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.

Phase advance after one or three simulated dawns in humans.

A specially designed apparatus that can simulate the waveform of the dawn or dusk signal at any latitude and any day of the year has been shown to phase shift the circadian pacemaker in rodents and primates at a fraction of the illuminance previously used. Until recently, it was considered that rather high illuminances or rather long exposure episodes to room light were necessary to phase shift human circadian rhythms. This experiment shows that, under controlled conditions of a modified constant routine protocol, a single dawn signal is sufficient to phase advance the timing of the onset of secretion of the pineal hormone melatonin. The significant phase advance of salivary melatonin of 20 minutes, which is enhanced to 34 minutes after three consecutive dawn signals, is small, but appears to be of sufficient magnitude to entrain the human circadian pacemaker, which has an endogenous period of about 24.2h.

The human circadian pacemaker can see by the dawn's early light.

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 findings suggest that a naturalistic dawn signal is sufficient to forestall this natural delay drift. Zeitgeber transduction and circadian system response are hypothesized to be tuned to the time-rate-of-change of naturalistic twilight signals.

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.

Bright light therapy in focus: lamp emission spectra and ocular safety.

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.

Effects of twilights on circadian entrainment patterns and reentrainment rates in squirrel monkeys.

Entrainment patterns of the circadian rhythms of body temperature and locomotor activity were compared in 6 squirrel monkeys (Saimiri sciureus) exposed to daily illumination cycles with abrupt transitions between light and darkness (LD-rectangular) or with gradual dawn and dusk transitions simulating natural twilights at the equator (LD-twilight). Daytime light intensity was 500 lux, and the total amount of light emitted per day was the same in the two conditions. Mean daytime body temperature levels were stable in LD-rectangular but increased gradually in LD-twilight, reaching peak levels during the dusk twilight. Locomotor activity showed a similar pattern, but with an additional, secondary peak near the end of dawn. Activity duration was about 0.5 h longer in LD-twilight than in LD-rectangular, but the time of activity midpoint was similar in the two conditions. Reentrainment of the body temperature rhythm was faster following an 8-h advance of the LD cycle than following an 8-h delay, but did not differ significantly between the two LD conditions. These results provide no evidence that the inclusion of twilight transitions affected the strength of the LD zeitgeber, and suggest that the observed differences in the daily patterns reflected direct effects of light intensity on locomotor activity and body temperature rather than an effect of twilights on circadian entrainment mechanisms.

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.

Twilight transitions promote circadian entrainment to lengthening light-dark cycles.

The upper limits of entrainment of the circadian activity rhythm were compared in hamsters initially exposed to daily light-dark (LD) cycles with either abrupt (LD-rectangular) or simulated twilight (LD-twilight) transitions. Daytime illuminance (10 lx) and the total amount of light emitted per day were the same under the two LD cycles. One-half of the animals in each condition had access to dark nest boxes. The period of the LD cycles was then increased from 24 to 26 h, by 5 min per day. All animals in LD-twilight remained entrained to the lengthening cycle, whereas 60% of those in LD-rectangular began to free run well before the period of the cycle reached 26 h. These effects were independent of nest box availability. The lengthening LD cycles exerted clear aftereffects on the period of the rhythms in constant darkness, the magnitude of which was related to the efficacy of prior entrainment. The results indicate that twilight transitions raise the upper limit of entrainment to LD cycles, suggesting that their inclusion increases the strength of the LD zeitgeber.

Photic entrainment in hamsters: effects of simulated twilights and nest box availability.

Entrainment of wheel-running activity rhythms was compared in hamsters exposed to daily light-dark (LD) cycles with abrupt transitions between 0 and 10 lux or with artificial twilights simulating summer solstice conditions at 41 degrees N latitude but truncated at 10 lux. The photoperiod in LD-rectangular was set at 16.24 h, equating the total light (in lux.min) emitted under the two schedules. The LD cycles were maintained for 35 days and were followed by 14 days of constant darkness (DD). Half the animals in each condition had access to a dark nest box connected to the outer compartment by a tunnel, the remaining animals being confined to a single compartment. Body temperature and locomotor activity inside the nest boxes were recorded by telemetry. Movements between the nest box and the outer compartment were monitored and the data were used to calculate light exposure at different times of the day. In all groups, the phase angle difference between wheel-running onset and dusk was more positive than that between activity offset and dawn. Hamsters with access to nest boxes, however, had later onsets, earlier offsets, and shorter activity durations (alpha s) than those without. These effects could be accounted for by the difference in light exposure between the nest and no-nest animals, particularly light exposure in the morning. The inclusion of twilights also resulted in later onsets and shorter alpha s, but the differences were relatively small and were only observed in the nest animals. The day-to-day variability in activity onset was negatively correlated with onset time and was smaller in the twilight/nest animals than in the other three groups. Most animals showed an expansion of alpha during the first few days of DD, resulting from a rapid advance of activity onsets relative to offsets. The period of the rhythms, determined from the first five activity onsets in DD, was negatively correlated with the balance of evening and morning light exposure. These results are discussed in the context of nonparametric entrainment of compound pacemakers.