Circadian Rhythm Dysregulation in Offspring of Parents With Bipolar Disorder

This study aims to 1) investigate the differences and variances in circadian rhythms at several levels, including physical activity, dim light melatonin onset, diurnal patterns of cortisol, and body temperature between the offspring of patients with bipolar disorder (BD) and offspring of healthy parents by using a high-risk study design; and 2) determine whether these indicators correlate with psychopathological symptoms as measured by the psychometric measurements.

Study Overview

• Status: Unknown
• Conditions: Bipolar Disorder

Detailed Description

Bipolar disorder (BD), characterized by episodes of mania or hypomania with frequent depressive episodes, is commonly found in the general population with a lifetime prevalence of 1-2% in the world. The morbidities and mortality associated with bipolar disorder are huge and the repercussion on their family members is considerate. Nonetheless, there is no existing well-established prevention strategy that may prevent this distressing mental disorder. A major reason is that there was limited understanding of the prodromal phase of BD. On the other hand, the genetic background determines about 60-85% of risk variance of BD. In other words, the offspring carries significant risk and propensity to develop future BD. Limited existing studies suggested that offspring of patients with BD have a higher rate of sleep and circadian disturbances and mental disorders than those offspring of parents without BD. Nonetheless, it is still unclear whether sleep and circadian disturbances are prodromal markers or risk factors for the development of bipolar disorder in this high-risk population.

In light of our research and other studies' preliminary findings on the relationship between circadian rhythms dysregulation and BD and robust heritability in BD, we hypothesize that

1. Circadian rhythm dysregulations are prodromal features and endophenotypes of BD. The offspring of BD parents will have more circadian rhythm dysregulations than those offspring of healthy controls;
2. The biologic indices of circadian rhythm dysregulations will be correlated with subsyndromal psychopathology.

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

• Study Contact: Name: Jihui Zhang, PhD; Phone Number: (852) 39197647; Email: jihui.zhang@cuhk.edu.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Department of psychiatry, Faculty of Medicine, The Chinese University of Hong Kong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with BD will be recruited from psychiatry outpatient clinics in Hong Kong and mainland China. Healthy parents will be recruited from our on-going community-based projects. In addition, the investigators will also recruit subjects through public advertisement through various media such as Facebook, poster, and emails. In view of the potential sex differences in these circadian rhythms indicators of interest, the adolescent offspring of healthy parents will be age- and sex-matched to the adolescent offspring of BD parents.

Description

1. Case offspring

Inclusion criteria:

1) aged 6-21 years old; 2) having at least one biological parent with a lifetime or current diagnosis of bipolar disorder; 3) being able to read, write and understand Chinese; 4) both the offspring and her/his parent(s) agree to sign the informed consent form

Exclusion criteria:

1) having lifetime history or current diagnosis of bipolar disorder; 2) having no good ability to attend this project, such as patients with dementia and mental retardation.

2. Control offspring

Inclusion criteria:

1) aged 6-21 years old; 2) having no biological parent(s) with lifetime or current diagnosis of mood disorders. 3) being able to read, write and understand Chinese; 4) both the offspring and her/his parent(s) agree to sign the informed consent form.

Exclusion criteria:

1) having lifetime history or current diagnosis of bipolar disorder. 2) having no good ability to attend this project, such as patients with dementia and mental retardation.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Case offspring; Inclusion criteria: 1) aged 6-21 years old; 2) having at least one biological parent with a lifetime or current diagnosis of bipolar disorder; 3) being able to read, write and understand Chinese; 4) both the offspring and her/his parent(s) agree to sign the informed consent form Exclusion criteria: 1) having lifetime history or current diagnosis of bipolar disorder; 2) having no good ability to attend this project, such as patients with dementia and mental retardation.
Control offspring; Inclusion criteria: 1) aged 6-21 years old; 2) having no biological parent(s) with lifetime or current diagnosis of mood disorders. 3) being able to read, write and understand Chinese; 4) both the offspring and her/his parent(s) agree to sign the informed consent form. Exclusion criteria: 1) having lifetime history or current diagnosis of bipolar disorder. 2) having no good ability to attend this project, such as patients with dementia and mental retardation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dim light melatonin onset (DLMO, free day)	The subjects will be instructed to arrive at our sleep laboratory 9 hours before their usual bedtime. Saliva samples will be collected into clear sterile tubes every 30 minutes for eight hours, starting six hours before and 2 hours after individual's habitual bedtime. Subjects will be asked to stay in the light-controlled study room (<30 lux in any direction of gaze) and remain awake and sit quietly.	9 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Actigraphy and sleep diary	One-week Actigraphy (GENEActiv) and sleep diary will be employed to continuously measure sleep/wake patterns and physical activity.	one week
Body temperature	Consecutive one-week period Skin temperature will be measured by iButton DS1921H (Dallas, Maxim) at 3 places: right on the middle of the frontal aspect of the thigh, abdomen (1 cm above the navel), and the right infraclavicular area. It has been demonstrated that iButton has satisfactory validity, reliability, and utility in the measurements of circadian rhythms and sleep/wake cycles.	one week
Circadian rhythm pattern of salivary cortisol (free day)	Subjects will be instructed to collect saliva samples using salivettes upon awakening (0 minute, 15 minutes, 30 minutes, and 45 minutes to measure cortisol awakening response) and then every 4 hours to measure the circadian rhythm patterns of cortisol secretion.	24 hours
24-Hour Urinary 6-sulphatoxymelatonin (aMT6s) Assessment	During the night of DLMO measure, all subjects will be instructed to collect a 24-h urinary samples (nearly 1000 mL) for the urinary 6-sulfatoxymelatonin assessment.	24 hours
Sleep macroarchitecture by polysomnography	One-night polysomnographic assessment will be measured to document the sleep architecture, together with DLMO measure. The recordings include electro-oculogram (EOG), electroencephalogram (EEG), electromyogram (EMG; monitoring over chin and bilateral anterior tibialis muscles), electrocardiogram (ECG), nasal-oral airflow and respiratory movements. The PSG data will be scored according to the most updated scoring manual of the American Academy of Sleep Medicine.	One-night (nearly 8 hours)
The rates of chronotype and sleep disorders	Chronotype will be estimated by the Morningness-eveningness Questionnaire (MEQ) or the Children's ChronoType Questionnaire (CCTQ). Sleep disorders, such as insomnia and delayed sleep phase disorder, will be also determined by the Diagnostic Interview for Sleep Patterns and Disorders (DISP).	nearly one hour

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Collaborators: Kowloon Hospital; The Affiliated Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital); Shenzhen Nanshan Center for Chronic Disease Control; Shenzhen Baoan Center for Chronic Disease Control; Shenzhen Longgang Center for Chronic Disease Control; Shenzhen Futian Center for Chronic Disease Control
• Investigators: Study Chair: Yun Kwok Wing, MBChB, Chinese University of Hong Kong; Study Director: Siu Ping Lam, Shatin Hospital; Study Director: Shirley Xin Li, PhD, Hong Kong University; Study Director: Roger Man Kin Ng, PhD, Kowloon Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2017
• Primary Completion (Anticipated): February 28, 2020
• Study Completion (Anticipated): June 28, 2020

Study Registration Dates

• First Submitted: July 5, 2018
• First Submitted That Met QC Criteria: August 31, 2018
• First Posted (Actual): September 4, 2018

Study Record Updates

• Last Update Posted (Actual): September 4, 2018
• Last Update Submitted That Met QC Criteria: August 31, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Bipolar disorder; Circadian Rhythm Disorders; Endophenotypes; High-risk offspring
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Bipolar and Related Disorders; Disease; Bipolar Disorder
• Other Study ID Numbers: 03140636

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No