Triple Chronotherapy in Adolescents

Study Overview
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Brief Summary
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Study Purpose This study is a randomized controlled trial examining the effectiveness of TCT in the acute treatment of depression and suicidality in adolescents compared to usual treatment care, which includes individual and group therapy, and medication adjustments. All potential participants will be identified at admission to the Psychiatric Youth Inpatient Unit of Billings Clinic and invited to participate. The length of participation is 2 months. Study Design The primary research question of this RCT is whether adjunctive TCT in depressed adolescents is more effective in the management of depression symptoms and in reducing suicidal ideation at two months follow-up, than those adolescents who are receiving usual care. A total of three aims are proposed. Hypothesis: Adjunctive TCT is more effective in the management of depression symptoms and in reducing suicidal ideation at two month follow-up than those adolescents who are receiving usual care. The first aim is to track the trajectories of depression symptoms, suicidal ideation, and insomnia severity in participants receiving TCT and in those receiving treatment as usual over 4 days of initial treatment, thereby answering the question of whether adjunctive TCT can effectively reduce the severity of depression, insomnia and suicidal ideation. The second aim is to examine whether TCT is more effective than usual care in sustaining treatment effects to the end of study period (2 months follow-up), therefore answering the question whether the effectiveness of the 4-day intervention of adjunctive TCT arm is sustainable up to the end of a two-month follow-up. Hypothesis: TCT is more effective than usual care in sustaining treatment effects to the end of the study period than usual care. The third aim is to assess the link to the clinical outcomes (change in depression symptoms, suicidal ideation, insomnia severity, and disease-associated quality of life) and patient satisfaction with the treatment. Hypothesis: Clinical outcomes (depression symptoms, suicidal ideation, insomnia, and disease-related quality of life) and patient satisfaction are more effective than usual care alone.

Detailed Description
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According to the Centers for Disease Control, almost 11% of youth will have met criteria for a depressive disorder by the time they are 18 years of age. Depression can significantly impact quality of life and is associated with increased risk of suicide, the second leading cause of death among individuals between ages 10 -24 years. While evidence-based treatments for the management of depression in adolescents exist, social stigma, perception that depression can be self-managed without treatment and side effects of antidepressants all pose treatment barriers. Moreover, the two most widely used evidence-based treatments, antidepressants and cognitive behavioral therapy, have medium to small effect sizes, and a significant need exists to develop more effective strategies to manage depression in adolescents. Adjunctive treatments for depression such as electroconvulsive therapy, transcranial magnetic stimulation, and ketamine have been shown to be effective in producing an antidepressant response in the adult population; however, none are yet recommended for safe use in adolescents. Moreover, ketamine and electroconvulsive therapy are associated with significant side effects, making each a less desirable treatment for depression among adolescent patients and their families. Chronotherapy, defined as the therapeutic manipulation of sleep-wake cycles, is a promising approach for the treatment of adolescent depression. The study of chronotherapeutic interventions as an adjunctive treatment for depression began in the 1970s, when investigators noted a rapid, albeit transient, antidepressant response to sleep deprivation. Another chronotherapeutic technique, bright light therapy, has consistently shown benefit in the treatment of seasonal affective disorders. Its use in the treatment of non-seasonal unipolar and bipolar depression has also shown promising results. Combination chronotherapeutics, such as triple chronotherapy (TCT), have also been trialed with some demonstrated efficacy. TCT is an approach that combines sleep deprivation, bright light therapy, and sleep phase advancement in the acute treatment of depression. One of the first open label TCT studies enrolled 143 consecutive patients; of the 141 adults who completed the study, a significant acute antidepressant response was found in up to 70% of patients with bipolar depression, and a sustained response in up to 55% of patients at 1-month. A more recent randomized control trial of 75 adults employed an abbreviated protocol that included one night of sleep deprivation, three nights of sleep phase advancement, and bright light therapy in each of the four mornings of the intervention. This study demonstrated similar, accelerated antidepressant responses along with a decrease in suicidality and improved sleep quality. Although evidence is growing for the use of TCT to manage acute depression and suicidality in adults, studies in the adolescent population are lacking. It was hypothesized by Gest et al. (2014) that the use of chronotherapy in adolescents could be an effective treatment modality, and researchers were urged to explore this area. In 2016, Gest et al. compared combined sleep deprivation and bright light therapy to bright light therapy alone in adolescents and found a significant antidepressant response to bright light therapy alone, but no significant benefit was gained with the addition of one night of total sleep deprivation. Sleep phase advancement was absent in this study. No studies were found that examined the use of comprehensive TCT in adolescents compared to usual practice in the inpatient setting.

Official Title
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Adjunctive Triple Chronotherapy in the Acute Treatment of Depression and Suicidality in the Adolescent Population: A Randomized Controlled Trial

Conditions
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Depressive Disorder, Major, Bipolar Depression, Suicidal Ideation

Intervention / Treatment
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* Behavioral: Triple Chronotherapy
* Behavioral: Treatment as Usual


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be 12-17 years of age Must verbalize motivation for treatment Must provide informed assent; parent or guardian must provide consent Must be diagnosed with moderate to severe unipolar or bipolar depression. Severity of depression is determined using the Patient Health Questionnaire-9 (PHQ-9 modified for Adolescents [PHQ-A]). A score of 10 or more indicates moderate-severe depression Exclusion Criteria: Active psychosis Manic state Younger than 12 years of age or older than 17 years of age Seizure disorder Pregnancy Lack of assent and consent Previous TCT treatment

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized Control Trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Triple Chronotherapy<br>Four-day intervention, with 24-hour total sleep deprivation, 3-days of sleep phase advancement and daily bright light therapy. | Behavioral: Triple Chronotherapy<br>* Day 0: One night of total sleep deprivation. The first 24 hours are spent with 1:1 nursing care for provision of comfort measures to stimulate wakefulness and to encourage completion of the intervention. Day 1-4: Sleep phase advancement Day 1: Sleep from 6 PM to 1 AM Day 2: Sleep from 8 PM to 3 AM Day 3: Sleep from 10 PM and 5 AM Day 4: Awaken at 5 AM; discharge following light therapy On days 1-4 patients will receive bright light therapy at 7am to 7:30am using a 10,000 Verilux light box. At discharge patients will be given a light box, strongly advised to continue the maintenance sleep schedule and bright light therapy at 7am daily for 30 minutes. Patients will be scheduled for follow-up appointments at 1-week, 1-month and 2-month following discharge.<br>|
| Active Comparator: Treatment as Usual<br>Normal inpatient care, including pharmacotherapy, psychotherapy, milieu therapy and social work interventions | Behavioral: Treatment as Usual<br>* Normal inpatient care, including pharmacotherapy, psychotherapy, milieu therapy and social work interventions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Health Questionnaire -Adolescent version (PHQ-A) | Measuring the change score of pre-post PHQ-A; a score of 5-9 indicates mild depression with watchful waiting and repeat test, 10-14 indicates moderate depression that should be followed up with due consideration as to counseling and/or pharmacotherapy, 15-19 signifies moderately severe depression what requires initiation of pharmacotherapy and/or psychotherapy, and a score of 20-27 is interpreted as severe depression with immediate initiation of pharmacotherapy and referral to a mental health specialist for psychotherapy and collaborative management. | PHQ-A the day prior to total sleep deprivation, and then again over the next 3 consecutive days. | 
| Columbia Suicide Severity Rating Scale | Measuring the change score of pre-post C-SSRS; 5 potential questions- yes/no questions indicating suicidal behavior and ideation; optimum score = 0. | Daily throughout the treatment (Days 0-4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Health Questionnaire-Adolescent version (PHQ-A) | Measuring the change score of pre-post PHQ-A; a score of 5-9 indicates mild depression with watchful waiting and repeat test, 10-14 indicates moderate depression that should be followed up with due consideration as to counseling and/or pharmacotherapy, 15-19 signifies moderately severe depression what requires initiation of pharmacotherapy and/or psychotherapy, and a score of 20-27 is interpreted as severe depression with immediate initiation of pharmacotherapy and referral to a mental health specialist for psychotherapy and collaborative management | PHQ-A the day prior to total sleep deprivation, and then again over the next 3 consecutive days, at 1-month and at 2-month | 
| Youth Quality of life Questionnaire | Youth Quality of Life Instrument-Short Form (YQOL-SF); 16-questions each having a 0-10 score, higher scores indicate better quality of life. | Day 0 and repeat measure at 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bright Light Therapy, Sleep Deprivation, Adolescent, Depression, Suicidal Ideation