Clinical trial NCT02862210: Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia
Official title: Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Frontotemporal Dementia (FTD)
Keywords: Lithium
Lithium Carbonate
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Alzheimer's Drug Discovery Foundation
First posted: 2016-08-10
Enrollment: 17
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Frontotemporal dementia (FTD) is a progressive neurodegenerative illness that affects the frontal and anterior temporal lobes of the brain. Changes in behavior, including agitation, aggression, and repetitive behaviors, are common symptoms in FTD. The investigators currently do not have good medications to treat these symptoms in FTD, and the medications the investigators use often have side effects. In this project, the investigators will test the use of low-dose lithium, compared to a placebo pill, for the treatment of behavioral symptoms in FTD. Lithium greatly reduces the behavioral symptoms of bipolar disorder, and many have found low-dose lithium to be well-tolerated in patients with dementia. Lithium appears to inhibit the creation of a protein involved in many cases of FTD called tau.

Detailed description: Behavioral symptoms of Frontotemporal dementia (FTD), including agitation, aggression, and inappropriate repetitive behaviors are common, distressing to patients and caregivers, often lead to institutionalization, and can be very difficult and expensive to treat. There is a dearth of medication for treating these symptoms in FTD. Typically, antidepressants and antipsychotic medications are prescribed - which low efficacy and, with the latter class, carry serious adverse effects such as parkinsonism and increased cardiovascular-related mortality. The investigators propose a study of the efficacy of lithium carbonate compared to placebo in the treatment of agitation, aggression, and inappropriate repetitive behaviors in 60 patients with FTD in a randomized, double-blind, two-arm parallel 12-week trial. Lithium is a highly effective treatment for mania and symptoms of agitation or aggression in bipolar disorder. It also inhibits tau aggregation and phosphorylation, leading to considerable interest in its use as a disease-modifying treatment for tauopathies such as FTD and Alzheimer's disease. Unfortunately, earlier trials using typical doses (i.e., doses prescribed for treatment of bipolar disorder) showed high incidence of serious adverse effects (including confusion and delirium). For this proposed study the investigators will: 1) use lower doses and lower target serum concentrations than have preceding trials (shown in preliminary data from a Columbia study and data from other labs to be well-tolerated) and 2) target behavioral symptoms rather than cognitive outcomes.

Eligibility criteria: Inclusion Criteria:

* Age 40-85
* A diagnosis of behavioral variant FTD (bv-FTD) or semantic variant Primary Progressive Aphasia (sv-PPA, which is generally accompanied by a behavioral syndrome), or agrammatic/non-fluent Primary Progressive Aphasia (nfv-PPA) with behavioral symptoms
* Neuropsychiatric Inventory (NPI) agitation/aggression subscale score ≥4 or disinhibition subscale score ≥ 4 or repetitive behavior subscale ≥ 4 or total score ≥ 6. On each subscale, a score higher than 4 represents moderate to severe symptoms
* Folstein Mini-Mental State Examination (MMSE) score 5-26/30
* An study partner (usually a family member) is required to provide information during interviews about the patient
* Capacity to consent. Subjects without capacity to consent must have capacity to appoint a surrogate
* Structural MRI or CT scan after symptom onset

Exclusion Criteria:

* Medical contraindication or history of intolerability to lithium, falls in the last month, current abnormal thyroid functions (T3, T4 or thyroid stimulating hormone (TSH); treated hypothyroidism with normal thyroid function tests will not lead to exclusion), creatinine level \> 1.5 mg/100 ml or glomerular filtration rate \< 44 ml/min/1.73m2 will also lead to exclusion
* The diagnosis of bipolar disorder or schizophrenia or schizoaffective disorder
* Alcohol or substance use disorder in the prior 6 months
* Current diagnosis of other major neurological disorder, e.g., Alzheimer's Disease (AD), stroke with residual clinical deficits, multiple sclerosis, Parkinson's disease. Subjects with MRI or CT evidence of cerebrovascular disease but without clinical signs of stroke will be included
* Sitting blood pressure \> 150/90 mm Hg, unstable cardiac disease, severe or unstable medical illness
* Use of medications, including diuretics, known to have adverse effects when combined with lithium. Use of antipsychotic medications will be permitted
* Current major depression or suicidality or dangerous behavior with risk of harm to self and others
* Corrected QT interval (QTc) interval \> 460 ms at the time of baseline electrocardiogram (EKG)
* Woman of child-bearing potential

Primary outcomes:
measure: Change in Agitation and Aggression as Measured by the Neuropsychiatric Inventory Scale (NPI)
timeFrame: 12 weeks
Secondary outcomes:
measure: Number of Responders in the Lithium and Placebo Groups
timeFrame: 12 weeks
Other outcomes:
measure: Change in Motor Symptoms as Measured by the NPI
timeFrame: 12 weeks
measure: Presence of Adverse Events as Measured by the Treatment Emergent Symptoms Scale (TESS)
timeFrame: 12 weeks
measure: The Relationship Between Changes in Brain-derived Neurotropic Factor (BDNF) Serum Levels and Changes in NPI "Agitation/Aggression" Score
timeFrame: Baseline and 12 weeks
measure: The Relationship Between Changes in Brain-derived Neurotropic Factor (BDNF) Serum Levels and Changes in NPI "Aberrant Motor Behavior" Score
timeFrame: Baseline and 12 weeks
Locations:
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
Study officials:
affiliation: Brown University
name: Edward Huey, MD
role: PRINCIPAL_INVESTIGATOR
References: