Plasma leptin in men and women with seasonal affective disorder and in healthy matched controls.

Seasonal affective disorder (SAD) is a specific clinical entity characterized by recurrent episodes of depression, which typically occur during the winter with periods of remission during the spring and summer. These depression episodes are accompanied by hyperphagia with cravings for carbohydrates and moderate weight gain, and usually respond to light therapy. We examined potential relationships between leptin, a hormone known to affect appetite and weight regulation, and seasonal changes in mood and appetite by measuring plasma leptin, clinical severity of depression, appetite scores, and body mass index (BMI) in 19 women and 8 men with SAD and matched controls (20 women and 8 men) in the summer and winter. Plasma leptin was positively correlated with BMI in patients and controls during both seasons. Women and men with SAD both experienced depression in the winter, which was associated with increased appetite, caloric intake, and carbohydrate craving. Increased body weight during the winter in subjects with SAD was paralleled by a lack of concomitant changes in plasma leptin, which suggests that leptin sensitivity to changes in body weight may be influenced by seasons in subjects with SAD, similar to seasonal mammals.

A circadian signal of change of season in patients with seasonal affective disorder.

BACKGROUND: In animals, the circadian pacemaker regulates seasonal changes in behavior by transmitting a signal of day length to other sites in the organism. The signal is expressed reciprocally in the duration of nocturnal melatonin secretion, which is longer in winter than in summer. We investigated whether such a signal could mediate the effects of change of season on patients with seasonal affective disorder. METHODS: The duration of melatonin secretion in constant dim light was measured in winter and in summer in 55 patients and 55 matched healthy volunteers. Levels of melatonin were measured in plasma samples that were obtained every 30 minutes for 24 hours in each season. RESULTS: Patients and volunteers responded differently to change of season. In patients, the duration of the nocturnal period of active melatonin secretion was longer in winter than in summer (9.0 +/- 1.3 vs 8.4 +/- 1.3 hours; P=.001) but in healthy volunteers there was no change (9.0 +/- 1.6 vs 8.9 +/- 1.2 hours; P=.5). CONCLUSIONS: The results show that patients with seasonal affective disorder generate a biological signal of change of season that is absent in healthy volunteers and that is similar to the signal that mammals use to regulate seasonal changes in their behavior. While not proving causality, this finding is consistent with the hypothesis that neural circuits that mediate the effects of seasonal changes in day length on mammalian behavior mediate effects of season and light treatment on seasonal affective disorder.

Early response to light therapy partially predicts long-term antidepressant effects in patients with seasonal affective disorder.

OBJECTIVE: To determine if the antidepressant effect of 1 hour of light therapy is predictive of the response after 1 and 2 weeks of treatment in patients with seasonal affective disorder (SAD). PATIENTS: Twelve patients with SAD. SETTING: National Institutes of Health Clinical Center, Bethesda, Md. INTERVENTIONS: Light therapy for 2 weeks. OUTCOME MEASURES: Scores on the Seasonal Affective Disorder Version of the Hamilton Depression Rating Scale (SIGH-SAD) on 4 occasions (before and after 1 hour of light therapy and after 1 and 2 weeks of therapy) in the winter when the patients were depressed. Change on typical and atypical depressive scores at these time points were compared. RESULTS: Improvement of atypical depressive symptoms after 1 hour of light therapy positively correlated with improvement after 2 weeks of therapy. CONCLUSION: In patients with SAD, the early response to light therapy may predict some aspects of long-term response to light therapy, but these results should be treated with caution until replicated.

A patient who changed my practice: Herb Kern, the first light therapy patient.

This paper presents the case of Herb Kern, the first patient with clear-cut seasonal mood cycles in whom light therapy was used to reverse depression. His successful treatment was an inspiration to the author to define the syndrome of Seasonal Affective Disorder (SAD) and use light therapy as a systematic controlled treatment for this condition. This is an example of how a single patient can lead to the recognition of a common condition and a novel treatment modality.

Seasonal mood change and neuroticism: the same construct?

The personality trait of neuroticism has been found to be associated with a polymorphism in the regulatory region of the serotonin (5-HT) transporter gene (5-HTTLPR). This same genetic polymorphism has also been associated with seasonal changes in mood and behavior, or seasonality. The purpose of the current study was to determine whether seasonality and neuroticism are actually the same construct given that they are both associated with the same genetic polymorphism. We administered the Seasonal Pattern Assessment Questionnaire (SPAQ), which measures the severity of seasonality, and the Revised NEO Personality Inventory (NEO-PI-R), which measures the severity of neuroticism, to 45 subjects diagnosed with seasonal affective disorder (SAD). SAD is a clinical expression of seasonality in which patients develop a major depressive disorder in the winter that remits in the summer and can be treated with light therapy. No significant correlation was found between neuroticism and seasonality. We conclude that seasonality and neuroticism are not the same construct, even though the 5-HTTLPR polymorphism is a genetic risk factor for each.

The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder.

BACKGROUND: Information-transducing heterotrimeric G proteins have been implicated previously in the mechanism of action of mood stabilizers and in the pathophysiology of mood disorders. Mononuclear leukocytes of patients with unipolar and bipolar depression have been characterized by reduced measures of the stimulatory and inhibitory G proteins. In this study, patients with seasonal affective disorder (SAD) were measured for mononuclear leukocyte G protein levels while depressed during the winter, following light therapy, and in remission during the summer. METHODS: Twenty-six patients with SAD and 28 healthy subjects were assessed in the study. The immunoreactivities of Gs alpha, Gi alpha, and Gbeta subunit proteins were determined by Western blot analysis of mononuclear leukocyte membranes with selective polyclonal antibodies for the various G subunit proteins, followed by densitometric quantitation using an image analysis system. RESULTS: Untreated patients with SAD and winter, atypical-type depression showed significantly reduced mononuclear leukocyte immunoreactive levels of Gs alpha and Gi alpha proteins, similar to previous observations in patients with nonseasonal major depression. The reduced G protein levels were normalized with 2 weeks of light therapy. The same patients while in remission during the summer had G protein levels that were similar to those of healthy subjects. CONCLUSIONS: G protein-immunoreactive measures in patients with SAD are suggested as a state marker for winter depression, which is normalized by light treatment and during the summer. We speculate that light may exert its effects via normalization of transducin (Gt protein) levels, which are thought to be reduced in winter depression.

Greater improvement in summer than with light treatment in winter in patients with seasonal affective disorder.

OBJECTIVE: The authors sought to compare the degree of mood improvement after light treatment with mood improvement in the subsequent summer in patients with seasonal affective disorder. METHOD: By using the Seasonal Affective Disorder Version of the Hamilton Depression Rating Scale, the authors rated 15 patients with seasonal affective disorder on three occasions: during winter when the patients were depressed, during winter following 2 weeks of light therapy, and during the following summer. They compared the three conditions by using Friedman's analysis of variance and the Wilcoxon signed ranks test. RESULTS: The patients' scores on the depression scale were significantly higher after 2 weeks of light therapy in winter than during the following summer. CONCLUSIONS: Light treatment for 2 weeks in winter is only partially effective when compared to summer. Further studies will be necessary to assess if summer's light or other factors are the main contributors to this difference.

Effects of tryptophan depletion vs catecholamine depletion in patients with seasonal affective disorder in remission with light therapy.

BACKGROUND: Although hypotheses about the therapeutic mechanism of action of light therapy have focused on serotonergic mechanisms, the potential role, if any, of catecholaminergic pathways has not been fully explored. METHODS: Sixteen patients with seasonal affective disorder who had responded to a standard regimen of daily 10000-lux light therapy were enrolled in a double-blind, placebo-controlled, randomized crossover study. We compared the effects of tryptophan depletion with catecholamine depletion and sham depletion. Ingestion of a tryptophan-free amino acid beverage plus amino acid capsules was used to deplete tryptophan. Administration of the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine was used to deplete catecholamines. Diphenhydramine hydrochloride was used as an active placebo during sham depletion. The effects of these interventions were evaluated with measures of depression, plasma tryptophan levels, and plasma catecholamine metabolites. RESULTS: Tryptophan depletion significantly decreased plasma total and free tryptophan levels. Catecholamine depletion significantly decreased plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels. Both tryptophan depletion and catecholamine depletion, compared with sham depletion, induced a robust increase (P<.001, repeated-measures analysis of variance) in depressive symptoms as measured with the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version. CONCLUSIONS: The beneficial effects of light therapy in the treatment of seasonal affective disorder are reversed by both tryptophan depletion and catecholamine depletion. These findings confirm previous work showing that serotonin plays an important role in the mechanism of action of light therapy and provide new evidence that brain catecholaminergic systems may also be involved.

Lack of seasonal variation of symptoms in patients with chronic fatigue syndrome.

Several of the symptoms involved in chronic fatigue syndrome (CFS) such as fatigue, hypersomnia, hyperphagia, weight gain, and mood show seasonal variations in the general population. The aim of this study was to investigate whether patients with CFS experience seasonal fluctuations in these symptoms as well. Seasonal variation of symptoms was assessed in a group of 41 patients with CFS and 41 controls closely matched for age, gender, and city of residence. Participants were recruited across the US and were asked to complete the Seasonal Pattern Assessment Questionnaire (SPAQ) and the Profile of Mood States (POMS). CFS patients showed significantly lower scores on multiple SPAQ-derived measures as compared with controls. These included seasonal variation in energy, mood, appetite, weight, and sleep length. Patients also reported a significantly reduced sensitivity toward sunny, dry, and long days than controls. No association was noted between intensity of seasonal changes and severity of depressive symptoms. Patients with CFS exhibit an abnormally reduced seasonal variation in mood and behavior and would not be expected to benefit from light therapy.

Case series: pediatric seasonal affective disorder. A follow-up report.

Six subjects who as children had received a diagnosis of seasonal affective disorder consented to participate in a 7-year follow-up study. Structured and semistructured interviews were conducted to assess the course of illness, response to treatment, and current clinical state. Seasonal patterns of symptoms and response to light therapy remained relatively stable over a 7-year period. Two subjects were using adjunctive fluoxetine. Seasonal affective disorder can occur in children and adolescents, responds to light therapy, and should be considered in the differential diagnosis of pediatric affective symptoms or cyclic school performance.

Seasonal variation in core temperature regulation during sleep in patients with winter seasonal affective disorder.

Nocturnal core temperature during sleep is elevated during depression compared with remission in nonseasonally depressed patients. Similarly, nocturnal core temperature is higher during winter depression compared with remission induced by light treatment in seasonal affective disorder (SAD) patients. We investigated whether nocturnal core temperature in SAD patients naturally becomes lower in summer (during remission) compared with winter (during depression). Twenty-four-hour core temperature profiles were obtained in winter and summer in 22 SAD patients and 22 controls. The nocturnal core temperature minima were lower in summer compared with winter in SAD patients (p < .005), but not controls (p > .4). The seasonal changes in nocturnal core temperatures in SAD patients may reflect a unique physiological responsiveness of SAD patients to the change of seasons, and may be intimately related to the seasonal disturbances of mood and energy that are characteristic of SAD.

A controlled trial of light therapy for the treatment of pediatric seasonal affective disorder.

OBJECTIVE: To evaluate the efficacy of light therapy for the treatment of pediatric seasonal affective disorder (SAD). METHOD: 28 children (aged 7 to 17 years) at two geographically distinct sites were enrolled in a double-blind, placebo-controlled, crossover trial of bright-light treatment. Subjects initially entered a week-long baseline period during which they wore dark glasses for an hour a day. They were then randomly assigned to receive either active treatment (1 hour of bright-light therapy plus 2 hours of dawn simulation) or placebo (1 hour of clear goggles plus 5 minutes of low-intensity dawn simulation) for 1 week. The treatment phase was followed by a second dark-glasses phase lasting 1 to 2 weeks. After this phase, the children received the alternate treatment. Response was measured using the parent and child versions of the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders version (SIGH-SAD). RESULTS: Data were analyzed as change from baseline. SIGH-SAD-P total depression scores were significantly decreased from baseline during light therapy compared with placebo (one-way analysis of variance, rho = .009), and no differences were found between the placebo and control phases. Subscores of atypical and typical depression were also significantly decreased during the active treatment (rho = .004 and .028, respectively). A similar trend was noted with the SIGH-SAD-C, but this did not reach significance. At the end of the study, 78% of the parents questioned and 80% of the children questioned rated light therapy as the phase during which the child "felt best." CONCLUSION: Light therapy appears to be an effective treatment for pediatric SAD.

Effects of meta-chlorophenylpiperazine infusions in patients with seasonal affective disorder and healthy control subjects. Diurnal responses and nocturnal regulatory mechanisms.

BACKGROUND: Multiple lines of evidence suggest that brain serotonergic systems may be disturbed in seasonal affective disorder (SAD). Previously, we found that the serotonergic agent meta-chlorophenylpiperazine (m-CPP) produced increases in activation and euphoria in depressed patients with SAD, but not in patients with SAD following light treatment or in the summer, nor in healthy control subjects in any condition. In the present study, we attempted to replicate and extend this finding using better methods. METHODS: Seventeen outpatients with SAD and 15 control subjects underwent successive 3-week periods of bright light treatment and light avoidance in a randomized order. During the third week of each condition, on 2 different occasions, subjects were admitted to the hospital for a night of sleep (core temperatures were recorded), followed by infusions of m-CPP (0.08 mg/kg) or placebo the next morning. Dependent measures included the 24-item National Institute of Mental Health Self-Rating Scale, plasma corticotropin, cortisol, prolactin, growth hormone, and norepinephrine concentrations, and core temperatures. RESULTS: Meta-chlorophenylpiperazine produced (1) significant increases in "activation-euphoria" ratings only in depressed patients with SAD in the untreated condition and (2) blunted corticotropin and norepinephrine responses in patients with SAD compared with controls across both light treatment conditions. In both groups, light treatment was associated with significant reductions in nocturnal core temperatures, which were correlated with similarly significant reductions in mean diurnal growth hormone concentrations. In patients with SAD, (1) the reductions in nocturnal core temperatures also were correlated with the reductions in baseline depression ratings and (2) the reductions in mean growth hormone concentrations were significantly smaller compared with controls. CONCLUSIONS: The abnormal m-CPP-induced activation-euphoria responses represent a replicated state marker of winter depression in patients with SAD. The blunted m-CPP-induced responsiveness of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system may represent traitlike abnormalities. The improvements in mood following light treatment in patients with SAD seem to be associated with the lowering of nocturnal core temperatures. The findings, although not easily explained based on a uniform abnormality of serotonin receptors, are nonetheless compatible with the notion that selected regions of the central nervous system are deficient in serotonin transmission during winter depression.

Winter seasonal affective disorder: a follow-up study of the first 59 patients of the National Institute of Mental Health Seasonal Studies Program.

OBJECTIVE: The purpose of this study was to characterize the long-term course of patients with seasonal affective disorder. METHOD: The first 59 patients with winter seasonal affective disorder who had entered winter protocols were retrospectively followed up after a mean interval of 8.8 years. Detailed life charts were constructed through use of a semistructured interview and collateral records. RESULTS: The disorder of 25 patients (42%) remained purely seasonal, with regular recurrences of winter depression and no depression or treatment through any summer. The course of illness was complicated by varying degrees of nonseasonal depression in 26 patients (44%). The disorders of eight patients (14%) had fully remitted. Certain features of the group with complicated seasonal affective disorder suggested that they were more severely ill. Twenty-four patients (41%) continued to use light treatment regularly throughout the follow-up period. Light treatment was preferred to medication for winter recurrences, although antidepressants had been used in the winter by most (63%) of the patients who still used lights at follow-up. CONCLUSIONS: The pattern of winter depressions and summer remissions remained fairly persistent over time in this group of patients. The temporal distribution of depressive episodes both within and across individual patients was consistent with the results of several recent follow-up studies of seasonal affective disorder, providing support for the predictive and construct validity of the Rosenthal et al. diagnosis of winter seasonal affective disorder. Light treatment, while remaining a safe and satisfactory treatment for many, may be insufficient for more severely ill patients. The appearance of nonseasonal depressions in patients with winter seasonal affective disorder may be associated with greater severity of illness and less responsiveness to light treatment.

Circadian profiles of cortisol, prolactin, and thyrotropin in seasonal affective disorder.

To determine whether circadian profiles of various plasma hormones are abnormal in patients with winter seasonal affective disorder (SAD), we obtained 24-hour profiles of plasma cortisol, prolactin, and thyrotropin in subsets of a sample of 22 depressed patients with SAD on and off light therapy and in subsets of a sample of 24 normal controls. Cortisol levels did not differ between patients and controls, and levels in patients were not affected by light therapy. Prolactin levels were lower in patients than in controls throughout the day (p < 0.03) but were unaffected by light therapy. Independent of patient vs. control status, prolactin levels were higher in women than in men throughout the day (p < 0.003). Thyrotropin levels were no different in patients and controls, but levels in patients were lower following light therapy (p < 0.05).

The phototherapy light visor: more to it than meets the eye.

OBJECTIVE: The purpose of the study was to ascertain whether phototherapy light visors provide an effective treatment for seasonal affective disorder. Previous studies have demonstrated a moderate response rate but have failed to find any difference in efficacy between light intensities. METHOD: Subjects were randomly assigned to receive, over a 2-week treatment period, 30 minutes of morning phototherapy with a light visor that emitted either a dim (30-lux) red light or a bright (600-lux) white light. Raters were blind to treatment, and patients were unaware of the alternatives. Response was assessed by using the structured 21-item Hamilton Depression Rating Scale, with an eight-item addendum for atypical depressive symptoms. Fifty-seven patients were enrolled across two sites. RESULTS: Patients assigned to the different visors had similar baseline depression scores and similar expectations of outcome. Hamilton depression scale scores declined by 34.6% for subjects given bright white light and by 40.9% for subjects given dim red light. Scores for atypical depressive symptoms fell by 44.1% for patients assigned the bright white light visors and by 49.0% for patients assigned the dim red light visors. Altogether, 39.3% of the patients who received red light and 41.4% of the patients who received bright white light showed a full clinical response. CONCLUSIONS: There were no significant differences in therapeutic response between patients who were treated with red or white light. The results of this study suggest that the phototherapy light visor may function as an elaborate placebo. Alternative explanations, however, are considered.