Managing Agitation in Alzheimer’s Disease: Medical Approaches

Until recently, there was no FDA-approved pharmacologic treatment for agitation in Alzheimer’s disease. Instead, clinicians typically use existing drugs off-label, including antipsychotics, antidepressants, acetylcholinesterase inhibitors (eg, donepezil), and N-methyl D-aspartate (NMDA) antagonist therapy (eg, memantine).¹

However, overuse of antipsychotic medications has been associated with increased mortality in elderly patients with cognitive impairment, resulting in FDA warnings.^3,4

In addition, studies show limited efficacy with pharmacologic therapy, with one systematic review and network meta-analysis finding that nonpharmacologic interventions were generally more effective than off-label pharmacologic interventions.⁵

The first FDA-approved drug for agitation in Alzheimer’s disease, brexpiprazole, is a serotonin–dopamine activity modulator. It works as a partial agonist at the serotonin 5-HT1A and dopamine D2 receptors and as an antagonist at the 5-HT2A receptors.^6,7 It is indicated for treatment on a continuous basis, not as an as-needed treatment.⁷

By acting as a partial agonist at 5-HT1A receptors, brexpiprazole mimics the effects of serotonin to a milder degree, thereby enhancing serotonin transmission, which is associated with improved socialization and fewer aggressive outbursts.^2,8

The partial D2 receptor agonism allows brexpiprazole to stimulate D2 receptors under low dopamine conditions while attenuating their activation when dopamine levels are high. This reduces the potential for adverse effects such as extrapyramidal symptoms. It also prevents overactive dopamine signaling from worsening aggression and irritability.^8,9

As an antagonist at 5-HT2A receptors, brexpiprazole blocks serotonin’s overstimulation of dopamine receptors, which can exacerbate agitation. 5-HT2A antagonism also disinhibits dopamine and norepinephrine release in the prefrontal cortex, enhancing executive control over emotions.^8,9

Therefore, brexpiprazole can rebalance neurotransmitter disruption and restore equilibrium between emotional drives and cognitive control in key brain regions to alleviate agitation in dementia.

Brexpiprazole was approved for use in the treatment of agitation associated with dementia due to Alzheimer’s disease based on two 12-week phase 3 trials in patients with Alzheimer’s disease and agitation.⁷

In the first study, treatment with brexpiprazole 2 mg daily demonstrated a significantly greater improvement in the Cohen-Mansfield Agitation Inventory (CMAI) total scores versus placebo (adjusted mean difference, –3.77; confidence limits, –7.38 to –0.17; t(316) = –2.06; P = .040; mixed model for repeated measures [MMRM]). In a second study, treatment with brexpiprazole ranging from 0.5 to 2 mg daily did not demonstrate superiority over placebo in terms of the CMAI total score change from baseline through week 12; however, a post hoc analysis in patients randomized to brexpiprazole 2 mg daily compared with placebo did show a significant separation of curves and treatment effect on the CMAI total score change primary outcome versus placebo (–5.06; –8.99 to –1.13; t(144) = –2.54; P = .012; MMRM).¹⁰  

In study 2, Clinical Global Impression–severity of illness (CGI-S) scores were significantly improved in patients receiving brexpiprazole at doses ranging from 0.5 to 2 mg daily (–0.31; –0.55 to –0.06; t(222) = –2.42; nominal P = .016; MMRM), but significant improvements in CGI-S scores were not observed in study 1 at the fixed dose of brexpiprazole 2 mg daily. Treatment-emergent adverse events included headache, insomnia, somnolence, dizziness, and urinary tract infection. However, adverse events related to treatment were primarily mild to moderate in severity.¹⁰