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.

The Relationship Between Childhood Trauma and Poor Sleep Health in Adulthood.

OBJECTIVE: Childhood trauma has been related to adverse behavioral, mental, and health outcomes later in life. Sleep may be a potential mechanism through which childhood trauma is related to adverse health. The current retrospective study aimed to characterize the relationship between childhood trauma exposure and sleep health, a novel multidimensional measure of sleep. METHODS: Participants (N = 161; mean [standard deviation] age = 59.85 [9.06] years; 67.7% female) retrospectively reported trauma exposure using the Trauma History Questionnaire. Childhood trauma was defined as the number of reported traumatic events before 18 years of age. Trauma exposure after 18 years of age and across the life-span was also recorded. Sleep health was derived both from diary- and actigraphy-assessed measures of sleep regularity, timing, efficiency, and duration, subjective sleep satisfaction, and daytime sleepiness from the Epworth Sleepiness Scale. The relationships between childhood trauma exposure and sleep health were examined using hierarchical linear regression, controlling for relevant covariates. RESULTS: In unadjusted models, a greater number of childhood trauma exposures were associated with poorer diary- and actigraphy-measured sleep health in adulthood. After adjustment for current stress, depression history, and other sociodemographic covariates, greater childhood trauma remained significantly associated with poorer sleep health (diary: ß = -0.20, ΔR = 0.032; actigraphy: ß = -0.19, ΔR = 0.027). Trauma exposure after 18 years of age and across the life-span did not relate to diary- or actigraphy-based sleep health. CONCLUSIONS: Childhood trauma may affect sleep health in adulthood. These findings align with the growing body of evidence linking childhood trauma to adverse health outcomes later in life.

The impact of substance use disorders on recovery from bipolar depression: Results from the Systematic Treatment Enhancement Program for Bipolar Disorder psychosocial treatment trial.

OBJECTIVE: Up to 60% of patients with bipolar disorder develop a substance use disorder during their lifetime. The purpose of this paper was to assess the impact of substance use disorders on depression recovery among bipolar patients randomly assigned to different psychotropic medications and psychosocial interventions. We hypothesized that patients with a comorbid substance use disorder would benefit less from psychotherapy regardless of treatment intensity/length compared to patients without a comorbid substance use disorder. METHOD: We conducted post hoc analyses among bipolar disorder patients ( n = 270) with and without comorbid substance use disorders enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder randomized psychosocial intervention trial. All patients entered during or shortly after the onset of a bipolar depressive episode. Logistic regression and Cox proportional hazard models were used to assess whether current or past substance use disorders moderated the response of patients to intensive psychosocial intervention or brief psychoeducation with collaborative care, operationalized as full recovery from an episode of bipolar depression. RESULTS: Current comorbid substance use disorders significantly predicted likelihood of recovery (odds ratio = 2.25, p = 0.025) and time to recovery (odds ratio = 1.71, p = 0.006) from bipolar depression. We found that 74.5% of patients with a current substance use disorder, compared to 56.5% without a current substance use disorder, recovered from bipolar depression. Past substance use disorders did not predict likelihood of recovery or time to recovery. Current substance use disorders did not significantly moderate response to intensive psychotherapy versus collaborative care. CONCLUSION: Contrary to our hypotheses, bipolar disorder participants with a current comorbid substance use disorder were more likely to recover from psychosocial treatment for bipolar depression than patients without a current comorbid substance use disorder. If this finding is replicated, it has implications for the ordering of treatment for patients with comorbid bipolar disorder and substance use disorders.

Do Sleep Disturbances Predict or Moderate the Response to Psychotherapy in Bipolar Disorder?

This study examined whether sleep disturbance predicted or moderated responses to psychotherapy in participants who participated in STEP-BD, a national, multisite study that examined the effectiveness of different treatment combinations for bipolar disorder. Participants received either a brief psychosocial intervention called collaborative care (CC; n = 130) or intensive psychotherapy (IP; n = 163), with study-based pharmacotherapy. Participants (N = 243) were defined as current (past week) short sleepers (<6 hours/night), normal sleepers (6.5-8.5 hours/night), and long sleepers (≥9 hours/night), according to reported average nightly sleep duration the week before randomization. Sleep disturbances did not predict the likelihood of recovery nor time until recovery from a depressive episode. There was no difference in recovery rates between IP versus CC for normal sleepers, and medium effect sizes were observed for differences in short and long sleepers. In this study, sleep did not play a major role in predicting or moderating response to psychotherapy in bipolar disorder.

Affective instability and the course of bipolar depression: results from the STEP-BD randomised controlled trial of psychosocial treatment.

BACKGROUND: Little is known about predictors of recovery from bipolar depression. AIMS: We investigated affective instability (a pattern of frequent and large mood shifts over time) as a predictor of recovery from episodes of bipolar depression and as a moderator of response to psychosocial treatment for acute depression. METHOD: A total of 252 out-patients with DSM-IV bipolar I or II disorder and who were depressed enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and were randomised to one of three types of intensive psychotherapy for depression (n= 141) or a brief psychoeducational intervention (n= 111). All analyses were by intention-to-treat. RESULTS: Degree of instability of symptoms of depression and mania predicted a lower likelihood of recovery and longer time until recovery, independent of the concurrent effects of symptom severity. Affective instability did not moderate the effects of psychosocial treatment on recovery from depression. CONCLUSIONS: Affective instability may be a clinically relevant characteristic that influences the course of bipolar depression.

Computerized Adaptive Diagnosis and Testing of Mental Health Disorders.

In this review we explore recent developments in computerized adaptive diagnostic screening and computerized adaptive testing for the presence and severity of mental health disorders such as depression, anxiety, and mania. The statistical methodology is unique in that it is based on multidimensional item response theory (severity) and random forests (diagnosis) instead of traditional mental health measurement based on classical test theory (a simple total score) or unidimensional item response theory. We show that the information contained in large item banks consisting of hundreds of symptom items can be efficiently calibrated using multidimensional item response theory, and the information contained in these large item banks can be precisely extracted using adaptive administration of a small set of items for each individual. In terms of diagnosis, computerized adaptive diagnostic screening can accurately track an hour-long face-to-face clinician diagnostic interview for major depressive disorder (as an example) in less than a minute using an average of four questions with unprecedented high sensitivity and specificity. Directions for future research and applications are discussed.

Medical burden, body mass index and the outcome of psychosocial interventions for bipolar depression.

OBJECTIVE: Individuals with bipolar disorder experience a disproportionately high incidence of medical co-morbidity and obesity. These health-related problems are a barrier to recovery from mood episodes and have been linked with unfavorable responses to pharmacological treatment. However, little is known about whether and how these characteristics affect responses to adjunctive psychotherapy. METHOD: Embedded in the Systematic Treatment Enhancement Program for Bipolar Disorder was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy plus pharmacotherapy with collaborative care (a three-session psycho-educational intervention) plus pharmacotherapy. We conducted a post-hoc analysis to evaluate whether medical burden and body mass index predicted and/or moderated the likelihood of recovery and time until recovery from a depressive episode among patients in the two treatments. RESULTS: Participants who had medical co-morbidity and body mass index data constituted 199 of the 293 patients in the original Systematic Treatment Enhancement Program for Bipolar Disorder trial. Higher medical burden predicted a lower likelihood of recovery from depression in both treatment conditions (odds ratio = 0.89), but did not moderate responses to intensive psychotherapy vs collaborative care. Intensive psychotherapy yielded superior recovery rates for individuals of normal body mass index (odds ratio= 2.39) compared with collaborative care, but not among individuals who were overweight or obese. CONCLUSION: Medical co-morbidity and body weight impacts symptom improvement and attention to this co-morbidity may inform the development of more personalized treatments for bipolar disorder.

Social rhythm disrupting events increase the risk of recurrence among individuals with bipolar disorder.

OBJECTIVES: As outlined in the social zeitgeber hypothesis, social rhythm disrupting (SRD) life events begin a cascade of social and biological rhythm disruption that may lead to the onset of affective episodes in those vulnerable to bipolar disorder. Thus, the study of SRD events is particularly important in individuals with this chronic condition. The purpose of the current study was to evaluate (i) the extent to which SRD life events increased the risk of recurrence of a bipolar mood episode, and (ii) whether the social rhythm disruption associated with the event conferred an increased risk of recurrence, after accounting for the level of threat associated with the life event. METHODS: We examined the effect of SRD events on recurrence during preventative treatment in a sample of 118 patients with bipolar disorder who achieved remission from an acute episode after receiving psychotherapy and pharmacotherapy. Life events were measured with the Bedford College Life Events and Difficulty Schedule and were rated for degree of SRD and threat. RESULTS: Time-dependent Cox proportional hazards models showed that having a higher SRD rating was significantly associated with an increased risk of recurrence, even when accounting for the threat effect of a life event and psychosocial treatment (hazard ratio = 1.33, 95% confidence interval: 1.04-1.70, p = 0.023). However, this finding fell below conventional levels of statistical significance when accounting for other covariates. CONCLUSIONS: Our findings lend partial support to the social zeitgeber hypothesis.

An Integrated Risk Reduction Intervention can reduce body mass index in individuals being treated for bipolar I disorder: results from a randomized trial.

OBJECTIVES: We conducted a randomized, controlled trial comparing the efficacy of an Integrated Risk Reduction Intervention (IRRI) to a control condition with the objective of improving mood stability and psychosocial functioning by reducing cardiometabolic risk factors in overweight/obese patients with bipolar I disorder. METHODS: A total of 122 patients were recruited from our outpatient services and randomly allocated to IRRI (n = 61) or psychiatric care with medical monitoring (n = 61). Individuals allocated to IRRI received psychiatric treatment and assessment, medical monitoring by a nurse, and a healthy lifestyle program from a lifestyle coach. Those allocated to the control condition received psychiatric treatment and assessment and referral, if indicated, for medical problems. A mixed-effects model was used to examine the impact of the interventions on body mass index (BMI). Exploratory moderator analyses were used to characterize those individuals likely to benefit from each treatment approach. RESULTS: Analyses were conducted on data for the IRRI (n = 58) and control (n = 56) participants with ≥ 1 study visit. IRRI was associated with a significantly greater rate of decrease in BMI (d = -0.51, 95% confidence interval: -0.91 to -0.14). Three variables (C-reactive protein, total cholesterol, and instability of total sleep time) contributed to a combined moderator of faster decrease in BMI with IRRI treatment. CONCLUSIONS: Overweight/obese patients with bipolar disorder can make modest improvements in BMI, even when taking medications with known potential for weight gain. Our finding that a combination of three baseline variables provides a profile of patients likely to benefit from IRRI will need to be tested further to evaluate its utility in clinical practice.

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk.

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1ß, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

Is Interpersonal Psychotherapy Infinitely Adaptable? A Compendium of the Multiple Modifications of IPT.

We employed standard literature search techniques and surveyed participants on the International Society for Interpersonal Psychotherapy listserve (isiptlist@googlegroups.com) to catalogue the multiple and highly creative ways in which Klerman's and Weissman's original concept of interpersonal psychotherapy (IPT) has been modified to meet the needs of a vast range of patient populations. Focusing first on adaptations of the individual treatment model for subgroups of adult patients, we next describe further adaptations of four major off-shoots of IPT: interpersonal counseling (IPC), IPT for adolescents (IPT-A), group IPT (IPT-G) and most recently, brief IPT (IPT-B). We then discuss IPT "in-laws," those treatments that have married IPT with of other forms of psychotherapy for patients with bipolar disorder, panic symptomatology, and substance abuse. We conclude with that although there have been myriad successful adaptations of IPT, there remain some conditions for which IPT adaptations have not been found to be efficacious.

Major depressive disorder: new clinical, neurobiological, and treatment perspectives.

In this Seminar we discuss developments from the past 5 years in the diagnosis, neurobiology, and treatment of major depressive disorder. For diagnosis, psychiatric and medical comorbidity have been emphasised as important factors in improving the appropriate assessment and management of depression. Advances in neurobiology have also increased, and we aim to indicate genetic, molecular, and neuroimaging studies that are relevant for assessment and treatment selection of this disorder. Further studies of depression-specific psychotherapies, the continued application of antidepressants, the development of new treatment compounds, and the status of new somatic treatments are also discussed. We address two treatment-related issues: suicide risk with selective serotonin reuptake inhibitors, and the safety of antidepressants in pregnancy. Although clear advances have been made, no fully satisfactory treatments for major depression are available.

Clinical staging in psychiatry: a cross-cutting model of diagnosis with heuristic and practical value.

Staging models are used routinely in general medicine for potentially serious or chronic physical disorders such as diabetes, arthritis and cancers, describing the links between biomarkers, clinical phenotypes and disease extension, and promoting a personalised or stratified medicine approach to treatment planning. Clinical staging involves a detailed description of where an individual exists on a continuum of disorder progression from stage 0 (an at-risk or latency stage) through to stage IV (late or end-stage disease). The approach is popular owing to its clinical utility and is increasingly being applied in psychiatry. The concept offers an informed approach to research and the active promotion of indicated prevention and early intervention strategies. We suggest that for young persons with emerging bipolar disorder, such transdiagnostic staging models could provide a framework that better reflects the developmental psychopathology and matches the complex longitudinal inter-relationships between subsyndromal and syndromal mood, psychotic and other disorders.

Application of an ex vivo cellular model of circadian variation for bipolar disorder research: a proof of concept study.

OBJECTIVES: Disruption of circadian function has been observed in several human disorders, including bipolar disorder (BD). Research into these disorders can be facilitated by human cellular models that evaluate external factors (zeitgebers) that impact circadian pacemaker activity. Incorporating a firefly luciferase reporter system into human fibroblasts provides a facile, bioluminescent readout that estimates circadian phase, while leaving the cells intact. We evaluated whether this system can be adapted to clinical BD research and whether it can incorporate zeitgeber challenge paradigms. METHODS: Fibroblasts from patients with bipolar I disorder (BD-I) (n = 13) and controls (n = 12) were infected ex vivo with a lentiviral reporter incorporating the promoter sequences for Bmal1, a circadian gene to drive expression of the firefly luciferase gene. Following synchronization, the bioluminescence was used to estimate period length. Phase response curves (PRCs) were also generated following forskolin challenge and the phase response patterns were characterized. RESULTS: Period length and PRCs could be estimated reliably from the constructs. There were no significant case-control differences in period length, with a nonsignificant trend for differences in PRCs following the phase-setting experiments. CONCLUSIONS: An ex vivo cellular fibroblast-based model can be used to investigate circadian function in BD-I. It can be generated from specific individuals and this could usefully complement ongoing circadian clinical research.

Comparison of five actigraphy scoring methods with bipolar disorder.

The goal of this study was to compare 5 actigraphy scoring methods in a sample of 18 remitted patients with bipolar disorder. Actigraphy records were processed using five different scoring methods relying on the sleep diary; the event-marker; the software-provided automatic algorithm; the automatic algorithm supplemented by the event-marker; visual inspection (VI) only. The algorithm and the VI methods differed from the other methods for many actigraphy parameters of interest. Particularly, the algorithm method yielded longer sleep duration, and the VI method yielded shorter sleep latency compared to the other methods. The present findings provide guidance for the selection of signal processing method based on sleep parameters of interest, time-cue sources and availability, and related scoring time costs for the study.

Photosensitivity and panic-agoraphobic spectrum: a pilot study.

BACKGROUND: The aims of this study were to assess photosensitivity (photophobia and photophilia) in panic disorder (PD) patients compared to healthy controls, and to evaluate the correlation between photosensitivity and panic-agoraphobic spectrum self-report (PAS-SR) scores. METHODS: The PAS-SR and Photosensitivity Assessment Questionnaires were administered to 24 PD subjects and 33 healthy controls. RESULTS: Compared to controls, PD patients showed significantly higher levels of photophobia and lower levels of photophilia items. The PAS-SR total score was positively correlated with the photophobia score. CONCLUSIONS: This study shows a strong correlation between PD and photophobia. However, whether photophobia develops before or after the onset of PD remains unclear. Further research is warranted to assess the potential role of light stimuli exposure in the onset, course and outcome of PD.

Long day's journey into sleep.

My long day's journey into sleep began as an adolescent trying to manage my evening chronotype. The relief, I felt when my undergraduate finals were scheduled at night and as a medical student being able to select psychiatry over surgery deepened my interest in sleep and chronobiology. That interest was allowed to flourish at the National Institute of Mental Health and then at Yale Medical School in setting up a sleep laboratory. The decision to move to the University of Pittsburgh in 1973 led to a 42-year adventure in which we were able to initiate research efforts on the psychobiology of depression. Our interest in social zeitgebers (daily routines) led directly to the development and testing of a treatment intervention for mood disorders, interpersonal, and social rhythm therapy. Our continued emphasis on sleep and circadian rhythms convinced us that sleep and circadian factors were central to all of health, based on the importance of connectivity between sleep and major metabolic and cell functions. This ongoing research motivated our strong desire to study the developmental aspects of sleep. Our success was influenced immensely by the presence of young scientists and a strong subsequent interest in career mentoring. Finally, as we left Pittsburgh in 2015, we became involved in the field of continuous objective monitoring using the commercial smartphone's behavioral sensing capabilities. Our journey is not over. We hope to explore the potential of these remarkable devices to improve our understanding of sleep/wake and circadian factors across all of health.

Corrigendum: Personalized digital intervention for depression based on social rhythm principles adds significantly to outpatient treatment.

[This corrects the article DOI: 10.3389/fdgth.2022.870522.].

A randomized pilot study of psychotherapy and quetiapine for the acute treatment of bipolar II depression.

OBJECTIVES: The differential roles of psychotherapy and pharmacotherapy in the management of bipolar (BP) II depression are unknown. As a first step toward exploring this issue, we conducted a pilot study to evaluate the feasibility and acceptability of comparing a BP-specific psychotherapy [Interpersonal and Social Rhythm Therapy (IPSRT)] to quetiapine as treatments for BP-II depression. METHODS: Unmedicated individuals (n = 25) meeting DSM-IV criteria for BP-II disorder, currently depressed, were randomly assigned to weekly sessions of IPSRT (n = 14) or quetiapine (n = 11), flexibly dosed from 25-300 mg. Participants were assessed with weekly measures of mood and followed for 12 weeks. Treatment preference was queried prior to randomization. RESULTS: Using mixed effects models, both groups showed significant declines in the 25-item Hamilton Rating Scale for Depression [F(1,21) = 44, p < 0.0001] and Young Mania Rating Scale [F(1,21) = 20, p = 0.0002] scores over time but no group-by-time interactions. Dropout rates were 21% (n = 3) and 27% (n = 3) in the IPSRT and quetiapine groups, respectively. Overall response rates (defined as ≥ 50% reduction in depression scores without an increase in mania scores) were 29% (n = 4) in the IPSRT group and 27% (n = 3) in the quetiapine group. Measures of treatment satisfaction were high in both groups. Treatment preference was not associated with outcomes. CONCLUSIONS: Outcomes in participants with BP-II depression assigned to IPSRT monotherapy or quetiapine did not differ over 12 weeks in this small study. Follow-up trials should examine characteristics that predict differential response to psychotherapy and pharmacotherapy.