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The Director of the University of Rochester Alzheimer's Disease Care, Research and Education Program discussed the landscape of care in Alzheimer symptom management.
Anton P. Porsteinsson, MD
Anton P. Porsteinsson, MD, the Director of the University of Rochester Alzheimer's Disease Care, Research and Education Program, sat with NeurologyLive to discuss a multitude of topics surrounding his research and the state of care for Alzheimer disease.
The discussion included an overview of the currently ongoing s-CitAD study, which Porsteinsson noted is also somewhat of an attempt to address clinical trial design—intentionally seeking patients from a cohort more reflective of the real world. He also spoke about the prevalence of psychiatric symptoms in Alzheimer disease, and what’s in the pipeline for the treatment of agitation, specifically.
NeurologyLive: Could you tell us about the s-CitAD study, its design, and how it came about?
Anton P. Porsteinsson, MD: The s-CitAD study stands for s-citalopram for the treatment of agitation in dementia, and we’re particularly focusing on Alzheimer disease. It is based on a previous study that we did with citalopram in patients with Alzheimer disease that were agitated that showed a meaningful efficacy but had some tolerability issues. When we looked at the details of that study, we found that citalopram has 2 isomers, r-citalopram and s-citalopram—which is the active component.
For the citalopram study it appeared that the side effects we saw—QT prolongation and slight decreases in the scores on the MMSE—were associated with the r-citalopram isomer, but the benefits, in terms of reduced agitation and reduced other psychiatric symptoms, were associated with the s-citalopram active isomer of citalopram.
So, we looked at that data and applied to the NIA and got funding for a study looking at s-citalopram, but we’re also using that study to understand more the impact of a simple, straightforward, psychosocial intervention on people with agitation.
The s-CitAD study starts with a 3-week lead-in, where we do a psychosocial intervention in patients with Alzheimer disease who have a moderate-to-severe form of agitation, according to the International Psychiatric Association’s agitation in Alzheimer disease criteria. Those that qualify for the study get a psychosocial intervention and we observe them for 3 weeks. Those that improve on the psychosocial intervention alone get transferred to an observational cohort that we follow, and those that do not improve are then randomized to either s-citalopram or placebo.
The double-blind phase is 12 weeks, where we compare placebo to 15 mg daily of s-citalopram. At the week 12 visit, once all the outcome measures are completed, we actually unblind the treatment, and based on the information in the unblinding, the site PI can decide how to treat each participant for the next 12 weeks.
What we hope to answer here is basically: Is s-citalopram beneficial in patients with agitation and Alzheimer, who are the patients that are more likely to respond to s-citalopram versus placebo, who are the patients that are going to respond to a non-pharmacological intervention—to the psychosocial intervention—how long does that effect last, and what’s the scope or degree of improvement with a non-pharmacological intervention that’s the type of intervention that you can actually apply in clinical practice.
And when is the study set to get underway?
AP: The study has started. We recruited the first participant 12 weeks ago, and we have about 25 sites that are ultimately going to be participating in this study. We have 10 of them up and going, and we are bringing on the next 15 over the next month or 2, and at that point I expect the study to be fully operational and up and running, and we’ll focus on recruitment.
What sets this trial apart from previous examinations with citalopram and other trials in Alzheimer disease?
AP: What we are particularly proud of with the s-citalopram study is that it gives us an opportunity to really rethink the design and the execution of clinical trials in agitation and Alzheimer's disease. Number 1, we're hoping to recruit a real-world population. Number 2, we have very limited restrictions on who comes in, so the entry criteria are quite liberal.
We tried to make this reflective of how we should operate in the clinic—that is, that a pharmacological intervention shouldn't be the first thing that you think about. That everybody with agitation and dementia should have a psychosocial intervention alongside pharmacological treatment if that is required.
How much of the focus in Alzheimer treatment is on the neuropsychiatric symptoms, and how prevalent are they?
AP: Neuropsychiatric symptoms in Alzheimer's disease and other dementia are basically universal. If you don't have neuropsychiatric symptoms, you're going to develop them at some point during the disease. A lot of the focus has been on agitation, but there are other neuropsychiatric symptoms that are also quite debilitating. At this meeting, we have focused on apathy, which really stands for decreased initiative, decreased get up and end goal, and flatness of effect, and we're working to come up with consensus criteria that will facilitate research operations as well as a path for regulatory approval. In addition to that, we're looking at psychosis and Alzheimer's disease, which is a really troublesome component, just as psychosis is in Parkinson's disease and other neurodegenerative disorders. So, there's quite a bit of an interest in seeing not only safe and well-tolerated, but also effective treatments for that as well.
What’re you excited for, either in the pipeline or in Alzheimer as a whole?
AP: Looking at agitation, there are a few programs underway right now. Obviously, I’m particular to the s-CitAD study because we had such a favorable response on the efficacy end before. The other 2 studies focus on dextromethorphan, which is a drug I think most clinicians have used for decades. You can inhibit the breakdown of dextromethorphan with an additional compound. So, we, on one hand, have Avanir’s dextromethorphan/quinidine combination (Neudexta), and on the other hand, we have dextromethorphan combined with bupropion (AXS-05) from Axsome Therapeutics.
The combinations drugs basically lead to much higher levels of dextromethorphan in the bloodstream, to the point that it actually becomes central nervous system active. That seems to, according to preliminary data, be helpful possibly in agitation, and there’s good data for kind of pseudobulbar affect for this approach.
Transcript edited for clarity.