Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi-disciplinary literature review and agenda for future research from the ISBD task force on chronobiology.

AIM: Symptoms of bipolar disorder (BD) include changes in mood, activity, energy, sleep, and appetite. Since many of these processes are regulated by circadian function, circadian rhythm disturbance has been examined as a biological feature underlying BD. The International Society for Bipolar Disorders Chronobiology Task Force (CTF) was commissioned to review evidence for neurobiological and behavioral mechanisms pertinent to BD. METHOD: Drawing upon expertise in animal models, biomarkers, physiology, and behavior, CTF analyzed the relevant cross-disciplinary literature to precisely frame the discussion around circadian rhythm disruption in BD, highlight key findings, and for the first time integrate findings across levels of analysis to develop an internally consistent, coherent theoretical framework. RESULTS: Evidence from multiple sources implicates the circadian system in mood regulation, with corresponding associations with BD diagnoses and mood-related traits reported across genetic, cellular, physiological, and behavioral domains. However, circadian disruption does not appear to be specific to BD and is present across a variety of high-risk, prodromal, and syndromic psychiatric disorders. Substantial variability and ambiguity among the definitions, concepts and assumptions underlying the research have limited replication and the emergence of consensus findings. CONCLUSIONS: Future research in circadian rhythms and its role in BD is warranted. Well-powered studies that carefully define associations between BD-related and chronobiologically-related constructs, and integrate across levels of analysis will be most illuminating.

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.

Light Therapy for Patients With Bipolar Depression: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Bipolar disorder (BD) is challenging to treat, and fewer treatments are available for depressive episodes compared to mania. Light therapy is an evidence-based nonpharmacological treatment for seasonal and nonseasonal major depression, but fewer studies have examined its efficacy for patients with BD. Hence, we reviewed the evidence for adjunctive light therapy as a treatment for bipolar depression. METHODS: We conducted a systematic review of databases from inception to June 30, 2019, for randomized, double-blind, placebo-controlled trials of light therapy in patients with BD (CRD42019128996). The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes included clinical response, remission, acceptability, and treatment-emergent mood switches. We quantitatively pooled outcomes using meta-analysis with random-effects models. RESULTS: We identified seven trials representing 259 patients with BD. Light therapy was associated with a significant improvement in Hamilton Depression Rating Scale score (standardized mean difference = 0.43, 95% confidence interval [CI], 0.04 to 0.82, P = 0.03). There was also a significant difference in favor of light therapy for clinical response (odds ratio [OR] = 2.32; 95% CI, 1.12 to 4.81; P = 0.024) but not for remission. There was no difference in affective switches between active light and control conditions (OR = 1.30; 95% CI, 0.38 to 4.44; P = 0.67). Study limitations included different light treatment parameters, small sample sizes, short treatment durations, and variable quality across trials. CONCLUSION: There is positive but nonconclusive evidence that adjunctive light therapy reduces symptoms of bipolar depression and increases clinical response. Light therapy is well tolerated with no increased risk of affective switch.

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.

Perinatal photoperiod associations with bipolar disorder and depression: A systematic literature review and cross-sectional analysis of the UK Biobank database.

Season-of-birth associations with psychiatric disorders point to environmental (co-)aetiological factors such as natural photoperiod that, if clarified, may allow interventions toward prevention. We systematically reviewed the literature concerning season-of-birth and bipolar disorder and depression and explored associations between the perinatal natural photoperiod and these outcomes in a cross-sectional analysis of the UK Biobank database. We used mean daily photoperiod and relative photoperiod range (relative to the mean) in the 3rd trimester and, separately, in the first 3 months post birth as metrics. From review, increased risk of depression with late spring birth is compatible with increased odds of probable single episode-, probable recurrent-, and diagnosed depression (OR 2.85 95 %CI 1.6-5.08, OR 2.20 95 %CI 1.57-3.1, and OR 1.48 95 %CI 1.11-1.97, respectively) with increasing 3rd trimester relative photoperiod range for participants who experienced relatively non-extreme daily photoperiods. Risk of bipolar disorder with winter-spring birth contrasted with no consistent patterns of perinatal photoperiod metric associations with bipolar disorder in the UK Biobank. As natural photoperiod varies by both time-of-year and latitude, perinatal natural photoperiods (and a hypothesized mechanism of action via the circadian timing system and/or serotonergic circuitry associated with the dorsal raphe nucleus) may reconcile inconsistencies in season-of-birth associations. Further studies are warranted.

Association between solar insolation and a history of suicide attempts in bipolar I disorder.

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p < 0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.

The potential influence of LED lighting on mental illness.

OBJECTIVES: Two recent scientific breakthroughs may alter the treatment of mental illness, as discussed in this narrative review. The first was the invention of white light-emitting diodes (LEDs), which enabled an ongoing, rapid transition to energy-efficient LEDs for lighting, and the use of LEDs to backlight digital devices. The second was the discovery of melanopsin-expressing photosensitive retinal ganglion cells, which detect environmental irradiance and mediate non-image forming (NIF) functions including circadian entrainment, melatonin secretion, alertness, sleep regulation and the pupillary light reflex. These two breakthroughs are interrelated because unlike conventional lighting, white LEDs have a dominant spectral wavelength in the blue light range, near the peak sensitivity for the melanopsin system. METHODS: Pertinent articles were identified. RESULTS: Blue light exposure may suppress melatonin, increase alertness, and interfere with sleep in young, healthy volunteers and in animals. Areas of concern in mental illness include the influence of blue light on sleep, other circadian-mediated symptoms, prescribed treatments that target the circadian system, measurement using digital apps and devices, and adolescent sensitivity to blue light. CONCLUSIONS: While knowledge in both fields is expanding rapidly, future developments must address the potential impact of blue light on NIF functions for healthy individuals and those with mental illness.

Reward Dysfunction in the Manic Spectrum: Unable to Win? The Use of Biographical Information to Refine Neurobiological Modeling.

OBJECTIVE: The manic spectrum is thought to be characterized by a hypersensitive biobehavioral reward system, the behavioral activation system. Evidence for this framework comes from questionnaire-based, self-report data collected in cross-sectional and prospective studies of mania, mania in remission, and proneness to hypomania, and from functional neuroimaging investigations of brain reward circuit activity during incentivized choice protocols. Although heightened reward anticipation is consistently documented, the status of later goal attainment activity, hedonic responses, and satiety reactions is less clear. This report examines the status of such reward receipt processes as they operate in the manic spectrum. METHODS: A case report of a typical subject with bipolar II disorder with a hyperthymic temperament is presented using longitudinal, biographical data. RESULTS: Diminished reward receipt, pleasure, and satiety were demonstrated indicating impaired hedonic processing in hyperthymic temperament. This impairment indicates a dissociation between early, intensified reward pursuit processes and later, blunted, reward attainment activity. CONCLUSIONS: The experience and neural correlates of hedonic processing may be impaired in the manic spectrum. Possible mechanisms for this impairment and its dissociation from the earlier stage of reward processing characterized by hyperactive reward pursuit are considered. Clinical reports and longitudinal, life-based follow-up can provide important data to supplement more experimentally based neurobiological models of reward dysfunction in bipolar disorders.

Influence of light exposure during early life on the age of onset of bipolar disorder.

BACKGROUND: Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association. METHODS: Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4 N and 70.7 N, and 1.2 S and 41.3 S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation. RESULTS: More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model. CONCLUSIONS: Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life.

Outpatient triple chronotherapy for bipolar depression: case report.

There is an urgent need for rapid, effective, and safe treatments for bipolar depression. Triple chronotherapy is a combination of sleep deprivation, sleep phase advance, and bright light therapy that has been shown to induce accelerated and sustained remissions in bipolar depression. This case report describes the first outpatient program designed to administer triple chronotherapy and reviews the organizational and clinical requirements for providing such care.