Repurposed Noradrenergic Drugs Show Small Benefits in Alzheimer Disease Cognition, Apathy


In a meta-analysis spanning 10 studies of 1300 patients with Alzheimer disease, global cognition, as measured by the Mini-Mental State Examination or ADAS-Cog, was improved using noradrenergic drugs.

Paresh Malhotra, MA, BMBCh, PhD, FRCP, Department of Brain Sciences, Imperial College London

Paresh Malhotra, MA, BMBCh, PhD, FRCP

Small positive effects of improved global cognition and apathy were observed in patients with Alzheimer disease (AD) on repurposed noradrenergic drugs, according to a recently published meta-analysis. Notably, because of the variability in results across studies, investigators suggested considering several factors before designing future clinical trials, including targeting appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments.1

The use of noradrenergic drugs had a small, but significant positive impact on global cognition using the Mini-Mental State Examination (MMSE) or Alzheimer’s Disease Assessment Scale–Cognitive Subscale across 10 studies (n = 1300; standardized mean difference [SMD], 0.14; 95% CI, 0.03-0.25; P = .01; I2 = 0%). The apathy meta-analysis included 8 trials and detected a large positive effect of noradrenergic drugs (SMD, 0.45; 95% CI, 0.16-0.73; P = .0002; I2 = 58%), although results were limited by potential heterogeneity.

Senior investigator Paresh Malhotra, MA, BMBCh, PhD, FRCP, Department of Brain Sciences, Imperial College London, and colleagues gathered data from 19 randomized controlled trials (n = 1811) from 1980 to 2021 to assess the efficacy of drugs with principally noradrenergic action and their effects on cognition and neuropsychiatric symptoms in AD. Of the 19 studies, 6 were judged as “good” quality, 7 as “fair” quality, and 6 “poor” quality.

The AD studies were prospective, randomized controlled trials, with treatment duration between 2 and 52 weeks. Each trial ranged from 5 to 346 participants with a mean age between 60 and 85 years old. Norepinephrine reuptake inhibitors (NRIs; 9 studies) were the most common drug class used, followed by α1-AR antagonists (4 studies), α2-AR agonists (3 studies) α2-AR antagonists (2 studies) and ß-AR antagonists/blockers (1 study). The analysis included studies of propranolol, ORM-12741, besipirdine, guanfacine, clonidine, prazosin, mirtazapine, nicergoline, atomoxetine, modafinil, methylphenidate, and buproprion.

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Aside from cognition and apathy, the pooled effects seen did not support any effect of these drugs on agitation (SMD, 0.11; 95% CI, –0.07 to 0.30; P = 0.24; I2 = 0%) or general measures of neuropsychiatric symptoms (SMD, 0.10; 95% CI, –0.09 to 0.30; P = 0.30; I2 = 37%) compared with placebo. Additional meta-regression analysis showed that mean age, sex, duration of treatment, and year of publication were not significantly associated with effect sizes in either global cognition or apathy meta-analyses (P >.05).

On cognitive subdomains, overall pooled effect was not significant for measures of attention (SMD, 0.01; 95% CI, −0.17 to 0.19; P = .91; I2 = 0%), episodic verbal memory (SMD, −0.04; 95% CI, −0.23 to 0.15; P = .71; I2 = 0%), episodic visual memory (SMD, 0.25; 95% CI, −0.16 to 0.65; P = .24; I2 = 49%), executive functions and working memory (SMD, 0.04; 95% CI, −0.24 to 0.32; P = .77; I2 = 51%) and visuospatial abilities (SMD, −0.16; 95% CI, −0.58 to 0.26; P = .45; I2 = 0%). Noradrenergic drugs did have a significant, medium-sized positive effect on semantic memory (SMD, 0.20; 95% CI, 0.01-0.39; P = .04; I2 = 0%); however, this effect was not significant after removal of 4 poor quality studies (SMD, 0.14; 95% CI, –0.13 to 0.41; P = .032; I2 = 38%).

In the "interpretations and implications” section of the study, the investigators emphasized the need assess the variability across studies to plan for future trials. Among those factors, they noted that cognitive performance may be optimal at an intermediate level of noradrenergic tone, in accordance with the Yerkes-Dodson arousal curve and therefore potentially suggesting these treatments are maximally effective only at a specific dose.

In terms of AR agonists and antagonists, Malhotra et al pointed to evidence of multiple effective different treatment strategies. "Recall that some presynaptic receptors are inhibitory on NA release, such that antagonism can paradoxically increase NA neurotransmission. In addition, receptor subtypes can have opposing actions in different locations within the brain. With the inverted–U shape response to noradrenergic stimulation, stimulation and inhibition may be helpful at different stages of illness and for different cognitive or behavioral domains. Further evidence is required to differentiate the effects of individual drugs."

They added, "At present, neither our meta-analysis of global cognition nor apathy, both of which showed positive effects of treatment, included trials evaluating agents that had opposing effects on the same receptor subtype."

Additionally, for future considerations, they noted that the optimal effect of these treatments may not come from one neurotransmitter system. Previous research has suggested that noradrenergic therapies may be most effective when used in tandem with cholinergic approaches.2 Lastly, the study investigators pointed out that clinicians need to weigh the benefits against potential adverse effects, including cardiac risks, especially in people with multimorbidity.

1. David MCB, Del Giovane M, Liu KY, et al. Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. Published online July 5, 2022. doi:10.1136/jnnp-2022-329136
2. Mohs RC, Shiovitz TM, Tariot PN, et al. Atomoxetine augmentation of cholinesterase inhibitor therapy in patients with Alzheimer disease: 6-month, randomized, double-blind, placebo-controlled, parallel-trial study. Am J Geriatr Psychiatry 2009;17:752-759. doi:10.1097/JGP.0b013e3181aad585
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