A genomic study will help to predict which patients with schizophrenia might benefit from early treatment with clozapine

There is a very effective drug for the treatment of patients with schizophrenia, clozapine, but it has a drawback. Its use is associated with an adverse effect that, although is not very frequent, can be very serious: agranulocytosis, a disorder that significantly compromises the immune system. Therefore, clozapine is indicated for patients who do not respond adequately to first- and second-line drugs.

One of the problems that psychiatrists face in making this decision is the lack of tools to predict which patients will not fully respond to the first lines of treatment. Until now, it is necessary to try and wait to see the results, which can take weeks, months or years. All this time, the patients who do not respond adequately present relapses and/or admissions, compromising their functionality and quality of life and worsening their long-term prognosis.

Now, a study in which Dr. Justo Pinzón Espinosa, a researcher from the Mental Health Group of the Research Institute of the Hospital de la Santa Creu i Sant Pau – IIB Sant Pau -led by Dr. María Portella-, signs as first author shared with Dr. Bochao Lin, from the University of Maastricht and led by Dr. Jurjen Luykx, from the University of Utrecht, brings to the table a novel genomic tool. This would help to predict which patients will respond poorly to conventional treatments and, therefore, would be early candidates for treatment with clozapine. In this way, symptom control, quality of life and its evolution could be improved.

The study was carried out as part of the doctoral thesis of Dr. Pinzón Espinosa at the University of Barcelona, whose directors are Dr. Narcís Cardoner Álvarez, head of the Psychiatry service at Hospital de Sant Pau and Dr. Jurjen J. Luykx , from the Department of Psychiatry of the University of Utrecht and the University Medical Center Utrecht, in the Netherlands.


Schizophrenia is a serious mental disorder that affects about 24 million people worldwide, that is, 1 in 300 individuals. It is characterized by a significant deficiency in the way reality is perceived and by changes in behavior and affective and cognitive symptoms that can significantly affect the quality of life of patients. It most frequently appears at the end of adolescence or between 20 and 30 years of age, and in men it usually manifests earlier than in women.

Clozapine is an antipsychotic indicated for the treatment of resistant schizophrenia, or in patients who present serious adverse reactions to other drugs. It is estimated that more than a third of people with this disease can achieve complete remission of symptoms with proper treatment. Some patients experience recurrent worsening and remission of symptoms throughout life, and others a gradual worsening of symptoms over time.

As explained by Dr. Pinzón Espinosa, “approximately one in three patients is resistant to treatment. This implies that we give them a drug and, if it doesn’t work, we go to the second line. If it fails again, then we switch to clozapine, but a couple of years may have passed along the way and the patient may have had serious relapses, with all that this implies in their affective, family, and work daily lives… we are talking about very patient patients. Most of them are young, and for many of them exacerbations can mean dropping out of school, sick leave, relationship problems, isolation at home and, above all, mental suffering”.

In this study, published in the journal JAMA Psychiatry, the polygenic risk score for schizophrenia (PRS-SCZ) was used and “for the first time in the world we have been able to discern which group of patients has the highest polygenic load of risk of schizophrenia, associating its severity with genetic factors and stratifying them to predict their need for treatment with clozapine six years from now”, details Dr. Pinzón.

“In most diseases, such as high blood pressure, diabetes, heart attack or schizophrenia, multiple altered genes are involved that gradually add risk. When you add up all the alterations, you can determine if a specific person has a higher or lower risk of developing a disease. It is what we call genetic predisposition”, explains Dr. Pinzón.

“We know that schizophrenia has up to 80 percent genetic component. What we have achieved in this study is to be able to predict the poor response of patients to first-line treatments and second line through their genomic data, with which we can detect patients who are candidates to receive clozapine in the first line, saving them episodes of exacerbation, loss of functionality and suffering, being able to go directly to a treatment that will be effective for them”.

The researchers analyzed data from 2,300 participants from two cohorts from Belgium, Turkey, the Netherlands, and Spain. Genomic information from patients, their siblings, parents, as well as unrelated healthy controls was studied and compared with worldwide databases of the Psychiatric Genomics Consortium.


These findings represent a great advance to be able to personalize the treatments in patients with schizophrenia. “This tool is the first step towards what we are looking for, which is precision psychiatry or personalized medicine applied to psychiatry”, in the words of Dr. Pinzón.

For its part, a group of researchers from the University of Utrecht led by Dr. Luykx has carried out a study in which they analyzed the genomic variants that help predict which patients have a higher risk of developing agranulocytosis secondary to treatment with clozapine. Now, among the next steps, a prospective study is planned to help validate this tool in order to transfer it to clinical practice.

 Reference article 

  • Bochao D. Lin, PhD; Justo Pinzón-Espinosa, MD, MSc; Elodie Blouzard, MSc; Marte Z. van der Horst, MD; Cynthia Okhuijsen-Pfeifer, PhD; Kristel R. van Eijk, PhD; Sinan Guloksuz, MD, PhD; Wouter J. Peyrot, MD, PhD; Jurjen J. Luykx, MD, PhD; for the Genetic Risk and Outcome of Psychosis (GROUP) and Clozapine International Consortium (CLOZIN) Investigators. JAMA Psychiatry. 2023;80(2):181-185. doi:10.1001/jamapsychiatry.2022.4234

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