Treating schizophrenia can involve finding what works best for you. However, when symptoms persist despite multiple trials of medication, you may be living with treatment-resistant schizophrenia (TRS).
Hallucinations, delusions, and disorganized thinking that accompany schizophrenia can be challenging to manage. Known as symptoms of psychosis, these experiences indicate a lapse in the ability to distinguish reality.
Medications can help control psychosis and the other symptoms of schizophrenia. When symptoms don’t respond to first-line medication options, treatment-resistant schizophrenia (TRS) is suspected.
TRS doesn’t respond to two or more medications, each taken at a sufficient dose and duration with proper adherence. This means that even when medications are prescribed at an effective dose for the recommended amount of time and taken exactly as directed, they don’t effectively manage your symptoms.
TRS isn’t an official diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR). This is the primary clinical guidebook used in the United States and many other countries for diagnosing mental health conditions. Instead, it’s a clinical term used by medical professionals to describe schizophrenia following a specific treatment pattern.
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Overall, schizophrenia is considered a rare mental health disorder, affecting approximately
TRS isn’t recognized as a diagnosis apart from treatment-responsive schizophrenia.
TRS exists with the same set of symptoms, which are divided into two categories outlined in the DSM-5-TR: positive and negative.
Positive symptoms
Positive symptoms add to your current function and ability. Positive symptoms of schizophrenia include:
- delusions
- hallucinations
- disorganized thoughts
- disorganized behavior
Negative symptoms
Negative symptoms are those that take away from your baseline abilities. In schizophrenia, these include:
- blunted affect (diminished emotional expression)
- alogia (speech quantity reduction)
- avolition (lack of motivation and goal-directed activity)
- asociality (withdrawal)
- anhedonia (diminished pleasure experience)
The earlier 2020 review notes the persistent presence of negative or positive symptoms may indicate TRS. However, it’s the continued experience of positive symptoms that’s considered a defining feature of this condition.
Much is yet to be understood about the best therapeutic approaches for TRS.
Some experts believe that TRS may be a true subtype of schizophrenia, with different pathological markers, which require non-traditional treatment approaches.
Currently, both the American Psychiatric Association (APA) and the British Association of Psychopharmacology (BAP) consider the atypical antipsychotic medication clozapine to be the main treatment of choice for TRS.
Clozapine is the only medication with proven efficacy against TRS.
However, medication is just one component of effective treatment.
Candace Kotkin-De Carvalho, a licensed clinical social worker from Morris Plains, New Jersey, explains that treating TRS with a multidisciplinary approach involving medication, psychotherapy, and alternative interventions can yield favorable outcomes.
“People living with this condition should also take steps to improve their overall health and well-being, such as participating in physical activity, engaging with others socially, and practicing healthy sleep habits,” she says.
Why isn’t clozapine the first-line antipsychotic for all schizophrenia cases?
If clozapine is useful when other antipsychotics fail, you may wonder why it’s not considered a first-line approach.
In the United States, clozapine comes with a Food and Drug Administration (FDA) black box warning for serious health complications, including:
- agranulocytosis
- seizures
- myocarditis
- adverse cardiovascular and respiratory effects
- increased mortality in older adults with dementia-related psychosis
Due to these potential complications, medical professionals require weekly bloodwork for the first 6 months of using clozapine. After 6 months, patients must undergo biweekly bloodwork for another 6 months and monthly bloodwork for the remainder of treatment.
Managing clozapine-treatment-resistant schizophrenia
Approximately 40% to 70% of clozapine-treated people living with schizophrenia don’t respond to the medication. When clozapine is ineffective, experts may refer to this as ultra-TRS, although like TRS, this isn’t an official DSM-5-TR diagnosis.
Clinicians may try a joint approach to managing ultra-TRS. This involves using clozapine in conjunction with supportive therapies and other pharmacological agents like brexpiprazole or aripiprazole.
In a small 2019 study of 10 TRS and schizoaffective disorder cases, researchers noted that pimavanserin, an antipsychotic for treating Parkinson’s disease, saw success when clozapine was ineffective.
Psychotherapy and other interventions are also part of managing TRS. These approaches may include:
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The research found that other supportive therapies, including metacognitive training, family intervention, and virtual reality intervention, also helped manage positive symptoms of schizophrenia.
Music therapy, body-oriented intervention, and occupational therapy showed promise for managing negative symptoms.
The exact causes of TRS are unknown. However, research suggests there are several structural and functional brain alterations between TRS and treatment-responsive schizophrenia.
Differences noted in TRS include:
- a greater reduction of gray matter, particularly in frontal regions of the brain
- a decreased thickness of the dorsolateral prefrontal cortex
- an increased basal ganglia white matter volume
- decreased global functioning connectivity in thalamocortical circuits and thalamic subregions
Not all cases of TRS present with different neurobiology (relating to the nervous system) than treatment-responsive cases. For this reason, many researchers are reluctant to indicate neurobiology as the only underlying cause of TRS.
Other factors may increase the risk of TRS. A 2019 study of more than 1,000 people found treatment resistance was more likely with:
- an early age onset of psychosis
- issues with functioning before symptom development
Causes of schizophrenia
The causes of schizophrenia, treatment-resistant or otherwise, are also a point of ongoing research. To date, multiple factors have been found to potentially increase the chances you’ll experience schizophrenia, such as:
- genetics
- substance use
- exposure to certain environmental factors before birth
- certain autoimmune disorders
- dysfunction of the neurotransmitters dopamine and glutamate
If schizophrenia symptoms persist even after you’ve been on two full courses of different medications, you may be experiencing TRS.
Clozapine, an antipsychotic medication proven effective in some TRS cases, may be your doctor’s next recommendation.
Schizophrenia is a lifelong condition, and clozapine or other medications may help ease symptoms. However, effective treatment often involves a dynamic approach, including social and functional supports and behavioral therapy approaches.