Sleep and Healthy Aging Research for Depression (SHARE-D) Study

Depression in Old Age Clinical Trial

— SHARE-D  

Official title:

Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03256760
• Other study ID #: 16-000583
• Status: Recruiting
• Phase: Phase 1
• Start date: January 1, 2018
• Est. completion date: May 30, 2023

Study information

• Verified date: September 2022
• Source: University of California, Los Angeles
• Contact: Michael Irwin, MD
• Phone: 3108258281
• Email: mirwin1[@]ucla.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Late-life depression is a significant public health concern, and effective interventions for prevention and treatment are needed. Insomnia and inflammation are modifiable targets for depression prevention, and this study is significant in using an experimental approach (i.e., inflammatory challenge) to probe acute inflammatory- and depression responses as a function of insomnia, which will inform identification of molecular targets for pharmacologic interventions, and improvement of insomnia treatments to prevent depression in older adults.

Project

Description:

This study (SHARE-D) will use an inflammatory challenge (i.e., endotoxin) to probe acute inflammatory- and depression responses (primary outcome) in older adults as a function of insomnia. Older adults with insomnia show chronic inflammation; sleep disturbance also activates inflammatory signaling; chronic inflammation primes acute inflammatory responses; chronic inflammation, as well as acute inflammatory reactivity, predict depression over the following year; and finally, endotoxin induces acute inflammation along with depressive symptoms, with preliminary evidence that "two-hits" (i.e., sleep disturbance and inflammatory challenge) are associated with exaggerated increases in depression, especially in women. In this placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (60-80 y; stratified by sex) with insomnia (n=60) vs. comparisons without insomnia (n=100), the investigators hypothesize that older adults with insomnia will show heightened inflammatory- and affective responding to inflammatory challenge as compared to those without insomnia. The investigation aims to: 1) examine differences in depressive symptoms and measures of negative affect responding as a function of insomnia and inflammatory challenge; 2) examine differences in measures of positive affect responding as a function of insomnia and inflammatory challenge; and 3) examine differences in experimentally-induced inflammation in relation to depressive symptoms and measures of negative- and positive affect responding as a function of insomnia.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: May 30, 2023
• Est. primary completion date: May 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years to 80 Years

Eligibility

• Inclusion Criteria:

• Participants will be required to be in good general health (as evaluated during the phone and in-person baseline session)

• Participants will be aged 60 to 80 years.

• Half the participants (N=80) will be those with insomnia disorder as diagnosed by the Structured Clinical Interview for Diagnosis, Diagnostic Statistical Manual 5 and the Duke Structured Interview for Sleep Disorders, .

• The other half will be those without insomnia identified as not having insomnia by any of these assessments.

• Exclusion Criteria: Following a structured telephone interview, prospective participants with the following conditions will not advance to the in-person baseline session:

• Presence of chronic mental or physical illness (except for insomnia)

• History of allergies, autoimmune, liver, or other severe chronic diseases,

• Current and regular use of prescription medications such as steroids, non-steroid anti-inflammatory drugs, aspirin, immune modifying drugs, opioid analgesics, statins, antihypertensive drugs, anti-arrhythmic drugs, and antidepressant medications (none in the last 6 months); and nightshift work or time zone shifts (> 3hrs) within the previous 6 weeks, or previous history of fainting during blood draws.

• Presence of co-morbid medical conditions not limited to but including cardiovascular (e.g., history of acute coronary event, stroke) and neurological diseases (e.g., Parkinson's disease), as well as pain disorders;

• Presence of comorbid inflammatory disorders such as rheumatoid arthritis or other autoimmune disorders;

• Presence of an uncontrolled medical condition that is deemed by the investigators to interfere with the proposed study procedures, or to put the study participant at undue risk;

• Presence of chronic infection, which may elevate proinflammatory cytokines;

• Presence of an acute infectious illness in the two weeks prior to an experimental session.

• Current Axis I psychiatric disorders as determined by the Research Version of the Structured Clinical Interview including a current major depressive disorder and substance dependence (a prior history of depression is not an exclusion criterion, which will be considered for a pre-planned sensitivity analysis and will be used as a pre-classification variable in the generation of the two groups, and in the randomization schedule);

• Lifetime history of suicide attempt or inpatient psychiatric admission. Sleep Disorders:

• Current history of sleep apnea or nocturnal myoclonus;

• Phase-shift disorder, which will be identified by the Structured Clinical Interview and the Duke Structured Interview for Sleep Disorders ; Medication and Substance Use:

• Current and/or past regular use of hormone-containing medications including steroids;

• Current and/or past regular use of non-steroid anti-inflammatory drugs;

• Current and/or past regular use of immune modifying drugs that target specific immune responses such as cytokine antagonists;

• Current and/or past regular use of analgesics such as opioids;

• Current and/or past regular use of cardiovascular medications, including antihypertensive, antiarrhythmic, antianginal, and anticoagulant drugs;

• Use of antidepressant medications or other psychotropic medications; (16) current smoking or excessive caffeine use (>600 mg/day) because of the known effects on proinflammatory cytokine levels;

• Evidence of recreational drug use from urine test. Health Factors:

• Body mass index > 35 because of the effects of obesity on proinflammatory cytokine activity and also on risk for sleep disordered breathing;

• Any clinically significant abnormality on screening laboratory tests

• Clinically significant abnormalities in electrocardiogram

Related Conditions & MeSH terms

• Depression
• Depression in Old Age
• Depressive Disorder

Intervention

Biological:
• Endotoxin
Endotoxin
• Placebo
Placebo

Locations

Country	Name	City	State
United States	Cousins Center for Psychoneuroimmunology, UCLA Neuropsychiatric Institute	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Michael Irwin, MD

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Feelings of Social Disconnection	Using the Feelings of Social Disconnection Scale, participant rated the extent to which they were feeling the ''following feelings right now" on a 5-point Likert scale (1-not at all, to 5- very much so): (1) ''I feel like being around other people," (2) ''I feel like being alone," (3) ''I feel overly sensitive around others (e.g., my feelings are easily hurt)," (4) ''I feel connected to others," and (5) ''I feel disconnected from others." Items 1 and 4 were reverse-coded, and scores were averaged at each time point to create a measure of self-reported social disconnection. Each timepoint is scored and analyses examine the temporal profile of change with assessment every hour	12 hours
Other	Physical symptoms	Physical "sickness" symptoms which have been related to the administration of endotoxin are assessed during the experimental protocol; these sickness symptoms include self-reported rating of severity of muscle pain, shivering, nausea, breathing, difficulties, and fatigue	12 hours
Other	Psychiatric symptoms	The Brief Symptom Inventory will be used assesses a wide variety of psychiatric symptoms	6 hours
Other	Systemic marker of inflammation as indexed by interleukin-6	Systemic inflammation as measured by circulating levels of interleukin-6 in plasma in pg/ml. Each timepoint is assayed and analyses examine the temporal profile of change with assessment every hour	12 hours
Other	Genomic marker of inflammation	Transcriptional profile of inflammation as measured by Conserved Translational Response to Adversity in circulating peripheral blood mononuclear cells	about 2 hours
Other	UCLA Loneliness Scale	UCLA Loneliness scale is a 10-item scale designed to measure one's subjective feelings of loneliness as well as feelings of social isolation. Participants rate each item as either O ("I often feel this way"), S ("I sometimes feel this way"), R ("I rarely feel this way"), N ("I never feel this way").	6 hours
Other	Social Status	MacArthur Scale of Subjective Social Status (i.e., Social Ladder) will be used to evaluate perceived social status	6 hours
Other	Perceived Social Support	Social Support Questionnaire Scale will be used to evaluated perceived social support	6 hours
Other	Social Attachment	The Attachment Style Questions will be used to evaluate feelings of social attachment. This scale is reported 18 items that rates how you feel generally experience in relationships, not just in what is happening in a current relationship.	6 hours
Other	Sensitivity to Social Rejection	Sensitivity to social rejection is examined by Fear of Negative Evaluation Scale and Mehrabian Rejection Sensitivity Scale	6 hours
Other	Cyberball Social Exclusion Task	The Cyberball Social Exclusion Task is a virtual ball-toss game in which a participant plays with two other players (virtual) on a computer. Abruptly, the others exclude the participant, only throwing to one another. After completion of the task, the degree of perceived ostracism was was evaluated by a 20-item ostracism distress or social exclusion scale.	2 hours
Other	Cognitive Processing	Increasing evidence indicates that inflammatory challenge acutely alters measures of cognitive performance, including spatial learning and memory. We use a virtual Morris Water Maze task (REF: https://pubmed.ncbi.nlm.nih.gov/19121374/) to assess computerized spatial learning and memory, followed by a Room Reconstruction Task (REF: https://pubmed.ncbi.nlm.nih.gov/10779831/) to assess the ability of cognitive mapping under real-life conditions.	5.5 hours
Other	Mechanical Temporal Summation	Temporal summation reflects the endogenous capacity to enhance pain and will be assessed by calculating the windup ratio as a primary outcome for SHARE-Pain (or SHARE-P). Higher values are indicative of greater pain facilitation. Multiple pinprick probes were used (#3, #5, #6, and #7). The windup ratio will be calculated and z-scored within each probe. The z-scored windup ratios will then be averaged across probes to create an aggregate temporal summation index. Change scores will also be used to calculate temporal summation by subtracting the peak pain rating during 10 successive pinpricks from the pain rating during a single pinprick. The change scores will also be z-scored and averaged across probes. The windup ratio will be a primary outcome, whereas the change score metric will be a secondary outcome for SHARE-P.	5.5. hours
Other	Conditioned Pain Modulation	Conditioned pain modulation assesses the degree to which one noxious stimulus reduces pain produced by a second noxious stimulus and is a measure of endogenous capacity for pain inhibition. It is calculated by taking the percent change in pressure pain threshold during the cold pressor task compared to the pressure pain threshold assessed just prior to cold water submersion. Larger values indicate better pain inhibitory capacity. This variable is a primary outcome for the SHARE-P. Raw difference scores will also be reported as a secondary outcome.	5.5 hours
Other	Affective Pain Modulation	Affective pain modulation refers to the ability of negative emotions to enhance pain while positive emotions reduce pain. Participants will be asked to rate their pain on a 0 (no sensation) to 100 (intolerable) scale to two thermal stimuli (46°C and 48°C) presented in a randomized order throughout each condition.Self-reported pain will be compared across the three conditions (negative, positive, neutral). Affective pain modulation is a primary outcome for SHARE-	5.5
Other	Pressure Pain Threshold-Trapezius muscle	Pressure pain threshold is the pressure that first elicits pain, such that lower values indicate greater pain sensitivity. Pressure pain threshold was assessed at three sites: trapezius, masseter, and middle insertion of the quadriceps. Four trials were completed at each site (two on the left side two on the right side). All threholds will be z-scored within each site and averaged across sites to create an index score. Pressure pain threshold is a secondary outcome for SHARE-P.	5.5 hours
Other	Heat Pain Threshold	The first thermal stimulus that participants self-report as painful (averaged across two trials). Lower values indicate enhanced pain sensitivity. This is a secondary outcome variable for the SHARE-P sub-study.	5.5 hours
Other	Heat Pain Tolerance	The thermal stimulus at which the participant identifies the pain as intolerable (averaged across two trials). Lower values represent greater pain sensitivity. This is a secondary outcome variable for the SHARE-P sub-study.	5.5 hours
Other	Cold Pain Tolerance	Cold pain tolerance is measured as the time it takes for the participant to withdraw their hand from cold water bath (2°C), such that shorter durations reflect greater pain sensitivity. (Secondary outcome for SHARE-P).	5.5
Other	Pain Pain Threshold. Masseter muscle and middle of quadriceps	Pressure pain threshold is the first mechanical stimulus that a participant self-reports as painful, such that lower values indicate greater pain sensitivity. Pressure pain threshold is the average of two readings and will be reported separately for the masseter muscle and middle of the quadriceps. These are tertiary outcomes for SHARE-P.	5.5 hours
Other	Pain Intensity	Pain intensity ratings will be assessed daily using a Visual Analogue Scale and averaged across the two week period to determine the Pain Intensity Index. These ratings will be made at baseline, 3mo, 6mo, 9mo, and 12mo and are considered a primary outcome for the longitudinal component of SHARE-P.	12 months
Other	Depressive symptoms	Depressive symptoms will be assessed at baseline, 3mo, 6mo, 9mo, and 12mo using the Patient Health Questionnaire - 9 item (PHQ-9). This is a primary outcome for the longitudinal component of SHARE-P.	12 months
Other	Graded Chronic Pain Scale	Pain intensity and pain-related disability are assessed at baseline, 3mo, 6mo, 9mo, and 12mo using the Graded Chronic Pain Scale (3-month version). This is a secondary outcome for the SHARE-P study.	12 months
Other	Affective Disturbance	o Affective disturbance is assessed daily during a 2-week period by having participants rate the extent to which they feel three positive (happy, calm, agreeable) and three negative emotions (sad, anxious, annoyed) on a 0 (not at all) to 100 (extremely) scale. Daily positive affect and negative affect are calculated by averaging across the three positive and negative emotion words, respectively. Participants complete these measures at baseline, 3mo, 6mo, 9mo and 12mo. This is a secondary outcome for SHARE-P.	12 months
Other	Sleep Continuity	Electronic sleep diaries will be administered daily for two weeks at baseline, 3mo, 6mo, 9mo, and 12mo. Sleep diaries will be used to assess sleep continuity, including (1) latency to initial sleep onset, (2) frequency of nightly awakenings, (3) wake after sleep onset, (4) total sleep time, and (5) sleep efficiency (total sleep time/time in bed). These are considered secondary outcomes for SHARE-P.	12 months
Other	Total Sleep Time	Participants will receive an ActiGraph (wrist triaxial accelerometer) to wear for a 2-week period at baseline, 3mo, 6mo, 9mo, and 12mo to measure total sleep time (secondary outcome for SHARE-P).	12 months
Primary	Depressed Mood Subscale of the Profile of Mood States (POMS)	The Depressed Mood Subscale of the POMS is a self-and observer rated assessment of depressed mood in which severity of depressed mood is rated using a visual analog scale from 1 to 5 (5 being most severe). Each timepoint is scored and analyses examine the temporal profile of change with assessment every hour	12 hours
Primary	Depressed mood and depressive symptoms as measured by the Montgomery Asberg Depression Rating Scale (MADRS)	Depressed mood and depressive symptom severity by self-reported assessment using the Montgomery Asberg Depression Rating scale with a range from 0 to 54 with a higher score indicating more severe depressive symptoms. Each timepoint is scored and analyses examine the temporal profile of change with assessment every 2 hours	8 hours
Secondary	Hamilton Depression Rating Scale	The Hamilton Depression Rating Scale is on the most widely used scales in depression, which is adapted to evaluate acute changes in depressive symptoms. A trained interviewer, blind to the experimental condition, make ratings of items of depressed mood, feelings of guilt, loss of interest, retardation/agitation, anxiety, and somatic symptoms using items from the Hamilton Depression Rating Scale. The 17-item version will be used.	8 hours
Secondary	Emotion Facial Recognition Task	This is a computer-based test that includes color photographs of facial expression of evoked-or felt-emotions: happy, sad, angry, fearful, disgusted, and nonemotional or neutral. Participants rate the emotional valence using a scale of 0-8 of each expression.	about 2 hours
Secondary	Emotion Intensity Task	This is a computer-based test used along with emotion facial recognition to test subjective ratings of perceived intensity in response to facially-expressed emotions	about 2 hours
Secondary	Probabilistic Reward Task	This is a probabilistic reward task that is administered using computerized reward-learning task rooted in signal detection theory that yields an objective measurement of participant's ability to modulate behavior as a function of rewards. The variable that will be scored is termed response bias (RB), which reflects participants' preference for the stimulus paired with more frequent rewards.	about 2 hours
Secondary	Effort Expenditure for Reward Task	Similar to the Reward Learning Task, this is a computer based reward task to evaluate reward processing in the context of monetary reward.	about 2 hours
Secondary	Social Reward Task	This will evaluate another component of reward by subjective reports and task sensitivity to general social rewards	about 2 hours
Secondary	Snaith-Hamilton Pleasure Scale	The Snaith-Hamilton Pleasure Scale (SHAPS) is a self-administered questionnaire with 14 items assessing four domains of pleasure response/hedonic experience: interest/pastimes, social interaction, sensory experience, and food/drink, with each item scored from 1 to 4.	8 hours
Secondary	Temporal Experience of Pleasure Scale	This self-report scale rates interest in 10 different activities, how much a person is interested in doing that activity right now	8 hours