Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials.

INTRODUCTION: Botulinum toxin A (BTA) injection into the glabellar region is currently being studied as a treatment for major depressive disorder (MDD). Here we explore efficacy data of this novel approach in a pooled analysis. METHODS: A literature search revealed 3 RCTs on this topic. Individual patient data and clinical end points shared by these 3 trials were pooled and analyzed as one study (n=134) using multiple regression models with random effects. RESULTS: In the pooled sample, the BTA (n=59) and the placebo group (n=75) did not differ in the baseline variables. Efficacy outcomes revealed BTA superiority over placebo: Improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale 6 weeks after baseline was 45.7% for BTA vs. 14.6% for placebo (p<0.0001), corresponding to a BTA response rate of 54.2% (vs. 10.7%) and a BTA remission rate of 30.5% (vs. 6.7%). DISCUSSION: Equalling the status of a meta-analysis, this study increases evidence that a single treatment of BTA into the glabellar region can reduce symptoms of MDD. Further studies are needed to better understand how BTA exerts its mood-lifting effect.

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.

Band-specific electroencephalogram and brain cooling abnormalities during NREM sleep in patients with winter depression.

BACKGROUND: We previously reported that delta wave activity and facial skin temperatures, an index of brain cooling activity, were both abnormal during sleep in patients with winter depression (SAD). Because other electroencephalographic (EEG) frequencies may also convey relevant thermal, homeostatic, and circadian information, we sought to spectrally analyze delta, theta, alpha, and sigma frequencies during sleep from 23 patients with SAD and 23 healthy control subjects. METHODS: We computed means for delta, theta, alpha, and sigma power during both NREM and REM sleep. We also generated 22 cross-correlation functions for each group by crossing facial and rectal temperature with each other, as well as with delta, theta, alpha, and sigma frequencies. RESULTS: We found that delta, theta, and alpha frequency activities were all increased during NREM, but not REM sleep, in patients with SAD. In addition, there were significant and abnormal cross-correlations between facial temperatures and delta and theta frequencies during NREM sleep in patients with SAD. CONCLUSIONS: Patients with winter depression exhibit correlated abnormalities of sleep homeostasis and brain cooling during NREM sleep. Their EEG profiles during NREM sleep resemble the EEG profiles of subjects who have been sleep deprived. Further studies of NREM sleep homeostasis in patients with SAD seem warranted.

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.

Self-reported sensitivity to chemical exposures in five clinical populations and healthy controls.

Two hundred and twenty-five subjects, including normal volunteers and patients with previously documented seasonal affective disorder (SAD), chronic fatigue syndrome (CFS), Cushing's syndrome, Addison's disease and obsessive-compulsive disorder (OCD), completed a self-rated inventory of reported sensitivity to various chemical exposures. Patients with CFS, Addison's disease and SAD self-reported more sensitivity to chemical exposures than normal controls. In addition, women reported more sensitivity than men. This report suggests that chemical sensitivity may be a relevant area to explore in certain medical and psychiatric populations. A possible relationship between reported chemical sensitivity and hypothalamic-pituitary-adrenal (HPA)-axis functioning is discussed.

Ultradian oscillations in cranial thermoregulation and electroencephalographic slow-wave activity during sleep are abnormal in humans with annual winter depression.

The level of core body, and presumably brain temperature during sleep varies with clinical state in patients with seasonal affective disorder (SAD), becoming elevated during winter depression and lowered during clinical remission induced by either light treatment or summer. During sleep, brain temperatures are in part determined by the level of brain cooling activity, which may be reflected by facial skin temperatures. In many animals, the level of brain cooling activity oscillates across the NREM-REM sleep cycle. Facial skin temperatures during sleep in patients with winter depression are abnormally low and uncorrelated with rectal temperatures, although their relationship to EEG-defined sleep stages remains unknown. We therefore measured the sleep EEG, core body and facial skin temperatures in 23 patients with winter depression and 23 healthy controls, and tested the hypothesis that ultradian oscillations in facial skin temperatures exist in humans and are abnormal in patients with winter depression. We found that facial skin temperatures oscillated significantly across the NREM-REM sleep cycle, and were again significantly lower and uncorrelated with rectal temperatures in patients with winter depression. Mean slow-wave activity and NREM episode duration were significantly greater in patients with winter depression, whereas the intraepisodic dynamics of slow-wave activity were normal in patients with winter depression. These results suggest that brain cooling activity oscillates in an ultradian manner during sleep in humans and is reduced during winter depression, and provide additional support for the hypothesis that brain temperatures are elevated during winter depression.

Summer and winter patterns of seasonality in Chinese college students: a replication.

The goal of this study is to replicate an earlier epidemiological finding of seasonal changes in mood and behavior among Chinese medical students using an independent study population. Three hundred nineteen college students were surveyed with a Chinese version of the Seasonal Pattern Assessment Questionnaire (SPAQ) and the Beck Depression Inventory (BDI) in Jining, China, during March of 1996. The frequency of seasonal patterns and prevalence rates of seasonal affective disorder (SAD) were estimated and compared with data from the medical student survey conducted in the same city. The mean Global Seasonality Score (GSS) of this college student sample was 9.9 +/- 4.9; 84% of the subjects reported some problems with the changing seasons. Summer difficulties were more prevalent than winter difficulties by a ratio of 1.9 to 1 (38.9% v 20.1%). The estimated rates of summer SAD and subsyndromal-SAD (s-SAD) were 7.5% and 11.9%, respectively, as compared with the corresponding winter figures of 5.6% and 6.3%. In addition, the prevalence estimates of winter pattern or winter SADs were higher in males than in females, but the corresponding summer figures showed no gender difference. Compared with the data from the medical student survey, this college student sample had a higher GSS (P < .01) but comparable summer to winter and female to male ratios for the prevalence of SADs (P > .05). These results replicate our previous findings that seasonal problems are common in China, but the predominant problems are summer difficulties rather than winter difficulties, and there is no female preponderance in the prevalence estimates of such problems. Both findings stand in contrast to most Western studies but are consistent with the only other published study performed in the Orient.

Seasonal variations in mood and behavior among Chinese medical students.

OBJECTIVE: The goal of this study was to estimate the frequency of seasonal variations in mood and behavior among Chinese medical students. METHOD: A total of 1,358 medical students were surveyed with Chinese versions of the Seasonal Pattern Assessment Questionnaire and the Beck Depression Inventory in Jining, China. RESULTS: The mean global seasonality score was 8.3 (SD=3.6) out of a possible 24; 81.7% (N=1,110) of the subjects reported some trouble adapting to changing seasons. Summer difficulties were more common than winter difficulties by a ratio of 3:2; estimated rates of summer seasonal affective disorder and subsyndromal seasonal affective disorder were 4.4% and 8.0%, respectively, compared with corresponding winter rates of 2.4% and 5.7%. CONCLUSIONS: These results suggest that seasonal variations in mood and behavior are common in China. The predominance of summer difficulties stands in contrast to that in most Western studies and is consistent with the only other published study performed in Asia.

Pleiotropy of the serotonin transporter gene for seasonality and neuroticism.

Pleiotropy refers to the ability of a single gene to influence multiple traits. A polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) has previously been found to be associated both with the personality trait of neuroticism and with seasonal changes in mood and behavior, or seasonality. Hypothesizing that the contribution of the serotonin transporter gene to seasonality is specific, i.e. independent of neuroticism, we measured 5-HTTLPR genotypes and both psychological traits in 236 healthy volunteers. The results indicated that the 5-HTTLPR contributions to variation in the two traits are largely independent; approximately three-quarters of the effect of the gene on seasonality are not related to its effects on neuroticism. Moreover, the gene has a larger effect on the covariation between neuroticism and seasonality than it does on either trait alone. Sibling-pair analysis confirmed that the effects of the 5-HTTLPR are due to genetic pleiotropy rather than population stratification.

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 role of genetic factors in the etiology of seasonal affective disorder and seasonality.

The study of the genetic basis of seasonal affective disorder (SAD), a condition where depressions in fall and winter alternate with nondepressed periods in the spring and summer, has recently received attention. The data on the genetics of seasonal affective disorders are of three types: 1. Familiality: Studies on the prevalence of psychiatric disorders among relatives of patients with SAD suggested a familial contribution to the development of SAD; 2. Heritability: A survey of a cohort of twins showed that genetic effects exert a global influence across a variety of behavioral traits and accounted for at least 29% of the variance in seasonality in men and women; 3. Molecular genetic research: two genetic variants related to serotonergic transmission, the 5-HTTLPR and the 5-HT2A-1438G/A gene promoter polymorphisms, are associated with SAD; the former but not the latter polymorphism is related to seasonality. Future research may clarify the role of different genes in the development of SAD.

Serotonin hypothesis of winter depression: behavioral and neuroendocrine effects of the 5-HT(1A) receptor partial agonist ipsapirone in patients with seasonal affective disorder and healthy control subjects.

Winter depressions in seasonal affective disorder (SAD) are associated with central serotonergic (5-HT) dysfunction. SAD patients demonstrate rather specific, state-dependent, abnormal increases in 'activation-euphoria' ratings following intravenous infusion of the 5-HT receptor agonist meta-chlorophenylpiperazine (m-CPP). Several studies are also consistent with abnormal serotonergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis in SAD. Here, we investigated the effects of the 5-HT1A receptor partial agonist ipsapirone, which produces behavioral effects and HPA-axis activation, to further characterize the 5-HT receptor subtype-specificity of these disturbances in SAD. Eighteen SAD patients and 18 control subjects completed two drug challenges (ipsapirone 0.3 mg/kg and placebo) separated by 3-5 days in randomized order. We measured behavioral responses with the NIMH self-rating scale, and plasma ACTH, cortisol, and prolactin concentrations. Compared with placebo, ipsapirone was associated with significant increases in self-rated 'functional deficit' and 'altered self-reality', and in each of the hormones. There were no differences between groups on any measures. The level of depression in SAD patients was inversely correlated with their ipsapirone-induced cortisol responses. There were significant drug x order effects on baseline 'anxiety' scores, ACTH and cortisol concentrations, such that subjects were significantly more stressed (higher 'anxiety', ACTH and cortisol) prior to their first challenge compared with their second. In conclusion, post-synaptic 5-HT1A receptors appear to function normally in SAD. The previously observed m-CPP-induced behavioral abnormality may be mediated by either 5-HT2C or 5-HT7 receptors.

Gender differences in glycosylated hemoglobin levels in seasonal affective disorder patients and controls.

Seasonal affective disorder (SAD) has been shown to manifest different symptoms in female and male patients. Specifically, women with SAD have been shown to have greater increases in overeating, weight gain, and increased sleep as compared with their male counterparts. Given these dietary changes, we predicted that female SAD patients would exhibit increased glycosylated hemoglobin (HbA1) levels, indicative of chronically elevated glucose levels. Twenty-two patients (15 women and seven men) and matched controls were enrolled during the winter season and tested for HbA1 levels. A three-way analysis of variance (ANOVA; gender x group x season) was insignificant and the result was a negative study. After the initial hypothesis was rejected, we undertook a post-hoc analysis of the data, from which emerged that in winter, women patients had higher HbA1 levels as compared with matched controls. As our original hypothesis was rejected, we cannot accept the results of the post-hoc study. However, numerous other studies have demonstrated that female and male SAD patients differ in their pathophysiology, and are suggestive that in future analyses ought to consider analyzing subjects separately across gender.

Association between seasonal affective disorder and the 5-HT2A promoter polymorphism, -1438G/A.

Genes involved in serotonin metabolism are good candidates for the pathogenesis of seasonal affective disorder (SAD). A functional variant in the serotonin transporter promoter, 5-HTTLPR, has recently been shown to be associated with SAD and seasonality. The purpose of this study was to determine whether -1438G/A, a polymorphism in the 5-HT2A promoter, is associated with SAD and seasonality, and whether it has additive effects with 5-HTTLPR on seasonality. Sixty-seven individuals with SAD and 69 normal volunteers, all screened with the SCID and diagnosed according to DSM-III-R criteria, were genotyped for the -1 438G/A 5-HT2A promoter polymorphism. All had been previously genotyped for 5-HTTLPR and had been assessed for seasonality by the Global Seasonality Scale. There was a significant increase in the frequency of the -1438A variant allele of the 5-HT2A promoter polymorphism in SAD patients (0.47) compared to matched controls (0.36) (P < 0.01). The difference in genotype distribution was also significant (P < 0.05). We found no association between the -1438G/A polymorphism and seasonality scores, and there was no additive effect with 5-HTTLPR on seasonality. In conclusion, we have shown that the -1438G/A 5-HT2A promoter variant is associated with SAD but not with seasonality. We suggest that the association may instead be with the depressive symptoms of SAD. However, these results should be treated with caution until replicated because of the possibility of false-positive findings in case-control association studies.