Clinical trial NCT02129348: Treatment of Psychosis and Agitation in Alzheimer's Disease
Official title: Treatment of Psychosis and Agitation in Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Psychosis
Agitation
Keywords: Alzheimer's disease
psychosis
agitation
aggression
Lithium
delusions
hallucinations
Lead sponsor: New York State Psychiatric Institute
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2014-05-02
Enrollment: 77
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Detailed description: 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.

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.

Primary outcomes:
measure: Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score
timeFrame: Assessed at screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
Secondary outcomes:
measure: 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
timeFrame: Week 12
measure: Clinical Global Impression (CGI) Behavior Change
timeFrame: Week 12
measure: Young Mania Rating Scale
timeFrame: Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
measure: Treatment Emergent Signs and Symptoms
timeFrame: Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
measure: Simpson-Angus Scale
timeFrame: Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
measure: Basic Activities of Daily Living (BADL)
timeFrame: Assessed at Week 0, Week2, Week 4, Week 6, Week 8, Week 10, Week 12
measure: Zarit Caregiver Burden Interview
timeFrame: Assessed at Week 0, Week 4, Week 8, Week 10, Week 12
Other outcomes:
measure: Folstein Mini-Mental Status Exam
timeFrame: Assessed at Screening, Week 12
measure: Severe Impairment Battery
timeFrame: Assessed at Week 0, Week 12
Locations:
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Belmont
country: United States
facility: McLean Hospital
state: Massachusetts
city: New York
country: United States
facility: New York State Psychiatric Institute
state: New York
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: Columbia University
name: DP Devanand, MD
role: PRINCIPAL_INVESTIGATOR
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