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Today on throwback Thursday: Are newer antipsychotics better for cognition than their older, typical forbearers? 

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Published On: 10/06/22

Duration: 12 minutes, 40 seconds

Referenced Article: “Do Antipsychotics Improve Cognition?,” The Carlat Psychiatry Report, May 2019 Chris Aiken, MD and Kellie Newsome, PMHNP have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

Kellie Newsome: Today on throwback Thursday: Are newer antipsychotics better for cognition than their older, typical forbearers? 

Chris Aiken: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. 

Kellie Newsome: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

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

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

Chris 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 Newsome: What have we learned since them?

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

Chris 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 Newsome: 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.

Chris 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 Newsome: This episode first aired in May of 2019, and we’re updating it here with new research and CME credits. Here’s a sneak preview of the CME test you’ll find in the show note links:

Which antipsychotic improved cognition in a randomized controlled trial of stable patients with bipolar disorder?

A. Lurasidone

B. Pimozide

C. Cariprazine

D. Aripiprazole

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

Chris 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 Newsome: Okay, so what about the others?

Chris 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 Newsome: 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.

Chris 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 Newsome: What is it?

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

Kellie Newsome: Australia? The land down under?

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

I hope you’ll join us next Monday for…

Chris Aiken:  In that episode we found flaws in the studies that casted doubt on typical antipsychotics, causing us to question the whole notion that atypicals are better for cognition. After it was published, a new study – the Nessy trial – gives a different take. This study randomized just over 100 patients with schizophrenia to an atypical antipsychotic, or one of those older atypicals. The atypicals were aripiprazole, olanzapine, and quetiapine, and typicals were haloperidol and flupentixol. This time, the results tipped the balance a bit in favor of the atypicals, at least in terms of verbal fluency. In the short term, both groups improved in the cognitive domain that arguably matters most – executive functioning, but only the atypicals brought improvements in verbal fluency. In the long-term – after 6 months, the atypical group also saw improvement in working memory, but it was really at this 6 month period that the differences became more stark. At this point the patients on the older antipsychotics actually had a decline in executive functioning, while the ones on atypicals saw continued improvement. 

So are we ready to conclude that atypicals are better than typicals? Maybe, but I should point out that each of the 3 the atypicals they chose in that study have some evidence on their own to improve cognition in schizophrenia. Again, they were quetiapine, aripiprazole, and olanzapine. And, on the other hand, one of the typical antipsychotics they chose – haloperidol – ranked at the bottom for cognitive outcomes in a new network meta-analysis of 54 antipsychotic trials. 

Overall, we stand by our conclusion that if antipsychotics improve cognition, it’s a very small effect, and most of the benefits are due to treatment of the illness itself. These are complicated drugs, used in complicated illnesses, and their effects are varied. Some of their pharmacodynamic effects might improve cognition, while others – such as on the anticholinergic and metabolic systems – might make them worse.

Kellie Newsome: Thank you for joining us on throwback Thursdays. If you’d like to earn CME credits, follow the link in the show notes. Subscribe to the full journal with the promo code PODCAST, and follow us online where Dr. Aiken is releasing a daily dose of psychiatric research on his linked in and twitter feeds, @ChrisAikenMD.