing circadian rhythms
before eastward flight: a strategy to prevent or reduce jet lag. Sleep.
2005;28(1):33-44. STUDY OBJECTIVES: To develop a practical pre-eastward flight treatment to advance circadian rhythms as much as possible but not misalign them with sleep. DESIGN: One group had their sleep schedule advanced by 1 hour per day and another by 2 hours per day. SETTING: Baseline at home, treatment in lab. PARTICIPANTS: Young healthy adults (11 men, 15 women) between the ages of 22 and 36 years. INTERVENTIONS: Three days of a gradually advancing sleep schedule (1 or 2 hours per day) plus intermittent morning bright light (one-half hour approximately 5000 lux, one-half hour of <60 lux) for 3.5 hours. MEASUREMENTS AND RESULTS: The dim light melatonin onset was assessed before and after the 3-day treatment. Subjects completed daily sleep logs and symptom questionnaires and wore wrist activity monitors. The dim light melatonin onset advanced more in the 2-hours-per-day group than in the 1-hour-per-day group (median phase advances of 1.9 and 1.4 hours), but the difference between the means (1.8 and 1.5 hours) was not statistically significant. By the third treatment day, circadian rhythms were misaligned relative to the sleep schedule, and subjects had difficulty falling asleep in the 2-hours-per-day group, but this was not the case in the 1-hour-per-day group. Nevertheless, the 2-hours-per-day group did slightly better on the symptom questionnaires. In general, sleep disturbance and other side effects were small. CONCLUSIONS: A gradually advancing sleep schedule with intermittent morning bright light can be used to advance circadian rhythms before eastward flight and, thus, theoretically, prevent or reduce subsequent jet lag. Given the morning light treatment used here, advancing the sleep schedule 2 hours per day is not better than advancing it 1 hour per day because it was too fast for the advance in circadian rhythms. A diagram is provided to help the traveler plan a preflight schedule. |
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| Boulos,
Z. Bright light treatment for jet lag and shift work. In: Seasonal Affective Disorder and Beyond: Light Treatment of SAD and Non-SAD Conditions, R.W. Lam, Ed. Washington, D.C.:American Psychiatric Press; 1998, 253-288. The phase response curve (PRC) can be used to predict the degree and direction of a circadian phase shift one will have based on the timing of exposure to bright light. Once the initial circadian rhythm phase for an individual is estimated, bright light can then be used to shift the rhythm. This chapter focuses on phase shifts in sufferers of jet lag or in shift workers. Results from laboratory studies and from field tests are presented. |
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| Campbell
SS, Dawson D, and Anderson MW. Alleviation of sleep maintenance insomnia with timed exposure to bright light. Journal of the American Geriatric Society 1993;41:829-836. OBJECTIVE: Half of the population over 65 suffers from chronic sleep disturbance. As a consequence, almost 40% of hypnotic medications are prescribed to people over age 60. Yet, hypnotics are often of little benefit in this population. As such, an effective non-drug alternative could prove important in the management of age-related sleep maintenance insomnia. The current study sought to evaluate the efficacy of bright light exposure in the treatment of sleep maintenance insomnia. DESIGN: Following baseline sleep and circadian rhythms assessment, subjects with sleep-maintenance insomnia were treated with timed exposure to either bright white light or dim red light for 12 consecutive days. Sleep and circadian rhythms recordings were subsequently obtained and measures of sleep quality were compared to assess efficacy of the treatments. SETTING: Baseline and post-treatment sleep and circadian rhythms assessments took place in the Laboratory of Human Chronobiology, Department of Psychiatry, Cornell University Medical College. The treatment phase of the study was conducted in participants' homes. PARTICIPANTS: Sixteen men and women between the ages of 62 and 81 years were studied. All subjects were free of hypnotic medication, and all had experienced sleep disturbance for at least 1 year prior to entering the study. RESULTS: Exposure to bright light resulted in substantial changes in sleep quality. Waking time within sleep was reduced by an hour, and sleep efficiency improved from 77.5% to 90%, without altering time spent in bed. Increased sleep time was in the form of Stage 2 sleep, REM sleep, and slow wave sleep. The effects were remarkably consistent across subjects. CONCLUSIONS: The findings demonstrate the effectiveness of timed exposure to bright light in the treatment of age-related sleep maintenance insomnia. With further refinement of treatment regimens, this non-drug intervention may prove useful in a large proportion of sleep disturbed elderly. |
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| Campbell
SS, Terman M, Lewy, AJ, et al. Light treatment for sleep disorders: consensus report. V. Age-related disturbances. Journal of Biological Rhythms 1995;10:151-154. Sleep maintenance insomnia is a major complaint among the elderly. As a result, an inordinate proportion of sleeping pill prescriptions go to individuals over 65 y of age. Because of the substantial problems associated with use of hypnotics in older populations, efforts have been made to develop nondrug treatments for age-related sleep disturbance, including timed exposure to bright light. Such bright light treatments are based on the assumption that age-related sleep disturbance is the consequence of alterations in the usual temporal relationship between body temperature and sleep. Although studies are limited, results strongly suggest that evening bright light exposure is beneficial in alleviating sleep maintenance insomnia in healthy elderly subjects. Less consistent, but generally positive, findings have been reported with regard to bright light treatment of sleep and behavioral disturbance in demented patients. For both groups, it is likely that homeostatic factors also contribute to sleep disturbance, and these may be less influenced by bright light interventions. |
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| Terman
M, Lewy AJ, Dijk DJ, et al. Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances. Journal of Biological Rhythms 1995;10:135-147. Advanced and delayed sleep phase disorders, and the hypersomnia that can accompany winter depression, have been treated successfully by appropriately timed artificial bright light exposure. Under entrainment to the 24-h day-night cycle, the sleep-wake pattern may assume various phase relationships to the circadian pacemaker, as indexed, for example, by abnormally long or short intervals between the onset of melatonin production or the core body temperature minimum and wake-up time. Advanced and delayed sleep phase syndromes and non-24-h sleep-wake syndrome have been variously ascribed to abnormal intrinsic circadian periodicity, deficiency of the entrainment mechanism, or--most simply--patterns of daily light exposure insufficient for adequate phase resetting. The timing of sleep is influenced by underlying circadian phase, but psychosocial constraints also play a major role. Exposure to light early or late in the subjective night has been used therapeutically to produce corrective phase delays or advances, respectively, in both the sleep pattern and circadian rhythms. Supplemental light exposure in fall and winter can reduce the hypersomnia of winter depression, although the therapeutic effect may be less dependent on timing. |
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| Boulos
Z, Macchi MM, Sturchler MP, et al. Light visor treatment for jet lag after westward travel across six time zones. Aviation, Space and Environmental Medicine. 2002;73:953-963. INTRODUCTION: The aim of this field study was to evaluate the efficacy of a light treatment for jet lag, using a head-mounted light visor, following a westward flight across six time zones. METHODS: There were 20 subjects who were exposed to bright white light (3000 lux) or dim red light (10 lux) for 3 h on the first two evenings after a flight from Zurich to New York. Salivary dim light melatonin onset (DLMO), assessed 2 d before and 2 d after the flight, provided a measure of circadian phase. Sleep was recorded by actigraphy, while post-flight performance testing and subjective scales provided additional indices of jet lag severity. RESULTS: The DLMO measurements showed a larger phase delay in the bright light than in the dim light group (2.59 h vs. 1.58 h, p < 0.02). There was no overall difference in sleep efficiency (SE) between the two groups, but a significant Group x Night interaction reflected a small increase across the first two post-flight nights in the bright light group, and a small decrease in the dim light group. Reaction time on one of two performance tests was consistently faster in the dim light group, but was unrelated to circadian phase or to prior sleep. There were no major group differences in subjective sleep quality, daytime sleepiness, jet lag severity, or mood. DISCUSSION: This is the first full-scale study to show that bright light treatment can accelerate circadian reentrainment following transmeridian travel. However, the effect on reentrainment rate was modest, and was not accompanied by any improvement in sleep, performance, or subjective assessments of jet lag symptoms. |
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| Revell
VL, Eastman CI. How to trick mother nature into letting you fly around or stay up all night. Journal of Biological Rhythms. 2005;20:353-365. Night shift work and rapid transmeridian travel result in a misalignment between circadian rhythms and the new times for sleep, wake, and work, which has health and safety implications for both the individual involved and the general public. Entrainment to the new sleep/wake schedule requires circadian rhythms to be phase-shifted, but this is often slow or impeded. The authors show superimposed light and melatonin PRCs to explain how to appropriately time these zeitgebers to promote circadian adaptation. They review studies in which bright light and melatonin were administered to try to counteract jet lag or to produce circadian adaptation to night work. They demonstrate how jet lag could be prevented entirely if rhythms are shifted before the flight using their preflight plan and discuss the combination of interventions that they now recommend for night shift workers. |
Treatment of sleep disorders with melatonin
| Hughes
RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep 1998;21(1):52-68. The present investigation used a placebo-controlled, double-blind, crossover design to assess the sleep-promoting effect of three melatonin replacement delivery strategies in a group of patients with age-related sleep-maintenance insomnia. Subjects alternated between treatment and "washout" conditions in 2-week trials. The specific treatment strategies for a high physiological dose (0.5 mg) of melatonin were: (1) EARLY: An immediate-release dose taken 30 minutes before bedtime; (2) CONTINUOUS: A controlled-release dose taken 30 minutes before bedtime; (3) LATE: An immediate-release dose taken 4 hours after bedtime. The EARLY and LATE treatments yielded significant and unambiguous reductions in core body temperature. All three melatonin treatments shortened latencies to persistent sleep, demonstrating that high physiological doses of melatonin can promote sleep in this population. Despite this effect on sleep latency, however, melatonin was not effective in sustaining sleep. No treatment improved total sleep time, sleep efficiency, or wake after sleep onset. Likewise, melatonin did not improve subjective self-reports of nighttime sleep and daytime alertness. Correlational analyses comparing sleep in the placebo condition with melatonin production revealed that melatonin levels were not correlated with sleep. Furthermore, low melatonin producers were not preferentially responsive to melatonin replacement. Total sleep time and sleep efficiency were correlated with the timing of the endogenous melatonin rhythm, and particularly with the phase-relationship between habitual bedtime and the phase of the circadian timing system. |
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| Hughes
RJ and Lewy AJ. Light and melatonin treatment of circadian sleep disorders. In: Seasonal Affective Disorder and Beyond: Light Treatment of SAD and Non-SAD Conditions, RW Lam, Ed. Washington, D.C.:American Psychiatric Press;1998,221-252. Three subtypes of circadian phase sleep disorders are identified and discussed, based on the melatonin phase and habitual sleeping pattern relative to normal sleep. Light treatment can be used to treat these disturbances. It appears that exogenous melatonin also affects the circadian phase. Optimal treatments using light, melatonin, or both are discussed. |
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| Zhdanova
IV, Wurtman RJ, Morabito C, et al. Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. Sleep 1996;19:423-431. Low oral doses of melatonin raise serum melatonin concentrations to those normally occurring nocturnally and facilitate polysomnographically assessed sleep onset when given at different time points throughout the day, without altering mood or performance on the morning following treatment. In the present study, 12 young healthy volunteers, free of sleep disturbances, received 0.3 or 1.0 mg of melatonin or placebo at 2100 hours, 2-4 hours prior to their habitual bedtime. Polysomnographic recording of overnight sleep began at 2200 hours and continued until 0700 hours the following morning, when subjects were awakened. Sleep onset latency and latency to stage 2 sleep were significantly decreased as a result of melatonin treatment. Neither dose of melatonin significantly altered sleep architecture. Administration of the lower dose of melatonin (0.3 mg) at 2100 hours elevated serum melatonin to levels within the normal nocturnal range (113 +/- 13.5 pg./ml) at the time the sleep test was initiated. Neither melatonin dose caused "hangover effects", as assessed by self-reports or by mood and performance tests administered on the morning following treatment. These observations provide additional evidence that nocturnal melatonin secretion has a sleep-promoting function. They also indicate that an increase in serum melatonin concentrations, within the normal physiologic range, does not significantly alter sleep architecture in subjects with normal sleep who receive the treatment several hours prior to their habitual bedtime. |
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| Haimov
I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep. 1995;18:598-603. Changes in sleep-wake patterns are among the hallmarks of biological aging. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before desired bedtime. The tablets were either 2 mg melatonin administered as sustained-release or fast-release formulations, or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2-month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonin-deficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep. |
Safety of bright light therapy
| Gallin
PF, Terman M, Remé CE, et al. Ophthalmologic examination of patients with seasonal affective disorder, before and after bright light therapy. American Journal of Ophthalmology 1995;119:202-210. PURPOSE: We assessed the potential ocular hazards of bright light therapy for patients with seasonal affective disorder, after both short- and long-term treatment, and identified prospective patients with pre-existing ocular abnormalities. METHODS: Fifty patients with seasonal affective disorder received daily exposure to artificial light in the morning or evening for 30 minutes at an illuminance level of 10,000 lux (irradiant dose, 0.016 J/cm2). Ophthalmologic examinations were performed before and after short-term treatment (two to eight weeks) and after three to six years of use during the fall and winter months. Over the four years of patient intake, the eye examination included subsets of the following tests: visual acuity, intraocular pressure, slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, color vision, visual field, fundus photography, Amsler grid, ocular motility, pupillary reactions, contrast sensitivity, stereopsis, and the macular stress test. RESULTS: No ocular changes were detected after short-term treatment. Long-term treatment (three to six years) of 17 patients, with cumulative exposure durations of 60 to 1,250 hours, also resulted in no ocular abnormalities. CONCLUSIONS: Light therapy yields about 75% clinical remissions. It is effective as an antidepressant and appears safe for the eyes. Current knowledge is insufficient to specify any definite ocular contraindications for bright light therapy, although we recommend that patients with preexisting ocular abnormalities and those using photosensitizing drugs undergo treatment only with periodic ophthalmologic examination. |
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| Remé
CE, Rol P, Grothmann K, et al. Bright light therapy in focus: lamp emission spectra and ocular safety. Technology and Health Care 1996;4:403-413. In recent years, bright light treatment of seasonal affective disorder (SAD), recurrent depressions in fall and winter, has been discovered. Newer applications include circadian sleep phase disorder, shift work and jet lag. Apart from creating the visual signal, light can modify retinal structure and physiology. UV and visible light lead to distinct lesions of ocular tissues under certain experimental and naturalistic conditions. In light therapy, a large variety of fixtures is used but the spectral emission of lamps is mostly unknown to the user and clinician leading to the potential hazard of ocular lesions. Therefore, we have analyzed a wide selection of light sources commonly used for treatment. We measured the spectral emission and calculated irradiant doses for several light therapy regimens. Based on these measurements, potential hazards are analyzed, physiological mechanisms of light action are discussed and safety measures for bright light therapy are proposed. They include recommendations for lamps devoid of damaging spectral emissions and standardized therapy fixtures, ophthalmological monitoring of patients with eye diseases and control by optometrists for patients with healthy eyes who are likely to undergo light treatment for extended periods. |
Light treatment methodology
| Terman
M. Evolving applications of light therapy. Sleep Med Rev. 2007;11-497-507. The psychiatric intervention, light therapy, grew from an intensive 25-year research focus on seasonal affective disorder (SAD). Dosing and timing strategies have been honed to optimize the antidepressant effect, and efficacy relative to placebo has provided the evidence base for widespread implementation. A persistent question has been whether the model system for SAD has wider utility for psychiatric disturbance, even beyond depression. The circadian phase-shifting capacity of timed light exposure is universal, and chronobiological factors are at play across the disease spectrum. Recent promising initiatives extend to light treatment for nonseasonal major depressive disorder and bipolar depression, including drug- and electroconvulsive therapy-resistant cases. With light therapy, patients with antepartum depression may find an alternative to medication during pregnancy. Cognitive improvement under light therapy has been noted in adult attention deficit hyperactivity disorder. Motor function in Parkinson's disease has improved in parallel with the antidepressant effect of light therapy. The rest-activity disturbance of elderly dementia has been partially allayed under light therapy. In a new initiative, three major chronotherapeutic inventions-light therapy, sleep deprivation (wake therapy) and sleep time displacement (sleep phase advance therapy) are being combined to snap hospitalized patients out of deep depression and maintain long-term improvement. |
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| Kennedy
SH, Lam RW, Cohen NL, et al. Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments. Canadian Journal of Psychiatry. 2001;46 (Suppl 1):38S-58S. BACKGROUND: The Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments partnered to produce clinical guidelines for psychiatrists for the treatment of depressive disorders. METHODS: A standard guidelines development process was followed. Relevant literature was identified using a computerized Medline search supplemented by review of bibliographies. Operational criteria were used to rate the quality of scientific evidence, and the line of treatment recommendations included consensus clinical opinion. This section, "Medications and Other Biological Treatments," is 1 of 7 articles that were drafted and reviewed by clinicians. Revised drafts underwent national and international expert peer review. RESULTS: Evidence-based recommendations are presented for 1) choosing an antidepressant, based on efficacy, tolerability, and safety; 2) the optimal use of antidepressants, including augmentation, combination, and switching strategies; 3) maintenance treatment; and 4) electroconvulsive therapy (ECT), light therapy, and additional somatic treatments. Evidence from metaanalyses is presented first, followed by conclusions from randomized controlled trials (RCTs) and, if appropriate, open-label data. CONCLUSIONS: There is significant evidence to support the role of selective serotonin reuptake inhibitors (SSRIs), novel agents, and classic agents in the treatment of major depressive disorder (MDD). There is also evidence to support the use of somatic treatments, including ECT and light therapy, for some patients with MDD. There is limited evidence for the use of specific medications to treat subtypes of MDD. There is emerging evidence to support augmentation and combination strategies for patients previously nonresponsive to medication. |
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| Terman
M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectrums. 2005;10:647-63. Bright light therapy for seasonal affective disorder (SAD) has been investigated and applied for over 20 years. Physicians and clinicians are increasingly confident that bright light therapy is a potent, specifically active, nonpharmaceutical treatment modality. Indeed, the domain of light treatment is moving beyond SAD, to nonseasonal depression (unipolar and bipolar), seasonal flare-ups of bulimia nervosa, circadian sleep phase disorders, and more. Light therapy is simple to deliver to outpatients and inpatients alike, although the optimum dosing of light and treatment time of day requires individual adjustment. The side-effect profile is favorable in comparison with medications, although the clinician must remain vigilant about emergent hypomania and autonomic hyperactivation, especially during the first few days of treatment. Importantly, light therapy provides a compatible adjunct to antidepressant medication, which can result in accelerated improvement and fewer residual symptoms. |
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| Terman
M, Terman JS. Light therapy. In: Principles and Practice of Sleep Medicine, 4th edition. Edited by Kryger MH, Roth T, Dement WC. Philadelphia, Elsevier, 2005, pp 1424-1442. The susceptibility of the circadian system to selective phase shifting by timed light exposure has broad implications for the treatment of sleep-phase and depressive disorders. Light therapies have been devised that can normalize the patterns of delayed sleep phase syndrome (through circadian phase advances) and advanced sleep phase syndrome (through circadian phase delays). Doctors and patients need to become cognizant of the daily intervals when light exposure—and darkness—can facilitate or hamper adjustment. The primary intervals lie at the edges of the “subjective night,” which coincide with the tails of the nocturnal melatonin cycle, but they can be inferred clinically through a chronotype questionnaire. The lighting schedule may have to be continually adjusted as the subjective night shifts gradually in the desired direction. The treatment strategy for seasonal and nonseasonal depressive disorders is similar. In winter depression, the magnitude of phase advances correlates with the degree of mood improvement, and the optimum timing of light therapy must be specified relative to circadian rather than solar time. Apart from its use as a monotherapy, light therapy in both outpatient and inpatient trials indicates that light therapy accelerates remission of nonseasonal depression in conjunction with medication. Exploratory applications for treatment of antepartum and premenstrual depression, bulimia nervosa, sleep disruption of senile dementia, and shift work and jet lag disturbance are considered. The chapter provides the clinician with guidelines for selecting lighting apparatus based on safety, efficacy, and comfort factors; summarizes adverse effects of light overdose; and offers a straightforward protocol for selecting treatment time of day. |
Parkinson's disease and light
| Willis GL, Kelly AM,
Kennedy GA. Compromised circadian function in Parkinson's disease: enucleation augments disease severity in the unilateral model. Behav Brain Res. 2008;193:37-47. Like enucleation, lateral hypothalamic (LH) lesions sever the connection between the retina and the pineal thereby simulating ambient exposure to constant darkness. While LH lesions have been employed to study either circadian function or Parkinson's disease (PD) independently, the application of such lesions to study circadian involvement specifically in this disease has never been attempted. In the present study, unilateral lesions of the LH, which compromise nigro-striatal dopamine (NSD) function, were combined with enucleation ipsilateral or contralateral to the hemisphere where 6-hydroxydopamine was applied. In addition to the observation that hemi-enucleation produced patterns of motor function that were grossly atypical compared to visually intact rats, hemi-enucleation ipsilateral to t he side of NSD system denervation produced impairment of horizontal movement, limb retraction, ambulation and spontaneous or l-dopa induced turning. This impairment was more severe than that seen in rats with unilateral 6-OHDA lesions alone. Furthermore, hemi-enucleation contralateral to the side of unilateral NSD system denervation resulted in significantly improved performance on several parameters. While the rate of mortality in rats receiving unilateral 6-OHDA plus ipsilateral enucleation was similar to that occurring after bilateral lesions, it was not accompanied by severe weight loss and wasting that typically occurs in the acute stages of experimental PD. These results demonstrate the importance of the visual and circadian systems in PD and are consistent with reports that identify impaired circadian involvement as a major component in a wide range of neurological and neuropsychiatric conditions. |
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| Willis GL. Intraocular microinjections repair experimental Parkinson's disease. Brain Res. 2008;27;1217:119-131. Circadian involvement in Parkinson's disease (PD) and more specifically in nigro-striatal dopamine (NSD) function is of increasing interest to the neurosciences. Given that bright light therapy is of therapeutic value in PD, possible mechanisms underlying retinal involvement in this phenomenon was explored further by administering anti-Parkinsonian chemotherapies into the vitreus humour directly adjacent to the retina. 2 microl of a 100 mM solution of L-Dopa significantly improved motor function in the later stages of degeneration and during the day while the injection of 2 microl of a 10 mM solution of the melatonin receptor antagonist ML-23 improved motor function in the early stages of PD and during the dark phase of the light/dark cycle. The results suggest that the function of nigral cells is regulated by a more global system embracing circadian physiology that extends from the retina to the pineal. Furthermore, the induction of PD is characterised by an imbalance between melatonin and dopamine (DA) whereby this ratio is elevated at least 6 to 1 in favour of melatonin. The commonly observed treatment failures and side effects of DA replacement therapy probably result from increasing endogenous DA without taking parallel melatonin dysfunction into account. The proposed integrated function of the NSD and circadian systems may permit therapeutic targeting at a level which is safer, more effective and without the side effects of systemically administered regimens of DA replacement. |
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| Willis GL, Turner EJ Primary and secondary features of Parkinson's disease improve with strategic exposure to bright light: a case series study. Chronobiol Int. 2007;24(3):521-37. The antagonism of melatonin in models of Parkinson's disease (PD) can reduce the severity of motor impairment associated with dopamine (DA) degeneration. In consideration of the potent antidepressant effects of bright light therapy (LT), that LT suppresses melatonin secretion, that depression is commonly observed in PD, and that exposure to constant light facilitates recovery from experimental PD, the object of the present study was to strategically administer LT to PD patients and observe the effects on depression, insomnia, and motor performance. Twelve patients diagnosed with PD were exposed to white fluorescent light for 1-1.5 h at an intensity of 1000 to 1500 lux once daily commencing 1 h prior to the usual time of sleep onset, approximately 22:00 h in most patients. All patients were assessed before LT commenced and at two weeks, five weeks, and regular intervals thereafter. Within two weeks after commencing LT, marked improvement in bradykinaesia and rigidity was observed in most patients. Tremor was not affected by LT treatment; however, agitation, dyskinaesia, and psychiatric side effects were reduced, as verified by decreased requirement for DA replacement therapy. Elevated mood, improved sleep, decreased seborrhea, reduced impotence, and increased appetite were observed after LT. LT permitted the reduction of the dose of L-dopa, bromocriptine, or deprenyl in some patients by up to 50% without loss of symptom control. Factors limiting the efficacy of LT included multiple disease states, treatment compliance, polypharmacy, emotional stress, advanced age, and predominance of positive symptoms. The results of this case series study confirms previous work describing light as efficacious in the treatment of PD and suggest that controlled trials may help to elucidate how LT might be used strategically as an adjunct therapy to improve the morbidity of PD patients. |