Depression, Insomnia, Suicidal Ideation
Conditions
Keywords
Insomnia, Depression, Suicidal ideation, Zolpidem CR, Placebo
Brief summary
Epidemiologic reports have linked insomnia to suicidal ideation and suicide death. However, no studies have determined whether treating insomnia decreases the risk of suicidality. We have new data indicating that (1) the link between insomnia and suicidal ideation holds true in clinical trials of depressed insomniacs, (2) dysfunctional cognitions about sleep are related to suicidal ideas, and (3) treatment of insomnia with hypnotics leads to a reduction of suicidal ideation. We now propose to test whether cautious use of hypnotics in suicidal, depressed insomniacs may reduce suicide risk in a multi-site clinical trial.
Detailed description
Primary Aim: We will assess the effect of treating insomnia with hypnotic medication on the intensity of suicidal ideation in depressed outpatients with insomnia and suicidal ideation. -Hypothesis 1. Treatment of depressed, insomniac and suicidal outpatients with open-label fluoxetine (FLX) and blinded zolpidem controlled release (ZOL) will reduce suicidal ideation more than treatment with FLX and blinded placebo. Secondary Aim: We will examine whether reduced suicidal ideation in depressed insomniacs is mediated through reduced dysfunctional beliefs about sleep, reduced hopelessness, or fewer nightmares. * Hypothesis 2a. Reduction in suicidal ideation will be mediated through reductions in dysfunctional beliefs about sleep. * Hypothesis 2b. Reduction in suicidal ideation will be mediated through reductions in hopelessness. * Hypothesis 2c. Reduction in suicidal ideation is mediated through fewer nightmares. Tertiary Aim: We will confirm findings from our prior pilot studies that treatment of insomnia in depressed insomniacs leads to improvements in health-related quality of life, especially in women. Exploratory Aim: We will archive actigraphy data to permit future examination to confirm our preliminary data that actigraphic activity decreases as suicidal ideation resolves. Overview of the Need for and Management of a Collaborative Application: The sample sizes required to satisfy the Aims are relatively large, necessitating the pooled recruiting resources of 3 sites. Georgia Regents University (GRU) will serve both as the coordinating/data management site, as well as a recruiting site, with Duke and Wisconsin as recruiting sites. Project management will be coordinated through an Executive Committee of site principal investigators, under the supervision of a Data and Safety Monitoring Board. Impact on the Field: This application has the potential to change providers' practice in the approach to treating insomnia in depressed patients with mild-moderate suicidal ideation. It may also reveal the mechanisms whereby insomnia increases the risk for suicidal ideation and behavior, and begin to examine whether there is an actigraphic signature for reductions in suicidal ideation. When these lessons are applied to the clinical world, they can be applied with low cost.
Interventions
DRUGZolpidem-CR
Zolpidem 6.25 mg or 12.5 mg in tablet form at nighttime 15 minutes before bed for 8 weeks
DRUGPlacebo
Placebo in tablet form at nighttime 15 minutes before bed for 8 weeks
Sponsors
National Institute of Mental Health (NIMH)
Wake Forest University Health Sciences
University of Wisconsin, Madison
Duke University
Augusta University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Persons 18-65 years of age * Persons with confirmed DSM-IV diagnosis of MDE by SCID * Persons with Research Diagnostic Criteria diagnosis of insomnia * Persons free of all psychotropic medications for one week before baseline assessment, except that prior FLX treatment will require 4 weeks of abstinence, and MAOIs will require 2 weeks of abstinence. * Persons with Scale for Suicide Ideation (SSI) scores \>2 * Persons with Hamilton Rating Scale for Depression (HRSD24) score \>20 * Persons with Mini Mental State Exam (MMSE) score \>24 * Persons with Insomnia Severity Index (ISI) score \> 7 * Persons with habitual sleep latency \> or = 30 minutes or wake time in the middle of the night of \> or = 30 minutes, and sleep efficiency \< 85%
Exclusion criteria
* Non-English speaking, reading, writing persons * Persons who pose imminent danger to self or others * Persons with severe suicidal ideation (C-SSRS Suicidal Ideation Score \>3) * Persons with clinical diagnosis of dementia * Persons with active or past diagnosis of alcohol or substance abuse, bipolar disorder, schizophrenia per the SCID * Persons who screen positive for moderate-severe sleep apnea (AHI \>10) or a prior sleep laboratory-confirmed diagnosis of a primary sleep disorder, such as sleep apnea or periodic limb movement disorder. * Persons with BMI \> 50 * Persons with a self-reported history of napping \> 2 times per week (as these are associated with sleep apnea and periodic limb movement disorder in depressed insomniacs) * Persons who might be harmed by exposure to hypnotics, including pregnant women and patients with respiratory conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Columbia Suicide Severity Rating Scale (C-SSRS): the Suicidal Ideation Scale | 8 weeks of treatment | The suicide ideation scale of the C-SSRS is rated 0-5, with 0 meaning no suicidal ideation, 1 meaning a wish t be dead, 2 meaning non-specific active suicidal thoughts, 3 meaning active suicidal ideation with any methods but no plan or intent, 4 meaning active suicidal ideation with some intent but no specific plan, and 5 meaning active suicidal ideation with intent and a specific plan |
| Scale for Suicide Ideation Index (SSI) | Over 8 weeks of treatment | This is the total score for the Scale for Suicide Ideation. It has 19 items, each scored 0-2, for a maximum of 38 points. Higher scores indicate worse suicidal ideation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Rating Scale for Depression (HAM-D) | 8 weeks of treatment | This version of the Hamilton Rating Scale for Depression uses 24 items, with a possible total score ranging from 0-74, with higher scores indicating worse depression |
| Dysfunctional Beliefs and Attitudes About Sleep | 8 weeks of treatment | The Dysfunctional Beliefs and Attitudes About Sleep scale has 16 items and is self administered. Each item is scored 0-10. The total score is an average of the scores of the 16 items. Hence the range of the total score is also 0-10, with higher scores indicating greater dysfunctional beliefs about sleep |
| Disturbing Dreams and Nightmares Severity Index (DDNSI) | 8 weeks of treatment | This self-rated scale has 5 items, with asymmetric weighting of each item. The range of the total score is 0-37, with higher scores indicating worse nightmares |
| Insomnia Severity Index (ISI) | 8 weeks of treatment | The Insomnia Severity Index is self rated. It has 7 items, each scored 0-4. Therefore the range of scores is 0-28, with higher scores indicating worse insomnia |
| Beck Hopelessness Scale (BHS) | 8 weeks of treatment | The Beck Hopelessness Scale is self administered and has 20 'true/false' choices. Some items are reversed scored. The range of scores for the total is 0-20, with higher scores indicating greater hopelessness |
Other
| Measure | Time frame | Description |
|---|---|---|
| Basis-32 - the Daily Living and Role Functioning (DLRF) Subscale | 8 weeks of treatment | This is one of the subscales of the Basis 32. It is self-administered. This subscale has 7 items, each scored 0-4. The totals score is an average of the scores of these 7 items. Higher scores indicate more difficulty with daily living and role functioning. |
| Actigraphy | 8 weeks of treatment | This device measures arm motion over time, reported as average actigraphic activity Level. The scale is reported as a continuous measure ranging from 0-200, and reported as the average score for each hour for all 24-hours of the day. Higher score represent greater c=activity at that point in time |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zolpidem-CR Zolpidem 6.25 or 12.5 mg in tablet form at nighttime 15 minutes before bed for 8 weeks
Zolpidem-CR: Zolpidem 6.25 mg or 12.5 mg in tablet form at nighttime 15 minutes before bed for 8 weeks | 51 |
| Placebo Placebo in tablet form at nighttime 15 minutes before bed for 8 weeks
Placebo: Placebo in tablet form at nighttime 15 minutes before bed for 8 weeks | 52 |
| Total | 103 |
Baseline characteristics
| Characteristic | Zolpidem-CR | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 51 Participants | 52 Participants | 103 Participants |
| Age, Continuous | 39.7 years STANDARD_DEVIATION 14.5 | 41.2 years STANDARD_DEVIATION 12 | 40.5 years STANDARD_DEVIATION 13.2 |
| Columbia Suicide Severity Rating Scale (C-SSRS) - suicide ideation scale | 1.71 units on a scale STANDARD_DEVIATION 10.3 | 1.58 units on a scale STANDARD_DEVIATION 10.2 | 1.64 units on a scale STANDARD_DEVIATION 1.02 |
| Disturbing Dreams Nightmare Severity Index | 10.5 units on a scale STANDARD_DEVIATION 8.8 | 10.2 units on a scale STANDARD_DEVIATION 7.7 | 10.3 units on a scale STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 51 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hamilton Rating Scale for Depression -24 | 28.7 units on a scale STANDARD_DEVIATION 4.7 | 29.6 units on a scale STANDARD_DEVIATION 7 | 29.1 units on a scale STANDARD_DEVIATION 5.9 |
| Insomnia Severity Index | 20.6 units on a scale STANDARD_DEVIATION 3.9 | 21.1 units on a scale STANDARD_DEVIATION 4.3 | 20.8 units on a scale STANDARD_DEVIATION 4.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 16 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 34 Participants | 68 Participants |
| Region of Enrollment United States | 51 participants | 52 participants | 103 participants |
| Scale for Suicide Ideation | 12.2 units on a scale STANDARD_DEVIATION 5.3 | 11.8 units on a scale STANDARD_DEVIATION 5.3 | 12.0 units on a scale STANDARD_DEVIATION 5.3 |
| Sex: Female, Male Female | 32 Participants | 32 Participants | 64 Participants |
| Sex: Female, Male Male | 19 Participants | 20 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 52 |
| other Total, other adverse events | 31 / 51 | 37 / 52 |
| serious Total, serious adverse events | 1 / 51 | 0 / 52 |
Outcome results
Primary
Columbia Suicide Severity Rating Scale (C-SSRS): the Suicidal Ideation Scale
The suicide ideation scale of the C-SSRS is rated 0-5, with 0 meaning no suicidal ideation, 1 meaning a wish t be dead, 2 meaning non-specific active suicidal thoughts, 3 meaning active suicidal ideation with any methods but no plan or intent, 4 meaning active suicidal ideation with some intent but no specific plan, and 5 meaning active suicidal ideation with intent and a specific plan
Time frame: 8 weeks of treatment
Population: all evaluable randomized participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Columbia Suicide Severity Rating Scale (C-SSRS): the Suicidal Ideation Scale | 0.5447 units on a scale | Standard Error 0.0869 |
| Placebo | Columbia Suicide Severity Rating Scale (C-SSRS): the Suicidal Ideation Scale | 0.8067 units on a scale | Standard Error 0.0875 |
Primary
Scale for Suicide Ideation Index (SSI)
This is the total score for the Scale for Suicide Ideation. It has 19 items, each scored 0-2, for a maximum of 38 points. Higher scores indicate worse suicidal ideation
Time frame: Over 8 weeks of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Scale for Suicide Ideation Index (SSI) | 4.66 units on a scale | Standard Error 0.58 |
| Placebo | Scale for Suicide Ideation Index (SSI) | 5.25 units on a scale | Standard Error 0.59 |
Secondary
Beck Hopelessness Scale (BHS)
The Beck Hopelessness Scale is self administered and has 20 'true/false' choices. Some items are reversed scored. The range of scores for the total is 0-20, with higher scores indicating greater hopelessness
Time frame: 8 weeks of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Beck Hopelessness Scale (BHS) | 9.40 units on a scale | Standard Error 0.58 |
| Placebo | Beck Hopelessness Scale (BHS) | 9.63 units on a scale | Standard Error 0.58 |
Secondary
Disturbing Dreams and Nightmares Severity Index (DDNSI)
This self-rated scale has 5 items, with asymmetric weighting of each item. The range of the total score is 0-37, with higher scores indicating worse nightmares
Time frame: 8 weeks of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Disturbing Dreams and Nightmares Severity Index (DDNSI) | 5.74 units on a scale | Standard Error 0.71 |
| Placebo | Disturbing Dreams and Nightmares Severity Index (DDNSI) | 6.44 units on a scale | Standard Error 0.718 |
Secondary
Dysfunctional Beliefs and Attitudes About Sleep
The Dysfunctional Beliefs and Attitudes About Sleep scale has 16 items and is self administered. Each item is scored 0-10. The total score is an average of the scores of the 16 items. Hence the range of the total score is also 0-10, with higher scores indicating greater dysfunctional beliefs about sleep
Time frame: 8 weeks of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Dysfunctional Beliefs and Attitudes About Sleep | 6.03 units on a scale | Standard Error 0.171 |
| Placebo | Dysfunctional Beliefs and Attitudes About Sleep | 6.07 units on a scale | Standard Error 0.171 |
Secondary
Hamilton Rating Scale for Depression (HAM-D)
This version of the Hamilton Rating Scale for Depression uses 24 items, with a possible total score ranging from 0-74, with higher scores indicating worse depression
Time frame: 8 weeks of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Hamilton Rating Scale for Depression (HAM-D) | 14.93 units on a scale | Standard Error 0.87 |
| Placebo | Hamilton Rating Scale for Depression (HAM-D) | 15.89 units on a scale | Standard Error 0.88 |
Secondary
Insomnia Severity Index (ISI)
The Insomnia Severity Index is self rated. It has 7 items, each scored 0-4. Therefore the range of scores is 0-28, with higher scores indicating worse insomnia
Time frame: 8 weeks of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Insomnia Severity Index (ISI) | 11.28 units on a scale | Standard Error 0.62 |
| Placebo | Insomnia Severity Index (ISI) | 13.72 units on a scale | Standard Error 0.63 |
Other Pre-specified
Actigraphy
This device measures arm motion over time, reported as average actigraphic activity Level. The scale is reported as a continuous measure ranging from 0-200, and reported as the average score for each hour for all 24-hours of the day. Higher score represent greater c=activity at that point in time
Time frame: 8 weeks of treatment
Population: participants with depression, insomnia, and suicidality
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Actigraphy | 150 units on a scale | Standard Error 30 |
| Placebo | Actigraphy | 170 units on a scale | Standard Error 30 |
Other Pre-specified
Basis-32 - the Daily Living and Role Functioning (DLRF) Subscale
This is one of the subscales of the Basis 32. It is self-administered. This subscale has 7 items, each scored 0-4. The totals score is an average of the scores of these 7 items. Higher scores indicate more difficulty with daily living and role functioning.
Time frame: 8 weeks of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem-CR | Basis-32 - the Daily Living and Role Functioning (DLRF) Subscale | 1.51 units on a scale | Standard Error 0.102 |
| Placebo | Basis-32 - the Daily Living and Role Functioning (DLRF) Subscale | 1.60 units on a scale | Standard Error 0.102 |