Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Treatment of Psychosis and Agitation in Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02129348
Recruitment Status : Completed
First Posted : May 2, 2014
Last Update Posted : April 29, 2020
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Davangere P. Devanand, New York State Psychiatric Institute

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.


Condition or disease Intervention/treatment Phase
Alzheimer's Disease Psychosis Agitation Drug: Lithium Drug: Placebo Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 77 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Treatment of Psychosis and Agitation in Alzheimer's Disease
Study Start Date : June 2014
Actual Primary Completion Date : January 2020
Actual Study Completion Date : January 2020


Arm Intervention/treatment
Active Comparator: Lithium Treatment Group

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
Other Name: lithium carbonate

Placebo Comparator: Placebo Group

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



Primary Outcome Measures :
  1. Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression domain score [ Time Frame: Screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Assessment used to examine behavioral disturbances in patients with dementia. Each behavior is assessed for frequency and severity.


Secondary Outcome Measures :
  1. Change in NPI core score defined as sum score of NPI domains of agitation/aggression, delusions and hallucinations, with response defined as ≥ 30% in this score and a CGI Behavior change score of 1 or 2 (much or very much improved). [ Time Frame: Screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Used to assess a patient's overall behavior prior to, and after taking the study medication (Lithium or placebo).

  2. Clinical Global Impression (CGI) Behavior [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Assessment used to determine changes in the patients behavior prior to, and after beginning study medication (Lithium or placebo).

  3. Young Mania Rating Scale [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Used to assess manic symptoms experienced by the patient in the prior two days. Each mania item on the scale is rated for severity.

  4. Treatment Emergent Signs and Symptoms (TESS) [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Scale used to assess if symptoms not present at screening emerge after treatment begins. Each symptom is assigned a "yes" or "no" response based on patient and caregiver report.

  5. Simpson-Angus Scale [ Time Frame: Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 ]
    Five point scale used to assess pseudoparkinsonism in patients. Symptoms assess include gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation.

  6. Basic Activities of Daily Living (BADL) [ Time Frame: Week 4, Week 8, Week 10, Week 12 ]
    Assesses if the patient can perform six basic ADLs on his own. These include bathing, dressing, toileting, transferring, continence, and feeding.

  7. Zarit Caregiver Burden Interview [ Time Frame: Week 0, Week 4, Week 8, Week 10, Week 12 ]
    Twenty-two item questionnaire, where the caregiver is asked to rank statements on a 5-point scale (never to nearly always).

  8. Clinical Dementia Rating Scale (CDR) [ Time Frame: Week 0, Week 12 ]
    Scale used to rate the severity of dementia symptoms raging from 0-3.


Other Outcome Measures:
  1. Folstein Mini-Mental Status Exam [ Time Frame: Screening, Week 12 ]
    30 item questionnaire used to assess degree of cognitive impairment. Orientation, registration, attention/calculation, recall, language, repetitions and commands are assessed,

  2. Severe Impairment Battery [ Time Frame: Week 0, Week 12 ]
    Neuropsychological test used to assess a patient's cognitive ability. The patient is asked to complete small tasks such as drawing shapes and printing their name. They are also asked to remember certain names and objects, such as a cup and a spoon, and the evaluator's first name.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  1. 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.

  2. 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.
  3. Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, or bipolar 1 disorder (DSM-IV TR criteria).
  4. Current or recent (past 6 months) alcohol or substance dependence (DSM-IV TR criteria).
  5. Current major depression or suicidality as assessed by the study psychiatrist.
  6. Suicidal behavior or dangerous behavior with serious safety risk or risk of physical harm to self or others.
  7. Parkinson's disease, Lewy body disease, multiple sclerosis, CNS infection, Huntington's disease, amyotrophic lateral sclerosis, other major neurological disorder.
  8. Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (smallinfarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion.
  9. Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases will be excluded, but past history of successfully treated cancer will not lead to exclusion.
  10. QTc interval > 460 ms at the time of baseline EKG is an exclusion criterion for treatment.
  11. Hypernatremia as determined by serum sodium level > 150 meq/L.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02129348


Locations
Layout table for location information
United States, Florida
University of Miami Miller School of Medicine
Miami, Florida, United States, 33136
United States, Massachusetts
McLean Hospital
Belmont, Massachusetts, United States, 02478
United States, New York
New York State Psychiatric Institute
New York, New York, United States, 10032
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75235
Sponsors and Collaborators
New York State Psychiatric Institute
National Institute on Aging (NIA)
Investigators
Layout table for investigator information
Principal Investigator: DP Devanand, MD Columbia University

Publications:
Haddad P, Wieck A, Yarrow M, Denham P. 1999. The Lithium Side Effects Rating Scale (LISERS); development of a self-rating instrument. Eur Neuropsychopharmacol 9(s5): 231-232.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Davangere P. Devanand, Professor of Clinical Psychiatry and Neurology, New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT02129348    
Other Study ID Numbers: #6915
1R01AG047146-01 ( U.S. NIH Grant/Contract )
First Posted: May 2, 2014    Key Record Dates
Last Update Posted: April 29, 2020
Last Verified: April 2020
Keywords provided by Davangere P. Devanand, New York State Psychiatric Institute:
Alzheimer's disease
psychosis
agitation
aggression
Lithium
delusions
hallucinations
Additional relevant MeSH terms:
Layout table for MeSH terms
Alzheimer Disease
Psychomotor Agitation
Psychotic Disorders
Mental Disorders
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Dyskinesias
Neurologic Manifestations
Psychomotor Disorders
Neurobehavioral Manifestations
Signs and Symptoms
Lithium Carbonate
Antidepressive Agents
Psychotropic Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs