Overview

What Is Treatment-Resistant Schizophrenia?

The general consensus among experts is that TRS is a condition in which an individual’s symptoms haven’t responded to two or more antipsychotic medicines given at a therapeutic dose for at least six weeks. Additionally, there needs to be proof that the patient was taking the medicines with adequate adherence (meaning they’re taking their medication consistently and as directed).

Studies suggest that TRS occurs in about 22 percent of people who have a first episode of psychosis (meaning the first time schizophrenia symptoms appear) and in 39.5 percent of those who have had multiple episodes of psychosis.

Schizophrenia, itself, is an uncommon mental health condition, affecting less than 1 percent of the U.S. population.

Although people with TRS don’t benefit from taking standard medicines, having a diagnosis of TRS doesn’t mean your symptoms won’t respond to other therapies. “TRS does not mean someone is ‘resistant’ to getting help,” says Robert O. Cotes, MD, co-director of the Clinical and Research Program for Psychosis at Grady Health System at Emory University School of Medicine in Atlanta. “People with TRS can still achieve meaningful recovery and lead fulfilling lives.”

Types of Treatment-Resistant Schizophrenia

TRS can be classified into two categories:

Primary TRS This means your condition has been treatment-resistant from the very beginning.
Secondary TRS This means your symptoms might respond to antipsychotics initially but become resistant over time, especially after relapses (recurring symptoms).

Signs and Symptoms of Treatment-Resistant Schizophrenia

People with TRS generally experience the same symptoms as those with classic schizophrenia. “The difference is patients with treatment-resistant illness continue to [have] symptoms, even though they’ve been treated, at least to a moderate degree,” says John M. Kane, MD, a professor of psychiatry and molecular medicine at Feinstein Institutes for Medical Research at Northwell Health in New York, who has performed research on treatment-resistant schizophrenia.

Symptoms of schizophrenia are divided into several categories: positive, negative, disorganized, and cognitive symptoms.

Positive symptoms are symptoms that are abnormally present and involve psychosis, a detachment from reality. Examples include:

Hallucinations (seeing, hearing, or feeling things that really aren’t there)
Delusions (a strong belief in something that’s clearly not true)
Paranoia

Negative symptoms are the absence of expected ways for an individual to interact with their surroundings. They may include:

Lack of motivation to set and accomplish goals (avolition)
Emotional flatness
Social withdrawal
Speaking little even when forced to interact

Disorganized symptoms often involve problems with thinking, speech, and behavior. These symptoms may cause an individual to think or speak in ways that don’t make sense or to move in unusual ways, such as spinning around for no clear reason. Cognitive symptoms can involve problems with concentration, attention, and memory.

People with TRS can experience any of the above symptoms, but persistent positive symptoms are considered a hallmark feature of the condition.

Causes and Risk Factors of Treatment-Resistant Schizophrenia?

The exact cause of TRS is unknown. There are some theories as to why it happens in some people and not others. They include:

Neurotransmitter Dysfunction Some medicines traditionally used to treat schizophrenia are dopamine receptor antagonists, which work by blocking the effects of the neurotransmitter dopamine in the brain.
“The possibility is that those individuals who are treatment resistant have a dysregulation of other neurotransmitters [chemical messengers in the brain] besides dopamine, and therefore, the dopamine antagonists are not exerting a therapeutic effect,” says Dr. Kane.
Repeated Episodes of Psychosis People who experience more episodes of psychosis may become increasingly resistant to medications, notes Kane. “Research has suggested that when patients relapse, when they have a psychotic relapse, they’re not as responsive to medications as they were previously,” he says.
Neuroinflammation Some studies have found that chronic inflammation in the brain and nervous system may make TRS more likely for some people.

Although anyone can develop TRS, research suggests people with TRS are more likely than others to have:

Schizophrenia symptoms that began at a younger age
Longer periods of untreated psychosis
A history of substance abuse
A lack of treatment adherence
A lower level of education

How Is Treatment-Resistant Schizophrenia Diagnosed?

Doctors diagnose TRS by asking about your symptoms and evaluating your condition.

To receive a schizophrenia diagnosis, you must experience at least two of the following symptoms persistently for at least six months:

Delusions
Hallucinations
Disorganized speech
Catatonic behavior, which can range from hyperactivity to coma-like inactivity
Reduced ability to function in ways like inability to keep up one’s hygiene

The criteria also specifies that at least one of the symptoms must be delusions, hallucinations, or disorganized speech.

To qualify for a diagnosis of TRS, you have to first be diagnosed with schizophrenia. Additionally, you must have experienced little or no improvement after taking at least two antipsychotic medications at therapeutic doses as directed for at least six weeks.

An accurate and early diagnosis of schizophrenia and TRS can increase your odds of better health and treatment outcomes. “Unfortunately, there’s often a long delay in [schizophrenia] diagnosis, and there’s data suggesting that a long interval between the onset of symptoms and treatment is associated with a poor response once the treatment begins,” says Kane.

Treatment and Medication Options for Treatment-Resistant Schizophrenia?

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.

Some studies have suggested that a specific type of psychotherapy (talk therapy), called cognitive behavioral therapy (CBT), can be helpful for people with TRS, though further research is needed to confirm this.

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.

Complications of Treatment-Resistant Schizophrenia

If TRS is untreated or ignored, it can lead to complications, such as:

Lower quality of life
Functional impairment
Drug or alcohol dependence
Hospitalization
Higher medical costs
Suicidal thoughts

Research also suggests that TRS may put considerable strain on those who care for someone with the condition. According to research, caregivers often report stress from lost productivity and income, and have an increased risk for depression and anxiety.

Common Questions & Answers

What does it mean to be treatment-resistant?

Treatment-resistant schizophrenia (TRS) means you don’t get better after taking standard treatments for schizophrenia. To be diagnosed with TRS, your symptoms must fail to respond to two or more antipsychotics at a therapeutic dose for at least six weeks. You also need to prove that you took those medicines with adequate adherence.

What’s the best treatment for treatment-resistant schizophrenia?

Clozapine is considered the gold-standard treatment for TRS and is the only FDA-approved medication for this use. Although clozapine can be very effective, it can cause serious side effects, which may make some doctors hesitant to prescribe it.

What are the outcomes of treatment-resistant schizophrenia?

About half of people with TRS will respond to clozapine, which is considered the gold-standard treatment for this condition. For some, the medication can be life-changing.

How can you help someone with treatment-resistant schizophrenia?

The best way to help someone with TRS is to make sure they are seeing a professional mental healthcare provider who can help them find a suitable treatment option.

Angela D. Harper, MD

Medical Reviewer

Angela D. Harper, MD, is in private practice at Columbia Psychiatric Associates in South Carolina, where she provides evaluations, medication management, and psychotherapy for adults.

A distinguished fellow of the American Psychiatric Association, Dr. Harper has worked as a psychiatrist throughout her career, serving a large number of patients in various settings, including a psychiatric hospital on the inpatient psychiatric and addiction units, a community mental health center, and a 350-bed nursing home and rehab facility. She has provided legal case consultation for a number of attorneys.

Harper graduated magna cum laude from Furman University with a bachelor's degree and cum laude from the University of South Carolina School of Medicine, where she also completed her residency in adult psychiatry. During residency, she won numerous awards, including the Laughlin Fellowship from the American College of Psychiatrists, the Ginsberg Fellowship from the American Association of Directors of Psychiatric Residency Training, and resident of the year and resident medical student teacher of the year. She was also the member-in-training trustee to the American Psychiatric Association board of trustees during her last two years of residency training.

Harper volunteered for a five-year term on her medical school's admission committee, has given numerous presentations, and has taught medical students and residents. She currently supervises a nurse practitioner. She is passionate about volunteering for the state medical board's medical disciplinary commission, on which she has served since 2015.

She and her husband are avid travelers and have been to over 55 countries and territories.

See full bio

Julie Lynn Marks

Author

Julie Marks is a freelance writer with more than 20 years of experience covering health, lifestyle, and science topics. In addition to writing for Everyday Health, her work has been featured in WebMD, SELF, Healthline, A&E, Psych Central, Verywell Health, and more. Her goal is to compose helpful articles that readers can easily understand and use to improve their well-being. She is passionate about healthy living and delivering important medical information through her writing.

Prior to her freelance career, Marks was a supervising producer of medical programming for Ivanhoe Broadcast News. She is a Telly award winner and Freddie award finalist. When she’s not writing, she enjoys spending time with her husband and four children, traveling, and cheering on the UCF Knights.

See full bio

Everyday Health follows strict sourcing guidelines to ensure the accuracy of its content, outlined in our editorial policy. We use only trustworthy sources, including peer-reviewed studies, board-certified medical experts, patients with lived experience, and information from top institutions.

Resources

Nucifora Jr FC et al. Treatment Resistant Schizophrenia: Clinical, Biological, and Therapeutic Perspectives. Neurobiology of Disease. August 29, 2018.
Howes OD et al. Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. American Journal of Psychiatry. December 6, 2016.
Diniz E et al. Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates. Brazilian Journal of Psychiatry. September 17, 2023.
What Is Schizophrenia? American Psychiatric Association. March 2024.
Correll CU et al. Treatment-Resistant Schizophrenia: Definition, Predictors, and Therapy Options. The Journal of Clinical Psychiatry. September 7, 2021.
Potkin SG et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. Schizophrenia. January 7, 2020.
Dopamine Antagonists. Cleveland Clinic. May 9, 2023.
Bozzatello P et al. Predictive Factors of Treatment Resistance in First Episode of Psychosis: A Systematic Review. Frontiers in Psychiatry. February 26, 2019.
Diagnosing Schizophrenia. NYU Langone Health.
Jiaqian S et al. Association between treatment resistance and cognitive function in schizophrenia. Singapore Medical Journal. October 2024.
Taipale H et al. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry. February 2020.
de Filippis R et al. Clozapine Management in Schizophrenia Inpatients: A 5-Year Prospective Observational Study of Its Safety and Tolerability Profile. Neuropsychiatric Disease and Treatment. July 2021.
Clozapine. MedlinePlus. January 15, 2022.
Information on Clozapine. U.S. Food and Drug Administration. February 24, 2025.
Katella K. 3 Things to Know About Cobenfy, the New Schizophrenia Drug. Yale Medicine. November 12, 2024.
Kennedy JL et al. The social and economic burden of treatment-resistant schizophrenia. International Clinical Psychopharmacology. March 2014.
Kamil SH et al. Caregivers of individuals with schizophrenia: who are they and what are their challenges? Current Opinion in Psychiatry. May 2019.

Schizophrenia

What Is Treatment-Resistant Schizophrenia?

Overview