Treatment-resistant schizophrenia (TRS) means you have symptoms of schizophrenia that don’t respond to standard antipsychotic medications . Although TRS can be debilitating and challenging to manage, know that treatment-resistant doesn’t mean untreatable. It may take time and some trial and error to find the right treatment, but TRS can improve with certain therapies.e60dc2a1-f33c-4a05-9b50-8e3e8e597629610655e8-e8af-45b3-8fe4-22a6e493920b
Overview Definition 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).e60dc2a1-f33c-4a05-9b50-8e3e8e5976294615c1d4-ab8f-42ed-9d26-a285eb11ee17 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298a492094-4458-4755-abce-7668139996c9 Schizophrenia, itself, is an uncommon mental health condition, affecting less than 1 percent of the U.S. population.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e1ce85b6-4332-4458-ad5d-e5ef154f8c3e 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:e60dc2a1-f33c-4a05-9b50-8e3e8e597629a97595d6-aa5f-4ea0-851a-93466f4013a2 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 Symptoms 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:e60dc2a1-f33c-4a05-9b50-8e3e8e5976299b2ad50c-7a81-4459-9943-d9d538f1d5b3 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:e60dc2a1-f33c-4a05-9b50-8e3e8e5976299b2ad50c-7a81-4459-9943-d9d538f1d5b3 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976299b2ad50c-7a81-4459-9943-d9d538f1d5b3 People with TRS can experience any of the above symptoms, but persistent positive symptoms are considered a hallmark feature of the condition.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296fe5288f-d629-4726-9127-3e1972a43450
Causes and Risk Factors of Treatment-Resistant Schizophrenia? Causes 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976294e99ad76-5207-4178-8e31-d558872b3feb “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.e60dc2a1-f33c-4a05-9b50-8e3e8e59762951bd1ed2-421c-443c-9c07-a3d8fe930a1a Although anyone can develop TRS, research suggests people with TRS are more likely than others to have:e60dc2a1-f33c-4a05-9b50-8e3e8e597629559bf074-4a1f-4886-809f-8ca00623b7c9 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? Diagnosis 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:e60dc2a1-f33c-4a05-9b50-8e3e8e597629b2afe59a-443d-47aa-8b9a-b2a799726181 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629b2afe59a-443d-47aa-8b9a-b2a799726181 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? Treatment 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298cd4e146-15e2-4cf8-9813-1f8d0e1e35fc About half of patients with TRS who take clozapine will have meaningful symptom relief.e60dc2a1-f33c-4a05-9b50-8e3e8e597629a30493d5-225e-4274-a29c-195ceda01c4c 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.e60dc2a1-f33c-4a05-9b50-8e3e8e59762979764b1a-d489-4b70-a8ba-2d0d9279ab36 Studies show only about 5 to 20 percent of people who are eligible for clozapine receive it.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296ac3bb7f-e53c-4ba1-83f1-e3a5a5817052 “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.)e60dc2a1-f33c-4a05-9b50-8e3e8e597629c758953b-9942-4421-9315-f49ee6382550 Also, clinicians have to monitor patients’ blood frequently while they take the medicine. “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:e60dc2a1-f33c-4a05-9b50-8e3e8e5976296f177cb6-dd39-44d4-bc0b-799038938c57 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296f177cb6-dd39-44d4-bc0b-799038938c57 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296f177cb6-dd39-44d4-bc0b-799038938c57 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296f177cb6-dd39-44d4-bc0b-799038938c57 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.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297dd2230d-88fa-4e4e-a00a-7010977e38c5 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.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e757e86d-5404-4231-a6f9-493d2de513ba “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 Complications If TRS is untreated or ignored, it can lead to complications, such as:e60dc2a1-f33c-4a05-9b50-8e3e8e5976297c9ee5fb-f0ea-41b7-b3e8-046da3e17987e60dc2a1-f33c-4a05-9b50-8e3e8e59762934951cf3-2977-4b18-a924-41f239df28a3 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 .e60dc2a1-f33c-4a05-9b50-8e3e8e59762929bf3e84-274f-4c0d-afc5-48cecf62ae2b
The Takeaway Treatment-resistant schizophrenia (TRS) is a debilitating mental health condition that doesn’t respond to standard antipsychotic medications. Symptoms, such as hallucinations and delusions that persist even with treatment, are key signs and symptoms of TRS. Despite the name “treatment-resistant,” there are therapies to help treat TRS. Clozapine, the only FDA-approved therapy for TRS, can be life-changing for many people.
Resources We Trust Mayo Clinic: SchizophreniaCleveland Clinic: SchizophreniaAmerican Psychological Association: What Is Schizophrenia?National Institute of Mental Health: SchizophreniaNational Alliance on Mental Illness: Schizophrenia
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