At the American Psychiatric Association 2023 Annual Meeting, a Presidential Session titled “Novel Drug Treatments for Psychiatric Disorders” was chaired by Maurizio Fava, MD, psychiatrist-in-chief at the Massachusetts General Hospital. Dr. Fava introduced the first presenter, John Michael Kane, MD, director and a professor at the Institute of Behavioral Science, Feinstein Institutes for Medical Research.
Dr. Kane’s presentation focused on psychopharmacological treatments for patients with schizophrenia. He briefly covered the background of medications used in schizophrenia, starting in the 1950s with the first antipsychotic, chlorpromazine. While chlorpromazine and other first-generation antipsychotics like haloperidol and loxapine were effective, they were associated with serious neurological adverse effects.
In an effort to develop treatments with fewer side effects, researchers synthesized several tricyclic compounds, including clozapine. Clozapine and other “atypical” antipsychotics were less likely to cause adverse neurological symptoms, though they were associated with metabolic side effects.
Dr. Kane explained that these conventional treatments all function at the dopamine D2 receptor and have comparable efficacy, except for clozapine, which has been shown to be significantly more effective than other antipsychotics.
Despite the advancements, improving negative symptoms and cognitive dysfunction in schizophrenia is a significant unmet need, according to Dr. Kane. He showed data suggesting clozapine is underutilized, and that roughly 30% of patients who are on clozapine qualify as treatment resistant due to inadequate response.
Within this context, Dr. Kane turned to recent approvals and ongoing studies on agents with novel mechanisms of action. In addition to other dopamine receptors, new schizophrenia treatments target the cannabinoid, cholinergic, muscarinic, GABA, glutamate, and trace amine-associated receptor (TAAR) systems, among others.
Dr. Kane listed some recently approved medications, including:
- Lumaterperone, which simultaneously modulates the serotonin, dopamine, and glutamate systems.
- Olanzapine plus samidorphan, which was recently approved in combination to reduce the metabolic effects of olanzapine.
- Sublingual dexmedetomidine, which was approved as a treatment for acute agitation.
Dr. Kane went on to highlight medications being evaluated in ongoing trials, including:
- Pimavanserin, a selective 5-HT2A inverse agonist and antagonist, which is being explored in the treatment of negative symptoms of schizophrenia.
- Ulotaront, a TAAR1 agonist with 5-HT1A activity that has been effective in treating symptoms of schizophrenia exacerbation.
- Xanomeline plus trospium chloride, also called KarXT, an M1/M4-preferring muscarinic agonist that yielded significant improvement in Positive and Negative Syndrome Scale total score compared with placebo.
While Dr. Kane acknowledged the promise inherent in novel mechanisms of treatment, he advised that “we should not assume that they will be more effective than current agents until appropriate studies are conducted.” He also pointed to an increased placebo effect in more recent trials as a growing issue for consideration.
In closing, Dr. Kane emphasized that these are just a small number of recent developments in psychopharmacological treatments for schizophrenia, and he added that he hopes to see novel agents in the future that meaningfully affect the long-term trajectory of illness.
