Unlike the typical antipsychotics, atypicals improve both cognitive and psychotic symptoms of schizophrenia, so they must have procognitive effects of their own that can be harnessed in mood disorders, ADHD, and even dementia. The problem is that the data show the opposite.

Publication Date: 5/27/19
Runtime: 8 mins, 35 seconds
Article Referenced: "Ask the Editor: Can Antipsychotics Enhance Cognition?," The Carlat Psychiatry Report, May 2019

Transcript:

Kellie: Yesterday when I was outside getting some sun, I was thinking about some of my patients and how it is that their symptoms get better, but their functioning doesn’t.

Dr. Aiken: In this episode, we’ll touch on that and how psychiatric medications affect cognition.

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Kellie: Welcome to Episode 3 of The Carlat Psychiatry Podcast, brought to you by The Carlat Psychiatry Report, a CME publication keeping psychiatry honest since 2003. I’m Kellie Newsome, a psychiatric NP student and a dedicated reader of every issue.

Dr. Aiken: And I’m Chris Aiken, the editor-in-chief of The Carlat Psychiatry Report.

Kellie: One thing I learned from this issue is how medication can affect cognition.

Dr. Aiken: Yes, and it’s something that medications need to do because like you were saying, a lot of times patients symptoms get better, but their functioning does not. They remain on disability. This is a common problem, for example, in bipolar disorder where even when the patients have no symptoms of mania and depression, 30% to 60% of them continue to have cognitive problems and continue to be on disability.

Kellie: I remember there being some hope that antipsychotics would improve cognition.

Dr. Aiken: Yes. I went to a lot of pharmaceutical-sponsored talks myself where the speaker seemed to imply that atypical antipsychotics would improve cognition and improve the patient’s function. We touched on that in this issue and I’m just going to talk a little bit about what I learned.

First of all, where did that idea come from? Well, it turns out that when these medications came out, there were some studies suggesting that the atypicals were much better at improving cognition than the older, conventional antipsychotics. In fact, we’ve known for a while that the older antipsychotics do not improve cognition. They make it worse.

Well, it turns out that those early studies were flawed. Basically, they had two groups: the older antipsychotics and the newer antipsychotics in schizophrenia. But the older antipsychotics were dosed high. And what happens when you dose antipsychotics high? You get more extrapyramidal side effects like muscle stiffness and then the patients get put on benztropine/Cogentin, which is an anticholinergic that treats extrapyramidal side effects.

But benztropine, as well as high doses themselves are notorious for impairing cognition. So, it was not a fair comparison. We had low dose atypicals compared to high dose conventional antipsychotics. 

Kellie: What have we learned since them?

Dr. Aiken: Well, another larger trial came out about 10 years ago called the CATIE trial and in this one, the two groups were more evenly matched. The older conventional antipsychotics and the newer atypical ones. And the CATIE trial did look at cognitive outcomes. Basically, they found no difference between the groups. So, that kind of squelches any hope that the atypicals are improving cognition in schizophrenia.

Kellie: That CADIE was an NIH-funded trial. I’m not quite so sure what I think about that.

Dr. Aiken: Well, when it’s an NIH-funded trial, we’re more trusting of the results because we know that there’s not as much of a bias from industry sponsorship.

Kellie: Oh, okay. So, you’ve mentioned that anticholinergics impair cognition, which reminds me that a lot of antidepressants have a lot of those anticholinergic properties in them.

Dr. Aiken: Yes. We touched on that in a separate article. Anticholinergics are getting kind of a bad rep lately. We’ve had a few articles on this. There have been a lot of studies coming out showing that various anticholinergics increase the risk of dementia. So, they’re not only impairing cognition in the moment when you take them, but they’re increasing the risk of dementia down the line. We know that, for example, about even Benadryl/diphenhydramine, an anticholinergic that’s over the counter. And in this issue, we talked about the different antidepressants and new research. I won’t go into all of it, but showing that certain ones increase the risk of dementia, while other ones do not.

Kellie: Back to the antipsychotics, and they seem to all be very different. Could there be any that actually do improve cognition?

Dr. Aiken: For many years, people pointed their finger at aripiprazole/Abilify as the shining star, perhaps because it’s a partial dopamine agonist, so they’re thinking may this, like Ritalin and Adderall, will treat ADHD and improve cognition.

So, to back up a little bit, there was this implication that because the atypicals improved cognition and schizophrenia, which they don’t, they would also improve cognition in other disorders like depression and bipolar and even dementia. We now know that’s definitely not true. And ADHD. 

So, aripiprazole/Abilify was put forth as a potential treatment for ADHD. Some of you all may have heard about this. And, what happened? Industry-sponsored, randomized control trials – there were at least two of them. It did nothing. So, aripiprazole doesn’t seem to be the one.

Kellie: Okay, so what about the others?

Dr. Aiken: Overall, it’s hard find any atypical that reliably improves cognition and in a lot of the studies when it seems like they do, they’re really just making the psychosis better. And when  psychosis gets better, cognition improves.

But I did find one study, one point of light which was on lurasidone/Latuda, an atypical that’s FDA-approved for bipolar depression. And in this study, it was industry-sponsored, they took people with bipolar disorder were euthymic, had no manic or depressive symptoms – at least not significantly – but had cognitive problems. And they put half of them on Latuda and half of them on a sugar pill and after about six weeks, cognition significantly improved with the Latuda.

That surprised me. I wouldn’t have thought that placing someone on an antipsychotic which can impair cognition through various ways, anticholinergic, there’s studies showing that they reduce blood flow in the frontal lobes. I wouldn’t have thought this would have happened. So, that was a surprise. It’s not something I’m ready to rest my hat on right now and I would have a lot of qualms about adding an antipsychotic just to improve cognition when it carries so many other side effects: weight gain, metabolic side effect, tardive dyskinesia.

So, I’m really at a loss to think of who I would give lurasidone to just to improve their cognition. But there may be. Perhaps patients who are significantly disabled because they have cognitive problems. It may be worth a try.

Kellie: Okay, so if we cut to the chase here, it’s just not really a good idea in general to be prescribing antipsychotics to improve cognition.

Dr. Aiken: Yes. We’re just not there yet. The Latuda data is too early to tell, and the other studies didn’t pan out. But next week, we’ll be talking about something that just might improve cognition and mood.

Kellie: What is it?

Dr. Aiken: Well, it’s actually something that comes from your homeland.

Kellie: Australia? The land down under?

Dr. Aiken: That’s right. Australia. Not only brought us lithium but lately, they’ve been bringing us news about a diet that treats depression.

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I hope you’ll join us next Monday for more of that and please send us any of your questions or feedback of all things psychiatric to asktheeditor@thecarlatreport.com. We’ll try to answer as many listener questions as we can.

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