Why This Potential New Medication for Schizophrenia Is Important

This post was written by Eugene Rubin, MD, Ph.D., and Charles Zorumski, MD.

Schizophrenia is a severe, chronic disorder characterized by "positive" symptoms such as hallucinations, delusions (fixed, false beliefs), and thought disorder; "negative" symptoms such as constricted affect and diminished social interactions; and "cognitive" symptoms such as problems with attention and memory. Currently available medications influence the dopamine neurotransmitter system and help diminish positive symptoms, but they have little influence on negative or cognitive symptoms. Importantly, these dopaminergic-based medications can have significant side effects, including movement and metabolic dysfunction. Some of these drugs cause substantial weight gain. Long-term use is associated with increased mortality. Due to the nature of the illness and discomfort from side effects, 40 percent or more of individuals with schizophrenia are unable to comply with treatment.

In a paper recently published in the journal Lancet, Inder Kaul and colleagues reported results of a phase-3 clinical trial of xanomeline-trospium (KarXT) in the treatment of individuals hospitalized for exacerbation of symptoms of schizophrenia. This was a large, randomized, double-blind, placebo-controlled study involving patients in 22 different U.S. hospitals.

How KarXT works

KarXT is a combination of two drugs: xanomeline and trospium. Neither acts on the dopaminergic system. Xanomeline is an agonist (stimulator) of specific acetylcholine muscarinic receptors throughout the body, including the brain. Earlier studies suggested that stimulating the brain’s acetylcholine receptors can have antipsychotic properties. However, xanomeline’s stimulation of acetylcholinergic receptors outside the brain can lead to intolerable side effects. Trospium, the second component of KarXT, blocks these peripheral (non-brain) muscarinic receptors. Trospium does not enter the brain and, therefore, it blocks peripheral cholinergic stimulation without influencing xanomeline’s effects on the brain. Thus, many of the cholinergic side effects of xanomeline are prevented.

Results of the KarXT trial

Kaul et al. reported the results of a 5-week study that compared KarXT to placebo in 252 adults (18 to 65 years old) with schizophrenia who were hospitalized because of an exacerbation of psychotic symptoms. Those who were experiencing their first treated episode of schizophrenia were excluded from the study as were those who had been diagnosed with any other primary psychiatric disorder within 12 months of screening. Patients who agreed to participate in the study discontinued psychiatric medications for at least a week prior to receiving the study medications. All remained hospitalized for the duration of the study.

Participants were randomly assigned to receive either KarXT or placebo orally twice a day for five weeks. Symptoms of schizophrenia were measured at screening, baseline, and weekly during the study with the Positive and Negative Syndrome Scale (PANSS), a research instrument commonly used in studies of schizophrenia. The primary endpoint of the study was the change in total PANSS scores from baseline to week 5. Positive and negative symptoms were also followed using PANSS subscales. Participants and investigators were unaware of treatment group assignments.

Was KarXT beneficial? A meaningful response was defined as a 30 percent or greater reduction in total PANSS score by week 5. Using this definition, 55 percent of persons on KarXT responded versus 28 percent on placebo. This difference was both statistically significant and clinically meaningful. Importantly, both positive and negative symptoms improved. The difference between KarXT and placebo was evident by three weeks and further increased at five weeks. Although the study ended after five weeks, the shape of the response curve suggests that further improvements in the KarXT group would be likely over time.

Side effects were primarily gastrointestinal and occurred in both the KarXT and placebo groups, although they were higher in the KarXT group. The rates of serious or severe adverse events were low and occurred in both treatment groups to about the same degree.

The effects of KarXT on cognitive symptoms were not reported in this study. However, earlier results suggested that KarXT may also improve cognitive symptoms.

This is the first phase-3 study of KarXT. The drug is currently under review by the U.S. FDA for the treatment of schizophrenia.

Why this study is important

Assuming that additional phase 3 studies confirm these results, KarXT could represent a major leap in antipsychotic psychopharmacology because its mechanism of action is distinct from all current antipsychotics. In addition, this agent appears to decrease not only positive symptoms but also negative symptoms.

Because KarXT works via a different mechanism of action than other drugs used to treat schizophrenia, would it lead to further improvement if it were added to treatment regimens for those only partially responding to their current antipsychotics? Pharmacological treatment strategies involving combinations of drugs with different mechanisms of action are common in treatment of hypertension and other medical disorders. Such a strategy might be successful in treating schizophrenia. In fact, a study examining KarXT as adjunctive therapy in people who are insufficiently responding to their current medications is currently in progress.

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Over the next five years, it is likely that several agents with unique mechanisms of action will be developed to help persons suffering from schizophrenia. Such treatments together with early psychosocial interventions could help these individuals enjoy a much improved quality of life.