Treatment of Psychosis and Agitation in Alzheimer’s Disease

Investigator: Elizabeth Crocco

Institutional Protocol #: 20150554

National Clinical Trials Identifier: NCT02129348

Funding Agency/Sponsor: National Institute on Aging

Division: Psychiatry

Therapeutic Area: Other

Phase: Phase II

Enrolling Sites: University of Miami Medical Group

Enrolling Since: 1/25/2016


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

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.,

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

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

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

11. Hypernatremia as determined by serum sodium level > 150 meq/L.

Gender: All

Minimum Age: N/A

Maximum Age: N/A

Accepts healthy volunteers: No

Please note that this is written for scientific review, and if there are any questions or clarifications needed, please contact

Belinda Robertson, Clinical Research Coordinator
(305) 243 2891


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