Circadian time of morning light administration and therapeutic response in winter depression.

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.

Bright light therapy: side effects and benefits across the symptom spectrum.

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 symptoms. 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.

Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial.

OBJECTIVE: The goals of this study were to validate a new rating scale for measuring severity of jet lag and to compare the efficacy of contrasting melatonin regimens to alleviate jet lag. METHOD: This was a randomized, double-blind trial of placebo and three alternative regimens of melatonin (5.0 mg at bedtime, 0.5 mg at bedtime, and 0.5 mg taken on a shifting schedule) for jet lag. The subjects were 257 Norwegian physicians who had visited New York for 5 days. Jet lag ratings were made on the day of travel from New York back to Oslo (6 hours eastward) and for the next 6 days in Norway. The main outcome measures were scale and item scores from a new, syndrome-specific instrument, the Columbia Jet Lag Scale, that identifies prominent daytime symptoms of jet lag distress. RESULTS: There was a marked increase in total jet lag score in all four treatment groups on the first day at home, followed by progressive improvement over the next 5 days. However, there were no significant group differences or group-by-time interactions. In addition, there was no group effect for sleep onset, time of awakening, hours slept, or hours napping. Ratings on a summary jet lag item were highly correlated with total jet lag scores (from a low of r = 0.54 on the day of travel to a high of r = 0.80 on day 3). The internal consistency of the total jet lag score was high on each day of the study. CONCLUSIONS: The use of melatonin for preventing jet lag needs further study.

Summer mood in winter depressives: validation of a structured interview.

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.

Photopic and scotopic light detection in patients with seasonal affective disorder and control subjects.

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.

Chronic fatigue syndrome and seasonal affective disorder: comorbidity, diagnostic overlap, and implications for treatment.

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.

A controlled trial of timed bright light and negative air ionization for treatment of winter depression.

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.

Predictors of response and nonresponse to light treatment for winter depression.

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.

Circadian phase-response curves for simulated dawn and dusk twilights in hamsters.

Phase shifts of the circadian rhythm of wheel-running activity were compared in Syrian hamsters maintained in constant darkness and exposed to 1-h naturalistic dawn or dusk twilight ramps (0.003-10 lx), or to 1-h rectangular light pulses (1 lx) providing equal photon exposure. The phase-response curves (PRCs) for dusk and rectangular pulses were virtually identical and resembled the PRC for dawn pulses, except that the mean phase advance caused by dawn pulses at circadian time 19 (CT 19) was approximately 1 h smaller. This difference could not be accounted for by differences in the amount of wheel-running observed during light pulse exposure, because the animals ran more during dusk pulses than during either of the other two pulse types. In a second experiment, 15-min rectangular light pulses (1 lx) immediately preceded by a 47-min dawn ramp caused smaller phase delays at CT 13 than rectangular pulses alone, despite a 40% increase in total photon exposure, but phase advances at CT 19 did not differ between the two light treatments. These results indicate that phase shifts of the circadian pacemaker in hamsters are determined primarily, though not entirely, by total photon exposure. They also indicate that dawn pulses may be less effective than dusk or rectangular pulses at certain circadian phases, possibly due to light adaptation during the early portion of the dawn twilight.

Ophthalmologic examination of patients with seasonal affective disorder, before and after bright light therapy.

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.

Treatment of seasonal affective disorder with a high-output negative ionizer.

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.

Rod outer segment disk shedding in rats with lesions of the suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) of the hypothalamus constitutes a major pacemaker for circadian rhythms in mammals. Rod outer segment (ROS) disk shedding follows a circadian rhythm that persists after pre-chiasmatic optic nerve section (ONS) (Teirstein et al., Invest. Ophthalmol. Vis. Sci., 19 (1980) 1268-1273), suggesting local oscillatory control. However, entrainment and phase-shifting to light-dark (LD) cycles are disrupted, suggesting that central efferent signals are involved in phase control. In the present experiment, lesions of the SCN were administered to 45 rats, resulting in complete behavioral arrhythmicity in 24 rats, dampened rhythmicity in 11 rats and robust rhythms in 10 rats. The extent of lesions was verified by histological and immunocytochemical methods. After screening for presence or absence of activity rhythms, rats were assigned to separate groups for ROS disk shedding analysis at four phases relative to the (LD) 12:12 cycle: 1.5 h after light onset, 1.5 h after dark onset, and at corresponding phases immediately upon release into 24 h of constant darkness. The disk shedding pattern, with relatively high phagosome numbers during the early light phase and low numbers at nighttime, was similar for behaviorally arrhythmic, dampened and rhythmic groups. These data indicate an independence of the disk shedding rhythm from possible SCN humoral or neuronal efferent influences.

Is seasonal affective disorder a variant of atypical depression? Differential response to light therapy.

Similar symptomatology has been described for both seasonal affective disorder (SAD) and atypical depression. For example, hyperphagia, hypersomnia, and intense lethargy are common to both, suggesting that they might be subtypes of the same disorder. If SAD and atypical depression are different manifestations of the same underlying pathophysiology, treatment effective for one might also benefit the other. Bright artificial lights (2500 lux, 6-8 a.m. and p.m.) were significantly less effective in treating eight patients diagnosed as having atypical depression without a seasonal pattern than 25 SAD patients. Differential treatment outcome suggests that SAD and atypical depression are separate disorders.

Efficacy of brief, intense light exposure for treatment of winter depression.

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.

Light therapy for seasonal affective disorder. A review of efficacy.

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.

Response of the melatonin cycle to phototherapy for Seasonal Affective Disorder. Short note.

It is well-established that human nocturnal melatonin secretion is suppressed by presentation of artificial light greater than 2,000 lux, a level that is also therapeutically effective in alleviating winter depression symptoms of Seasonal Affective Disorder [SAD]. Furthermore, early-morning bright light induces phase advances of the melatonin cycle in SAD patients (Lewy et al., 1987a). The functional significance of melatonin in SAD remains unclear. With plasma melatonin sampled at 20-min intervals in a series of overnight studies, we found marked phase delays of the cycle, relative to that previously reported for normals, in 4/5 depressed SAD patients. 2,500 lux light exposure at 6-8 a.m. resulted in exponentially declining melatonin levels that approached low daytime baselines within two hours (t1/2 = 45.52 min). All five patients showed clinical remissions as well as phase advances of the melatonin cycle of 0.75 to 3.27 hours (mean, 1.94 +/- 0.84 hours) after one week of daily exposure from 6-8 a.m. and p.m. These results suggest that the combination of early morning and early evening light exposures induces circadian phase adjustments similar to those of morning light alone, by impacting a photosensitive interval when, in SAD, melatonin secretion overshoots its normal nocturnal phase.

Effects of illumination level on the rat's rhythmicity of brain self-stimulation behavior.

Rhythmic patterns in the rat's brain self-stimulation behavior were analyzed across levels of illumination, including conditions of constant illumination (LL), constant darkness (DD), and light-dark cycles (LD 12:12). LD entrainment was achieved with light intensities ranging from 0.25 to 440 lux, and little or no change was found in the phase-angle difference between the dominant spectral peak and the light transitions. Under constant conditions, the circadian period (tau) increased in proportion to illumination level, with means ranging from 24.10 h (DD) to 25.90 h (LL 440 lux). tau increased linearly as a function of long I within the range of 0.25 to 30 lux, yielding a change of 0.28 h for a 10-fold increment in illumination level, a value which closely matches Aschoff's [3] preliminary estimate of delta tau/delta ILL for the rat. The circadian spectral component was influenced by several factors. (1) Re-entrainment protocol. Given a succession of LL conditions without entrainment segments in between, circadian rhythmicity was obscured at high illumination levels. (2) Duration of LL exposure. Even following an entrainment segment, long-term LL resulted in reduced power or loss of the circadian component. (3) LD vs LL. Spectral power was consistently higher under entrainment than under corresponding LL intensities, and there was a trend toward reduced power as a function of LL intensity. A wide range of ultradian spectral components was found across conditions. Under entrainment, most such components were harmonics of the circadian fundamental; under constant conditions, the frequency relationships were relatively variable.