There are treatment options available for people whose symptoms don’t respond to standard antipsychotic medicines.
Clozapine
The atypical antipsychotic clozapine (Clozaril) is the only medication approved by the U.S. Food and Drug Administration (FDA) to treat TRS.
About half of patients with TRS who take clozapine will have meaningful symptom relief.
Studies show clozapine is associated with a significantly decreased risk of death from any cause, heart disease, or suicide. It’s also the only FDA-approved medicine for decreasing suicidal thoughts or behaviors in people with schizophrenia.
Studies show only about 5 to 20 percent of people who are eligible for clozapine receive it.
“Unfortunately, there are many patients that are not offered a trial of clozapine even though they meet criteria of treatment resistance,” says Kane. “And, there’s a subset of patients for whom clozapine can be life-changing, so it’s a shame when it’s not offered.”
Many providers aren’t well-educated about the benefits of clozapine or don’t feel comfortable prescribing it, notes Kane. Some doctors may be hesitant to recommend the medicine because it can cause severe side effects. (Some serious side effects of clozapine can include seizures, heart problems, respiratory problems, and increased risk of death in elderly patients with dementia-related psychosis.)
Also, clinicians have to monitor patients’ blood frequently while they take the medicine.
However, the FDA announced that it no longer expects prescribers, pharmacies, and patients to participate in the risk evaluation and mitigation strategies (REMS) program for clozapine or to report results of absolute neutrophil count blood tests prior to pharmacies dispensing clozapine. The FDA deemed the REMS program no longer necessary for ensuring that the benefits of clozapine outweigh the risks for each patient. According to the FDA, this change is expected to help make clozapine more accessible.
“Rather than viewing clozapine as a last resort, it should be considered after two unsuccessful trials with other antipsychotics,” says Dr. Cotes. “Initiating clozapine promptly after identifying TRS is crucial, as delays in starting clozapine can reduce its effectiveness.”
Brain Stimulation
Some studies have suggested that brain stimulation techniques could help improve symptoms of TRS, though more research is still needed in this area. These include:
- Electroconvulsive Therapy (ECT) ECT uses an electric current to trigger a brief therapeutic seizure.
- Transcranial Magnetic Stimulation (TMS) TMS uses magnetic pulses to stimulate the brain.
Both ECT and TMS may require multiple treatments and possibly long-term maintenance for lasting results.
Psychotherapy
“Effective treatment for TRS goes beyond medication alone; It is essential to integrate evidence-based psychosocial interventions,” says Cotes.
Psychotherapy doesn’t pose the same side effects as drug therapies, which is one reason it can be advantageous. However, in order for psychotherapy to be effective, patients need to be engaged and consistently able to participate in it.
Other Medicines
Some doctors may treat TRS by combining multiple schizophrenia medications or by using higher doses of schizophrenia medications. However, high-quality studies have not proven that these strategies can benefit people with TRS.
Researchers continue to study potential new treatment options for TRS. In September 2024, the drug xanomeline and trospium chloride (Cobenfy) was approved to treat adults with schizophrenia. Instead of targeting dopamine receptors like other schizophrenia medicines, Cobenfy targets proteins in the brain called muscarinic receptors, which may have an indirect effect on dopamine.
“We don’t know yet if it will be helpful for patients who don’t respond to other medicines, but there will likely be clinical trials,” says Kane.