By Makoto Ishii, MD, PhD
Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College
This meta-analysis provides evidence that drugs modulating the noradrenergic system could be effective in treating cognitive symptoms and apathy in patients with Alzheimer’s disease.
David MCB, Del Giovane M, Liu KY, et al. Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: Systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2022; Jul 5:jnnp-2022-329136. doi: 10.1136/jnnp-2022-329136. [Online ahead of print].
Since current medications based on modulation of cholinergic and glutamatergic systems have modest symptomatic benefit for Alzheimer’s disease (AD) patients, there is a large, unmet need to develop drugs that provide more meaningful symptomatic relief. One possible therapeutic target is the neurotransmitter noradrenaline or norepinephrine. Several lines of evidence suggest that noradrenergic neurons originating from the locus coeruleus, which are responsible for the synthesis and release of noradrenaline, are targeted early in AD. Since noradrenaline has a critical role in arousal and cognition, the loss of the locus coeruleus and noradrenergic signaling likely is contributing to the cognitive and neuropsychiatric symptoms of AD.
In this meta-analysis, David and colleagues sought to assess the current evidence for the extent to which drugs modulating the noradrenergic system have a therapeutic benefit in AD. The authors searched MEDLINE, Embase, and clinicaltrials.gov from 1980 to 2021 to identify clinical trials of agents modulating the noradrenergic system in neurodegenerative diseases.
Inclusion criteria included peer-reviewed, placebo-controlled, prospective trials with drugs that acted principally on noradrenergic action. Drugs, such as trazodone and olanzapine, that have slight noradrenergic actions that are thought to be of secondary significance compared to their effects on other neurotransmitter systems, were excluded. Monoamine oxidase type-A inhibitors, but not type-B inhibitors, were included because of the potency of type-A inhibitors to elevate noradrenaline in the brain. Methylphenidate and mirtazapine both were included because of their significant effects on noradrenergic systems.
Out of 2,778 records identified through the three databases, 19 eligible AD and mild cognitive impairment (MCI) records were included for the final analysis. The most common drugs used in these studies were the norepinephrine reuptake inhibitors (nine studies), α1-adrenergic receptor antagonists (four studies), α2-adrenergic receptor antagonists (two studies), and β-adrenergic antagonists/blockers (one study). Although all eligible studies were included in the analysis, the study quality varied, with six studies of “good” quality, seven of “fair” quality, and six of “poor” quality.
Analyzing the 10 AD studies that assessed changes in global cognition from baseline, the overall pooled effect showed a small but significant positive effect of the noradrenergic drug compared with placebo (standardized mean difference [SMD], 0.14; 95% confidence interval [CI], 0.03 to 0.25; P = 0.01; I2 = 0%). Similar results were obtained after removing “poor” quality studies. Compared to cholinesterase inhibitors, the effect size of noradrenergic drugs on global cognition was between the effects of cholinesterase inhibitors in AD (SMD, 0.38; 95% CI, 0.28 to 31.1; I2 = 41.1%) and MCI (SMD, 0.06; 95% CI; -0.08 to 0.20; I2 = 76%).
When the various cognitive subdomains (e.g., semantic memory, episodic verbal memory, episodic visual memory, executive functions and working memory, and visuospatial abilities) were examined, the overall pooled effects of noradrenergic drugs compared with placebo were not significant after the removal of “poor” quality studies. Analyzing the eight studies that assessed apathy, there was a large positive effect of noradrenergic drugs (SMD, 0.45; 95% CI, 0.16 to 0.73; P = 0.003; I2 = 58%) that persisted and increased slightly after removing one study identified as an outlier and two “poor” quality studies (SMD, 0.49; 95% CI, 0.10 to 0.88; P = 0.01; I2 = 69%).
There was no significant overall pooled effect of noradrenergic drugs on agitation or general measures of neuropsychiatric symptoms compared with placebo.
COMMENTARY
This meta-analysis provides good evidence to suggest that drugs acting primarily on the noradrenergic system could be beneficial for the cognitive symptoms and apathy seen in AD. Limitations to this study include the diversity of drugs examined without any fixed pharmacokinetic or pharmacodynamic metrics for selecting which drug to include in the analysis, the different measures used for the same outcome across the studies, and the lack of modeling baseline performance or symptom severity that may contribute to variation in treatment response. Despite any limitations of this meta-analysis, this study reinforces the need for additional well-designed large Phase III clinical trials investigating the therapeutic effects of noradrenergic drugs in AD.
However, designing the optimal clinical trial may be challenging. The drugs investigated in this meta-analysis are diverse and included those with different mechanisms to modulate the noradrenergic system in addition to possibly having significant secondary effects on other neurotransmitter systems. Furthermore, the noradrenergic system is complex, with receptor subtypes having opposing actions depending on the locations within the brain. This may contribute to an inverted U-shape response to noradrenergic stimulation. Therefore, identifying the “optimal” noradrenergic drug and dose to test for future clinical studies is non-trivial.
The outcome measures also must be carefully selected. Based on this meta-analysis, global cognition and apathy should be assessed. Despite the negative findings in this meta-analysis, other cognitive domains and neuropsychiatric symptoms merit consideration as well. Finally, potential adverse effects, such as on the cardiovascular system, of noradrenergic drugs must be weighed against any beneficial effects, highlighting the need to develop appropriate eligibility criteria and the careful selection and screening of trial participants. Although designing and implementing the necessary clinical trials will be challenging, if successful, adding a therapeutic agent that can significantly ameliorate the symptoms of AD likely will lead to meaningful improvement in the quality of life for patients and their loved ones.
