Second-generation antidepressants for preventing seasonal affective disorder in adults.

BACKGROUND: Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring. The prevalence of SAD ranges from 1.5% to 9%, depending on latitude. The predictable seasonal aspect of SAD provides a promising opportunity for prevention. This review - one of four reviews on efficacy and safety of interventions to prevent SAD - focuses on second-generation antidepressants (SGAs). OBJECTIVES: To assess the efficacy and safety of SGAs (in comparison with other SGAs, placebo, light therapy, melatonin or agomelatine, psychological therapies or lifestyle interventions) in preventing SAD and improving patient-centred outcomes among adults with a history of SAD. SEARCH METHODS: We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 19 June 2018. An earlier search of these databases was conducted via the Cochrane Common Mental Disorders Controlled Trial Register (CCMD-CTR) (all years to 11 August 2015). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature, Web of Science, the Cochrane Library, the Allied and Complementary Medicine Database and international trial registers (to 19 June 2018). We also conducted a grey literature search and handsearched the reference lists of included studies and pertinent review articles. SELECTION CRITERIA: For efficacy, we included randomised controlled trials (RCTs) on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study. For adverse events, we planned to include non-randomised studies. Eligible studies compared a SGA versus another SGA, placebo, light therapy, psychological therapy, melatonin, agomelatine or lifestyle changes. We also intended to compare SGAs in combination with any of the comparator interventions versus placebo or the same comparator intervention as monotherapy. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text publications, extracted data and assessed risk of bias of included studies. When data were sufficient, we conducted random-effects (Mantel-Haenszel) meta-analyses. We assessed statistical heterogeneity by calculating the Chi2 statistic and the Cochran Q. We used the I2 statistic to estimate the magnitude of heterogeneity. We assessed publication bias by using funnel plots.We rated the strength of the evidence using the system developed by the GRADE Working Group. MAIN RESULTS: We identified 3745 citations after de-duplication of search results and excluded 3619 records during title and abstract reviews. We assessed 126 full-text papers for inclusion in the review, of which four publications (on three RCTs) providing data from 1100 people met eligibility criteria for this review. All three RCTs had methodological limitations due to high attrition rates.Overall, moderate-quality evidence indicates that bupropion XL is an efficacious intervention for prevention of recurrence of depressive episodes in people with a history of SAD (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.44 to 0.72; 3 RCTs, 1100 participants). However, bupropion XL leads to greater risk of headaches (moderate-quality evidence), insomnia and nausea (both low-quality evidence) when compared with placebo. Numbers needed to treat for additional beneficial outcomes (NNTBs) vary by baseline risks. For a population with a yearly recurrence rate of 30%, the NNTB is 8 (95% CI 6 to 12). For populations with yearly recurrence rates of 50% and 60%, NNTBs are 5 (95% CI 4 to 7) and 4 (95% CI 3 to 6), respectively.We could find no studies on other SGAs and no studies comparing SGAs with other interventions of interest, such as light therapy, psychological therapies, melatonin or agomelatine. AUTHORS' CONCLUSIONS: Available evidence indicates that bupropion XL is an effective intervention for prevention of recurrence of SAD. Nevertheless, even in a high-risk population, three out of four people will not benefit from preventive treatment with bupropion XL and will be at risk for harm. Clinicians need to discuss with patients advantages and disadvantages of preventive SGA treatment, and might want to consider offering other potentially efficacious interventions, which might confer a lower risk of adverse events. Given the lack of comparative evidence, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences.Future researchers need to assess the effectiveness and risk of harms of SGAs other than bupropion for prevention of SAD. Investigators also need to compare benefits and harms of pharmacological and non-pharmacological interventions.

Dopamine and light: effects on facial emotion recognition.

Bright light can affect mood states and social behaviours. Here, we tested potential interacting effects of light and dopamine on facial emotion recognition. Participants were 32 women with subsyndromal seasonal affective disorder tested in either a bright (3000 lux) or dim light (10 lux) environment. Each participant completed two test days, one following the ingestion of a phenylalanine/tyrosine-deficient mixture and one with a nutritionally balanced control mixture, both administered double blind in a randomised order. Approximately four hours post-ingestion participants completed a self-report measure of mood followed by a facial emotion recognition task. All testing took place between November and March when seasonal symptoms would be present. Following acute phenylalanine/tyrosine depletion (APTD), compared to the nutritionally balanced control mixture, participants in the dim light condition were more accurate at recognising sad faces, less likely to misclassify them, and faster at responding to them, effects that were independent of changes in mood. Effects of APTD on responses to sad faces in the bright light group were less consistent. There were no APTD effects on responses to other emotions, with one exception: a significant light × mixture interaction was seen for the reaction time to fear, but the pattern of effect was not predicted a priori or seen on other measures. Together, the results suggest that the processing of sad emotional stimuli might be greater when dopamine transmission is low. Bright light exposure, used for the treatment of both seasonal and non-seasonal mood disorders, might produce some of its benefits by preventing this effect.

Antidepressant-like effect of bright light is potentiated by L-serine administration in a mouse model of seasonal affective disorder.

Bright light therapy is used as the primary treatment for seasonal affective disorder; however, the mechanisms underlying its antidepressant effect are not fully understood. Previously, we found that C57BL/6J mice exhibit increased depression-like behavior during a short-day condition (SD) and have lowered brain serotonin (5-HT) content. This study analyzed the effect of bright light on depression-like behaviors and the brain serotonergic system using the C57BL/6J mice. In the mice maintained under SD, bright light treatment (1000 lx, daily 1 h exposure) for 1 week reduced immobility time in the forced swimming test and increased intake of saccharin solution in a saccharin intake test. However, the light treatment did not modify 5-HT content and selective 5-HT uptake in the amygdala, or temporal patterns of core body temperature and wheel-running activity throughout a day. In the next experiment, we attempted to enhance the effect of bright light by using L-serine, a precursor of D-serine that acts as an N-methyl-D-aspartic acid receptor coagonist. Daily subcutaneous injection of L-serine for 2 weeks prior to the bright light strongly reduced the immobility time in the forced swimming test, suggesting a synergistic effect of light and L-serine. Furthermore, bright light increased the total number of 5-HT-immunoreactive cells and cells that had colocalized 5-HT and c-Fos immunosignals in several subregions of the raphe nuclei. These effects were potentiated by prior injection of L-serine. These data suggest that the bright light may elicit an antidepressant-like effect via enhanced 5-HT signals in the brain and L-serine can enhance these effects.

Bupropion for the treatment of seasonal affective disorder.

INTRODUCTION: Seasonal affective disorder (SAD) is a psychiatric illness with recurring depressive episodes during particular seasons, mostly winter. Bupropion is effective in the preventive treatment of SAD and is probably also effective in the acute treatment of SAD. AREAS COVERED: This review covers the pharmacokinetics and pharmacodynamics of bupropion. The authors also evaluate bupropion's clinical efficacy as well as its safety and tolerability. EXPERT OPINION: Bupropion is available in an immediate release formulation, as well as a sustained release formulation and an extended release (XR) formulation. The XR formulation is recommended for SAD due to its ease of use and is the only formulation currently used as a therapy. Due to the predictable nature of SAD, the use of bupropion XR is considered a relevant treatment option. Bupropion's efficacy is shown in three trials that started in autumn at a time when SAD symptoms were not yet present although treatment effects were relatively small compared with a placebo. Bupropion was also shown to have efficacy in an open-label study. That being said, in order to reach definitive conclusions about its efficacy with acute treatment of SAD, more placebo-controlled trials are needed.

About the cover: St. John's wort.

Derived from the aerial parts of the plant, St. John's wort generally is used for depression, seasonal affective disorder, and anxiety. Products currently are standardized based on hypericin content, although the hyperforin and bioflavonoid contents are also believed responsible for activity. St. John's wort is metabolized primarily by the liver. Some studies comparing St. John's wort to standard antidepressants suggest that it may be as effective as imipramine or selective serotonin reuptake inhibitors (SSRIs) to treat mild to moderate depression. Results from another clinical trial indicate that the effectiveness of St. John's wort is comparable to paroxetine, an SSRI, in the treatment of moderate to severe depression and is well tolerated. But a meta-analysis shows that data are inconsistent. Studies also show possible efficacy in the management of anxiety and premenstrual syndrome, although additional research is necessary. St. John's wort can interact with many medications owing to induction of cytochrome P-450 3A4 and other mechanisms. Significant interactions include decreased efficacy of antiretrovirals, cyclosporine, tacrolimus, antiepileptics, irinotecan, and other chemotherapeutic agents. Serotonin syndrome may occur when St. John's wort is combined with sympathomimetics, antidepressants, or triptans. Frequently reported adverse events include nausea, headache, constipation, dizziness, confusion, fatigue, and dry mouth. St. John's wort should be used under medical supervision.

Therapeutic mechanism in seasonal affective disorder: do fluoxetine and light operate through advancing circadian phase?

In the context of Lewy's phase delay hypothesis, the present study tested whether effective treatment of winter Seasonal Affective Disorder (SAD) is mediated by advancing of circadian phase. Following a baseline week, 78 outpatients with SAD were randomized into 8 weeks of treatment with either fluoxetine and placebo light treatment or light treatment and placebo pill. Depression levels were measured on the Ham17+7 and the BDI-II, and circadian phase was estimated on the basis of daily sleep logs and self-reported morningness-eveningness. Among the 61 outpatients with complete data, both treatments were associated with significant antidepressant effect and phase advance. However, pre- and post-treatment comparisons found that the degree of symptom change did not correlate with the degree of phase change associated with treatment. The study therefore provides no evidence that circadian phase advance mediates the therapeutic mechanism in patients with SAD. Findings are discussed in terms of the limitations of the circadian measures employed.

Using metaanalysis to evaluate evidence: practical tips and traps.

Although practising evidence-based medicine is the goal of most physicians, it can be a real challenge to sift through the vast body of data to determine the best strategies. Most clinical guidelines regard replicated randomized controlled trials (RCTs), metaanalyses, and systematic reviews as the highest level of evidence to support treatment recommendations. High-quality metaanalyses can overcome many of the drawbacks of individual RCTs and qualitative reviews. They can reduce bias, provide adequate power to demonstrate real differences in outcomes, and resolve the results of inconsistent studies. This paper focuses on basic principles and terms used in metaanalysis, so that clinicians can appropriately evaluate and use their results to guide treatment decisions.

Utilización del carbonato de litio en el Instituto Psiquiátrico de Santiago: comparación entre dos servicios clínicos, variación estacional / Use of lithium carbonate at Instituto Psiquiátrico, Santiago: comparison of 2 clinical services, seasonal variation

El objetivo de este estudio es analizar el uso del carbonato de litio en pacientes hospitalizados en sectores de agudos en el Instituto Psiquiátrico de Santiago, desde 1985 a 1990, y comparar su uso en los dos servicios clínicos existentes en ese período. El estudio se llevó a cabo en los Servicios A y B del Instituto que tenían características similares en cuanto a tipo de pacientes. El instrumento usado para hacer las comparaciones fue la DDD (dosis diaria definida), fórmula que hace posible comparar el uso de fármacos entre distintos centros. Se buscó también variaciones estacionales en su utilización. Un masivo incremento en el uso del Carbonato de Litio se aprecia en los primeros seis años, el que se estabiliza en los últimos dos. Este hecho puede atribuirse a un menor diagnóstico de los trastornos afectivos y a una progresiva aceptación del uso del medicamento. También se encontró una gran diferencia en el uso del medicamento entre los dos servicios (A y B) lo que resulta difícil de explicar y podría estar relacionado con la aplicación de criterios diagnósticos diferentes en trastornos del ánimo versus esquizofrenia. En relación a la variación estacional se encontró un incremento mayor en primavera

Extrapineal melatonin and exogenous serotonin in seasonal affective disorder.

Visible light inhibits the binding of melatonin and serotonin to cultured human peripheral blood mononuclear leukocytes (PBMLs) in winter. The decreased binding switches the metabolism in PBMLs towards serotonin synthesis, resulting in the reduced production of melatonin. The ingestion of L-tryptophan during the day is hypothesized to increase the levels of melatonin, released from the gastrointestinal tract, in patients with winter seasonal affective disorder (SAD). Due to the relative shortage of light, coincident with a predisposed metabolic error, there would be no switch towards serotonin synthesis among winter SAD patients in winter. The rate of serotonin synthesis could thus remain inadequately low to maintain optimal mood in winter SAD patients.

Serotonina y trastornos de la conducta alimentaria / Serotonin and disorders of eating behaviour

En este trabajo se analizan las relaciones entre los trastornos de la conducta alimentaria y los sistemas de neurotransmisión centrales. Se presentan los aspectos neuroquímicos relacionados con el control del apetito, especialmente la contribución de los sistemas noradrenégico, serotoninérgico y neuropeptídico. Se revisan los hallazgos biológicos en la bulimia, en la anorexia nerviosa y en la voracidad por carbohidratos del trastorno afectivo estacional. Se discute el manejo farmacológico del apetito en clínica, especialmente las intervenciones sobre el sistema serotoninérgico. Se analiza la relación entre los subtipos de receptores serotoninérgicos y la conducta alimentaria. Se concluye que la serotonina es un modulador de los patrones de comer normales. Los pacientes con trastornos del comer tienen índices de disfunción del sistema serotoninérgico y los fármacos que actúan selectivamente sobre el sistema serotoninérgico ejercen importantes efectos sobre la conducta alimentaria

The efficacy of bupropion in winter depression: results of an open trial.

BACKGROUND: Seasonal affective disorder (SAD) refers to regularly recurring episodes of affective illness bearing a fixed relationship to season. Wintertime depression is its most widely recognized form. This study was undertaken to assess the efficacy of bupropion as a treatment for this disorder. METHOD: Fifteen consecutively presenting patients were treated with bupropion (200 to 400 mg/day). All met DSM-III-R criteria for major depression with a seasonal pattern. All were moderately to severely depressed. A modified version of the Hamilton Rating Scale for Depression (mHAM-D) including ratings of hypersomnia, increased appetite and carbohydrate craving, and weight gain was used to quantify the severity of illness. Up to 5 weeks of treatment was allowed before the subjects were categorized as nonresponders, partial responders, or responders. RESULTS: The mean +/- SD mHAM-D scores before and after treatment were 25.5 +/- 6.4 and 4.1 +/- 3.1, respectively. Ten (66.7%) of the subjects had a complete response to treatment (mHAM-D score less than or equal to 5). The other 5 (33.3%) had a partial response (mHAM-D score = 6-10). Five of the subjects had chronic pain and 3 had panic attacks restricted to episodes of depression. These problems resolved simultaneously with the symptoms of depression. CONCLUSION: The results of this open trial suggest that bupropion is an effective treatment for winter depression. However, controlled studies are required to confidently determine whether this is the case.

Seasonal relapses in affective disorder in the Tropics: a prospective follow-up of 12 patients.

Seasonal relapses of affective disorder are known. We report 12 patients who had season-linked relapses during a prospective follow-up period of 4 years. There were both winter and summer relapses of mania and depression. The centre is in the tropical zone, with lesser variation of sunshine and temperature than in more extreme latitudes. This may inference the pattern of relapse in affective disorder. Differences in relapses between tropical and temperate zones need to be investigated.