Schizophrenia Podcast

How Can We Assess Cognitive Functioning in Patients With Schizophrenia? And What Can We Do About It?

John M. Kane, MD; Philip D. Harvey, PhD

Disclosures

October 05, 2022

This transcript has been edited for clarity.

John Kane, MD: Hi. I'm Dr John Kane, professor of psychiatry and molecular medicine at The Donald and Barbara Zucker School of Medicine in Hempstead, New York. Welcome to Medscape's InDiscussion series on schizophrenia. Today we'll be discussing what should clinicians do to assess cognitive functioning and what can they do about it? First, let me introduce my guest, Philip Harvey, PhD, is Leonard M. Miller, professor of psychiatry, vice chair for research and director of the Division of Psychology at the University of Miami Miller School of Medicine. He's also a senior research health scientist at the Department of Veterans Affairs. Dr Harvey is one of the most highly cited and influential neuropsychologists in the US. He's won numerous awards. And I just want to mention the John Blair Barnwell Award, the highest award for clinical research across all scientific disciplines from the US Department of Veterans Affairs. He's won many other awards as well. So, Phil, welcome.

Philip D. Harvey, PhD: Thank you very much. Thanks for inviting me.

Kane: I think cognition is an area that a lot of clinicians find challenging, perhaps because they know that a huge proportion of patients with schizophrenia experience cognitive dysfunction, but they don't necessarily know how to measure it and they don't know what to do about it. They do have some sense that it really interferes with functioning. But I wondered if you could help us think through how clinicians should approach this. How do they measure it and what can they do about it?

Harvey: Well, I'm glad that clinicians are aware that cognitive impairment is important because it really does drive a lot of the disability in schizophrenia. The challenge, of course, is getting a neuropsychological assessment and then interpreting the results you get from the neuropsychological assessment. So I think that clinicians who are treating people with schizophrenia are going to have to think of other strategies to assess cognition, and we have some ideas about that.

Kane: What proportion of patients with schizophrenia do experience cognitive dysfunction, is it is it 80%?

Harvey: I think that's exactly right. We would say that 80% of people with schizophrenia test in the impaired range. But it's important to keep in mind that the others who don't test in the impaired range might have been functioning higher before they developed schizophrenia. So I think it's a general rule of thumb that everyone with schizophrenia is experiencing some degree of cognitive challenge, and for some it's really quite substantial.

Kane: Does it tend to get worse as the disease progresses, or does it remain relatively stable?

Harvey: Well, there's a big debate about that. And, you know, the idea that schizophrenia has a neurodevelopmental origin doesn't preclude neurodegeneration. A lot of the data suggests pretty substantial stability over time, at least throughout the middle years of life. And a very recent 25-year follow-up study suggested a decline in cognitive functioning that you could detect with neuropsychological tests but would never be able to visualize clinically.

Kane: Is cognitive dysfunction one of the domains that's affected even before the psychosis emerges?

Harvey: Yes, that's a really good point. The more impaired you are during the prodromal period, the more likely you are to actually convert to developing a psychotic condition. But cognitive impairments are detectable before the onset of other elements of the illness, for certain.

Kane: How far back does that go? How early in childhood or etc. does that begin to emerge?

Harvey: If you look at academic records and other archival information for people who did develop schizophrenia, you can detect it in early childhood. However, it's during adolescence and late adolescence where it's most salient. In fact, by the time that the prodromal state is detected clinically, virtually everyone in that state has some kind of cognitive dysfunction.

Kane: What should the average clinician do to assess cognitive functioning?

Harvey: Well, I'm not suggesting that you need to go out and get a neuropsychological assessment, because very often it's hard to get. They're not covered by insurance or not informative. But I think that we know now that people who have a lot of contact with people with schizophrenia are able to give a fairly reasonable estimate of their impairment, particularly if they're asked questions that are cognitively demanding and functionally relevant. Rich Keefe and I developed a rating scale that’s called the Schizophrenia Cognition Rating Scale. It was an article that was published in 2006 in the American Journal of Psychiatry, that scale has been extremely widely used since then. And in fact, we wrote a review paper regarding its use. The take home point from that study was that if you asked a high contact caregiver informant who had a lot of contact with someone with schizophrenia about their cognitive functioning, the results were remarkably convergent with the results of a formal neuropsychological assessment. So asking the right question to the right person will get you an answer that will bypass the need for expensive and maybe only marginally useful neuropsychological testing.

Kane: That’s very important. In talking to family members or informants, what usually stands out in their view as the most impactful cognitive dysfunction?

Harvey: Well I think that the combination of processing speed and executive dysfunction is most visible. People with schizophrenia do tend to be quite slow in completing tasks. And if your cognitive functioning is slowed, then every other task becomes overly demanding because it seems like it’s too fast for you. So the common complaints are "takes him or her forever to do things, can’t complete tasks and seems to have challenges initiating things", particularly initiating things spontaneously on their own.

Kane: And how does that intersect with negative symptoms? Because some of what you just described might also be part of that domain.

Harvey: It absolutely does intersect. And the combination of negative symptoms and cognitive impairments is particularly challenging. I think one of the things that differentiates avolition from cognitive impairment is that avolition means that people don’t really have the motivation to engage in anything. You can have avolition even if you have the ability to complete the tasks that you should be doing but are not making an effort to do so. So in a sense, the lack of motivation, lack of hedonic response to activities is one of the differentiators between negative symptoms and cognitive impairments.

Kane: And what if there’s no informant or family member available? What would you suggest then?

Harvey: We have found in our research that even second year psychiatry residents who’ve seen a patient a half a dozen times can give us a rating of their cognitive functioning that converges with their behavior. I think the most important thing is to have a focus on functioning. Very often when we talk to residents who are first starting to see people with schizophrenia. They’ll give us a very detailed description of the hallucinations and delusions that the person has but won’t be able to tell you if they have a job or live at home with their mother. So a functionally focused perspective, I think, will give you a lot of information.

Kane: How accurate are patients in their self-report of their own functioning?

Harvey: Actually, it’s very inaccurate. Patients can be both biased toward overestimating and underestimating their abilities. In a recent study we completed, we found that a substantial proportion of people thought they were much better than they were at various tasks. Others thought they were worse. And unfortunately, the people who actually did improve with practice didn’t notice it, and the ones who didn’t get any better thought they did. So I think external reference are really important and one should not believe that what someone’s telling you about their abilities or even their everyday functioning converges markedly with what’s actually going on.

Kane: Now that’s very important to know. Can you give us the reference on that study?

Harvey: Sure, it was a study of patients who were performing the Wisconsin Card Sorting Tests. The first author was Bianca Tercero. It was published in the Journal of Psychiatric Research last year, where we looked at people with schizophrenia who were doing the task, and at the end we asked them to give us a global estimate of how well they did. And what we discovered is that they relied entirely on their own trial by trial impression of their performance, despite getting feedback after every trial. Our comparison sample of people with bipolar disorder, were unable to inhibit their overestimation of their abilities, but they listened to the feedback. So at the end of the day, the bipolar patients gave us a global estimate of functioning on the test that was based on their performance, even though on a momentary basis they were off. The schizophrenia patients gave us an estimation of their performance that correlated zero with the actual performance of the test.

Kane: We’ve talked about how we go about assessing cognitive functioning in our patients. What would you recommend to the clinician in terms of what can they do about it?

Harvey: Well, just recently, there have been a couple of really interesting studies. People for years have been looking for a drug to enhance cognition. But concurrently, there are a lot of rehabilitation type interventions, including computerized cognitive training, that really do work and are very inexpensive and are accessible. There was a really good study done at UCLA by Keith Neuchterlein, where they showed that the combination of clinical stability and computerized cognitive training against the backdrop of a rehabilitation intervention led to substantial gains for first-episode patients.

Kane: Is that something that’s accessible to the average patient?

Harvey: There have been a number of studies recently looking at self-administered computerized cognitive training, showing rates of adherence that are similar to what happens if someone comes in in person and a number of the available and effective cognitive training interventions cost about $8 a month. So they’re really very inexpensive. And training for 3 or 4 months is usually an adequate dose. So we’re talking about an intervention that probably costs less than the anticipated cost of a single dose of an FDA-approved cognitive enhancing medication.

Kane: What’s your experience in terms of patients maintaining their engagement with these kinds of interventions?

Harvey: It’s the kind of thing you can monitor, because all these computerized cognitive training interventions have a dashboard. So you can see if people are engaging in training. We’ve published data suggesting that it’s a very simple thing to identify the level of engagement that is adequate to lead to cognitive gains. And for example, right now I’m running a clinical intervention in Los Angeles, where we’re training 100 people on cognitive and skills training, and I’m monitoring it 100% remotely, and it takes about 5 minutes a day. So, it’s the kind of thing that you can easily monitor. Some people won’t do it. On the other hand, the adherence rate to computerized cognitive training tends to be 70%. And we all know what the adherence rate to antipsychotic medication is, particularly oral antipsychotics.

Kane: That’s very encouraging. So let’s just double back for one second. You know, you mentioned the attempts over the years to develop new pharmacologic agents that might improve cognitive functioning. I know there have been a lot of disappointments in that regard and you’re emphasizing the importance of the rehabilitation interventions. But can you talk for a minute about some of the pharmacologic strategies? Is there anything that looks promising?

Harvey: There are certainly two promising treatments out there, one of which is targeting cognitive impairment. Specifically, it’s a GlyT1 (glycine transport) inhibitor that’s being developed by Boehringer Ingelheim. They were successful in the phase 2 study. They’re coming in probably within 9 months for their phase 3 study, and the drug actually worked. Interestingly, they’re also doing a study where they are combining that drug or placebo with computerized cognitive training. So we’ll be able to take a look and see whether augmentation of cognitive training with pharmacological interventions gives you a bigger boost than the cognitive training or the drug alone. That could be very promising. And just to briefly mention one other drug that has some promising data. It’s called KarXT, it’s a combination of a muscarinic M1 agonist and a peripheral M1 antagonist. It was formerly developed as xanomeline, and they have some very promising pilot data that I presented at the SIRS meeting suggesting, as you probably expect, that an M1 agonist that's tolerable actually improves cognition and that might not be limited just to people with schizophrenia.

Kane: And you’re also implying that the potential combination of these pharmacologic agents with nonpharmacologic interventions could be really key, right?

Harvey: Yes. And the combination of computerized cognitive training with psychosocial interventions is very promising too. Keeping in mind that every VA hospital in the country has to have a vocational rehabilitation intervention program. Our former colleague Susan McGurk has shown that if you take people who are in a vocational rehab program and not succeeding and just give them a fairly modest dose of computerized cognitive training, it leads to a very big boost in their likelihood of getting a job and keeping it.

Kane: That’s very encouraging. What other areas do you think we should emphasize to the clinician?

Harvey: Well, if you want to focus on functioning, there are ways to improve functioning without necessarily improving cognition. And one of them is long-acting injectable antipsychotics. So I think there’s a lot of evidence accruing that if you get someone who has periods of extended clinical stability, as you would induce with a long-acting injectable antipsychotic, you tend to find better functioning. Some people actually have the skills they need to perform. It’s just that being psychotic or having relapses or winding up in the hospital tends to lead to a sort of atrophy of their everyday functioning. So, I think a focus on long-term clinical stability above all else will certainly assist in people functioning better.

Kane: That’s very important. And that raises another question. There’s been some discussion about the impact of untreated psychosis or the duration of psychosis and does that impact cognition? If we see someone who has multiple relapses and long periods of psychosis, does that impact on their cognitive functioning?

Harvey: The evidence suggests that it does. Longitudinal studies starting at the time of the first episode done by both Rene Kahn, who’s now at Mount Sinai, the Icahn School of Medicine, and Nancy Andreasen of Iowa have shown that people who have multiple relapses and retreatments tend to both lose gray matter and also show impairments in cognitive function that are progressive over time. So it seems like clinical stability is quite important, and the idea of having people avoid relapses is probably important above and beyond the sort of psychosocial consequences of that event.

Kane: And what about the potential negative effects of medication? We know that the agents, which are highly anticholinergic, can have a negative effect on cognition. Are there any other drug effects that we should be concerned about?

Harvey: Well, I think the anticholinergic effects are clearly important, and they often accrue from other medications in addition to antipsychotics. A lot of people are on a whole host of other medications, and no one pays attention to their anticholinergic burden. We collected some data in a large sample of veterans and found that some of these people were performing 5 standard deviations below the rest of their cohort of veterans with serious mental illness. They found that anticholinergic burden was what explained it, not polygenic scores for worse schizophrenia or worse cognition, and that a lot of drugs have antihistaminergic effects which aren’t very good either.

Kane: So the clinician certainly needs to keep those things in mind. And I guess if a patient develops parkinsonian side effects and is treated with one of the anti-parkinsonian drugs, then that obviously could play a role in this phenomenon. There are many reasons why we want to reduce the adverse effects of antipsychotic drugs. And that’s certainly one of them.

Harvey: In fact, it’s been shown already that anticholinergic burden correlates with failure to make progress in both computerized cognitive training and psychosocial rehabilitation programs. So it’s really a wide-ranging adverse effect, again, not largely coming from antipsychotics, but the other combinations of medications that people are treated with. And any drug that causes weight gain is probably blocking the histamine receptor. And if you block the histamine receptor, you also get daytime sleepiness and sedation as well, which can in and of itself impact on your ability to function and on your cognitive performance.

Kane: What about the impact of sleep dysfunction and its role in cognition? Is that something that we see in schizophrenia?

Harvey: It’s clearly important. People with bad sleep have bad cognitive functioning. What we’ve seen in studies of people treated with antipsychotic medications that are associated with substantial antihistaminergic burden is that they are sleepy during the day, but then they sleep less well at night. Using ecological momentary assessments (EMA), we did a study where we showed that people who were treated with quetiapine were actually sleeping less at night and more during the day than people treated with another drug targeting Parkinson’s psychosis. So it really is an important thing to keep track of. But as we know, even people who are healthy and have only insomnia as a problem have a real challenge in reporting their sleep hygiene and a lot of people’s reports of how long it takes them to fall asleep or how long they sleep are really quite inaccurate.

Kane: Yeah, that’s an enormous problem. Sleep could be probably considered the 5th vital sign. But we do a terrible job of measuring it and monitoring it and understanding its implications.

Harvey: Yeah, but you can use a Fitbit or some other inexpensive actigraphy device and get a rough signal of someone’s sleep. Obviously not the same quality as a sleep study, but certainly worth the effort. And, if you have someone wear the Fitbit for 3 or 4 days, you can collect enough information about how they’re sleeping. So you can pass one Fitbit around to different patients.

Kane: And since you’re mentioning Fitbit, I know you’ve done a lot of work with remote monitoring and digital technology. And can you share with us some of the major lessons that have come out of that in relation to schizophrenia?

Harvey: Among the lessons that we are learning is that you can actually measure the consequences of negative symptoms and cognitive impairments quite directly. Because after all, if you’re sampling someone using ecological momentary assessment on a smart device, you can find out if they’re home or away, alone or with someone, and what they’re doing when they’re home. And we have found that people with schizophrenia do answer their EMA pages with relatively high fidelity, like 75%. So again, the idea that people with schizophrenia won’t train with technology or won’t utilize technology to cooperate with treatment is based on a lack of knowledge and experience. People with schizophrenia are actually more adherent in our studies than our healthy controls were.

Kane: And certainly those data are more accurate than what you get in a self-report.

Harvey: What we found in the study was that people with schizophrenia were giving us reports of their activities that were validly confirmed with GPS recordings. But their GPS confirmed reports of their social functioning on a momentary basis did not correlate at all with their 30-day self-assessment of their social functioning. So what happens is people will tell you that they’re really good at doing things they couldn’t have possibly done. Someone who tells you they’re excellent, they’re taking public transportation, but has been home and alone for 90 surveys over 30 days, is telling you something that can’t possibly be true. They’re telling you they’re good at doing something they couldn’t possibly do at home.

Kane: The role of these technological approaches is potentially very important. How long do you think it’s going to take before these kinds of tools become more routine in their use?

Harvey: Well, I think that people also underestimate how many people with serious mental illness actually have a smart device and use it. And I think that people underestimate the utility of this. I think that one of the challenges with technology-based surveys, is encouraging people to engage in the survey. When we have someone in a research study, we pay them for answering. In a clinical situation, you’d have to figure out some other kind of incentive. In a project that we’re doing with a major drugstore chain they’re actually giving people points for engaging in training to learn how to use their app.

Kane: You conveyed a lot of really important information. One key takeaway would be the value of significant others, family members, and informants in helping the clinician evaluate the patient’s cognitive functioning. Another is the potential value of the rehabilitation interventions that have been developed and shown to be useful. But we do have some medications that are under development which might enhance our ability to bring about such improvement, particularly when they’re combined with some of the nonpharmacologic interventions.

Harvey: That’s absolutely critical because cognitive enhancement alone is not going to lead to the spontaneous development of new skills. Getting a job involves knowing how to interview, how to prepare a resume and things like that. And if you’ve never done it, just because your cognition has improved the equivalent of 10 IQ points, you’re not going to have those skills. It’s like expecting that because someone’s cognition has improved, they’ll almost all of a sudden be able to play the piano when they never played it before. So every functional skill is something that you have to learn. It’s just that learning them is markedly facilitated by cognitive enhancement, whether it’s pharmacological or whether it’s cognitive training based.

Kane: Another key takeaway would be the potential role of some of the new technologies in enhancing our ability to both understand and monitor cognitive functioning and as you mentioned, even negative symptoms. And that will go a long way towards making our treatment decisions better informed.

Harvey: That is absolutely true. It’s really important to keep in mind that a lot of the reports you get about functioning are as inaccurate as the reports you get about adherence. So I think we always accept the idea that we’re not going to get accurate reports about adherence and hence long-acting injectables are good. We need to keep in mind that global judgments generated by patients about how good they are at things may be inaccurate and may require some more direct observation.

Kane: Phil, thanks so much for sharing that with us. Also, the work that you’ve done to further develop this area is very exciting. We look forward to more of that. Thanks so much for joining us. This is Dr John Kane for InDiscussion.

Resources

Schizophrenia

Schizophrenia Practice Essentials

The Schizophrenia Cognition Rating Scale: An Interview-Based Assessment and Its Relationship to Cognition, Real-World Functioning, and Functional Capacity

Comprehensive Review of the Research Employing the Schizophrenia Cognition Rating Scale (SCoRS)

Using a Meta-cognitive Wisconsin Card Sorting Test to Measure Introspective Accuracy and Biases in Schizophrenia and Bipolar Disorder

Developing a Cognitive Training Strategy for First-Episode Schizophrenia: Integrating Bottom-Up and Top-Down Approaches

Brain HQ

Training Engagement, Baseline Cognitive Functioning, and Cognitive Gains With Computerized Cognitive Training: A Cross-Diagnostic Study

Efficacy and Safety of the Novel Glycine Transporter Inhibitor BI 425809 Once Daily in Patients With Schizophrenia: A Double-Blind, Randomised, Placebo-Controlled Phase 2 Study

A Study to Test Long-term Safety of BI 425809 in People With Schizophrenia Who Took Part in a Previous CONNEX Study

Evaluation of the Efficacy of BI 425809 Pharmacotherapy in Patients With Schizophrenia Receiving Computerized Cognitive Training: Methodology for a Double-blind, Randomized, Parallel-group Trial

Karunatx.com. KarXT

F46. The Potential of M1 Agonists to Treat Cognitive Impairment: Evidence From a Phase 2 Study of KarXT in Schizophrenia (EMERGENT-1)

Cognitive Training and Supported Employment for Persons With Severe Mental Illness: One-Year Results From a Randomized Controlled Trial

Long-Acting Antipsychotic Therapies for Patients With Schizophrenia

Why Treating Early, Treating Well, and Treating for Life Is Important in Schizophrenia

Progressive Brain Change in Schizophrenia: A Prospective Longitudinal Study of First-Episode Schizophrenia

P515. Genomic Analyses of Schizophrenia and Bipolar Disorder Patients With Very Poor Outcomes

Challenges in Assessment of Daytime Sleepiness in Cognitively Impaired Populations Can Be Bypassed Through Use of Ecological Momentary Assessment

Evidence for Avolition in Bipolar Disorder? A 30-Day Ecological Momentary Assessment Comparison of Daily Activities in Bipolar Disorder and Schizophrenia

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