O desenvolvimento da cronomedicina : estudo dos ritmos biológicos e sono aplicados à depressão

A crescente morbimortalidade da depressão justifica a busca pelo aprimoramento do seu diagnóstico e por subtipos do transtorno que apresentem peculiaridades em relação ao tratamento clínico. Uma melhor compreensão das múltiplas facetas biológicas e psicológicas da depressão é fundamental para o desenvolvimento de terapêuticas mais eficazes. Neste contexto, a pesquisa em ritmos biológicos, incluindo o sono, representam linhas recentes e promissoras na investigação da etiologia, melhora do prognóstico e abordagem de tratamento no curso clínico da depressão. A ritmicidade das funções biológicas em mamíferos é mantida por um maquinário molecular complexo, e o principal estímulo ambiental que sincroniza os relógios biológicos é o ciclo claro-escuro. No entanto, as rotinas sociais também interferem nesse mecanismo, pois determinam a exposição à luz e os tempos de alimentação, bem como os padrões de atividade de repouso. Evidências clínicas descrevem que disfunções desse sistema temporizador estão presentes em uma variedade de condições clínicas mórbidas, como obesidade, diabetes, hipercolesterolemia, doenças cardiovasculares e câncer. As alterações de humor também foram amplamente estudadas em modelos de “desalinhamento” circadiano ou cronorruptura. Por exemplo, pacientes deprimidos apresentam um padrão distinto de movimento físico, tempo de reação motora e atividade psicomotora. Além disso, até 90% dos pacientes deprimidos reportam alterações de sono, como dificuldades em adormecer, permanecer dormindo e acordar de manhã mais cedo que o desejado. Esta tese explora as associações destes parâmetros de atividade motora e sono medidos subjetivamente (por questionários quantitativos) e objetivamente (pela actimetria) com a depressão. Inicialmente, descrevem-se dois estudos metodológicos que objetivam a validação de um instrumento quantitativo sobre higiene do sono, e o estudo dos impactos de períodos de não-uso (“off-wrist”) dos actímetros nos cálculos de parâmetros de atividade motora. A seguir, são descritos os estudos desenvolvidos que associam a avaliação subjetiva e objetiva do sono, dos ritmos de atividade e da exposição à luz com sintomas depressivos e com o transtorno depressivo maior. Esta tese documenta avanços metodológicos e provas de conceito que possibilitam a criação de novas hipóteses em estudos da associação entre ritmos biológicos e depressão. Além disso, os estudos descritos fornecem provas de que a depressão (e outros transtornos psiquiátricos) deve ser estudada sob a ótica da Cronomedicina, o estudo dos impactos do "tempo" na fisiologia, endocrinologia, metabolismo e comportamento em diferentes níveis organizacionais.The increasing morbidity and mortality of depression justifies the search for improvement of its diagnosis and of subtypes of the disorder that present peculiarities in terms of clinical treatment. A better understanding of the multiple biological and psychological facets of depression is essential for the development of more effective therapies. In this context, research on biological rhythms, including sleep, representes a recent and promising line of investigation of the etiology, improvement of the prognosis and treatment approach in the clinical course of depression. The rhythmicity of biological functions in mammals is maintained by complex molecular machinery, and the main environmental stimulus that synchronizes biological clocks is the light-dark cycle. However, social routines also interfere with this mechanism, as they determine exposure to light and feeding times, as well as resting activity patterns. Clinical evidence describes that dysfunctions of this timing system is present in a variety of morbid clinical conditions, such as obesity, diabetes, hypercholesterolemia, cardiovascular disease and cancer. Mood alterations have also been widely studied in models of circadian "misalignment" or “disruption”. For example, depressed patients have a distinct pattern of physical movement, motor reaction time and psychomotor activity. In addition, up to 90% of depressed patients report changes in sleep, such as difficulty falling asleep, staying asleep and waking up in the morning earlier than desired. This thesis explores the associations of these parameters of motor activity and sleep measured subjectively (by quantitative questionnaires) and objectively (by actimetry) with depression. Initially, two methodological studies are described that aim to validate a quantitative instrument on sleep hygiene, and to study the impacts of off-wrist periods of actimeters in the calculations of motor activity parameters. The following are the studies developed that associate the subjective and objective assessment of sleep, activity rhythms and exposure to light with depressive symptoms and major depressive disorder. This thesis documents methodological advances and proofs of concept that enable the creation of new hypotheses in studies of the association between biological rhythms and depression. In addition, the studies described provide evidence that depression (and other psychiatric disorders) should be examined from the perspective of Chronomedicine, the study of the impacts of "time" on physiology, endocrinology, metabolism and behavior at different organizational levels

Melatonin and depression : a translational perspective from animal models to clinical studies

Daily rhythm of melatonin synchronizes the body to the light/dark environmental cycle. Several hypotheses have been raised to understand the intersections between melatonin and depression, in which changes in rest-activity and sleep patterns are prominent. This review describes key experimental and clinical evidence that link melatonin with the etiopathology and symptomatology of depressive states, its role in the follow up of therapeutic response to antidepressants, as well as the clinical evidence of melatonin as MDD treatment. Melatonin, as an internal temporal cue contributing to circadian organization and best studied in the context of circadian misalignment, is also implicated in neuroplasticity. The monoaminergic systems that underly MDD and melatonin production overlap. In addition, the urinary metabolite 6-sulfatoxymelatonin (aMT6) has been proposed as biomarker for antidepressant responders, by revealing whether the blockage of noradrenaline uptake has taken place within 24 h from the first antidepressant dose. Even though animal models show benefits from melatonin supplementation on depressive-like behavior, clinical evidence is inconsistent vis-à-vis prophylactic or therapeutic benefits of melatonin or melatonin agonists in depression. We argue that the study of melatonin in MDD or other psychiatric disorders must take into account the specificities of melatonin as an integrating molecule, inextricably linked to entrainment, metabolism, immunity, neurotransmission, and cell homeostasis

How do stress, sleep quality, and chronotype associate with clinically significant depressive symptoms? A study of young male military recruits in compulsory service

Objective: Although studies have shown an association between poor sleep and chronotype with psychiatric problems in young adults, few have focused on identifying multiple concomitant risk factors. Methods: We assessed depressive symptoms (Beck Depression Inventory [BDI]), circadian typology (Morningness-Eveningness Questionnaire [MEQ]), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), perceived stress (Perceived Stress Scale [PSS]), social rhythm (Social Rhythm Metrics [SRM]), and salivary cortisol (morning, evening and night, n=37) in 236 men (all 18 years old). Separate analyses were conducted to understand how each PSQI domain was associated with depressive symptoms. Results: Depressive symptoms were more prevalent in individuals with higher perceived stress (prevalence ratio [PR] = 6.429, p o 0.001), evening types (PR = 2.58, p o 0.001) and poor sleepers (PR = 1.808, p = 0.046). Multivariate modeling showed that these three variables were independently associated with depressive symptoms (all p o 0.05). The PSQI items subjective sleep quality and sleep disturbances were significantly more prevalent in individuals with depressive symptoms (PR = 2.210, p = 0.009 and PR = 2.198, p = 0.008). Lower levels of morning cortisol were significantly associated with higher depressive scores (r = -0.335; p = 0.043). Conclusion: It is important to evaluate multiple factors related to sleep and chronotype in youth depression studies, since this can provide important tools for comprehending and managing mental health problems

Adaptation and validation of the Mood Rhythm Instrument for use in Brazilian adolescents

Objective: Adapt and validate the Mood Rhythm Instrument (MRhI), a self-reported questionnaire that assesses self-perceived rhythmicity of mood-related symptoms in adults, into a version that assesses and evaluates perceived mood-related symptoms in adolescents (MRhI-Y). Methods: Adaptation of the Brazilian Portuguese version of the MRhI for an adolescent population followed three steps: review by consultants, analysis by experts, and pilot testing through a visual analogue scale (VAS). The final questionnaire (MRhI-Y) was applied to 171 adolescents aged 12-17 years. Internal consistency was calculated using Cronbach’s alpha and McDonald’s omega. The psychometric properties of the MRhI-Y were evaluated using exploratory factor analysis (EFA). Results: The MRhI-Y was designed to use wording more appropriate for adolescents than that of the MRhI. Expert agreement about item quality ranged between 82 and 100%. Adolescents’ VAS ratings indicated good comprehension of the items. Cronbach’s alpha and McDonalds’ omega coefficients were 0.71 and 0.74. The EFA resulted in a three-factor solution (affective, cognitive, and somatic). Younger adolescents (ages 12 to 13) reported lower rhythmicity scores than older groups (ages 14 to 15 and 16 to 17), even controlling for chronotype. Conclusions: The Brazilian Portuguese version of the MRhI-Y presented adequate comprehension by adolescents and good internal consistency. The MRhI-Y is a promising tool to improve our understanding of the underlying characteristics of mood fluctuation in adolescence

6-Sulfatoxymelatonin predicts treatment response to fluoxetine in major depressive disorder

Background: To date, no biomarker has been able to predict antidepressant response at an early blockade of norepinephrine or serotonin uptake. The transient nocturnal increase in plasma melatonin levels is upregulated by blocking these uptakes. The aim of this study was to test whether fluoxetine increase in urinary 6-sulfatoxymelatonin (aMT6s) is an indicator of serotonin uptake blockade. Methods: A total of 20 women (35–45 years of age) recruited from the community had a diagnosis of major depressive disorder confirmed by the Structured Clinical Interview for DSM-IV. Depressive symptoms were evaluated by the Beck Depression Inventory (BDI). Participants were instructed to take 20 mg of fluoxetine every morning. Every 4 weeks, the dose could be increased by 20 mg until symptom remission. The concentration of aMT6s was evaluated in overnight urine samples collected 1 day before and 1 day after the first fluoxetine dose. Results: An increase in aMT6s correlated to a decrease in BDI score evaluated on day 45 (ρ=−0.67, p = 0.024) was observed. Conclusions: Nocturnal increase in urinary aMT6s after the first day of medication use links the early mechanism of action of fluoxetine to its clinical output 45 days later. Thus, the relationship between urinary aMT6s excretion 1 day before/1 day after is a biomarker for predicting clinical output earlier, reducing illness burden and health care costs