Cronoterapia para reducción de riesgo cardiovascular / Chronotherapy for reduction of cardiovascular risk

Diversos estudios prospectivos han demostrado de forma concordante que la elevación en la media de descanso de la presión arterial (PA) constituye un factor de riesgo cardiovascular (CV) significativo e independiente de la PA clínica, o de las medias de actividad o de 24horas derivadas de la monitorización ambulatoria de la PA. Además, múltiples ensayos clínicos de cronoterapia documentan, con pocas discrepancias debidas a deficiencias metodológicas, mayor eficacia en la reducción de la PA durante el sueño cuando los antihipertensivos se ingieren al acostarse en lugar de al levantarse. Estudios prospectivos recientes indican también que la cronoterapia antihipertensiva al acostarse reduce el riesgo de eventos CV no solo en población general, sino en los pacientes más vulnerables con edad avanzada, enfermedad renal, diabetes o hipertensión resistente. En su conjunto, estos resultados indican la necesidad de establecer una nueva definición de hipertensión, así como de estrategias adecuadas para su tratamiento

Numerous prospective studies establish that elevated asleep blood pressure (BP) constitutes a significant cardiovascular disease (CVD) risk factor, irrespective of daytime office BP measurements or awake and 24h BP measurements. Moreover, except for a small number of studies with flawed methodology, multiple clinical trials of high consistency document significantly better BP-lowering efficacy of hypertension medication and their combinations when ingested at bedtime compared to upon awakening as is customary. Additionally, recent trials conclude bedtime hypertension chronotherapy markedly reduces CVD risk not only in the general population, but also in more vulnerable patients of advanced age, with kidney disease, diabetes, or resistant hypertension. Collectively, these results call for a new definition of true arterial hypertension and its proper diagnosis and management

Sleep and major depressive disorder: a review of non-pharmacological chronotherapeutic treatments for unipolar depression.

Depression is a significant public health issue, made worse by the absence of response to antidepressant medications by many patients. Given the high degree of overlap between sleep and circadian complaints and depression, chronotherapies are a promising avenue for novel, effective, and fast-acting treatments for depression. A critical literature review was conducted of bright light therapy (BLT) as a treatment for unipolar depression. Additionally, a separate critical literature review was also conducted of several promising, non-pharmacological, combination chronotherapeutic treatments, including BLT, sleep deprivation/wake therapy, and sleep phase advance. Results of BLT as a treatment for depression are encouraging, especially when used as an adjunct to antidepressant medications. It may also be desirable in special populations, such as geriatric and perinatal patients. Overall, results from combination chronotherapies are encouraging, though none has strong empirical support. Combining chronotherapies is an avenue of treatment which should be further explored.

Cognitive "insomnia" processes in delayed sleep-wake phase disorder: Do they exist and are they responsive to chronobiological treatment?

OBJECTIVE: To systematically investigate whether cognitive "insomnia" processes are implicated in adolescent Delayed Sleep-Wake Phase Disorder (DSWPD) and to examine whether these processes are responsive to chronobiological treatment. METHOD: Sixty-three adolescents (M = 15.8 ± 2.2 years, 63.5% f) diagnosed with DSWPD and 40 good sleeping adolescents (M = 15.9 ± 2.4 years, 75% f) completed baseline measures of sleep, daytime functioning and cognitive "insomnia" processes (i.e., repetitive negative thinking, physiological hyperarousal, distress, sleep-related attention and monitoring, sleep misperception). Sixty DSWPD adolescents (M = 15.9 ± 2.2 y, 63% f) entered a treatment trial and received 3 weeks of light therapy. Sleep, daytime functioning, and insomnia were measured again post-treatment and at 3-month follow-up. RESULTS: Adolescents with DSWPD had significantly later sleep timing (d = 0.99-1.50), longer sleep latency (d = 1.14), and shorter total sleep time (d = 0.85) on school nights, compared with the good sleeping adolescents. There was evidence of cognitive "insomnia" symptoms, with the DSWPD group reporting more repetitive negative thinking (d = 0.70-1.02), trait hyperarousal (d = 0.55), distress (d = 2.19), sleep associated monitoring (d = 0.76), and sleep onset misperception (d = 1.29). Across treatment and follow-up, adolescents with DSWPD reported advanced sleep timing (d = 0.54-0.62), reduced sleep latency (d = 0.53), increased total sleep time (d = 0.49), and improved daytime functioning (d = 0.46-1.00). Repetitive negative thinking (d = 0.64-0.96), physiological arousal (d = 0.69), distress (d = 0.87), and sleep onset misperception (d = 0.37) also showed improvement. CONCLUSIONS: Cognitive "insomnia" processes may be implicated in the development and maintenance of DSWPD in adolescents. Many of these processes are amendable to chronobiological treatment; however, residual symptoms may place adolescents at risk of poor treatment outcome or relapse. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

[Psychiatry and circadian rhythms].

Circadian and seasonal rhythm disturbances are prominent in patients with psychiatric disorders. Properly timed and dosed light of specific spectral composition stabilises mood and sleep through serotonergic mechanisms and through input to the master circadian clock in the hypothalamus. Correctly administered, light can be used as an effective treatment for seasonal and non-seasonal depression and for stabilising the sleep-wake cycle. Blocking blue light in the evening may provide a non-pharmacological anti-manic tool. Current developments use dynamic lighting built into somatic and psychiatric hospitals to maximise the beneficial effects of light.

Agomelatine treatment corrects symptoms of depression and anxiety by restoring the disrupted melatonin circadian rhythms of rats exposed to chronic constant light.

Desynchronization of circadian rhythms is a hallmark of depression. The antidepressant agomelatine, which is an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist has advantages compared to the selective serotonin reuptake inhibitors as a circadian phase-shifting agent. The present study was designed to explore whether agomelatine is able to have an antidepressant effect on rats exposed to chronic constant light (CCL) for 6 weeks. Focus is also placed on whether this activity affects diurnal rhythms of depressive-like symptoms and is associated with restoration of impaired circadian rhythms in plasma melatonin and corticosterone. We report that CCL induced a depressive-like symptoms associated with decreased grooming in the splash test during the subjective light/inactive phase. Anhedonia-like deficit in the saccharine preference test and increased immobility in the forced swimming test were both detected during the subjective dark/active phase. The disturbed emotional fluctuations due to CCL were corrected by agomelatine treatment (40 mg/kg, i.p. for 3 weeks). Agomelatine also restored novelty-induced hypophagia, which reflects an anxiety state, during the subjective Light and Dark phase, respectively, in rats exposed to CCL. Parallel to the observed positive influence on behavior, this melatonin analogue restored impaired circadian patterns of plasma melatonin but not that of corticosterone. These findings demonstrated the antidepressant-like effect of agomelatine in rats exposed to CCL possibly exerted via correction of melatonin rhythms and are suggestive of the therapeutic potential of this drug in a subpopulation of people characterized by a melatonin deficit.

Bright Light as a Preventive Intervention for Depression in Late-Life: A Pilot Study on Feasibility, Acceptability, and Symptom Improvement.

OBJECTIVES: We examined the feasibility and acceptability of a portable bright light intervention and its impact on sleep disturbance and depressive symptoms in older adults. METHODS: One-arm prevention intervention pilot study of the Re-Timer (Re-Timer Pty Ltd, Adelaide, Australia) bright light device (worn 30 minutes daily for 2 weeks) in 1 older adults (age 65 + years) with subsyndromal symptoms of depression and poor sleep quality. Participants were assessed on intervention acceptability and adherence, depressive symptoms (Patient Health Questionnaire- 9), and sleep (Pittsburgh Sleep Quality Index, Insomnia Severity Index, actigraphy and daily diary reports). RESULTS: The Re-Timer device was rated positively by participants, and, on average, participants only missed 1 day of utilization. Although depressive symptoms declined and self-reported sleep improved, improvement was seen largely before the start of intervention. CONCLUSIONS: An effective preventive intervention that is targeted towards a high risk group of older adults has the potential to reduce distress and costly health service use.

Chronotherapeutic treatments for depression in youth.

Chronotherapeutics such as wake therapy and bright light therapy are well-established methods in treating adults with depressive disorders and are additionally beneficent for sleep regulation. Few studies concerning chronotherapeutics in juvenile depression exist, though the established treatments are insufficient and sleep disorders often co-occur. In this study, we investigate the impact of two types of chronotherapeutics on depressive symptoms and sleep behavior in a juvenile setting. Juvenile inpatients (n = 62) with moderate to severe depressive symptoms took part in either a combined setting consisting of one night wake therapy followed by 2 weeks bright light therapy or in a setting of bright light therapy alone. Depressive symptoms, general psychopathology, clinical impression and sleep behavior were measured before (T1), directly after (T2) and 2 weeks after intervention (T3). Depressive symptoms decreased while sleep quality increased in both groups. The bright light therapy alone group showed further improvement at T3 in regards to depressive symptoms. Correlation analyses indicated significant negative correlations between sleep quality and awaking after restorative sleep with the depressive symptoms. However, only awaking after restorative sleep had a predictive impact on treatment outcome. The present study provides first evidence for a positive impact of chronotherapeutic interventions on treatment outcome in depressed juvenile inpatients. Bright light therapy seems to stabilize and further enhance reduction of depressive symptoms during follow-up, whereas one night wake therapy does not have an additional long-lasting impact on depressive symptoms and sleep parameters.

Chronobiological Therapy for Mood Disorders.

Chronobiological therapies for mood disorders include manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance and the controlled exposure to light and darkness. Their antidepressant efficacy can overcome drug resistance and targets the core depressive symptoms including suicide, thus making them treatment options to be tried either alone or as adjunctive treatments combined with common psychopharmacological interventions. The specific pattern of mood change observed with chronobiological therapies is characterized by rapid and sustained effects, when used among themselves or combined with drugs. Effects sizes are the same reported for the most effective psychiatric treatments, but side effects are usually marginal or absent. New treatment protocols are developed to adapt them in different clinical settings. This review deals with the general principles of clinical chronobiology and the latest findings in this rapidly developing field.

Circadian rhythm disorders among adolescents: assessment and treatment options.

Delayed sleep phase disorder (DSPD) - a circadian rhythm sleep disorder - is most commonly seen in adolescents. The differential diagnosis between DSPD and conventional psychophysiological insomnia is important for correct therapeutic intervention. Adolescent DSPD sleep duration is commonly 9 hours or more. Depression may be comorbid with DSPD. DSPD has a negative impact on adolescent academic performance. DSPD treatments include bright light therapy, chronotherapeutic regimens, and administration of melatonin as a chronobiotic (as distinct from a soporific). Attention to non-photic and extrinsic factors including healthy sleep parameters is also important to enable better sleep and mood outcomes in adolescents.

Circadian rhythms and psychiatric illness.

PURPOSE OF REVIEW: The present review provides a conceptual introduction to sleep and circadian research in psychiatric illness, and discusses recent experimental and intervention findings in this area. RECENT FINDINGS: In this review, studies published since January 2011 on circadian disturbance and psychiatric illness have been summarized. SUMMARY: Exciting new results have increasingly utilized objective and validated instruments to measure the circadian system in experimental studies. Since 2011, treatment research has still predominantly utilized self-report measures as outcome variables. However, research in the treatment domain for sleep/circadian disturbances comorbid with psychiatric illness has advanced the field in its work to broaden the validation of existing sleep treatments to additional patient populations with comorbid sleep/circadian disruptions and address how to increase access to and affordability of treatment for sleep and circadian dysfunction for patients with psychiatric disorders, and how to combine psychosocial treatments with psychopharmacology to optimize treatment outcomes.

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Increasing sleep duration to lower beat-to-beat blood pressure: a pilot study.

Strong evidence has accumulated over the last several years, showing that low sleep quantity and/or quality plays an important role in the elevation of blood pressure. We hypothesized that increasing sleep duration serves as an effective behavioral strategy to reduce blood pressure in prehypertension or type 1 hypertension. Twenty-two participants with prehypertension or stage 1 hypertension, and habitual sleep durations of 7 h or less, participated in a 6-week intervention study. Subjects were randomized to a sleep extension group (48 ± 12 years, N = 13) aiming to increase bedtime by 1 h daily over a 6-week intervention period, or to a sleep maintenance group (47 ± 12 years, N = 9) aiming to maintain habitual bedtimes. Both groups received sleep hygiene instructions. Beat-to-beat blood pressure was monitored over 24 h, and 24-h urine and a fasting blood sample were collected pre- and post-intervention. Subjects in the sleep extension group increased their actigraphy-assessed daily sleep duration by 35 ± 9 min, while subjects in the sleep maintenance condition increased slightly by 4 ± 9 min (P = 0.03 for group effect). Systolic and diastolic beat-to-beat blood pressure averaged across the 24-h recording period significantly decreased from pre- to post-intervention visit in the sleep extension group by 14 ± 3 and 8 ± 3 mmHg, respectively (P < 0.05). Though the reduction of 7 ± 5 and 3 ± 4 mmHg in the sleep maintenance group was not significant, it did not differ from the blood pressure reduction in the sleep extension group (P = 0.15 for interaction effect). These changes were not paralleled by pre- to post-intervention changes in inflammatory or sympatho-adrenal markers, nor by changes in caloric intake. While these preliminary findings have to be interpreted with caution due to the small sample size, they encourage future investigations to test whether behavioral interventions designed to increase sleep duration serve as an effective strategy in the treatment of hypertension.

A 9-week randomized trial comparing a chronotherapeutic intervention (wake and light therapy) to exercise in major depressive disorder patients treated with duloxetine.

OBJECTIVE: The onset of action of antidepressants often takes 4 to 6 weeks. The antidepressant effect of wake therapy (sleep deprivation) comes within hours but carries a risk of relapse. The objective of this study was to investigate whether a new chronotherapeutic intervention combining wake therapy with bright light therapy and sleep time stabilization could induce a rapid and sustained augmentation of response and remission in major depressive disorder. METHOD: 75 adult patients with DSM-IV major depressive disorder, recruited from psychiatric wards, psychiatric specialist practices, or general medical practices between September 2005 and August 2008, were randomly assigned to a 9-week chronotherapeutic intervention using wake therapy, bright light therapy, and sleep time stabilization (n = 37) or a 9-week intervention using daily exercise (n = 38). Patients were evaluated at a psychiatric research unit. The study period had a 1-week run-in phase in which all patients began treatment with duloxetine. This phase was followed by a 1-week intervention phase in which patients in the wake therapy group did 3 wake therapies in combination with daily morning light therapy and sleep time stabilization and patients in the exercise group began daily exercise. This phase was followed by a 7-week continuation phase with daily light therapy and sleep time stabilization or daily exercise. The 17-item Hamilton Depression Rating Scale was the primary outcome measure, and the assessors were blinded to patients' treatment allocation. RESULTS: Both groups responded well to treatment. Patients in the wake therapy group did, however, have immediate and clinically significantly better response and remission compared to the exercise group. Thus, immediately after the intervention phase (week 2), response was obtained in 41.4% of wake therapy patients versus 12.8% of exercise patients (odds ratio [OR] = 4.8; 95% CI, 1.7-13.4; P = .003), and remission was obtained in 23.9% of wake therapy patients versus 5.4% of exercise patients (OR = 5.5; 95% CI, 1.7-17.8; P = .004). These superior response and remission rates obtained by the wake therapy patients were sustained for the whole study period. At week 9, response was obtained in 71.4% of wake therapy patients versus 47.3% of exercise patients (OR = 2.8; 95% CI, 1.1-7.3; P = .04), and remission was obtained in 45.6% of wake therapy patients and 23.1% of exercise patients (OR = 2.8; 95% CI, 1.1-7.3, P = .04). All treatment elements were well tolerated. CONCLUSIONS: Patients treated with wake therapy in combination with bright light therapy and sleep time stabilization had an augmented and sustained antidepressant response and remission compared to patients treated with exercise, who also had a clinically relevant antidepressant response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00149110.

Risk Evaluation and Mitigation Strategies (REMS) for extended-release and long-acting opioid analgesics: considerations for palliative care practice.

Prescription opioid analgesics are an essential treatment option for patients with moderate to severe pain. Over the last decade the increased medical use of these agents has contributed to a public health epidemic of abuse, addiction, and overdose-related deaths. These medications remain mainstays in both primary care and pain management practices. As palliative services are incorporated at earlier stages of the disease process and the number of individuals with chronic illness increases, palliative care specialists may encounter an increasing number of patients with opioid abuse and addiction problems. Extended-release (ER) and long-acting (LA) opioid formulations are administered to patients with moderate to severe chronic pain requiring around-the-clock analgesia. Given the large quantity of active ingredient contained within some dosage strengths, this medication class is associated with serious risks when taken improperly. In response to growing reports of abuse and overdose deaths, the US Food and Drug Administration (FDA) announced the need for a risk mitigation strategy for the entire class of medication. The class-wide Risk Evaluation and Mitigation Strategy (REMS) for ER/LA opioids will emphasize prescriber training and patient education to ensure that the therapeutic benefits outweigh the risks of addiction, unintentional overdose, and death. As primary care, pain management, and palliative care clinicians often encounter patients who require ER/LA opioids, an understanding of the suggested requirements and potential impact of this regulation is essential.

[Significance of a recent amendment on advance directives for psychiatric patients in Germany]. / Patientenverfügungsgesetz. Konsequenzen für die Behandlung psychisch Kranker.

Current legal regulations concerning the right of self-determination of subjects who are not competent to give consent have been in force since 2009. According to the new regulations, such subjects can exercise their right of self-determination through a legal guardian who will assess and impose their will. If there is an operative advance directive covering the specific case, the guardian is bound by the provisions laid down in it. Although primarily intended for end-of-life decisions, the law applies in all cases of a subject's inability to give consent, including the context of mental illness. It allows the persons concerned to define certain aspects of medical treatment in advance. On the one hand, the right of self-determination of mentally ill people is thus strengthened. On the other hand, the new regulations can also cause significant ethical conflict involving patients and their representatives as well as family members and practitioners. The present contribution presents the consequences of the amendment for the treatment of mentally ill people. Case studies are described in order to illustrate the new regulations in clinical situations.

The effect of vestibular stimulation in a four-hour sleep phase advance model of transient insomnia.

STUDY OBJECTIVES: To determine if vestibular stimulation is an effective therapy for transient insomnia in a sleep phase advance model. DESIGN: Multi-site, double-blind, randomized, parallel-group, sham-controlled trial SETTING: This study was carried out at 6 sites in the United States. PARTICIPANTS: 198 healthy normal sleepers. INTERVENTIONS: Bilateral electrical stimulation of the vestibular apparatus of the inner ear via electrodes on the skin of the mastoid process at a frequency of 0.5 Hz vs. sham stimulation. RESULTS: We did not find a significant effect of treatment on our primary outcome variable, latency to persistent sleep onset (LPS). However, our planned analysis identified that the mean latency to sleep onset on the multiple sleep latency test was a significant covariate. This led us to carry out post hoc analyses, which showed a significant effect of treatment on LPS in those subjects with a mean MSLT sleep onset latency > or = 14 minutes. CONCLUSIONS: Vestibular stimulation did not have a therapeutic effect in a model of transient insomnia in the overall population studied. However, this study provides preliminary evidence that vestibular stimulation may shorten sleep onset latency compared with sham therapy in the subset of subjects with mean MSLT sleep onset latency > or = 14 minutes.

[Mood, mood fluctuations and depression: role of the circadian rhythms]. / Hangulat, hangulatingadozások és depresszió: a cirkadián ritmusok szerepe.

The statement that circadian rhythmicity is an important component of mood regulation as well as a drive of mood disorders is supported by a growing body of evidence. Diurnal rhythms of the positive and negative components of mood as well as of the level of arousal depend on the circadian phase, the homeostatic sleep regulatory mechanisms and the harmonic interaction of the circadian and homeostatic processes. The chronopathological symptoms which are typical in depression and explain the blunted mood of depressive patients are of the phase-advance and phase-delay type characterized by a misalignment between the circadian rhythms and the sleep-wake schedules, best described by the phase-angle alterations. The abnormal phase angle between circadian rhythms and the timing of the sleep period could emerge from an interaction of the chronotypes and other constitutional factors with adverse environmental effects (inadequate zeitgebers) leading to a disharmony between the diurnal components of mood regulation and consequent extreme mood states. The aim of the chronotherapies of depression and of other affective disorders is that of resynchronizing the circadian rhythms or in other words to reconstitute the harmony between these subsystems. Pharmacological approaches, lifestyle changes and specific chronotherapeutic interventions might help to achieve this goal.

[Delayed sleep phase type sleep disorder and chronotherapy]. / Gecikmis Uyku Fazi Tipi Uyku Bozuklugu ve Kronoterapi.

Delayed sleep phase type sleep disorder is a circadian rhythm disorder that results in symptoms of sleep-onset insomnia and difficulty awakening at a desired time. Patients with delayed sleep phase-type sleep disorder can be treated with chronotherapy, light therapy, vitamin B12, or melatonin. Chronotherapy is a behavioral technique in which sleep time is systematically delayed. Herein we report a 48-year-old woman that presented with delayed sleep onset and describe chronotherapy as a treatment approach.

Modeling napping, post-lunch dip, and other variations in human sleep propensity.

STUDY OBJECTIVES: To model sleep propensity (SP) as a continuous variable across 24 hours and to model the post-noon nap zone, or post-lunch dip in performance, and the early evening trough in SP. METHODS: The present model is a variant of the 2-process model with 2 major modifications. (1) The circadian threshold process was replaced by sleep drive R, derived from REM sleep propensity, which shows a strong circadian modulation. (2) The model is based on a multiplicative interaction between the 2 input variables S and R. The model parameters S and R were estimated from experimental data. Thus, SP is modeled by multiplicative interaction of 2 sleep drives, S and R, the former of homeostatic, the latter of circadian nature. In short: SP = S x R. RESULTS: Under the condition of normal phase and duration of nighttime sleep, SP across 24 hours displays 4 characteristics, (a) a major peak at nighttime, (b) a secondary increase, which peaks post-noon, (c) a first local minimum at sleep offset in the morning, and (d) a second local minimum in the early evening hours. Model simulations with either delayed or advanced sleep times suggest that the magnitude of the post-noon nap zone depends on the phase of the major sleep period within 24 hours. While the nap zone is attenuated or disappears when night sleep is delayed, SP increases during daytime when night sleep is advanced. In all conditions, the evening local minimum of SP remained stable. CONCLUSIONS: SP can be modeled as a continuous variable, based on the multiplicative interaction of 2 basic sleep drives. The model predictions are in agreement with known variations of SP across 24 hours.

Late, but not early, wake therapy reduces morning plasma melatonin: relationship to mood in Premenstrual Dysphoric Disorder.

Wake therapy improves mood in Premenstrual Dysphoric Disorder (PMDD), a depressive disorder in DSM-IV. We tested the hypothesis that the therapeutic effect of wake therapy in PMDD is mediated by altering sleep phase with melatonin secretion. We measured plasma melatonin every 30 min (18:00-09:00 h) in 19 PMDD and 18 normal control (NC) women during mid-follicular (MF) and late luteal (LL) menstrual cycle phases, and during LL interventions with early wake therapy (EWT) (sleep 03:00-07:00 h)(control condition) vs. late wake therapy (LWT) (sleep 21:00-01:00 h)(active condition). Melatonin offset was delayed and duration was longer in the symptomatic LL vs. asymptomatic MF phase in both NC and PMDD subjects. LWT, but not EWT, advanced offset and shortened duration vs. the LL baseline, although they improved mood equally. Later baseline LL morning melatonin offset was associated with more depressed mood in PMDD patients, and longer melatonin duration in the MF phase predicted greater mood improvement following LWT. That LWT, but not EWT, advanced melatonin offset and shortened duration while they were equally effective in improving mood suggests that decreasing morning melatonin secretion is not necessary for the therapeutic effects of wake therapy in PMDD.