Treatment of Psychosis and Agitation in Alzheimer's Disease

Symptoms of psychosis or agitation are common in Alzheimer's disease. These symptoms are
associated with distress for the patient, an increased burden for caregivers, more rapid
cognitive decline, greater risk of institutionalization and mortality, and increased health
care costs. In a recent meta-analysis, caregiver education and behavior modification studies
revealed a small to medium effect size in treating agitation in these patients. However, none
of these studies were double-blind (difficult to achieve in such studies) and none had a
control group that received the same amount of staff time as the intervention group, thereby
biasing the results toward the active intervention.

Among the psychotropic medications that have been studied, only antipsychotics have shown
superiority over placebo for the treatment of psychosis and agitation in patients with
dementia.

However, most studies show only moderate superiority for antipsychotic over placebo and a few
studies have been negative. The side effects of antipsychotic medications include sedation,
extrapyramidal signs, tardive dyskinesia, weight gain, and the metabolic syndrome. A pooled
analysis from 17 short-term trials showed that the mortality rate in patients with dementia
receiving antipsychotic medications was 1.6 to 1.7 times as high (60-70% increase in
mortality rate) as the mortality rate in patients receiving placebo. These findings led the
FDA to issue a black-box warning for antipsychotic medication use in patients with dementia;
a more recent meta-analysis reported a slightly lower odds ratio of 1.54 (54% increase in
mortality rate).

Lithium has several different actions from anticonvulsants, though both are effective in
bipolar disorder, especially mania. Lithium is not being proposed here to treat mania in AD
though the investigators will monitor symptoms on the Young Mania Rating Scale. In patients
with AD, lithium has been studied for its putative cognitive enhancing effects. A few reports
suggest that chronic lithium use reduces the risk of dementia, but other data show increased
dementia risk with lithium use. A placebo-controlled, single-blind lithium trial showed no
cognitive effects in patients with AD, but a recent trial of lithium in 45 patients with mild
cognitive impairment (MCI, which often leads to clinically diagnosable AD) showed a small
advantage for lithium (n=24) over placebo (n=21) in attention and other cognitive domains.
None of these studies with lithium were intended to treat psychosis or agitation in AD, and
patients with these symptoms typically were excluded in these clinical trials.

There has been no systematic placebo-controlled trial of lithium to treat
agitation/aggression with or without psychosis in AD even though lithium is a highly
effective treatment for mania with psychosis and symptoms of agitation or aggression.
Nonetheless, the published studies of lithium to treat cognitive decline in older patients
show that low-dose lithium is safe in patients with MCI or AD.

Specific Aims and Hypotheses Specific Aim 1. To compare changes in agitation/aggression with
or without psychosis in patients with AD who receive 12 weeks of randomized, double-blind
treatment with lithium or placebo.

Primary Hypothesis. Over these 12 weeks, the agitation/aggression domain score on the
Neuropsychiatric Inventory (NPI) will decrease significantly more on lithium than placebo.

Secondary Hypothesis. Over these 12 weeks, the proportion of responders on lithium will be
significantly greater than the proportion of responders on placebo. Response is defined as a
30% decrease in NPI core score (defined as the sum of domains for agitation/aggression,
delusions and hallucinations) plus a CGI Change score of much improved or very much improved
(CGI based on these behavioral symptoms only). Exploratory hypothesis. Over these 12 weeks,
the psychosis score, measured by the sum of the NPI domain scores for delusions and
hallucinations, will decrease significantly more on lithium than placebo. Specific Aim 2. To
evaluate the tolerability of low dose lithium by assessing emergent somatic side effects over
the course of the 12-week trial on lithium compared to placebo. Specific Aim 3. To explore
associations between improvement on lithium (decrease in agitation/aggression and psychosis
scores) and serum brain-derived neurotrophic factor (BDNF) levels (baseline, 12 weeks), a SNP
in intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus, because these indices
are associated with lithium response in bipolar disorder. The investigators do not postulate
a specific mechanism of action for lithium in the investigators trial, but will evaluate
these three potential predictors of lithium response with the aim of improving patient
selection for personalized treatment. The investigators will examine BDNF serum levels as a
biomarker correlate of lithium treatment by correlating change in BDNF levels with change in
NPI agitation/aggression and psychosis scores.

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.