Comparison of psychotherapies for adult depression to pill placebo control groups: a meta-analysis.

BACKGROUND: The effects of antidepressants for treating depressive disorders have been overestimated because of selective publication of positive trials. Reanalyses that include unpublished trials have yielded reduced effect sizes. This in turn has led to claims that antidepressants have clinically insignificant advantages over placebo and that psychotherapy is therefore a better alternative. To test this, we conducted a meta-analysis of studies comparing psychotherapy with pill placebo. METHOD: Ten 10 studies comparing psychotherapies with pill placebo were identified. In total, 1240 patients were included in these studies. For each study, Hedges' g was calculated. Characteristics of the studies were extracted for subgroup and meta-regression analyses. RESULTS: The effect of psychotherapy compared to pill placebo at post-test was g = 0.25 [95% confidence interval (CI) 0.14-0.36, I² = 0%, 95% CI 0-58]. This effect size corresponds to a number needed to treat (NNT) of 7.14 (95% CI 5.00-12.82). The psychotherapy conditions scored 2.66 points lower on the Hamilton Depression Rating Scale (HAMD) than the placebo conditions, and 3.20 points lower on the Beck Depression Inventory (BDI). Some indications for publication bias were found (two missing studies). We found no significant differences between subgroups of the studies and in meta-regression analyses we found no significant association between baseline severity and effect size. CONCLUSIONS: Although there are differences between the role of placebo in psychotherapy and pharmacotherapy research, psychotherapy has an effect size that is comparable to that of antidepressant medications. Whether these effects should be deemed clinically relevant remains open to debate.

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.

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.

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.

Monorhinal odor identification and depression scores in patients with seasonal affective disorder.

BACKGROUND: Visual and olfactory pathways are interconnected. Olfactory deafferentation unmasks photoperiodic responsiveness in some nonphotoperiodic animals such as laboratory rats. By analogy, we hypothesized that olfactory deficits may unmask seasonal rhythms in certain individuals, namely those with seasonal affective disorder (SAD). Since previous studies suggest lateralized hemispheric dysfunction in SAD, and since olfactory neurons' primary projections are largely ipsilateral, we assessed olfactory identification performance on both the right and left side of the nose. METHODS: Twenty-four patients with SAD and 24 matched controls were studied using a phenyl ethyl alcohol detection threshold test bilaterally and the University of Pennsylvania Smell Identification Test unilaterally. Subjects rated their mood using the Self Assessment Mood Scale for SAD. Patients' testing was done in both 'depressed' and 'improved on light' states. RESULTS: No difference in olfactory performance was found between patients and controls or between patients before and after light treatment. However, right-side identification scores were negatively correlated with 'typical' depression scores (r = -0.56, P = 0.006), while left-side olfactory scores were not. Atypical depression scores were unrelated to olfactory performance. Similar correlations emerged between the olfactory identification laterality quotient (Right - Left)/(Right + Left) and typical depressive scores (r = - 0.64, P < 0.001) and total depression scores (r = - 0.59, P < 0.004). LIMITATIONS: We studied a demographically heterogeneous sample and did not control for menstrual factors. DISCUSSION: Our results add to previous evidence of lateralized hemispheric involvement in SAD and suggest that olfaction may be related to seasonal emotional rhythms in humans.

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.

Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep.

BACKGROUND: The modern practice of using artificial light to extend waking activities into the nighttime hours might be expected to precipitate or exacerbate bipolar illness, because it has been shown that modifying the timing and duration of sleep can induce mania in susceptible individuals. With this possibility in mind, we treated a patient with rapidly cycling bipolar illness by creating an environment that was likely to increase and to stabilize the number of hours that he slept each night. METHODS: We asked the patient to remain at bed rest in the dark for 14 hours each night (later this was gradually reduced to 10 hours). Over a period of several years, his clinical state was assessed with twice-daily self-ratings, once-weekly observer ratings, and continuous wrist motor activity recordings. Times of sleeping and waking were recorded with sleep logs, polygraphic recordings, and computer-based event recordings. RESULTS: The patient cycled rapidly between depression and mania and experienced marked fluctuations in the timing and duration of sleep when he slept according to his usual routine, but his sleep and mood stabilized when he adhered to a regimen of long nightly periods of enforced bed rest in the dark. CONCLUSIONS: Fostering sleep and stabilizing its timing by scheduling regular nightly periods of enforced bed rest in the dark may help to prevent mania and rapid cycling in bipolar patients.

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.

Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder.

Seasonal variations in mood and behavior (seasonality) and seasonal affective disorder (SAD) have been attributed to seasonal fluctuations in brain serotonin (5-HT). the short (s), as opposed to the long (l), allele of the 5-HT transporter linked polymorphism (5-HTTLPR) has been associated with neuroticism and depression. We hypothesized that this short allele would also be associated with SAD and with higher levels of seasonality. Ninety-seven SAD patients and 71 non-seasonal healthy controls with low seasonality levels were genotyped for 5-HTTLPR and compared statistically. Patients with SAD were less likely to have the l/l genotype (27.8% vs 47.9%; P < 0.01) and more likely to have the s allele (44.8% vs 32.4%; P < 0.02) as compared to controls. The three 5-HTTLPR genotypes were also differentially distributed in patients and controls (P < 0.03). The SAD patients with the l/l genotype had a lower mean seasonality score than did patients with the other two genotypes (mean +/- s.d. = 15.3 +/- 2.8 vs 17.1 +/- 3.4 respectively; P < 0.02). The 5-HTTLPR short allele contributes to the trait of seasonality and is a risk factor for SAD, providing further evidence for a relationship between genetic variation in the 5-HT transporter (5-HTT) and behavior.

Validation of the hypomania interview guide-seasonal affective disorder (HIGH-SAD) version in patients with rapid cycling bipolar disorder.

We validated the Hypomania Interview Guide-Seasonal Affective Disorder version (HIGH-SAD) in patients with rapid cycling bipolar disorder (RCBD). Fourteen outpatients were rated on six separate occasions (total = 84 visits). On each visit the patients were rated with the HIGH-SAD and the Young Mania Rating Scale (YMRS) in a counterbalanced order. Clinical assessment was completed at the end of the visit by the treating psychiatrist. Patients were assessed as hypomanic/manic on 22 of the visits. Pearson correlation coefficient between the YMRS total scores and the HIGH-SAD total scores for those 22 visits in which patients were hypomanic/manic was r = 0.629 (P < 0.05) and for all visits was r = 0.769 (P < 0.0001). Analysis with only one rating per patient yielded a Pearson correlation coefficient of r = 0.792 (P < 0.0004). We found that the HIGH-SAD was a valid scale for the measurement of hypomania in patients with RCBD. However, the scale does not differentiate hypomania from mania in this group of patients.

Effects of leuprolide-induced hypogonadism and testosterone replacement on sleep, melatonin, and prolactin secretion in men.

The possible role of gonadal steroids in regulating sleep and circadian rhythms in humans has received relatively little attention despite the importance of the topic to several clinical syndromes. Pharmacologically induced hypogonadism, with and without gonadal steroid replacement, provides an opportunity to examine these questions within a controlled experimental design. We used leuprolide acetate, with and without testosterone replacement, to study the role of testosterone in the regulation of sleep and of melatonin, PRL, and TSH secretion in men. Results from 10 men revealed significant decreases in 24-h PRL levels and in the percentage and time of stage 4 sleep in the hypogonadal state compared with testosterone replacement. There were no differences in melatonin or TSH secretion or in the timing or duration of sleep between the two hormonal conditions. These results indicate that testosterone has relatively specific and discrete effects on sleep and hormonal rhythms in men.

Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder.

BACKGROUND: The ready availability of exogenous melatonin means that its use in patients with mood disorders is probably not uncommon. Nonetheless, few controlled trials of exogenous melatonin in these patients have been conducted. METHOD: Five patients with rapid-cycling DSM-III-R bipolar disorder were treated with melatonin 10 mg q.d. at 10:00 p.m. for 12 weeks. Melatonin was added to a stable regimen of medication and administered in a double-blind, placebo-controlled fashion. RESULTS: Melantonin administration had no positive effects. One patient developed a free-running (unentrained) sleep-wake cycle after melatonin withdrawal. In addition, in both this and a second patient, there is evidence that the administration of exogenous melatonin may have suppressed the secretion of endogenous melatonin. CONCLUSION: The administration of melatonin had no significant effects on mood or sleep. However, melatonin withdrawal delayed sleep onset time and may have had some mild mood-elevating effects.

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.

Agreement between face-to-face and telephone-administered mood ratings in patients with rapid cycling bipolar disorder.

We examined the reliability and level of agreement between the telephone and face-to-face administration of two mood-rating scales (HIGH-SAD and SIGH-SAD) in patients with rapid cycling bipolar disorder (RCBD). Two clinicians administered the HIGH-SAD and SIGH-SAD to 14 outpatients with RCBD. Patients received consecutive phone and face-to-face mood ratings in a randomized order. Using a paired t-test, no significant differences were found when comparing HIGH-SAD and SIGH-SAD scores administered face-to-face and over the phone. There was a high correlation between the face-to-face and phone administration of both scales as measured by intraclass correlation (r = 0.94 for SIGH-SAD; r = 0.85 for HIGH-SAD). Our results support the use of phone-administered mood ratings as a reliable and convenient method to monitor patients with RCBD.

Seasonality and pituitary volume.

Pituitary volume in humans has been reported to change size in response to experimental manipulations of photoperiod, and to be increased during an episode of non-seasonal major depression. We wanted to determine whether pituitary volume changes either across the seasons or during an episode of winter depression. Nineteen patients with winter-seasonal affective disorder and 19 sex-, age-, height-, and weight-matched controls underwent magnetic resonance imaging of the pituitary gland in both winter and summer. Images were obtained using 0.7-mm contiguous slices and the areas of all slices were summed to compute the final volume for each gland. We found no main effects or interactions involving either diagnosis or season in our primary analysis. In a post-hoc analysis, we found a trend towards a season x gender effect (P = 0.06), such that pituitary volume increased slightly (+4.0%) across seasons in women, whereas it decreased slightly (-4.3%) across seasons in men. The results suggest that neither winter depression nor the change of seasons is associated with a significant change in pituitary size.

Diurnal variation in the direction of mood switches in patients with rapid-cycling bipolar disorder.

BACKGROUND: We assessed diurnal variation in the direction of mood switches in a sample of outpatients with rapid-cycling bipolar disorder who were on stable medication regimens. We predicted that patients would be more likely to switch from depression into mania or hypomania during the daytime hours and from mania/hypomania into depression overnight. METHOD: Fifteen patients with rapid-cycling bipolar disorder completed self-rated mood scales twice a day: once shortly after awakening and once at bedtime. Using 3 months of data for each patient, we performed categorical analyses (McNemar chi-square) to study the direction of mood switches between each day's morning and evening rating and between each evening rating and the subsequent morning rating. RESULTS: As predicted, switches that occurred between the morning and evening ratings were more likely to be from depression into mania/ hypomania or euthymia (64.3%) than in the opposite direction (35.6%; p < .0001). Similarly, switches that occurred between the evening rating and the next morning's ratings were more likely to be from mania/hypomania or euthymia into depression (64.8%) than in the opposite direction (35.2%; p < .0001). CONCLUSION: Extended wakefulness, exposure to light, increased activity, and/or endogenous rhythms could contribute to the elevation of mood during the course of the day. Sleep, darkness, reduced activity, and/or endogenous rhythms could contribute to the tendency to switch into depression overnight. Clinicians should attend to the time of day that clinical assessments are performed in patients with rapid-cycling bipolar disorder. Potential therapeutic implications include the use of light or activity during depression and use of induced sleep or exposure to darkness during mania/hypomania.