Background

Aripiprazole is an antipsychotic medication that was FDA-approved in 2002 for the treatment of schizophrenia and is widely used for related affective disorders, as well. Generic versions started becoming available in 2015. 

This drug affects multiple receptors, acting as a partial agonist at dopamine and serotonin 1A receptors, and an antagonist at serotonin 2A, α 1 adrenergic, and other receptors. 

Aripiprazole has been investigated for its effects on psychosis in patients with moderate to advanced AD, and is currently being investigated for agitation in this population. In the 1990s and early 2000s, several different atypical antipsychotics drugs were being widely prescribed to AD patients to alleviate their symptoms of psychosis and agitation, particularly in nursing homes. Soon after aripiprazole's approval, studies reported increased mortality, stroke, and faster cognitive decline, and meta-analyses reported this to be a class effect of both typical and atypical antipsychotics in this population, triggering an FDA warning (see Oct 2005 news). This led to calls for more research on treatment options for psychosis and agitation in AD (e.g. Ballard and Corbett, 2010). Aripiprazole is among the newer antipsychotic drugs with a lower side effect profile (De Deyn et al., 2013). 

Findings

Clinicaltrials.gov lists two Phase 3 studies on aripiprazole in psychosis in AD as having been conducted prior to the 2005 FDA warning. They were not randomized controlled trials (RCT), and dose and patient number is not listed. One Phase 3 RCT on 232 AD patients was conducted over a period of 10 years starting in 2000, evaluating doses ranging from 1 to 15 mg in an acute phase of 10 weeks plus an extension phase of 2.5 years. Results from this trial are posted on clinicaltrials.gov, and show no statistically significant difference on the primary outcome, the NPI.

In 2007, a peer-reviewed paper of a multicenter RCT not listed in clinicaltrials.gov reported 5 and 10 mg of aripiprazole to be safe and somewhat effective at reducing psychosis in Alzheimer's dementia (Mintzer et al., 2007). A subsequent paper reported that the drug did not improve psychotic symptoms but did improve psychological and behavioral symptoms such as agitation, anxiety, and depression in an RCT conducted in 256 nursing home residents with Alzheimer's dementia (Streim et al., 2008).

Between 2003 and 2005, Otsuka conducted a Phase 3 study comparing the tolerability of injecting aripiprazole solution or placebo intramuscularly during acute episodes of agitation in 129 patients with Alzheimer's or vascular or mixed dementia. This study was conducted in nursing homes in the United States, and reported to have shown both more side effects and more efficacy with aripiprazole injections than placebo (Rappaport et al., 2009).

Following the FDA warning, in August 2005 Otsuka started a Phase 4, five-year, open-label study at the University of California, San Diego, comparing side effects of aripiprazole, olanzapine, and risperidone in 406 people with a DSM-IV diagnosis that requires treatment with an antipsychotic medication. 

In June 2014, Otsuka started a Phase 3 trial in Japan enrolling 880 people with a clinical diagnosis of AD and an MMSE of between 1 and 22. The study compares a 10-week course of once-daily doses of 2, 3, or 6 mg aripiprazole or placebo for change from baseline on the Cohen Mansfield Agitation Inventory. The trial is set to run until July 2017. 

For all trials of aripiprazole in Alzheimer's dementia, see clinicaltrials.gov.