Treatment of Psychosis and Agitation in Alzheimer's Disease

NCT02129348 | Completed Phase 2 Results DMC

• 2 other identifiers: #69151R01AG047146-01
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 4

Brief Summary

Clinically, many patients with AD show no response or minimal response to antipsychotics for symptoms of agitation/aggression or psychosis, or they have intolerable side effects on these medications. Antipsychotics have a wide range of side effects, including the risk of increased mortality (60-70% higher rate of death on antipsychotic compared to placebo) that led to an FDA black box warning for patients with dementia; a more recent review and meta-analysis showed a 54% increased risk of mortality. In addition, some patients show only partial response to antipsychotics and symptoms persist. For these reasons, the investigators need to study alternative treatment strategies. Currently, there is no FDA-approved medication for the treatment of psychosis or agitation in AD. The investigators innovative project will examine the efficacy and side effects of low dose lithium treatment of agitation/aggression with or without psychosis in 80 patients with AD in a randomized, doubleblind, placebo-controlled, 12-week trial (essentially a Phase II trial). The results will determine the potential for a large-scale clinical trial (Phase III) to establish the utility of lithium in these patients.

Conditions

Alzheimer's Disease; Psychosis; Agitation

Keywords

Alzheimer's disease; psychosis; agitation; aggression; Lithium; delusions; hallucinations

Outcome Measures

Primary Outcomes (1)

• Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score

  Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain is the measure used that combines symptoms of agitation and aggression. Frequency X Severity rating score, range 0-12. Minimum score is 0, maximum score is 12. Higher score is a worse outcome and indicates more agitation and aggressive behavior.

  Assessed at screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12

Secondary Outcomes (7)

• Clinical Responder Defined as a 30% Decrease in NPI Core Score (Sum Score of NPI Domains of Agitation/Aggression, Delusions and Hallucinations) Together With a Clinical Global Impression (CGI) Behavior Change Score of 1 or 2

  Week 12

• Clinical Global Impression (CGI) Behavior Change

  Week 12

• Young Mania Rating Scale

  Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12

• Treatment Emergent Signs and Symptoms

  Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12

• Simpson-Angus Scale

  Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12

Other Outcomes (2)

• Folstein Mini-Mental Status Exam

  Assessed at Screening, Week 12

• Severe Impairment Battery

  Assessed at Week 0, Week 12

Study Arms (2)

Lithium Treatment Group

ACTIVE COMPARATOR

The patient will be started on lithium 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on lithium blood level. Blood will be drawn at each study visit. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced.

Drug: Lithium

Placebo Group

PLACEBO COMPARATOR

The patient will be started on placebo 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on sham lithium blood level. Blood will be drawn for sham lithium levels at weeks 2, 4, 6, 8, and 12. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced.

Drug: Placebo

Interventions

Lithium DRUG

Also known as: lithium carbonate

Lithium Treatment Group

Placebo DRUG

Placebo Group

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female adults.
• Diagnosis of possible or probable AD by standard NIA criteria (McKahnn et al, 1984; McKhann et all, 2011)
• Folstein MMSE 5-26 out of 30
• Neuropsychiatric Inventory (NPI) agitation/aggression subscale score \> 4. On each subscale (frequency X severity), a score higher than 4 represents moderate to severe symptoms.
• Female patients need to be post-menopausal
• Availability of informant; patients without an informant will not be recruited. Patients who lack capacity must have a surrogate.

You may not qualify if:

• Medical contraindication to lithium treatment or prior history of intolerability to lithium treatment.
• Contraindications to lithium in this study include: resting tremor causing functional impairment, history of falls in the last month, untreated thyroid disease or any abnormal thyroid function test (T3, T4, or TSH), creatinine level greater than 1.5 mg/100ml or a glomerular filtration rate less than 44ml/min/ 1.73m2; blood pressure \> 150/90 mm Hg; heart rate \< 50 bpm; unstable cardiac disease based on history, physical examination, and ECG.
• Medications, in combination with lithium, known to have adverse renal effects, including therapeutic or higher doses of diuretics, i.e. hydrochlorothiazide greater than 25mg daily or furosemide greater than 10mg daily. Whenever feasible, patients receiving concomitant antidepressants or antipsychotics will be washed off these medications for at least 24 hours before starting lithium. Patients who do not wish to discontinue antipsychotics or antidepressants, typically because of family member/caregiver objection, will be allowed to enter the trial provided there is no contraindication to concomitant lithium use with that specific psychotropic medication. During the trial, patients will be permitted to receive lorazepam as needed up to 1 mg/day for anxiety/insomnia, and non-benzodiazepine hypnotics, e.g., zolpidem.
• Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, or bipolar 1 disorder (DSM-IV TR criteria).
• Current or recent (past 6 months) alcohol or substance dependence (DSM-IV TR criteria).
• Current major depression or suicidality as assessed by the study psychiatrist.
• Suicidal behavior or dangerous behavior with serious safety risk or risk of physical harm to self or others.
• Parkinson's disease, Lewy body disease, multiple sclerosis, CNS infection, Huntington's disease, amyotrophic lateral sclerosis, other major neurological disorder.
• Hypernatremia as determined by serum sodium level \> 150 meq/L.

Sponsors & Collaborators

• New York State Psychiatric Institute: lead
• National Institute on Aging (NIA): collaborator

Study Sites (4)

University of Miami Miller School of Medicine

Miami, Florida, 33136, United States

Location

McLean Hospital

Belmont, Massachusetts, 02478, United States

Location

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75235, United States

Location

Related Publications (26)

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  PMID: 37732619 DERIVED

• Devanand DP, Crocco E, Forester BP, Husain MM, Lee S, Vahia IV, Andrews H, Simon-Pearson L, Imran N, Luca L, Huey ED, Deliyannides DA, Pelton GH. Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial. Am J Geriatr Psychiatry. 2022 Jan;30(1):32-42. doi: 10.1016/j.jagp.2021.04.014. Epub 2021 May 12.

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• Devanand DP, Strickler JG, Huey ED, Crocco E, Forester BP, Husain MM, Vahia IV, Andrews H, Wall MM, Pelton GH. Lithium Treatment for Agitation in Alzheimer's disease (Lit-AD): Clinical rationale and study design. Contemp Clin Trials. 2018 Aug;71:33-39. doi: 10.1016/j.cct.2018.05.019. Epub 2018 May 31.

  PMID: 29859917 DERIVED

Related Links

• Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial

MeSH Terms

Conditions

Alzheimer Disease; Psychotic Disorders; Psychomotor Agitation; Aggression; Delusions; Hallucinations

Interventions

Lithium; Lithium Carbonate

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Dyskinesias; Neurologic Manifestations; Psychomotor Disorders; Neurobehavioral Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior; Social Behavior; Perceptual Disorders

Intervention Hierarchy (Ancestors)

Metals, Alkali; Elements; Inorganic Chemicals; Metals, Light; Metals; Carbonates; Alkalies; Carbonic Acid; Carbon Compounds, Inorganic; Lithium Compounds

Results Point of Contact

• Title: Davangere Devanand, MD
• Organization: New York State Psychiatric Institute

dpd3@cumc.columbia.edu

646.774.8656

Study Officials

• DP Devanand, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Patients were randomized to lithium or placebo, 1:1, stratified by site, for 12 weeks. Randomization, developed by the statistician and executed by the NYSPI pharmacy, was stratified within each site by the presence of psychosis (NPI score ≥4 on delusions or hallucinations) with randomization sequences balanced in blocks of four. All study personnel and patients were masked to treatment assignment. After the final study visit, a psychiatrist independent of the study was unmasked and clinically treated the patient while study personnel remained blind.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Clinical Psychiatry and Neurology

Model Details: Participants were outpatients and recruited primarily from memory clinics and physician referrals at all four sites. Salient inclusion criteria were a diagnosis of possible or probable Alzheimer's disease by National Institute on Aging (NIA) criteria, score ≥4 on the Neuropsychiatric Inventory (NPI) domain score for agitation/aggression, Folstein Mini Mental State Exam (MMSE) range 5-26, and availability of an informant. Patients with current major depression or suicidality, alcohol/substance dependence in the prior 6 months, bipolar or other psychotic disorder, and specific neurological disorders were excluded.

Study Record Dates

• First Submitted: April 29, 2014
• First Posted: May 2, 2014
• Study Start: June 1, 2014
• Primary Completion: January 1, 2020
• Study Completion: January 1, 2020
• Last Updated: May 2, 2024
• Results First Posted: August 16, 2021

Record last verified: 2024-04

Locations

US (4)