More Research Needed for Treatment of Clozapine-Resistant Schizophrenia


Current evidence and data regarding clozapine-resistant schizophrenia is unclear, but new treatment options are on the horizon that could show promise.

The first 3 years after diagnosis of schizophrenia are a critical time to start clozapine treatment, said Megan J. Ehret, PharmD, MS, BCPP, professor and co-director of Mental Health Program University of Maryland School of Pharmacy in a session at the American Association of Psychiatric Pharmacists Conference 2024.

Mental health conditions, schizophrenia diagnosis and treatment with antipsychotic medication and psychotherapy. | Image Credit: Olivier Le Moal -

Image Credit: Olivier Le Moal -

Treatment resistance schizophrenia is classified as nonresponse to at least 2 antipsychotic medications. Currently, the gold standard for schizophrenia is clozapine, but patients can also have a nonresponse to this therapy as well.

“We're moving away from treatment resistant to difficult to treat. Telling a patient their treatment resistant makes it very challenging to get buy in on them . . . And so, there's movement and change in our language,” Ehret said in the session.

Clozapine nonresponse is defined as persistence of either positive, negative, or cognitive symptoms of schizophrenia of at least moderate severity after an adequate trial of clozapine. Patients with a nonresponse would have either 2 symptoms or more with at least moderate severity or 1 or more with at least a severe rating, according to Ehret. Current limitations for clozapine-resistance schizophrenia are considerable heterogeneity in randomized control trials as well as different or absent definitions of clozapine-resistant schizophrenia. Ehret said that in about half of the time clozapine is combined with another antipsychotic.

“Making sure that you have an adequate level of dosing is going to be vital to your patients,” Ehret said in the session. “Making sure that you've had it for an adequate time, that you have time to titrate to that minimum 2 to 3 months, sometimes more. It's for those with negative symptoms.”

The mean age of patients who have clozapine resistant schizophrenia is 38 years and the mean Positive Negative Syndrome Scale (PANSS) baseline is 79. Further, the Brief Psychiatric Rating Scale of patients who are clozapine resistant had a mean score of 40.9. Ehret recommended that providers and pharmacists should not discontinue clozapine or switch to an alternative pharmacological treatment. She recommended that providers should review the patient’s current symptoms, optimize clozapine, and potentially augment clozapine, but not replace the therapy. Further, she said that non-pharmacological treatments are also acceptable for some patients.

When considering patients, Ehret said that pharmacists and providers can predict clozapine resistance by considering risk factors, which include older age; greater severity of schizophrenia symptoms, especially negative symptoms; poorer function; and non-paranoid subtypes.

“40 to 70% of patients who have treatment resistant schizophrenia aren’t going to benefit from a monotherapy with clozapine,” Erhet said in the session.

Currently, the recommendation for patients with refractory positive symptoms or mixed symptoms is to combine clozapine with antipsychotics, such as aripiprazole and amisulpride, or to augment with electroconvulsive therapy (ECT). For patients with negative symptoms, clozapine should be combined with antidepressants, whereas for patients with aggression, mood stabilizers and other antipsychotics should be added to clozapine, according to Ehret.

There are currently limitations in treatment, with relatively lackluster data. For aripiprazole, Ehret highlighted 7 studies, but only 2 were high quality. Overall, data showed that there were statistically significant reductions for total psychosis scores, but not for positive or negative symptoms. When restricted to only data of higher quality, the significance was lost. However, real world outcomes showed that the combination of aripiprazole and clozapine is better than clozapine monotherapy. Additionally, for amisulpride, 3 studies did not show significant results.

For antidepressants, there are currently no specific studies investigating the augmented therapy of citalopram and escitalopram. There were 6 studies for fluoxetine, which showed significant reductions in total psychosis, but when only including the higher quality studies, the significant was also lost.

In 1 study of ECT, treatment included a bilateral course of ECT and clozapine, which reduced total psychosis scores. For that study, 6-month follow-up data should be available later this year. Ehret noted that PANSS scores in this trial were greater than 60 with a baseline of 101, indicating that patients had severe schizophrenia. Treatment showed that only 42% of 19 patients had a 10% or greater reduction in severity and only 1 individual had a 50% reduction or greater, according to Ehret.

Mood stabilizers have also been used, including lithium, lamotrigine, and valproic acid. Lithium has shown reductions in total psychosis and positive symptoms, but not negative symptoms. Valproic acid was similar, but there is a risk in pregnancy, according to Ehret, and lamotrigine had no improvements.

Studies have also investigated fluvoxamine, which can alter clozapine levels and ratios, but the studies have not reported on the changes in these levels, so the correlation between increased levels and improvement in positive symptoms is unclear. Further, studies have shown that risperidone augmentation had no significant differences across total psychosis compared to the placebo.

Ehret also discussed long acting injectables (LAI), including 5 retrospective observational studies that showed significant reduction in severity of global, positive, negative, depressive, and cognitive symptoms. Further, LAIs reduced the dose of medications, reduced the number and length of hospitalizations, and reduced emergency room visits. However, she said that LAIs require more research.

There are notable new medications in the pipeline, Ehret said. Lumateperone could introduce a new mechanism of action and is a 5-HT2A receptor antagonist. It has been shown to be well-tolerated and could be beneficial. Furthermore, xanomeline-trospium, a muscarinic receptor antagonist, is a strong candidate for augmentation strategies but could have gastrointestinal adverse events, according to Ehret.

Pimavanserin is also a 5-HT2A receptor antagonist that is being studies as an add-on therapy for negative symptoms of schizophrenia and for augmentation to antipsychotic medications. However, Ehret said that it has not helped positive symptoms. Ulotaront, a TAAR1 agonist, is currently in phase 3 clinical development for the treatment of schizophrenia. It has the potential to treat both negative and positive symptoms, but comes with adverse effects, according to Ehret.

Lastly, Ehret discussed LU AF 35700, an antagonist of dopamine 1, which has 2 clinical trials comparing the drug with risperidone or olanzapine. There have been no improvements seen over either drug, but it could be helpful as an add-on therapy with further research.

Ehret acknowledged that there needs to be new research in this area, including diagnostic investigations, risk factors, translational research, and management of schizophrenia.

“We can all work together. When our clinicians present these patients to us, or when we see them in practice, and they’re not responding to anything, not even clozapine,” Ehret said in the session. “Let’s take a step back from it and say, ‘let’s talk about diagnosis. I know it's out of our scope, but let's talk about diagnosis.’”


Ehret MJ. Management of Clozapine-Resistant Schizophrenia. American Association of Psychiatric Pharmacists Conference 2024; Orlando, Florida; April 7-10, 2024.

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