Extraocular light therapy in winter depression: a double-blind placebo-controlled study.

BACKGROUND: It has been hypothesized that the circadian pacemaker is phase delayed in seasonal affective disorder, (SAD) winter type, and that the phase advance resulting from morning ocular light accounts for the efficacy of light therapy. Extraocular light has been reported to produce phase-shifts of the human circadian pacemaker. This allows a double-blind, placebo-controlled study of light therapy in SAD. METHODS: Twenty-nine SAD patients participated. Clinical state was measured on days 1, 8, and 15 of the protocol. From days 4 through 8, 15 patients (4 M, 11 F) received extraocular light by fiberoptic illumination, and 14 (4 M, 10 F) placebo (no light) in the popliteal fossae, from 8 AM to 11 AM. In the evenings of days 3 and 8, the salivary dim light melatonin onset (DLMO) was assessed. Patients completed daily self-ratings on mood, alertness, and sleep. RESULTS: Both conditions showed a progressive improvement of clinical state over time. Between conditions, no significant differences were observed in clinical scores, the self-ratings on mood and alertness, and in timing of the DLMO before and directly after treatment. CONCLUSIONS: The response to extraocular light therapy in SAD patients did not exceed its placebo effect. Extraocular light did not induce a phase shift of the circadian pacemaker.

Body temperature and mood variations during forced desynchronization in winter depression: a preliminary report.

BACKGROUND: It has been suggested that certain abnormalities (e.g., in phase or amplitude) of the circadian pacemaker underlie seasonal affective disorder. METHODS: One male seasonal affective disorder patient (blind to the study design) participated in two 120-hour forced desynchrony experiments and was subjected to six 20-hour days, once during a depressive episode and once after recovery. Core body temperature was continuously measured. During wakefulness, the Adjective Mood Scale was completed at 2-hour intervals. RESULTS: Sleep-wake as well as pacemaker-related variations of mood were found, both when the subject was depressed and when he was euthymic. Compared with recovery, during the depressive episode the circadian temperature minimum and the circadian mood variation showed phase delays of approximately 1 and 2 hours, respectively. CONCLUSIONS: The data of this first seasonal affective disorder patient, participating in forced desynchrony experiments, may indicate a phase delay of the circadian pacemaker during a seasonal affective disorder episode.

Effects of light exposure and sleep displacement on dim light melatonin onset.

The purpose of the study was to induce in two different ways, a phase-angle difference between the circadian pacemaker and the imposed sleep-wake cycle in humans, we intended to: (i) shift the circadian pacemaker by exposure to bright light and keep the timing of the sleep-wake cycle fixed; and (ii) keep the timing of the circadian pacemaker fixed by a constant light-dark cycle and displace sleep. We monitored dim light melatonin onset (DLMO), core body temperature and sleep. DLMO was delayed significantly after 3 days of a 3-h delayed sleep-phase when compared with 3 days of sleep at a normal or 3-h advanced sleep-phase. The shifts in DLMO were not accompanied by shifts in body temperature, changes in waking-up time or by a change in the duration of the first rapid eye movement (REM) sleep episode. Three days of light exposure in the morning or evening resulted in shifts in DLMO of similar magnitude, but this was accompanied by shifts in the rhythm of body temperature, changes in waking-up time and in the duration of the first REM sleep episode. We conclude that the changes observed after light exposure reflect shifts in the circadian pacemaker. In contrast, we propose that the changes observed in DLMO after sleep displacement are not mediated by the circadian pacemaker. These results raise some doubts about the reliability of DLMO as a marker of circadian phase in cases of sleep disturbances. Finally, we initiate a search for changes in sleep that might be responsible for the unexpected effects on DLMO.

Sleep deprivation in depression: what do we know, where do we go?

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.

Prophylactic treatment of seasonal affective disorder (SAD) by using light visors: bright white or infrared light?

BACKGROUND: Thirty-eight patients with SAD participated in a light visor study addressing two questions. 1. Can the development of a depressive episode be prevented by daily exposure to bright light started before symptom onset in early fall and continued throughout the winter? 2. Does the light have to be visible in order to have beneficial effects? METHODS: Three groups participated in the study: I (n = 14) received bright white light (2500 lux); II, (n = 15) received infrared light (0.18 lux); III (n = 9, control group) did not receive any light treatment at all. RESULTS: Infrared light is just as effective as bright white light. Both are more effective than the control condition. CONCLUSIONS: Light visors can be effectively used to prevent the development of SAD. The fact that exposure to infrared light was as effective as exposure to bright white light questions the specific role of visible light in the treatment of SAD.

The prevalence of seasonal affective disorder in The Netherlands: a prospective and retrospective study of seasonal mood variation in the general population.

BACKGROUND: The aim of the present study was to assess the prevalence of seasonal affective disorder (SAD) in The Netherlands. METHODS: The subjects (n = 5356), randomly selected from community registers, were given the Seasonal Pattern Assessment Questionnaire and the Centre for Epidemiological Studies Depression Scale over a period of 13 months. The response rate was 52.6%. RESULTS: Three percent of the respondents met the criteria for winter SAD, 0.1% for summer SAD. The criteria for subsyndromal SAD, a milder form of SAD, were met by 8.5%, 0.3% of whom showed a summer pattern. Younger women received a diagnosis of SAD more often than men or older women. CONCLUSIONS: SAD subjects were significantly more often unemployed or on sick leave than other subjects. Respondents who met winter SAD criteria were significantly more depressed than healthy subjects, in both winter and summer. Finally, month of completion had no influence on the number of subjects meeting the SAD criteria.

Seasonal affective disorder and latitude: a review of the literature.

BACKGROUND: The aim of the study is to investigate the relationship between the prevalence of SAD and latitude. METHODS: An overview of the epidemiological literature on the prevalence of SAD is given and studies relevant for the latitudinal dependency of prevalence will be analyzed and discussed. RESULTS: The mean prevalence of SAD is two times higher in North America compared to Europe. Over all prevalence studies, the correlation between prevalence and latitude was not significant. A significant positive correlation was found between prevalence and latitude in North America. For Europe there was a trend in the same direction. CONCLUSIONS: The influence of latitude on prevalence seems to be small and other factors like climate, genetic vulnerability and social-cultural context can be expected to play a more important role. Additional controlled studies taking these factors into account are necessary to identify their influence.

Testing the hypothesis of a circadian phase disturbance underlying depressive mood in nonseasonal depression.

In a crossover design, 8 nonseasonal depressed subjects, selected on the presence of diurnal mood variations, and 8 sex- and age-matched controls were exposed to dim light (< 10 lux) in the evening (18:00-21:00 h) and bright light (2500 lux) in the morning (ML, 6:00-9:00 h), to dim light in the morning and bright light in the evening (EL), or to dim light both in the evening and in the morning (DL) during 3 consecutive days in each of these conditions. There were no initial phase differences between depressed and healthy subjects in the timing of dim light melatonin onset, sleep termination, and body temperature. The phase shifts after EL and ML in both healthy and depressed subjects were as expected on the basis of a human phase response curve. On average, there was no therapeutic effect of the light exposure in the depressed patients. Two patients improved, but these effects do not seem to be related to shifts in the circadian system.

The judgement of facial expressions by depressed patients, their partners and controls.

BACKGROUND: Research has shown that cognitive and interpersonal processes play significant roles in depression development and maintenance. Depressed patients judgments of emotions displayed in facial expressions, as well as those of their partners, allow for better understanding of these processes. METHODS: In this study, twenty major depression outpatients, their partners and control persons (matched on the sex and age of the partner) judged facial expressions as to the emotions they felt were portrayed, at the patients outpatient admission. It was expected that the patients would judge the facial expression more negatively and less positively than their partners and that the partners would judge more negatively and less positively than the controls. RESULTS: It was found that while both the patients and partners judged less positive emotions than the controls, the patients and partners did not judge the expressions differently. A trend in the same direction was found between the three groups as to judgment of negative emotions. CONCLUSION: These findings are related back to interpersonal and cognitive theories of depression. LIMITATION: A limitation of this study was the somewhat small patient population available for study. CLINICAL RELEVANCE: This study helps to shed light on the similarity between interpersonal and cognitive processes of depressed patients and their partners.

Endogenous and exogenous components in the circadian variation of core body temperature in humans.

Core body temperature is predominantly modulated by endogenous and exogenous components. In the present study we tested whether these two components can be reliably assessed in a protocol which lasts for only 120 h. In this so-called forced desynchrony protocol, 12 healthy male subjects (age 23.7 +/- 1.4 y) were subjected one by one to an artificial light/dark cycle of 20 h (10 lux vs. darkness). Core body temperature was measured continuously. The temperature data were analysed by an iterative method based on the assumption that the endogenous and exogenous components contribute to body temperature in an additive way. The results show that the average temperature curve is an almost perfect addition of the two components. The endogenous component differs from a sinusoid, and the relative contributions of the endogenous and exogenous components to the raw temperature curves differ substantially between the subjects. The average amount of unexplained variance in the individual data was 17%. Averaging of the body temperature curves over subjects reduced the unexplained variance to only 2%. This reduction in unexplained variance upon averaging over subjects must be due to the fact that most of the variance is either differently dependent on circadian phase for the various subjects or not dependent on circadian phase at all. The circadian pacemaker component revealed an average value of tau of 24.30 +/- 0.36 h, which is consistent with recent findings in the literature. We conclude that a short forced desynchrony protocol is sufficient for the distinction between the masking and pacemaker components of core body temperature. The same protocol can be used to study the influence of these components on all kinds of other physiological and psychological signals.

Non-verbal behavioral interactions of depressed patients with partners and strangers: the role of behavioral social support and involvement in depression persistence.

Excessive support seeking and lack of receiving social support have been associated with depression onset and unfavorable course of depression. It has been assumed that social support is effected by observable behaviors that express involvement. Twenty-five patients with major depression were studied during a social interaction with their partner and a similar interaction, with a stranger, matched on the sex and age of the partner. We anticipated that (1) partners would display less involvement behaviors to the depressed patients than would strangers and that (2) lack of involvement would predict an unfavorable course of depression, as assessed for depression remission within 6 months of admission. The social interactions, conducted at admission, were videotaped and the behaviors were assessed by ethological methods. The frequency and duration of behavioral elements were associated on the basis of statistical criteria into behavioral factors. Certain factors were supposed to express (lack of) involvement during an interaction. In the patient-partner interaction it was found that both participants displayed lower levels of involvement as compared to the patient-stranger interaction. The patients' low involvement was reflected by less Speech, less Eagerness (yes-nodding and no-shaking), less Speaking Effort (head movements, looking and gesturing during speech) and more Active Listening (intense touching of one's own body and head movements during listening). The partners' low involvement was also expressed by less Speech and more Active Listening, together with less Encouragement (yes-nodding and 'um-hum'-ing during listening). In addition, the partners displayed less Speech to patients who did not remit within 6 months, whereas patients and strangers behaviors were not related to depression remission. These findings supported our anticipations and the findings are related back to data on social support, involvement and to previous human ethological studies on depression.

Depression relapse and ethological measures.

Within the framework of interactional theories on depression, the question is raised whether depression relapse can be predicted by observable behavior of remitted patients and their interviewer during an interaction (i.e. discharge interview). Thirty-four patients were interviewed at hospital discharge and at a follow-up, 6 months later. Eight patients (23.5%) had relapsed at follow-up. Various behaviors of patients and interviewers were observed during an interview by ethological methods. One of the six patient behavioral factors, and none of the seven interviewer factors were related to relapse. Depression relapse patients displayed significantly less Active Listening (intense body touching and head movements during listening) during the interview at hospital discharge than those with stable remission. Results on Active Listening could not be explained by the degree of retardation (HRSD) and underlined the significance of interpersonal mechanisms in the onset and maintenance of depression.

Stress-induced changes in circadian rhythms of body temperature and activity in rats are not caused by pacemaker changes.

Previous work has shown that social stress in rats (i.e., defeat by an aggressive male conspecific) causes a variety of behavioral and physiological changes including alterations in the daily rhythms of body temperature and activity. To study the role of the circadian pacemaker in these stress-induced changes, three experiments were performed, successively addressing pacemaker period, phase, and sensitivity to light. In all experiments, rats were subjected to social stress by placing them in the home cage of a dominant conspecific for 1 h. This was done on 2 consecutive days, between the second and fifth hours of the activity phase. Experimental animals were attacked by the resident and lost the fight as indicated by submissive behavior. Control animals were placed in an unfamiliar but clean and empty cage for 1 h. In Experiment 1, the effects of social stress on the period of the free-running activity rhythm were studied. Rats were individually housed under constant dim red light. Activity was measured with infrared detectors. Social defeat caused a reduction of activity for a number of days, but the period of the free-running rhythm was not affected. In Experiment 2, the authors studied whether social defeat induced acute phase shifts. Body temperature and activity were measured by means of radiotelemetry with intraperitoneally implanted transmitters. After the social interactions, experimental animals were kept under constant dim red light. Social stress caused a profound reduction in the amplitude of the body temperature and activity rhythm, but no significant phase shifts occurred. In Experiment 3, the authors studied whether social defeat affected the circadian pacemaker's sensitivity to light given that the size of light-induced phase shifts is thought to reflect pacemaker amplitude. Again, body temperature and activity were measured by means of telemetry. After double social defeat, animals were kept under continuous dim red light. One day after the second conflict, animals were subjected to a single 1-h light pulse (300 lux) at circadian time 14. The light pulse induced a phase delay of the body temperature rhythm, but there were no significant differences between the stress and control groups. The data indicate that stress-induced changes in activity and temperature rhythm, as well as behavioral and physiological changes found in earlier experiments, are not caused by changes in the circadian pacemaker. More generally, the data support the notion that overt rhythms are not always a reliable indication of pacemaker function.

Will light brighten the future of the depressed patient?

The present explosive growth of interest in the therapeutic possibilities of exposure to light was triggered by a patient, Herbert Kern. He suffered from episodic depressive and manic complaints and discovered, by registering these over the years, a seasonal pattern in their occurrence. Discussions with scientists of the NIMH resulted in his participation in a bright light-treatment experiment when he was depressed in the winter of 1980-1981. He recovered. Next, the same group of investigators defined the criteria for a new syndrome, Seasonal Affective Disorder (SAD): a history of major affective disorder (according to the Research Diagnostic Criteria), at least two consecutive years in which the depressions have occurred during fall or winter and remitted in the following spring or summer, and the absence of any clear-cut seasonally changing psychosocial variable, such as work, stress and so on.

Nonverbal attunement between depressed patients and an interviewer predicts subsequent improvement.

Depressed patients' support-seeking behaviour and the responses to this behaviour by others (support-giving) are presumed to play a causal role in depression. In interactions between normals, attuning nonverbal behaviour (i.e., equalizing levels of specific behavioural activities) is important for satisfaction of the participants with the interaction. We investigated the attunement of nonverbal support-seeking and support-giving of 31 depressed patients and 1 interviewers during a 20-min admission interview. We defined attunement as the absolute difference between patients' and interviewers' nonverbal behaviour. It was found that the more attunement increased over the interview, the more favourable the subsequent course of depression was. The findings emphasize the potential role of interpersonal processes in depression.

Long-term changes in open field behaviour following a single social defeat in rats can be reversed by sleep deprivation.

The long-term consequences of a single social defeat on open field behaviour in rats were studied, with special emphasis on the time course of stress-induced changes. Animals were subjected to social defeat by placing them into the territory of an aggressive male conspecific for 1 h. After the defeat session experimental animals were returned to their home cage and their own room, receiving no further cues from the resident. Other animals serving as controls were placed in a clean and empty cage for 1 h. Five-minute open field tests were performed on days 1, 2, 7, 14, and 28 after defeat, with independent groups of rats. Locomotion of the animals was recorded and analyzed with an automated video system. Social defeat resulted in a strong subsequent reduction in open field activity, which lasted till at least 7 days after the conflict. Differences in total travelled distance were no longer significant 2 weeks after the conflict. The latency for moving to the outer ring of the open field arena after the start of the test was still significantly longer 4 weeks after defeat. The stress-induced reduction in open field locomotion could be reversed by 12-h sleep deprivation during the resting phase, an intervention known to have antidepressant effects in humans. Possible relevance of the present findings with respect to human affective disorders is discussed.

Changes in daily rhythms of body temperature and activity after a single social defeat in rats.

The long-term consequences of social stress on daily rhythms of body temperature and activity in rats were studied by means of radiotelemetry with intraperitoneally implanted transmitters. Rats were subjected to a single social defeat by placing them into the territory of a male conspecific for 1 h. Social defeat caused a sharp subsequent reduction in the amplitude of the daily temperature rhythm, which lasted for at least 4 days. The reduced amplitude was mainly due to higher temperatures during the circadian rest phase, i.e., the light period. Movement activity was less affected, but the decrease in activity during the dark phase after defeat correlated significantly with the temperature increase during the light phase. The stress-induced changes in daily rhythms of body temperature and activity are discussed in terms of their relevance to the role of rhythm-disturbances in the pathogenesis of affective disorders.

Changes in EEG power density of non-REM sleep in depressed patients during treatment with trazodone.

Recently, it was hypothesized that acute or cumulative suppression of non-REM sleep intensity might be related to the therapeutic effects of antidepressants. This intensity has been proposed to be expressed in the EEG power density in non-REM sleep. In the present study, the relationship was examined between the changes of EEG power density in non-REM sleep and the changes in clinical state in 8 depressed patients during treatment with trazodone. A 1-week wash-out period was followed by 1 week of placebo administration, a medication period of 5 weeks and a 1-week placebo period. To minimize systematic influences of sleep duration and non-REM-REM sleep alterations, EEG power was measured over the longest common amount of non-REM sleep stages 2-4 (168.5 min), accumulated from sleep onset onwards. During trazodone treatment, the 13- and 14-Hz bins showed a significant reduction in EEG power. No clear-cut change, however, was observed in the EEG power of the delta frequency range (1-4 Hz) which is considered to be the principle manifestation of non-REM sleep intensity. Furthermore, no overall significant relationship between EEG power suppression and clinical improvement could be demonstrated.

Light therapy for seasonal affective disorder. The effects of timing.

BACKGROUND: Sixty-eight patients with seasonal affective disorder participated in a 10,000-lux light treatment study in which two questions were addressed: do response rates differ when the light is applied at different times of the day and does short-term rank ordering of morning and evening light influence response rates? METHOD: Three groups of patients received a 4-day light treatment: (I) in the morning (8.00-8.30 a.m., n = 14), (II) in the afternoon (1.00-1.30 p.m., n = 15) or (III) in the evening (8.00-8.30 p.m., n = 12). Two additional groups of patients received two days of morning light treatment followed by two days of evening light (IV, n = 13) or vice versa (V, n = 14). RESULTS: Response rates for groups I, II and III were 69, 57 and 80% respectively, with no significant differences between them. Response rates for groups IV and V were 67 and 50% respectively; this difference was not significant and these percentages did not differ significantly from those of groups I and III. CONCLUSIONS: The results indicate that the timing of light treatment is not critical and that short-term rank ordering of morning and evening light does not influence therapeutic outcome.

The relationship between tiredness prior to sleep deprivation and the antidepressant response to sleep deprivation in depression.

Recently it was hypothesized that the antidepressant response to total sleep deprivation (SD) results from a disinhibition process induced by the increase of tiredness in the course of SD. In the present study, the role of tiredness in the antidepressant response to SD is further investigated. Seventy-two depressed patients scored subjective tiredness and depressed mood three times daily (in the morning, afternoon, and evening) on the days preceding and following SD. It was found that averaged tiredness on the day prior to SD was related to the SD response, when the severity of depression prior to SD had been held statistically constant. Also, when both severity of depression and diurnal variation of mood prior to SD were partialed out, tiredness showed a positive correlation with the SD response: patients who reported a relatively low degree of tiredness on the day preceding SD improved by SD. This result suggests that tiredness has an influence on SD effects, and that this influence is independent from that of the severity of depression. The findings are in accordance with current ideas on the role of tiredness as a mediating factor in the induction of the therapeutic effects of SD.