Several important insights have recently combined to provide “a new lens” on improving how people with schizophrenia are cared for. This new perspective is arguably important not only for all schizophrenia patients but for all medical professionals who prescribe medications for them.

One of the insights has its origins in BBRF Young Investigator grants awarded in 2003 and 2006 to Gregory A. Light, Ph.D. A second insight comes from a question asked a few years ago by one of Dr. Light’s former mentees at the University of California, San Diego, Yash B. Joshi, M.D., Ph.D., who received a BBRF Young Investigator grant in 2018.

In 2021, Dr. Joshi was the lead author of a study in the American Journal of Psychiatry published by a team whose senior member was Dr. Light and included eight other past BBRF grantees. The paper called to the attention of both psychiatrists and the broader medical community questions about how medicines are selected for schizophrenia patients and what the cumulative impact of these medicines might be upon one of the core symptoms of the illness: problems with the brain’s cognitive machinery.

THE PROBLEM OF COMORBIDITY

One bit of background provides context for the new insights of Drs. Light and Joshi: it has been known for many years that comorbidity is a major problem in caring for people with schizophrenia. Comorbidity refers to other conditions which can co-occur with schizophrenia. These include conditions affecting the brain and behavior, as well as illnesses occurring in the rest of the body. “Medical” comorbidities of schizophrenia include cardiovascular, pulmonary, neurological, and endocrine (hormone system) diseases. Regarding psychiatric comorbidities, depression occurs in about 50% of schizophrenia patients, and as many as half of these individuals also have a lifetime diagnosis of substance abuse. Anxiety, OCD, and panic disorder also co-occur with schizophrenia with a frequency that significantly exceeds their occurrence in the general population.

Because comorbidity is common in schizophrenia, it comes as no surprise that many patients are prescribed multiple medications. The recent insights of Drs. Light and Joshi suggest the wisdom of identifying in a comprehensive way the total complement of prescribed medications in each patient and assessing how those medications together may affect the patient’s overall condition. The problem, in other words, includes medications patients are prescribed for both psychiatric and “medical” reasons.

Drs. Light and Joshi have focused in particular on how the total complement of medicines prescribed for patients affects cognition. Cognitive impairment is a core symptom and a key disabling feature of schizophrenia. There’s a large literature documenting significant difficulties in attention, learning, memory, executive functioning, and social cognition (the ability to understand and successfully communicate with other people) in those living with schizophrenia and related disorders.

The antipsychotic medicines that most patients take to control symptoms such as hallucinations and delusions do not reduce cognitive impairment. And, as Drs. Light and Joshi point out, cognitive impairments are a core symptom of schizophrenia and contribute significantly to the difficulty patients have in functioning in society. It‘s related directly to limited skill acquisition, lower educational attainment, and reduced quality of life What do cognitive impairments have to do with medications? Dr. Joshi thought that medications might have quite a bit of impact, specifically in the area of cognition. The root of this thought is not controversial. Many studies have linked cognitive difficulties to problems with the brain’s cholinergic system. Dr. Joshi’s concern was that many medications prescribed for schizophrenia patients, from antipsychotics to antidepressants to some medicines for comorbid bodily ailments, could indirectly impact cognitive functioning by acting on the brain’s cholinergic system.

THE CHOLINERGIC SYSTEM IN THE BRAIN

The “cholinergic system” refers to signaling by the neurotransmitter acetylcholine, which is important for neurons throughout the body. In the brain, regions in which acetylcholine is active play an important role in learning, memory, stress response, and broadly, in cognitive functioning. Unlike some neurotransmitting chemicals, acetylcholine does not typically shut neurons on or off. It is rather a neuromodulator—in Dr. Joshi’s words, it acts more like the volume switch on a radio rather than the on-off switch.

Dr. Joshi was not the only doctor or scientist who knew that many medicines act to impede the operation of the cholinergic system—that they have “anticholinergic” properties. What gnawed at him was: how would such medicines affect cognition in a schizophrenia patient, assuming that the patient already had core symptoms impairing cognitive function? When patients take multiple medications, several of which had some known anticholinergic effect, might the combined anticholinergic impact of all the medications, regardless of their potential benefits on other individual symptoms that are being targeted, tend to intensify the cognitive problems that all schizophrenia patients have?

Drs. Joshi and Light had another concern in mind. Among the medicines with anticholinergic impact that schizophrenia patients might be taking, there is a class that is explicitly designed to have anti-cholinergic action. These medicines are often prescribed to patients with motorsystem side effects such as tardive dyskinesia and dystonia. Anticholinergic medicines help to control such symptoms, which ironically can be sideeffects of the antipsychotic medicines that patients need to take to control their hallucinations and delusions.

In their 2021 paper in the American Journal of Psychiatry, Drs. Joshi, Light and colleagues described the potential utility of calculating the total “anticholinergic burden” (ACB) of medications prescribed for chronic schizophrenia patients, using a sample of 1,120 individuals with known medication histories, 58% of whom lived in board-and-care or transitional living programs. The average age of participants was 46; nearly 70% were male; the average participant had been diagnosed with schizophrenia at age 22 and took a single antipsychotic medicine. One-third of participants also took an antidepressant medicine and/ or other medicines, including mood stabilizers, anti-anxiety agents such as benzodiazepines, or anticholinergic medicines (e.g., benztropine, diphenhydramine, trihexyphenidyl, hydroxyzine) to control antipsychotic motor side effects like involuntary movements.

Guided by previously established research protocols, the researchers assigned each prescribed medicine a numerical score, rating it on a scale from having no anticholinergic effect (0) to having a high effect (3). The study rated participants with a combined medication score of 3 or greater to have a “high” anticholinergic burden. In a prior study of healthy older adults, the team noted, scores of 3 or greater for 3 years or more were associated with a 50% increase in the odds of developing dementia over the study’s 11-year duration. What impact might ACB have in schizophrenia patients, who have underlying cognitive impairments?

“We found that many patients [in our study] have medication regimens with high anticholinergic burden, with an average score of 3.8,” the team reported. Overall, 63% of the 1,120 participants had a score of at least 3, and one-fourth had a very high score of 6 or greater. A few had scores as high as 15 to 20. Since participants in the study were not included if they had major medical issues, it’s likely the results probably underestimate the total anticholinergic burden in patients living in the community, many of whom do have medical comorbidities and likely have additional anticholinergic burden from medications prescribed to treat those conditions.

Consistent with findings in the prior study of healthy older adults, this study in schizophrenia patients by Drs. Joshi, Light and colleagues found that “anticholinergic burden was significantly associated with generalized impairments in cognitive functioning.” Antipsychotic medicines contributed more than half of the total anticholinergic burden, they said, with other medicines accounting for the remainder. There was no appreciable difference between firstand second-generation antipsychotics; most medicines in both categories had anticholinergic effects, although of varying magnitude.

Drs. Joshi and Light stress that their results point to the total score—total anticholinergic burden—as being the key factor in contributing to risk for cognitive impairments, as opposed to any particular medication or medications considered individually. This is a delicate and crucial point. They say it is important that their results be understood in the proper context: they are working “to optimize outcomes” in chronic schizophrenia patients. And, they stress, “psychotropic medications, especially antipsychotics, are critically important in [treating] schizophrenia, have substantially improved the lives and outcomes for countless patients living with the illness, and represent an essential staple of comprehensive treatment.”

“We are definitely not anti-medication,” Dr. Light says. “We want to keep people functioning at their best, keep them out of the streets, out of jails and prisons, and functioning better in their community.”

This guiding passion of both doctors and their colleagues inspired additional research leading to their second paper in the American Journal of Psychiatry, which appeared earlier this year. If it now seemed reasonable to consider using the total anticholinergic burden score of each patient to help inform which medicines to prescribe, it would be important to provide an objective measure of cognitive impairment that is specifically associated with total ACB score. Can the impact of ACB on cognitive function in patients be quantified in terms of patients’ ability to function? The answer turned out to be “yes.”

MEASURING THE IMPACT ON COGNITION

Dr. Light’s early-career research provided a plausible candidate, or a pair of them, to objectively measure functional impact. Called MMN and P3a, they are features of EEG (electroencephalogram) readouts of brain activity. When he received his first BBRF grant, Dr. Light was searching for ways in which cognition might be better understood in patients with schizophrenia by looking at how electrical waves measured by EEG are linked to cognition, symptoms, or functioning. MMN, or “mismatch negativity,” tests the brain’s ability to detect subtle changes in an otherwise repetitive background of sounds after an “oddball” occurs. People with a normally functioning brain can automatically detect an auditory oddball—say, a single rising tone in a long series of descending ones, or a long sound in a series of short ones. Normally, the brain makes these discriminations routinely and unconsciously, and can do so from our earliest days out of the womb. With his first BBRF grants, Dr. Light showed that schizophrenia patients had reduced MMN responses—the “oddball” tones were heard, but the brain responses to those tones were not well differentiated from responses to the other tones. Perhaps more important, he discovered that patients with the lowest responses in the MMN test had the greatest impairments in real-world, daily functioning.

The MMN indicator as measured with EEG turned out to be highly influential in research, in part because the measurement was obtained with absolutely no effort on the part of the study subject. “It can be measured in sleeping babies, in children, and adults with neuropsychiatric disorders,” says Dr. Light. “What it tells you is how the brain processes environmental sounds; how it uses that information to determine whether a sound is pertinent [or not], whether it requires you to act in response to it.” It became an objective biomarker in schizophrenia research and treatment development when Dr. Light and others showed that in patients, the MMN response over frontal brain regions was blunted. And it turned out, he explains, that lowered MMN response “is related to how well patients navigate through life, how they function in real-world settings.” P3a is another biomarker of cognitive function that is also muted in schizophrenia patients. It can be seen in the same EEG readout that displays the MMN response. “MMN occurs about 1/20 of a second before the P3a response, and like MMN, P3a is instant, immediate, and everybody has one.”

In their 2023 paper, Drs. Joshi, Light and colleagues wanted to know if the total anticholinergic medication burden of schizophrenia patients had any impact on the MMN and P3a biomarkers. Both were thought to be remarkably stable and insensitive to such factors as changes in medications. The team would test whether chronic schizophrenia patients with high total ACB scores differed in their MMN and P3a responses compared to patients with lower scores. 555 patients from the earlier study were used, all having fully documented ACB scores and EEG data. In a modification of the standard ACB scale, the investigators considered those patients with total ACB scores of 1 or 2 to be “low,” 3 or 4 to be “moderate,” 5 or 6 to be “high,” and 6 and over “very high.”

Contrary to the prior supposition that MMN and P3a were stable in schizophrenia, the team found that patients with higher ACB scores had even lower MMN and P3a responses relative to schizophrenia patients with lower total ACB scores. In fact, they discovered, a patient’s ACB score predicted what their MMN and P3a response would be.

How large was the effect? The team concluded that having a very high ACB score, i.e., 6 or greater—which pertains to roughly 1 patient in 4 —“may uniquely attenuate” the two biomarkers that reflect “the earliest stages of core information processing necessary for most higher-order cognitive functions.”

There are several important implications of this finding. One concerns the search for medicines that might boost cognitive function. It will take years and cost billions to develop such drugs. In the meantime, actions can be taken now that might potentially improve cognitive function in chronic schizophrenia patients.

MAKING MEDICATION TRADE-OFFS

The new data shows that patients with the highest ACB scores have the most muted MMN and P3a responses. This raises a crucial question. If patients with high ACB scores have significantly more muted MMN and P3a responses, and if these muted responses correlate with greater functional impairment due to cognitive dysfunction, then might one try to improve cognitive performance in patients by trying to lower their total ACB score? This could be done, at least in theory, by making trade-offs: swapping out medications with greater anticholinergic impact for ones that have lesser impact.

Medication swaps are conceivable but will not be easy in many cases. Some patients and their families are adamant about the effectiveness of specific medicines—for example, anticholinergics in helping to control motor dysfunctions; or a specific antipsychotic in helping to control the patient’s hallucinations and delusions. Coming up with a medication regimen is typically the result of many trial-anderror experiments. Finding a regimen that meets important treatment goals and to which the patient will adhere is no small thing.

“What Yash [Joshi]’s work has so nicely illustrated,” Dr. Light says, “is that when you look into the overall anticholinergic medication burden you can contemplate making trade-offs. You can think about whether a specific medicine you might want to swap out might be the thing that is enabling this patient to be somewhat functional. But it could also mean swapping out some of the medications people are taking for problems unrelated to schizophrenia with equally effective medicines with lower anticholinergic burden. The idea is that we should now be thinking carefully about piling on more burden in patients who already have a very high burden. What Yash’s work suggests is that there are pathways for providing better, more integrated care, even if it is just a little better in some cases.”

Dr. Joshi, who in addition to his research actively cares for schizophrenia patients at the VA Hospital in San Diego, says, “This is what I do in the clinic all the time. At the VA, I take care of a group of veterans who are uniquely vulnerable and require a high degree of mental and medical health care. Most have treatment-refractory symptoms. What if we had the ability to improve their cognitive functioning, even if it’s just a little bit?”

If such a thing were possible, would it be worth the effort? Both Drs. Light and Joshi think it may be well worth it in many cases. “Greg [Light] published a paper in 2017 showing us that those little ‘squiggles’ in the EEG readout have cascading effects to disability. What that means is, even a small change in MMN and P3a has outsized and additive impacts on cognitive symptoms, and ultimately, disability.” This, he notes, “is the subject of our next paper.”

Dr. Light says “This goes back to our early research made possible with my early BBRF grants. We began to speculate, beginning in EEG studies with healthy subjects, that if someone can automatically detect subtle changes in the environment, they will be better able to read another person’s facial gestures, body language changes, and function better.” These are the very abilities impaired in schizophrenia and reflected in the MMN and P3a indicators, and even more in those with high ACB scores. “A lot of communication is nonverbal, and it’s subtle. If you can accurately detect changes in pitch, or whether somebody is trying to convey humor, anger, sarcasm, frustration, sadness, you’re going to function more effectively in the real world.”

Drs. Light and Joshi think it makes sense for doctors to “take responsibility for the entire medication regimen in every patient,” as Dr. Joshi puts it, “and to consider it through the prism of the total anticholinergic burden that person has.” In Dr. Light’s view, “it’s one lens, a new lens, through which we can view the care of our patients.” It’s a lens that is commonly applied today in the care of healthy, older adults, to minimize risk of dementia and cognitive impairment. In schizophrenia patients, it is not widely considered, but easily could be: it’s a calculation that involves simple addition, made with existing tools.

“It might end up helping people just enough that they can function a little bit better,” Dr. Light says. And, the recent paper suggests, all the more for those with very high anticholinergic burden.

Written By Peter Tarr, Ph.D.

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