Sleep Therapies for Alzheimer's Disease

Overseen By Leah Harris, BA

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Stanford University

Must not be taking: Sleep medications, Antidepressants

Disqualifiers: Bipolar, Psychosis, Substance abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 11 weeks

150 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that your medications, including any dementia-related ones, be stable for at least 4 weeks before starting. If you are taking medications specifically for sleep disturbances or certain low-dose antidepressants for sleep, you must stop them more than two weeks (for antidepressants) or more than one week (for sleep medications) before the trial begins.

What data supports the effectiveness of Cognitive Behavioral Therapy for Insomnia (CBT-I) in treating sleep disturbances in Alzheimer's disease?

Research suggests that treating sleep disorders in Alzheimer's patients may target basic mechanisms of the disease, potentially modifying its course. Nonpharmacological approaches like CBT-I are recommended as a primary treatment strategy for sleep disturbances in Alzheimer's, given the complex interaction of factors contributing to insomnia in this population. ^{1 2 3 4 5}

Is Cognitive Behavioral Therapy for Insomnia (CBT-I) safe for humans?

The research articles provided do not contain specific safety data for Cognitive Behavioral Therapy for Insomnia (CBT-I) or its variants in humans. ^{3 4 5 6 7}

How is Desensitization Therapy for insomnia (DT-I) different from other treatments for Alzheimer's-related sleep issues?

Desensitization Therapy for insomnia (DT-I) is unique because it focuses on reducing presleep tension and intrusive thoughts, which can help people fall asleep faster and improve daytime functioning. Unlike other treatments, it specifically targets the mental state before sleep, which is particularly beneficial for those with Alzheimer's who experience sleep disturbances. ^{7 8 9 10 11}

What is the purpose of this trial?

Recent findings suggest that sleep disruption may contribute to the generation and maintenance of neuropsychiatric symptoms including anxiety, depression, agitation, irritation, and apathy while treating sleep disruption reduces these symptoms. Impairments in the neural systems that support emotion regulation may represent one causal mechanism mediating the relationship between sleep and emotional distress. However, this model has not yet been formally tested within a sample of individuals with or at risk for developing Alzheimer's Disease (AD) This proposal aims to test a mechanistic model in which sleep disturbance contributes to neuropsychiatric symptoms through impairments in fronto-limbic emotion regulation function in a sample of individuals at risk for developing, or at an early stage of AD. This study seeks to delineate the causal association between sleep disruption, fronto-limbic emotion regulation brain function, and neuropsychiatric symptoms. These aims will be achieved through a mechanistic, randomized 2-arm controlled trial design. 150 adults experiencing sleep disturbances and who also have cognitive impairment with the presence of at least mild neuropsychiatric symptoms will be randomized to receive either a sleep manipulation (Cognitive Behavioral Therapy for Insomnia CBT-I; n=75) or an active control (n=75). CBT-I improves sleep patterns through a combination of sleep restriction, stimulus control, mindfulness training, cognitive therapy targeting dysfunctional beliefs about sleep, and sleep hygiene education. Neuropsychiatric symptoms, fronto-limbic functioning, and sleep disruption will be assessed at baseline and at the end of the sleep manipulation through functional Magnetic Resonance Imaging (fMRI), clinical interviews, PSG recordings, and self-report questionnaires. Neuropsychiatric symptoms (anxiety and depression) and sleep disturbance (actigraphy, Insomnia Severity Index, and sleep diaries) will be assayed at baseline and each week throughout the sleep manipulation to assess week-to-week changes following an increasing number of CBT-I sessions. Wristwatch actigraphy will be acquired from baseline to the end of the sleep manipulation at week 11. Neuropsychiatric symptoms and sleep will be assessed again at six months post-manipulation.

Research Team

Andrea Goldstein-Piekarski

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for adults aged 50-90 with sleep disturbances and mild cognitive impairment or early-stage Alzheimer's, experiencing neuropsychiatric symptoms like anxiety or depression. Participants must live near Stanford University, have stable medication use, and a caregiver to assist them. Exclusions include severe mental health risks, substance abuse, certain medical conditions, previous specific therapies for insomnia within the last year, and unvaccinated individuals.

Inclusion Criteria

Fluent and literate in English

Written, informed consent

My medications, including those for dementia, have been the same for the last 4 weeks.

Exclusion Criteria

I have severe issues with my vision, hearing, or hand movement that could prevent me from following the study's requirements.

If you have had serious thoughts about hurting yourself or have made plans to hurt yourself recently, you cannot participate in the study.

You scored less than 20 on a memory and thinking test called the Mini-Mental State Examination (MMSE).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Cognitive Behavioral Therapy for Insomnia (CBT-I) or Desensitization Therapy for Insomnia (DT-I) over 11 weeks

11 weeks

Weekly sessions

Follow-up

Participants are monitored for neuropsychiatric symptoms and sleep disturbances post-treatment

6 months

Assessment at 6 months post-manipulation

Treatment Details

Interventions

• Cognitive Behavioral Therapy for Insomnia (CBT-I)
• Desensitization Therapy for insomnia (DT-I)

Trial Overview The study tests whether treating sleep problems can improve emotional distress in those at risk of or with early Alzheimer's Disease. It involves two treatments: Desensitization Therapy (DT-I) and Cognitive Behavioral Therapy (CBT-I), which includes mindfulness and sleep hygiene education. The effects on brain function related to emotion regulation will be measured using fMRI scans.

Participant Groups

Group I: Cognitive Behavioral Therapy for Insomina (CBT-I) Experimental Treatment 1 Intervention

CBT-I improves sleep through a combination of behavioral interventions (stimulus control (SC), sleep restriction (SR)), cognitive therapy (CT) as well as additional components such as mindfulness training and sleep hygiene education. SC is an intervention that re-establishes the connection between the bed/bedroom with sleep to help develop a more consistent sleep/wake pattern. SR leads to higher quality sleep by reducing excessive time spent in bed to the actual amount of sleep, thereby creating mild sleep deprivation and increasing the homeostatic sleep drive. Like CT for other disorders, CT for insomnia targets maladaptive thoughts and cognitions that may interfere with sleep.

Group II: Desensitization Therapy for Insomnia (DT-I) Active Control 1 Intervention

DT-I is a quasidesensitization treatment presented as a means of eliminating the "conditioned arousal," which prolongs nocturnal awakenings. DT-I has been validated as an active-placebo control condition. Therapists help each DT-I recipient develop a chronological 12-item hierarchy of common activities he/she does on awakening at night (e.g., opening eyes, clock watching). Therapists also help them develop 6 imaginal scenes of themselves engaged in neutral activities (e.g., reading the newspaper). Each session, DT-I recipients are taught to pair neutral scenes with items on the 12-item hierarchy so, by the end of the sixth session, all hierarchy items have been practiced with therapist assistance. Each session, the exercise is tape recorded and the patient is given this tape locked in a player. The patients are told to practice their exercises at home once each day, no less than 2 hours before bedtime, but to avoid using the tape or exercise during sleep periods.

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

Insomnia is particularly prevalent in Alzheimer's disease patients, requiring careful diagnosis and management due to its complex causes and potential to worsen disease progression.

While nonpharmacological treatments should be prioritized, pharmacotherapy may be necessary, with options like sedating antidepressants and melatonin being used despite limited high-quality evidence, and newer treatments like dual orexin receptor antagonists showing promise but needing further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Pharmacotherapy on Insomnia in Patients with Alzheimer's Disease. Roland, JP., Bliwise, DL.[2022]

The NITE-AD sleep education program significantly improved sleep quality in Alzheimer's disease patients, leading to fewer nighttime awakenings and reduced depression, as evidenced by a randomized controlled trial with 36 participants over 6 months.

Patients in the NITE-AD program maintained their sleep improvements and showed lower daytime sleepiness compared to control subjects, highlighting the effectiveness of behavioral techniques like sleep hygiene education and increased light exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nighttime insomnia treatment and education for Alzheimer's disease: a randomized, controlled trial. McCurry, SM., Gibbons, LE., Logsdon, RG., et al.[2022]

A systematic review of 38 studies found that most current treatments for sleep disturbances in Alzheimer's dementia are ineffective, highlighting a significant gap in effective interventions.

Among non-pharmacological options, bright light therapy (BLT) showed the best results, while pharmacological treatments were inconsistent and often limited by potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of sleep disturbance in Alzheimer's dementia. Salami, O., Lyketsos, C., Rao, V.[2021]

In a clinical trial involving 157 participants with Alzheimer's disease, melatonin did not show significant improvements in objective sleep measures compared to placebo, indicating it may not be an effective treatment for insomnia in this population.

However, there were some nonsignificant trends suggesting potential benefits, particularly with the 2.5-mg slow-release formulation, which showed improvements in caregiver-reported sleep quality without increasing adverse events, suggesting it may be safe for use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Singer, C., Tractenberg, RE., Kaye, J., et al.[2019]

Many patients with Alzheimer's disease experience significant sleep disruptions, which may not only be a symptom of the disease but could also contribute to its progression.

Research suggests that addressing these sleep disturbances could potentially target underlying mechanisms of Alzheimer's, indicating that effective sleep interventions might help modify the disease course, although further large-scale studies are needed to confirm this.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer's disease. Kent, BA., Feldman, HH., Nygaard, HB.[2022]

Patients with Alzheimer's disease often experience disrupted sleep, which can lead to nighttime agitation affecting up to 25% of patients, highlighting the need for effective sleep interventions.

While cholinesterase inhibitors may improve REM sleep, they can also cause insomnia; thus, there is a lack of randomized trials on sedative-hypnotics specifically for Alzheimer's patients, suggesting a need for further research into both pharmacologic and nonpharmacologic treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleep disorders in Alzheimer's disease and other dementias. Bliwise, DL.[2022]

The DREAMS-START program, a non-pharmacological therapy for sleep disturbances in dementia, was found to be feasible and acceptable, with 66% of eligible participants consenting to the study and 88% adhering to the intervention.

This study indicates that a structured approach to addressing sleep issues in dementia, involving family carers and evidence-based strategies, can be effectively implemented, which is crucial given the lack of effective treatments for sleep disturbances in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DREAMS-START (Dementia RElAted Manual for Sleep; STrAtegies for RelaTives) for people with dementia and sleep disturbances: a single-blind feasibility and acceptability randomized controlled trial. Livingston, G., Barber, JA., Kinnunen, KM., et al.[2021]

Intensive Sleep Retraining is a promising behavioral treatment for sleep onset insomnia that can significantly improve symptoms after just one session.

Recent advancements in technology allow this technique to be self-administered at home, potentially enhancing its accessibility and effectiveness as a complementary approach to cognitive-behavioral therapy for insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Wearable Device-Delivered Intensive Sleep Retraining as an Adjunctive Treatment to Kickstart Cognitive-Behavioral Therapy for Insomnia. Bensen-Boakes, DB., Murali, T., Lovato, N., et al.[2023]

Behavioral interventions, including education on sleep hygiene, showed improvements in sleep quantity and efficiency for community-dwelling Alzheimer's disease patients, as evidenced by actigraphic measurements taken over a 2-month period.

One patient maintained sleep improvements at a 6-month follow-up, highlighting the potential long-term benefits of these behavioral strategies in managing sleep disturbances in dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of sleep and nighttime disturbances in Alzheimer's disease: a behavior management approach. McCurry, SM., Logsdon, RG., Vitiello, MV., et al.[2007]

Intensive sleep re-training, a new therapy for chronic insomnia, shows rapid improvements in sleep and daytime functioning, comparable to traditional stimulus control therapy, but completed in just 24 hours during sleep deprivation.

Advancements in smartphone technology now allow this therapy to be more accessible to patients by using behavioral responses to measure sleep/wake states, rather than relying on complex EEG monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive Sleep Re-Training: From Bench to Bedside. Lack, L., Scott, H., Micic, G., et al.[2020]

In a study with 20 subjects, targeting both presleep tension and intrusive cognitions led to a greater reduction in the time it took to fall asleep and daytime impairment compared to focusing on presleep tension alone.

Modifying individuals' perceptions of sleep did not provide additional benefits over treating presleep tension, suggesting that addressing both tension and intrusive thoughts is more effective for improving sleep onset.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Behavioral treatment of presleep tension and intrusive cognitions in patients with severe predormital insomnia. Mitchell, KR.[2019]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Impact of Pharmacotherapy on Insomnia in Patients with Alzheimer's Disease. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Nighttime insomnia treatment and education for Alzheimer's disease: a randomized, controlled trial. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Treatment of sleep disturbance in Alzheimer's dementia. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer's disease. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Sleep disorders in Alzheimer's disease and other dementias. [2022]

7. England pubmed.ncbi.nlm.nih.gov

DREAMS-START (Dementia RElAted Manual for Sleep; STrAtegies for RelaTives) for people with dementia and sleep disturbances: a single-blind feasibility and acceptability randomized controlled trial. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Wearable Device-Delivered Intensive Sleep Retraining as an Adjunctive Treatment to Kickstart Cognitive-Behavioral Therapy for Insomnia. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of sleep and nighttime disturbances in Alzheimer's disease: a behavior management approach. [2007]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Intensive Sleep Re-Training: From Bench to Bedside. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Behavioral treatment of presleep tension and intrusive cognitions in patients with severe predormital insomnia. [2019]