A novel therapy that combines a muscarinic receptor agonist with an anticholinergic agent is associated with a greater reduction in psychosis symptoms, compared with placebo, new research shows.
Dr. Jeffrey Lieberman
In a randomized, phase 2 trial composed of nearly 200 participants, xanomeline-trospium (KarXT) was generally well tolerated and had none of the common side effects linked to current antipsychotics, including weight gain and extrapyramidal symptoms such as dystonia, parkinsonism, and tardive dyskinesia.
“The results showing robust therapeutic efficacy of a non–dopamine targeting antipsychotic drug is an important milestone in the advance of the therapeutics of schizophrenia and other psychotic disorders,” coinvestigator Jeffrey A. Lieberman, MD, professor and chairman in the department of psychiatry, Columbia University, New York, said in an interview.
If approved, the new agent will be a “landmark” drug, Dr. Lieberman added.
The study was published in the Feb. 25, 2021, issue of the New England Journal of Medicine.
Long journey
The journey to develop an effective schizophrenia drug that reduces psychosis symptoms without onerous side effects has been a long one full of excitement and disappointment.
First-generation antipsychotics, dating back to the 1950s, targeted the postsynaptic dopamine-2 (D2) receptor. At the time, it was a “breakthrough” similar in scope to insulin for diabetes or antibiotics for infections, said Dr. Lieberman.
That was followed by development of numerous “me too” drugs with the same mechanism of action. However, these drugs had significant side effects, especially neurologic adverse events such as parkinsonism.
In 1989, second-generation antipsychotics were introduced, beginning with clozapine. They still targeted the D2 receptor but were “kinder and gentler,” Dr. Lieberman noted. “They didn’t bind to [the receptor] with such affinity that it shut things down completely, so had fewer neurologic side effects.”
However, these agents had other adverse consequences, such as weight gain and other metabolic effects including hyperglycemia and hyperlipidemia.
Many have poor functional status and quality of life despite lifelong treatment with current antipsychotic agents.
“The pharmaceutical industry, biotech industry, and academic psychiatric community have been desperately trying to find novel strategies for antipsychotic drug development and asking, ‘Is D2 the only holy grail or are there other ways of treating psychotic symptoms of schizophrenia?’ ” Dr. Lieberman said.
Enter KarXT – a novel combination of xanomeline with trospium.
An ‘ingenious’ combination
Xanomeline, an oral muscarinic cholinergic receptor agonist, does not have direct effects on the dopamine receptor. Evidence suggests the muscarinic cholinergic system is involved in the pathophysiology of schizophrenia.
However, there may be dose-dependent adverse events with the medication, such as nausea, vomiting, diarrhea, sweating, and hypersalivation from stimulation of peripheral muscarinic cholinergic receptors.
That’s where trospium chloride, an oral panmuscarinic receptor antagonist approved for treating overactive bladder, comes in. It does not reach detectable levels in the cerebrospinal fluid and should avoid adverse central nervous system effects.
Dr. Lieberman said the idea of the drug combination is “ingenious.”
The new phase 2, multisite study included adult patients with a validated diagnosis of schizophrenia who were hospitalized with an acute exacerbation of psychosis, and who were free of antipsychotic medication for at least 2 weeks.
Participants were required to have a baseline Positive and Negative Syndrome Scale (PANSS) total score of 80 points or more.
In addition to seven positive symptom items, including delusions, hallucinations, and conceptual disorganization, the PANSS has seven negative symptom items. These include restricted emotional expression, paucity of speech, and diminished interest, social drive, and activity. Each item is scored from 1 to 7, with higher scores indicating more severe symptoms.
Patients also had to have a score on the Clinical Global Impression–Severity (CGI-S) scale of 4 or higher. Scores on the CGI-S range from 1 to 7, with higher scores indicating greater severity of illness.
The modified intention-to-treat analysis included patients randomly assigned to receive oral xanomeline-trospium (n = 83) or placebo (n = 87).
The dosing schedule was flexible, starting with 50 mg of xanomeline and 20 mg of trospium twice daily. The schedule increased to a maximum of 125 mg of xanomeline and 30 mg of trospium twice daily, with the option of lowering the dose if there were unacceptable side effects.
Mean scores at baseline for the treatment and placebo groups were 97.7 versus 96.6 for the PANSS total score, 26.4 versus 26.3 for the positive subscore, 22.6 versus 22.8 for the negative subscore, and 5.0 versus 4.9 in the CGI-S scale.