updating Sedative antidepressants and insomnia Antidepressivos sedativos e insônia Walter André dos Santos Moraes,1 Patrick Rademaker Burke,1 Pablo Lorenzon Coutinho,1 Christian Guilleminault,2 Aline Gomes Bittencourt,1 Sergio Tufik,1 Dalva Poyares1 1 Psychobiology Department, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil 2 Human Sleep Research Center, Department of Psychiatry and Behavioral Science, School of Medicine, Stanford University, Palo Alto, CA, USA Abstract Resumo Objective: The present review addresses the relationship between sleep Objetivo: Esta atualização aborda a relação entre sono e depressão e como and depression and how serotonergic transmission is implicated in both a transmissão serotoninérgica está envolvida em ambas condições. Método: conditions. Method: Literature searches were performed in the PubMed Foi realizada uma busca na literatura no PubMed e MedLine até março and MedLine databases up to March 2010. The terms searched were de 2010 com os termos “insônia”, “depressão”, “antidepressivos sedativos” e “insomnia”, “depression”, “sedative antidepressants” and “serotonin”. In “serotonina”. A fim de contemplar os antidepressivos sedativos mais utilizados order to pinpoint the sedative antidepressants most used to treat insomnia, no tratamento da insônia, 34 artigos ISI, principalmente revisões e estudos 34 ISI articles, mainly reviews and placebo-controlled clinical trials, were clínicos placebo-controlados, foram selecionados entre 317 artigos encontrados selected from 317 articles found in our primary search. Results: Sleep na busca inicial. Resultados: Alterações de sono podem aparecer meses antes problems may appear months before the diagnosis of clinical depression do diagnóstico clínico de depressão e persistir após a resolução da depressão. and persist after the resolution of depression. Treatment of insomnia O tratamento dos sintomas de insônia pode melhorar essa doença associada. symptoms may improve this comorbid disease. Some antidepressant Alguns antidepressivos também podem levar à insônia ou sonolência diurna. A drugs can also result in insomnia or daytime sleepiness. Serotonin (5-HT) serotonina (5-HT) demonstra um padrão complexo no que diz respeito ao sono demonstrates a complex pattern with respect to sleep and wakefulness e vigília, o que está relacionado com a variedade de subtipos do receptor 5-HT that is related to the array of 5-HT receptor subtypes involved in different envolvidos em diferentes funções fisiológicas. Acredita-se, atualmente, que a physiological functions. It is now believed that 5HT receptor stimulation 2 estimulação do receptor 5-HT2 esteja envolvida nas alterações da organização is subjacent to insomnia and changes in sleep organization related to do sono e insônia relacionada a alguns antidepressivos. Conclusão: Alguns the use of some antidepressants. Conclusion: Some drugs commonly medicamentos normalmente prescritos para o tratamento de depressão prescribed for the treatment of depression may worsen insomnia and podem piorar a insônia e dificultar a completa recuperação da depressão. Os impair full recovery from depression. 5-HT receptor antagonists are 2 antagonistas do receptor 5-HT2 são drogas promissoras para o tratamento, promising drugs for treatment strategies since they can improve comorbid pois podem melhorar a insônia e depressão associadas. insomnia and depression. Descritores: Neuroquímica; Antidepressivos; Sono; Transtorno depressivo; Descriptors: Neurochemistry; Antidepressive agents; Sleep; Depressive Psicofarmacologia disorder; Psychopharmacology Introduction refers to the quantitative need for sleep that builds up while a Sleep disorders have been reported as symptoms seen in many person is awake and declines during sleep, and is dependent on depressed patients.1 Insomnia may occur in 60-80% of patients how long a person is awake and on how active they are while with major depressive disorder and hypersomnia in approximately awake. The deficiency theory states that Process S in depressive 15-20%.2 Depressive symptoms are important risk factors for patients is deficient in the waking state, which is reflected in insomnia, and depression is considered an important comorbid reduced delta activity. Some authors have described how the delta condition in patients with chronic insomnia of any etiology.3 ratio (delta sleep duration from the first to the second rapid eye Insomnia and sleepiness may also occur as side effects of some movement – REM – period) is reduced in depressive patients.5-7 antidepressant drugs.4 Another model is based on experimental evidence on the reciprocal Different models have been proposed to explain changes in interaction between cholinergic REM-on and aminergic REM- sleep patterns associated with depression. Process S, for instance, off neurons.5,6 REM-suppressive antidepressant therapy supports Correspondence Patrick Rademaker Burke Psychobiology Department, Universidade Federal de São Paulo R. Napoleão de Barros, 925 04024-002 São Paulo, SP, Brasil Submitted: June 29, 2010 Phone: (+55 11) 2149-0155 Accepted: October 11, 2010 Email: [email protected] Revista Brasileira de Psiquiatria 2011 • vol 33 • nº 1 • mar2011 • 91 Moraes WAS et al. this model. Cholinergic/aminergic interaction is subject to both type had higher Beck Depression Inventory scores,10 indicating ultradian and circadian cycles. The internal coincidence model that patients with persistent insomnia were 1.8-3.5 times more supposes that there is a strong circadian oscillator controlling REM likely to remain depressed, compared with patients with no sleep and a weak oscillator controlling the wake–sleep cycle.5 In insomnia.10 This suggests that in addition to being a risk factor depressive patients the strong oscillator is in the advanced phase, for depressive episodes, persistent insomnia perpetuates the illness causing them to sleep late in relation to the biological clock.5 in some elderly patients.11 Consequently, managing insomnia may The activation model5 suggests that depressive patients present enhance the treatment outcome of this comorbid disease.8 There is altered regulation of cortical activation, so that they tend to a dearth of clinical trials examining the effectiveness of hypnotics remain in a hyper-activated state during wakefulness. If, on one in the treatment of depression associated with insomnia. Some hand, brain imaging of glucose metabolism supports the hyper- studies show that relief of sleep disturbance is often determinant activation theory, on the other hand, clinical evidence shows that of compliance with antidepressant treatment. hypo-activation symptoms are frequent and that unidimensional To date there have been few studies evaluating the efficacy of models are inadequate.5 antidepressant drugs in primary insomnia.1 A randomized trial compared the efficacy of trazodone therapy to zolpidem therapy Method and placebo for patients with primary insomnia.12 Compared This is an updated report which focuses on the relationship to zolpidem, trazodone was less effective in improving sleep between sleep, insomnia, 5HT and depression, with particular disturbances in those patients.12 Despite the widespread use of attention to sedative antidepressants in the context of insomnia. trazodone for insomnia, there are limited data available, most of Other effects of antidepressants, with the exception of sedation, them on insomnia associated with depression.12 More studies are are beyond the scope of this report. For concision, we included needed on the effect and long-term safety of trazodone in primary the most commonly prescribed compounds of this class, which insomnia and in the elderly, among whom its use is frequent. A included: trazodone, mirtazapine, agomelatine and doxepine randomized crossover study, using polysomnography and patient Literature searches were performed in the PubMed and MedLine reporting, evaluated doxepin therapy for adults with primary databases up to March 2010. The terms searched were “insomnia”, insomnia,1,13 and has shown its efficacy in improving sleep.13 “depression”, “sedative antidepressants“ and “serotonin“. We Trimipramine and paroxetine were also analyzed, but results were started with 317 references and have given priority to reviews not promising.1 Thus, there is no evidence that antidepressants (15), randomized placebo-controlled studies and other controlled are superior to the new nonbenzodiazepine hypnotics to treat studies (11), but also included update articles (2), cohort primary insomnia. and epidemiological studies (4), an open label study (1) and experimental data in humans and animals (3). Case reports and Selective serotonin reuptake inhibitors and their articles assessing other sedative-hypnotic substances were excluded. impact on sleep A total of 34 references were included. The most common sleep disturbances in depressed patients, as Among reviews and controlled studies we have included about documented in visually-scored polysomnograms, include: three articles for each of the mentioned sedative antidepressants. 1) Altered duration and sustenance of sleep. Total sleep time is reduced, due to an increase in sleep latency and wake time after The relationship between sleep and depression sleep onset (WASO), and early morning awakening. However, Depressive symptoms are the greatest and most consistent risk 15-20% present hypersomnia.5,14 Depressive individuals frequently factors for insomnia, which is often the presenting symptom in show sleep-stage changes and