Pioneer in Clozapine Research Wins Major Psychopharmacology Award
Abstract
Herbert Meltzer, M.D., describes how his studies of clozapine resulted in the first FDA approval of a medication to treat a symptom of schizophrenia beyond delusions and hallucinations.
To get to middle school in the 1950s, Herbert Meltzer would walk past Brooklyn State Hospital, the largest mental health hospital in Brooklyn, N.Y. It was on these daily walks that Meltzer first witnessed what he described as “the struggles of the mentally ill” and felt drawn to a career in psychiatry.
Great success in psychopharmacology often requires clinicians to have “one foot in the clinic and one foot in the laboratory,” says Herbert Meltzer, M.D.
Decades later, Meltzer, who earned his medical degree in1963, is known for his groundbreaking research, including the discovery that clozapine helps to reduce suicidality in patients with schizophrenia and efforts to advance the development of pimavanserin to treat Parkinson’s-related psychosis as well as other psychoses, including schizophrenia.
Last month, the International College of Neuropsychopharmacology (CINP) announced that it had selected Herbert Meltzer, M.D., a professor of psychiatry and director of the Translational Neuropharmacology Program at Northwestern University Feinberg School of Medicine, to receive its Pioneer in Psychopharmacology Award. This is a biennial honor given to individuals who have made major contributions to the field of psychopharmacology.
In an interview with Psychiatric News, Meltzer described his contributions to psychopharmacology and shared his thoughts on what’s next for the field.
Q: What do you see as your contribution to the field of psychopharmacology?
A: I was a pioneer in research related to the second wave of drug treatments for schizophrenia, which I helped to label as “atypical antipsychotic drugs”—in particular the drug clozapine.
In the 1980s I received permission from Sandoz (now Novartis) to study the mechanism of action of clozapine, including its ability to treat severe tardive dyskinesia. During the course of this work, I observed that clozapine decreased delusions and hallucinations in patients with tardive dyskinesia who had been resistant to the effects of typical antipsychotic drugs such as haloperidol. Additional tests revealed that clozapine was more effective for treating treatment-resistant schizophrenia than other antipsychotic drugs.
In 2003, as part of the International Suicide Prevention Trial (InterSePT), I led a group that discovered clozapine was not only effective in treating psychosis in treatment-resistant patients, but it demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia or schizoaffective disorder at high risk for suicide.
Prior to this study, the FDA approved drugs for schizophrenia that treated only psychosis associated with schizophrenia. Our findings led the FDA to approve clozapine as an indication for suicide.
We also discovered and published the first evidence showing that clozapine, as well as its active metabolite N-desmethylclozapine, could improve some domains of cognitive impairment in some patients with schizophrenia.
Q: Clozapine received some attention in 2015, after the Food and Drug Administration (FDA) modified its requirements for monitoring, prescribing, dispensing, and receiving clozapine. What do you think of the strategy?
A: The FDA’s risk evaluation and mitigation strategy (REMS) provided some help to remedy the underutilization of clozapine, but I believe additional changes in monitoring for agranulocytosis are needed.
Clozapine is the only drug approved for treatment-resistant schizophrenia and for suicide in schizophrenia yet it is not widely used for several reasons—one being the indefinite monitoring for agranulocytosis, a condition characterized by the loss of white blood cells.
Considering the very low risk of clozapine-induced agranulocytosis after a year of treatment, I do not believe monthly monitoring of white blood counts is effective and may deter some patients from starting or continuing treatment. I would like to see the FDA to consider stopping monthly monitoring of white blood counts after a year and review the current mitigation strategy with input from the community—the patients, their families, and clinicians.
Q: Pimavanserin is another medication you studied that has been in the news lately, after it became the first drug approved by the FDA to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease. Can you describe your research on this medication?
A: Roughly 25 years ago, Mark Brann, the founder of Acadia Pharmaceuticals and maker of pimavanserin, and I discussed creating a selective-serotonin 2A blocker that would lack the capacity to block dopamine D2 receptors (which are known to be responsible for the extrapyramidal side effects of typical antipsychotics) for the treatment of psychosis.
After identifying pimavanserin as a suitable drug candidate, it was necessary to determine how to test its antipsychotic potential. At that time, Acadia did not have the funds to test the drug as a treatment for schizophrenia, so I suggested that it be tested as a treatment for L-DOPA psychosis, which would require a smaller sample population and a shorter treatment period to determine its efficacy.
In 2010, my colleagues and I published the first paper showing that L-DOPA psychosis of Parkinson’s disease could be treated with pimavanserin, a non-dopamine blocker.
We later evaluated the efficacy of pimavanserin as an adjunctive therapy to other atypical antipsychotics for patients with schizophrenia. We found that patients who received a combination of pimavanserin and a low dose of risperidone showed significant improvements after 15 days compared with those who received the standard dose of risperidone, which required six weeks of treatment. Additionally, the side-effect burden of low-dose risperidone and pimavanserin was markedly less than that of standard-dose risperidone.
Q: Over the course of your career, you have witnessed several transitions in the field. What are your views on the field of psychopharmacology today?
A: Basic psychopharmacology is flourishing. Knowledge about how drugs work is expanding greatly. All signs point toward synaptic plasticity and gene expression as the major novel targets for treating neuropsychiatric disorders.
I think pharmacogenetics is a key to the future for psychopharmacology. Pharmacogenetics will allow clinicians to tailor medications with much less trial and error. The greatest challenges associated with new drug development and pharmacogenetics studies are the design and execution of clinical trials.
My current research includes a major focus on identifying genetic biomarkers for antipsychotic drug response and predictors of suicide attempts.
Q: What advice do you have for early career psychopharmacologists?
A: I think the secret to my success is that I have had one foot in the clinic and one foot in the laboratory. Witnessing the positive effects of clozapine on patients firsthand inspired me to seek how the medication works and question what medications might do this even better.
I would like to see more individuals leading research teams in psychopharmacology who have expertise in both clinical and basic science. ■
