Patients with winter depression (seasonal affective disorder) respond beneficially to sleep deprivation and bright light, but the mechanisms of these responses remain unknown. The study was designed to test whether afternoon/evening melatonin can prevent further relapse after sleep deprivation (presumably due to a pharmacologically induced advance shift of circadian phase). Compared to phase advancing by alteration of sleep-wake schedule or by bright light exposure, the melatonin intake is a more tolerated treatment procedure, and it provides a possibility of blind comparison between chronotherapeutic and placebo treatments. The depression was scored in 16 female patients with winter depression and 17 age-matched female controls before and after total night sleep deprivation and after subsequent six-day administration of melatonin (0.5 mg) or placebo under double blind conditions. The melatonin intake was scheduled at 17:00 in order to produce a phase advance of circadian rhythms. Sleep deprivation resulted in 38% reduction of depression score in patients, but it did not reduce depression score in controls. After subsequent treatment with placebo or melatonin, slight but significant improvement of mood was found in controls. These treatments also stabilized the antidepressant response to sleep deprivation in patients. However, neither differential effect of melatonin and placebo on depression score nor alteration of habitual sleep timing was found in patients and controls. Thus, the study results do not provide evidence for the antidepressant potential of melatonin in patients with winter depression under realistic clinical conditions. The finding of stabilization of mood in patients with placebo points to the contribution of psychological factors to the therapeutic action of this and other types of innovative treatments for winter depression. To include psychosocial aspects in the theoretical framework of seasonal depression, we conceptualized depression as an evolved feature of emotional response to psychosocial rather than physical environment. The seasonality of depression might be explained by cumulative effects of aperiodical psychosocial factors and periodical physical factors on one of the mechanisms of brain neurotransmission.

Although bright light treatment may alleviate the symptoms of winter depression, it still remains to be clarified whether chronobiological mechanisms are involved in this antidepressant response. We studied the therapeutic action of bright light in 61 women with and 36 women without winter depression at the medical academic hospital near Novosibirsk (55 degrees North). Bright light was administered with cool-white incandescent lamp for seven days, two hours daily. The treatment started from either 8:00 (n =29 patients and 16 controls) or 16:00 (n =24 and 14, respectively) or 18:00 ( n =8 and 6, respectively). The subsets of bright light-treated subjects were then restudied in wintertime before and after one-week vacation in Firuza resort (south of Turkmeniya, 38 degrees North) ( n =19 and 0, respectively), in summertime (n =42 and 18, respectively) and in the next winter before and after a week 30-min exposure in the morning hours to dim red light emitting "Light Cap (n =9 and 0, respectively). The results suggest that, in controls, mood slightly but statistically significantly improved after light treatment and in summer. In patients, the improvement of mood after one week of bright light was comparable with the effects of such "natural treatments as trips south and transition from winter to summer seasons. Although next winter response to 0.5-h dim light was clinically significant, it was significantly worse compared to the previous response to 2-h bright light. Our therapeutic results indicate that, despite the different potential phase-shifting effect of bright light administered in the morning and in the second half of the day, the responses to all treatments are equally beneficial. This finding provides evidence against the view that circadian phase shifts are the key to the pathogenesis of winter depression and efficacy of light therapy. Although several different physiological effects of light therapy might be involved in the antidepressant response, none of them seems to be of more importance compared to psychological components of this response. Ours and earlier published reports on the independence of beneficial action of bright light from treatment timing support the suggestion that, in the open investigational trials, the placebo effect accounts for a large portion of the antidepressant response. We also reviewed several facts pointing to the close dependence of antidepressant effects of non-drug therapy upon patients' expectations and researchers' enthusiasm. In sum, unlike patients' chronobiology, their psychology seems to be most powerful mediator of the clinical response to bright light.

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.

It is not clear whether shifting of sleep per se, without a concomitant change in the light-dark cycle, can induce a phase shift of the human circadian pacemaker. Two 9-day protocols (crossover, counterbalanced order) were completed by 4 men and 6 women (20-34 years) after adherence to a 2330 to 0800 h sleep episode at home for 2 weeks. Following a modified baseline constant routine (CR) protocol on day 2, they remained under continuous near-darkness (< 0.2 lux, including sleep) for 6 days. Four isocaloric meals were equally distributed during scheduled wakefulness, and their timing was held constant. Subjects remained supine in bed from 2100 to 0800 h on all days; sleep was fixed from 2330 to 0800 h in the control condition and was gradually advanced 20 min per day during the sleep advance condition until a 2-h difference had been attained. On day 9, a 25 to 27 h CR protocol (~0.1 lux) was carried out. Phase markers were the evening decline time of the core body temperature (CBT) rhythm and salivary melatonin onset (3 pg/ml threshhold). In the fixed sleep condition, the phase drift over 7 days ranged from +1.62 to –2.56 h (for both CBT and melatonin rhythms, which drifted in parallel). The drifts were consistently advanced in the sleep advance schedule by +0.66 ± 0.23 (SEM) h for CBT ( p = 0.02) and by 0.27 ± 0.14 h for melatonin rhythms ( p = 0.09). However, this advance was small to medium according to effect size. Sleep per se may feed back onto the circadian pacemaker, but it appears to be a weak zeitgeber in humans.

Seasonal affective disorder (SAD), winter type, is a relatively recently described syndrome of recurrent episodes of fall-winter depression, fatigue, social withdrawal, oversleeping, overeating, carbohydrate craving and weight gain. Bright light treatment (LT) reverses these symptoms, else they disappear in spring (47). Association of winter depression with reduced day length may suggest that photoperiodic time measurement plays a role in etiology of this disease. LT of the first patient with winter depression (25) was inspired by the facts that, in animals, the day length response is mediated by the circadian rhythm of melatonin (MLT) (14) and, in humans, the exposure to bright light is necessary to suppress MLT secretion (24). However, most investigations argue against the involvement of this hormone in SAD and LT. The reports of the efficacy of midday light (66) were considered to lend no support for the involvement of day length response in SAD pathogenesis and the mechanism by which LT works. MLT administered orally in the morning and early evening did not completely reverse the effects of LT, although it did reproduce the atypical depressive symptoms of SAD (social withdrawal, hyperphagia, appetite and weight increase, carbohydrate craving, hypersomnia, fatigability and reverse diurnal variations) (49). In another study (73), MLT given to SAD patients either in the morning or in the evening had no effect on depressive symptoms, while bright light did.

The aims of the study were to test whether nocturnal white light can normalize menstrual cycles in oligomenorrheic women, and whether the phase of the menstrual cycle in which light is given is important for the shortening effect. Twenty-five women with long menstrual cycles (35.9-53.4 days on average) were treated for 1-3 cycles, each of which was preceded and followed by at least two untreated cycles. Treatments were 100 watt bedside lights administered for 5 consecutive nights. They centered at three different phases of the menstrual cycle: 6-7th, 14-17th or 23-25th days of the treated cycle (early, middle or late treatment, respectively). On average, the treatment cycle lengths were modestly, but significantly reduced compared to the duration of baseline cycles (more than 11%). The difference in the effects of the early, middle and late treatment was not significant. However, if middle or late treatments were administered in the latter half of the interval between the menstrual cycle onset and probable time of ovulation, reductions of the treated cycle length were substantial (more than 20%, resulting in cycles less than 33 days on average; p<0.001). Other treatments produced only weak (up to 7%), if any, cycle reductions. Moreover, we found a strong correlation (p<0.001) between the duration of baseline cycle and differential effect of middle treatment (compared to early or late treatment). Middle treatments reduced treated cycle duration to the normal range in the subjects with shorter mean baseline cycles (<42 days), while in the subjects with longer duration of baseline cycle the shortening effect was produced by late treatments (p=0.005 and p=0.001, respectively). The results support the suggestion that a bedside lamp used on nights prior to ovulation can cause reduction of long menstrual cycles.

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.

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. (Chronobiology International, 17(5), 659–668, 2000)

The study examines objective characteristics of sleep in women (n=31) with and without seasonal affective disorder, winter type, before and after a week of light treatment (at either 0800-1000 h, 1600-1800 h or 1800-2000 h). Subsamples of 13 patients and 7 controls were studied additionally in summer, and, among these patients, 9 were also recorded in spring and fall. Ranking the results from the lowest to the largest degree of deviation of sleep structure in patients from the norm yields the sequence: spring -> summer -> winter after light treatment -> fall -> winter before light treatment. In winter before light treatment the total amounts and percentage of slow wave sleep were significantly lower in responders to light (n=13) compared to both nonresponders (n=8) and controls (n=10), while following light treatment the difference disappeared. The reduced amounts of slow wave sleep in the depressive state predicted higher reduction and low posttreatment scores on psychiatric scales. Light treatment and summer season showed similar effects on patients' sleep: they caused an increase of slow wave sleep and a decline of sleep stage 2. Our data do not suggest that time of light treatment is important to achieve an antidepressant effect. Moreover, phase shifting effects of light treatment and of changing season on sleep EEG were not considerable. At the same time, subjective ratings of arousal demonstrated an advance shift of the arousal rhythm after morning and a delay shift after afternoon LT. We did not find significant changes in total amounts and percentage of REM sleep over time. The data suggest that abnormally increased need for REM sleep results in the hypersomnia and may be considered as a trait marker of winter depression. An abnormal architecture of nonREM sleep appears to be a state marker of those patients who benefit from bright light administered during waking hours.

This constant routine study (n=9 men) compared the phase delay of the circadian system induced by a single pulse of evening light (5000 lx at 2100–2400 h) in the presence or absence of exogenous melatonin (5 mg p.o. at 2040 h). On the treatment day, light and melatonin protracted and accelerated, respectively, the evening decline in core body temperature (CBT). Subjective sleepiness ratings showed parallel shifts, the earlier the decline in CBT, the sleepier. On the post-treatment day, light induced a phase delay in the mid-range crossing time of CBT decline independent of whether melatonin was co-administered or not. Subjective sleepiness was delayed in parallel. The phase delay of the circadian system by evening light appears to be independent of an immediate hyperthermic effect and is not mediated by melatonin.

From 1987 to 1994, seasonal affective disorder (SAD) has been diagnosed using the Rosenthal or DSM-III-R criteria. No major differences between them have been found, except that the DSM-III-R criteria were more stringent and difficult to implement. Little attention has been paid to differences in the criterion of the quality of improvement in summer. This study compared two groups of winter depressives characterized by complete or incomplete summer remission. Incomplete summer remission is associated with increased heterogeneity of the demographic and clinical profile of the disorder and a shift of this profile to that of classical depression. The data support clinical use of the DSM-IV criterion 'full remission' in the diagnosis of SAD.

The study evaluates the phase-shift hypothesis for seasonal affective disorder (Lewy et al., 1987, 1988) in parallel-design comparison of effects of morning (800-1000) or afternoon (1600-1800) light treatment on mood and circadian phase. Subjective arousal, body temperature, melatonin and cortisol were measured at 800, 1200, 1600, 2000 and 2400 in 23 women with seasonal depression and 20 controls before and after a week of bright light (2 hours per day). The rates of clinical response to both treatments were similar. Comparison of circadian variations did not provide evidence for significant phase-delay in patients compared to controls. However, morning light produced significant phase advance in patients, but not in controls. Also we found that advance phase shifts in well-responded patients were more often than in patients with worse response and controls. Before light treatment phase concordance between different variables in patients was lower compared to either themselves after light treatment or controls before and after light treatment. Dependence of antidepressant response to light from pretreatment circadian phases was also observed. Those patients who responded worse to morning light tended to have advance circadian phases, while those who responded worse to afternoon light tended to have delay phases. Although some results are lending support for the phase-shift hypothesis, other explanations for mechanisms by which biological rhythms are implicated in winter depression and light treatment might be suggested.

A sample of 1644 adults in Alaska, Chukotka, Yakutiya, Western Siberia and Turkmenistan were surveyed to examine the relationship between seasonal depressive behavior and sleep-wake patterns. Interviews included items derived from the Seasonal Pattern Assessment Questionnaire, a 20 item general depression scale, and a 40 item sleep-wake questionnaire designed to assess the underlying mechanisms which regulate the cycles of sleep and wakefulness. Results show that subjects who suffer from seasonal depressive behavior, at latitudes ranging from 38-66 degrees North, are characterized by a sleep-wake pattern including 1) difficulty waking in the morning, 2) a low capacity to be awake at unusual times (out of sync with normal circadian patterns) and 3) a lower quality of nighttime sleep. Subjects with high levels of general depression suffer many of the same sleep problems, but this is not due to the measured association between seasonality and other depression. Disturbances in sleep-wake patterns may help to expand our understanding of the pathogenesis of seasonal depressive behavior, but further research to differentiate it from general depression is required.