Treatment of Psychosis and Agitation in Alzheimer's Disease
Condition: Alzheimer's Disease; Psychosis; Agitation
MeSH terms: Alzheimer Disease; Psychomotor Agitation; Psychotic Disorders; Mental Disorders
Intervention: Lithium; Placebo
Intervention MeSH terms: Lithium Carbonate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: 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.
Enrollment: 77.0
Sex: All
Healthy volunteers: No
Keywords: Alzheimer's disease; psychosis; agitation; aggression; Lithium; delusions; hallucinations

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.
    

Eligibility 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 (small infarcts, 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.