Timely Questions Emerging in Chronobiology: The Circadian Clock Keeps on Ticking.

Chronobiology investigations have revealed much about cellular and physiological clockworks but we are far from having a complete mechanistic understanding of the physiological and ecological implications. Here we present some unresolved questions in circadian biology research as posed by the editorial staff and guest contributors to the Journal of Circadian Rhythms. This collection of ideas is not meant to be comprehensive but does reveal the breadth of our observations on emerging trends in chronobiology and circadian biology. It is amazing what could be achieved with various expected innovations in technologies, techniques, and mathematical tools that are being developed. We fully expect strengthening mechanistic work will be linked to health care and environmental understandings of circadian function. Now that most clock genes are known, linking these to physiological, metabolic, and developmental traits requires investigations from the single molecule to the terrestrial ecological scales. Real answers are expected for these questions over the next decade. Where are the circadian clocks at a cellular level? How are clocks coupled cellularly to generate organism level outcomes? How do communities of circadian organisms rhythmically interact with each other? In what way does the natural genetic variation in populations sculpt community behaviors? How will methods development for circadian research be used in disparate academic and commercial endeavors? These and other questions make it a very exciting time to be working as a chronobiologist.

Reflections on Several Landmark Advances in Circadian Biology.

Circadian Biology intersects with diverse scientific domains, intricately woven into the fabric of organismal physiology and behavior. The rhythmic orchestration of life by the circadian clock serves as a focal point for researchers across disciplines. This retrospective examination delves into several of the scientific milestones that have fundamentally shaped our contemporary understanding of circadian rhythms. From deciphering the complexities of clock genes at a cellular level to exploring the nuances of coupled oscillators in whole organism responses to stimuli. The field has undergone significant evolution lately guided by genetics approaches. Our exploration here considers key moments in the circadian-research landscape, elucidating the trajectory of this discipline with a keen eye on scientific advancements and paradigm shifts.

Bright Light Therapy for Major Depressive Disorder in Adolescent Outpatients: A Preliminary Study.

BACKGROUND: Bright light therapy (BLT) has not been well-studied in adolescents with major depressive disorder, particularly in outpatient settings. METHODS: We conducted an 8-week clinical trial of BLT in adolescents recruited from a primary care practice with moderate to severe major depression. Acceptability and feasibility were defined by daily use of the light box and integration into daily routines. To assess treatment effects, we utilized the Short Mood and Feelings Questionnaire (SMFQ) and actigraphic sleep variables. RESULTS: Of the nine enrolled adolescents, the rate of daily use of the light therapy box was 100% at week 2, 78% at week 4 (n = 7), and 67% at weeks 6 and 8 (n = 6). Participants were better able to integrate midday BLT compared to morning BLT into their day-to-day routines. Mean depression scores improved during the 2-week placebo lead-in (dim red light-DRL) and continued to show significant improvement through 6 weeks of BLT. Sleep efficiency increased significantly (p = 0.046), and sleep onset latency showed a trend toward a significant decrease (p = 0.075) in the BLT phase compared to the DRL phase. CONCLUSION: Bright light treatment that was self-administered at home was feasible, acceptable, and effective for adolescent outpatients with depression. Findings support the development of larger, well-powered, controlled clinical trials of BLT in coordination with primary care.

Light Therapy for Adolescent Depression: A Scoping Review.

PURPOSE: Depressive disorders in adolescents are a major health concern associated with developmental, social, and educational impairment. Bright Light Therapy (BLT) is a feasible and effective treatment for depressive disorders in adults, but few controlled trials have been conducted with children or adolescents. This scoping review focuses on the current state of knowledge for BLT in the treatment of adolescent depression. We reviewed the literature for novel data and methodologic approaches using BLT and pediatric and young adult populations. RECENT FINDINGS: BLT is a tolerable treatment with few side effects. However, there is a marked lack of well-powered studies to support BLT as a treatment for depressive disorders in adolescent populations. Given evidence of tolerability and positive treatment effect on depression in the adult literature, research is needed to establish the efficacy, feasibility, and acceptability of BLT in adolescents.

Meta-analysis of sleep deprivation in the acute treatment of bipolar depression.

BACKGROUND: Sleep deprivation (SD) is an antidepressant intervention with multiple administration formats that has been investigated primarily with uncontrolled clinical trials and qualitative reviews of the literature. The validity and applicability of these findings to the treatment of bipolar depression (BPD) is uncertain. METHODS: A PRISMA-based systematic review of the literature and meta-analysis were conducted to determine the efficacy of SD in the treatment of BPD and to identify moderator variables that influence response rate. RESULTS: From a sample of 15 studies covering 384 patients, the overall, mean response rate to SD was 47.6% (CI 36.0%, 59.5%). This response rate compared post-SD to pre-SD depression scores, and not to a placebo control condition. Of several potential moderating variables examined, the use of adjunctive pharmacotherapy achieved statistical significance with response rates of 59.4% [CI 48.5, 69.5] for patients using adjunctive medication vs 27.4% [CI 17.8, 39.8] for patients not using adjunctive medication. CONCLUSIONS: This meta-analysis of SD in the treatment of BPD found an overall, response rate of almost 50%, reinforcing earlier estimates of efficacy. The use of adjunctive pharmacotherapy had a statistically significant moderating effect on SD response suggesting that clinical practice should routinely pair these interventions. These findings provide a higher level of evidence supporting the use of SD, especially when used with medication, and should inform future management guidelines for the treatment of BPD.

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology.

AIMS: To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. METHODS: PRISMA-based systematic review of the literature. RESULTS: The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. CONCLUSIONS: The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered.

Meta-Analysis of the Antidepressant Effects of Acute Sleep Deprivation.

OBJECTIVE: To provide a quantitative meta-analysis of the antidepressant effects of sleep deprivation to complement qualitative reviews addressing response rates. DATA SOURCES: English-language studies from 1974 to 2016 using the keywords sleep deprivation and depression searched through PubMed and PsycINFO databases. STUDY SELECTION: A total of 66 independent studies met criteria for inclusion: conducted experimental sleep deprivation, reported the percentage of the sample that responded to sleep deprivation, provided a priori definition of antidepressant response, and did not seamlessly combine sleep deprivation with other therapies (eg, chronotherapeutics, repetitive transcranial magnetic stimulation). DATA EXTRACTION: Data extracted included percentage of responders, type of sample (eg, bipolar, unipolar), type of sleep deprivation (eg, total, partial), demographics, medication use, type of outcome measure used, and definition of response (eg, 30% reduction in depression ratings). Data were analyzed with meta-analysis of proportions and a Poisson mixed-effects regression model. RESULTS: The overall response rate to sleep deprivation was 45% among studies that utilized a randomized control group and 50% among studies that did not. The response to sleep deprivation was not affected significantly by the type of sleep deprivation performed, the nature of the clinical sample, medication status, the definition of response used, or age and gender of the sample. CONCLUSIONS: These findings support a significant effect of sleep deprivation and suggest the need for future studies on the phenotypic nature of the antidepressant response to sleep deprivation, on the neurobiological mechanisms of action, and on moderators of the sleep deprivation treatment response in depression.

Circadian rhythm profiles in women with night eating syndrome.

Night eating syndrome (NES) is characterized by evening hyperphagia and frequent awakenings accompanied by food intake. Patients with NES display a delayed circadian pattern of food intake but retain a normal sleep-wake cycle. These characteristics initiated the current study, in which the phase and amplitude of behavioral and neuroendocrine circadian rhythms in patients with NES were evaluated. Fifteen women with NES (mean age +/- SD, 40.8 +/- 8.7 y) and 14 control subjects (38.6 +/- 9.5 y) were studied in the laboratory for 3 nights, with food intake measured daily. Blood also was collected for 25 h (every 2 h from 0800 to 2000 h, and then hourly from 2100 to 0900 h) and assayed for glucose and 7 hormones (insulin, ghrelin, leptin, melatonin, cortisol, thyroid-stimulating hormone [TSH] and prolactin). Statistical analyses utilized linear mixed-effects cosinor analysis. Control subjects displayed normal phases and amplitudes for all circadian rhythms. In contrast, patients with NES showed a phase delay in the timing of meals, and delayed circadian rhythms for total caloric, fat, and carbohydrate intake. In addition, phase delays of 1.0 to 2.8 h were found in 2 food-regulatory rhythms-leptin and insulin-and in the circadian melatonin rhythm (with a trend for a delay in the circadian cortisol rhythm). In contrast, circulating levels of ghrelin, the primary hormone that stimulates food intake, were phase advanced by 5.2 h. The glucose rhythm showed an inverted circadian pattern. Patients with NES also showed reduced amplitudes in the circadian rhythms of food intake, cortisol, ghrelin, and insulin, but increased TSH amplitude. Thus, patients with NES demonstrated significant changes in the timing and amplitude of various behavioral and physiological circadian markers involved in appetite and neuroendocrine regulation. As such, NES may result from dissociations between central (suprachiasmatic nucleus) timing mechanisms and putative oscillators elsewhere in the central nervous system or periphery, such as the stomach or liver. Considering these results, chronobiologic treatments for NES such as bright light therapy may be useful. Indeed, bright light therapy has shown efficacy in reducing night eating in case studies and should be evaluated in controlled clinical trials.

Bright light, negative air ions and auditory stimuli produce rapid mood changes in a student population: a placebo-controlled study.

BACKGROUND: Bright light and high-density negative air ion exposure are efficacious for winter and non-seasonal depression compared with a low-density negative ion placebo. Similarly, auditory stimuli improve mood in clinical populations. This study compared the short-term effects of bright light, an auditory stimulus, and high- and low-density negative ions on mood and alertness in mildly depressed and non-depressed adults. METHOD: One hundred and eighteen subjects, 69 women and 49 men (mean age+/-S.D., 19.4+/-1.7 years), participated once across the year. Subjects were randomly assigned to one of four conditions: bright light (10,000 lux; n=29), auditory stimuli (60 dB; n=30), or high-density (4.5x10(14) ions/s flow rate; n=29) or low-density (1.7x10(11) ions/s; n=30; placebo control) negative ions. Exposure was for 30 min on three consecutive evenings between 1900 and 2100 hours. Mood and alertness assessments, using standardized scales, occurred before, and 15 and 30 min during exposure. The Beck Depression Inventory classified subjects as depressed (> or =10; n=35) or non-depressed (<10; n=83). RESULTS: The three active stimuli, but not the low-density placebo, reduced depression, total mood disturbance (a global affect measure) and/or anger within 15-30 min. Neither testing season nor degree of depressive symptoms affected response to stimuli. CONCLUSIONS: The auditory stimulus, bright light and high-density ions all produced rapid mood changes - with small to medium effect sizes - in depressed and non-depressed subjects, compared with the low-density placebo, despite equivalent pre-study expectations. Thus, these stimuli improve mood acutely in a student sample, including a subset with depressive symptoms.

Sleep changes vary by odor perception in young adults.

Peppermint, a stimulating odor, increases alertness while awake and therefore may inhibit sleep. This study examined peppermint's effects on polysomnographic (PSG) sleep, alertness, and mood when presented before bedtime. Twenty-one healthy sleepers (mean age +/- S.D., 20.1 +/- 2.0 years) completed three consecutive laboratory sessions (adaptation, control, and stimulus nights). Peppermint reduced fatigue and improved mood and was rated as more pleasant, intense, stimulating, and elating than water. These perceptual qualities associated with sleep measures: subjects rating peppermint as very intense had more total sleep than those rating it as moderately intense, and also showed more slow-wave sleep (SWS) in the peppermint than control session. Furthermore, subjects who found peppermint stimulating showed more NREM and less REM sleep while those rating it as sedating took longer to reach SWS. Peppermint did not affect PSG sleep, however, when these perceptual qualities were not considered. Peppermint also produced gender-differentiated responses: it increased NREM sleep in women, but not men, and alertness in men, but not women, compared with the control. Thus, psychological factors, including individual differences in odor perception play an important role in physiological sleep and self-rated mood and alertness changes.

An olfactory stimulus modifies nighttime sleep in young men and women.

Aromatherapy is an anecdotal method for modifying sleep and mood. However, whether olfactory exposure to essential oils affects night-time objective sleep remains untested. Previous studies also demonstrate superior olfactory abilities in women. Therefore, this study investigated the effects of an olfactory stimulus on subsequent sleep and assessed gender differences in such effects. Thirty-one young healthy sleepers (16 men and 15 women, aged 18 to 30 yr, mean+/-SD, 20.5+/-2.4 yr) completed 3 consecutive overnight sessions in a sleep laboratory: one adaptation, one stimulus, and one control night (the latter 2 nights in counterbalanced order). Subjects received an intermittent presentation (first 2 min of each 10 min interval) of an olfactory (lavender oil) or a control (distilled water) stimulus between 23:10 and 23:40 h. Standard polysomnographic sleep and self-rated sleepiness and mood data were collected. Lavender increased the percentage of deep or slow-wave sleep (SWS) in men and women. All subjects reported higher vigor the morning after lavender exposure, corroborating the restorative SWS increase. Lavender also increased stage 2 (light) sleep, and decreased rapid-eye movement (REM) sleep and the amount of time to reach wake after first falling asleep (wake after sleep onset latency) in women, with opposite effects in men. Thus, lavender serves as a mild sedative and has practical applications as a novel, nonphotic method for promoting deep sleep in young men and women and for producing gender-dependent sleep effects.

Controlled trial of bright light and negative air ions for chronic depression.

BACKGROUND: This randomized controlled trial investigates the efficacy of two non-pharmacologic treatments, bright light and high-density negative air ions for non-seasonal chronic depression. Both methods have shown clinical success for seasonal affective disorder (SAD). METHOD: Patients were 24 (75%) women and 8 (25%) men, ages 22-65 years (mean age +/- S.D., 43.7 +/- 12.4 years), with Major Depressive Disorder, Single Episode (DSM-IV code, 296.2), Chronic (episode duration > or = 2 years). Patients were entered throughout the year and randomly assigned to exposure to bright light (10 000 lux, n = 10), or high-density (4.5 x 10(14) ions/s flow rate, n = 12) or low-density (1.7 x 10(11) ions/s, n = 10, placebo control) negative air ions. Home treatment sessions occurred for 1 h upon awakening for 5 weeks. Blinded raters assessed symptom severity weekly with the Structured Interview Guide for the Hamilton Depression Rating Scale--Seasonal Affective Disorder (SIGH-SAD) version. Evening saliva samples were obtained before and after treatment for ascertainment of circadian melatonin rhythm phase. RESULTS: SIGH-SAD score improvement was 53.7% for bright light and 51.1% for high-density ions v. 17.0% for low-density ions. Remission rates were 50%, 50% and 0% respectively. The presence or severity of atypical symptoms did not predict response to either treatment modality, nor were phase advances to light associated with positive response. CONCLUSIONS: Both bright light and negative air ions are effective for treatment of chronic depression. Remission rates are similar to those for SAD, but without a seasonal dependency or apparent mediation by circadian rhythm phase shifts. Combination treatment with antidepressant drugs may further enhance clinical response.

Late-night presentation of an auditory stimulus phase delays human circadian rhythms.

Although light is considered the primary entrainer of circadian rhythms in humans, nonphotic stimuli, including exercise and melatonin also phase shift the biological clock. Furthermore, in birds and nonhuman mammals, auditory stimuli are effective zeitgebers. This study investigated whether a nonphotic auditory stimulus phase shifts human circadian rhythms. Ten subjects (5 men and 5 women, ages 18-72, mean age +/- SD, 44.7 +/- 21.4 yr) completed two 4-day laboratory sessions in constant dim light (<20 lux). They received two consecutive presentations of either a 2-h auditory or control stimulus from 0100 to 0300 on the second and third nights (presentation order of the stimulus and control was counterbalanced). Core body temperature (CBT) was collected and stored in 2-min bins throughout the study and salivary melatonin was obtained every 30 min from 1900 to 2330 on the baseline and poststimulus/postcontrol nights. Circadian phase of dim light melatonin onset (DLMO) and of CBT minimum, before and after auditory or control presentation was assessed. The auditory stimulus produced significantly larger phase delays of the circadian melatonin (mean +/- SD, -0.89 +/- 0.40 h vs. -0.27 +/- 0.16 h) and CBT (-1.16 +/- 0.69 h vs. -0.44 +/- 0.27 h) rhythms than the control. Phase changes for the two circadian rhythms also positively correlated, indicating direct effects on the biological clock. In addition, the auditory stimulus significantly decreased fatigue compared with the control. This study is the first demonstration of an auditory stimulus phase-shifting circadian rhythms in humans, with shifts similar in size and direction to those of other nonphotic stimuli presented during the early subjective night. This novel stimulus may be a useful countermeasure to facilitate circadian adaptation after transmeridian travel or shift work.

Olfactory discrimination and transient mood change in young men and women: variation by season, mood state, and time of day.

Odor performance varies by clinical state and gender, though little is known about its variation by season or time of day. Many odors, including lavender, induce transient mood changes. This study explored discrimination differences between various lavender oil blends and their effects on transient mood in the morning and evening in depressed and nondepressed adults. We also determined seasonal influences on these measures. A total of 169 subjects, 98 women and 71 men (mean age +/- SD, 19.3 +/- 1.6 y) participated, with different subjects studied at different times of the year. The Beck Depression Inventory (BDI) classified subjects as depressed (score > or =10; N= 57) or nondepressed (score <10; N= 112). In the discrimination test, subjects compared pairs of two different lavender oil blends or a control. Transient change in mood was assessed by the Profile of Mood States (POMS) after each trial of five lavender blends interspersed by three control odors. Tests were conducted in the morning (08:00-10:00 h) and evening (18:00-20:00h). In all subjects, discrimination was significantly better for some odor pairs than for others, thus demonstrating test specificity. Discrimination was better overall in the fall than winter/spring and better in depressed than nondepressed subjects for specific odor pairs. No significant gender or time-of-day differences in discriminability were detected. There were, however, significant group differences in transient mood profiles. Current depressed state affected mood response, with lavender increasing anger in depressed subjects only. In addition, depressed subjects and men, whether or not depressed, exhibited diurnal mood variation, with better mood in the evening; the former group also showed more evening energy. All subjects were more confused in the morning than evening. Season also affected transient mood; winter/spring-tested subjects reported more vigor than fall-tested subjects. In addition, summer-tested subjects showed more tension in the morning, whereas fall-tested subjects showed the opposite pattern in the evening. In all subjects, lavender increased fatigue, tension, confusion, and total mood disturbance, and it decreased vigor. The study showed that both chronobiological (seasonal and time-of-day) and clinical factors modify discrimination and mood response to odors. Brief lavender odor presentation may serve as a nonphotic method for altering mood in young depressed and nondepressed adults particularly during the fall, a time of heightened discriminability.

Dimensions of temperament and bright light response in seasonal affective disorder.

Scale scores on the Tridimensional Personality Questionnaire (TPQ)-novelty seeking (NS), harm avoidance (HA), and reward dependence (RD)-can predict response to antidepressants. This study examined 89 patients with Bipolar Disorder (I, II) or Major Depressive Disorder, both with recurrent winter seasonal pattern. The TPQ was administered while the patients were depressed, following 10-14 days of bright light therapy (30 min, 10,000 lux) and after spontaneous springtime remission. The Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) assessed the severity of depression. At baseline, there were no significant differences between diagnostic subgroups or responders and non-responders on the TPQ or SIGH-SAD scales, though baseline RD scores were significantly higher in women than men. Furthermore, neither severity of depression nor magnitude of post-treatment clinical improvement was significantly correlated with baseline TPQ scores. Only HA scores decreased after treatment, with responders showing the greatest effect. HA scores also decreased from the baseline to springtime assessments for the group as a whole, with no difference between responders and non-responders. This is the first study to demonstrate that HA is state- rather than trait-dependent in seasonal affective disorder. The TPQ dimensions of temperament do not predict response to light therapy.