Treating schizophrenia can involve finding what works best for you, but 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 is suspected.

Treatment-resistant schizophrenia is schizophrenia that doesn’t respond to two or more medications, each with at least 6 weeks of treatment duration.

A 2020 review notes TRS impacts approximately 34% of people living with schizophrenia. However, estimates in earlier research suggest that the number could be as high as 50%.

Overall, schizophrenia is considered a rare mental health disorder, affecting approximately 0.32% of the global population.

Treatment-resistant schizophrenia (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 Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR). The two categories are positive and negative.

Positive symptoms

Positive symptoms are symptoms that are added to your current function and ability. Positive symptoms in 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)

While the 2020 review notes the persistent presence of negative or positive symptoms may indicate TRS, it’s the continued experience of positive symptoms that’s considered a defining feature of treatment-resistant schizophrenia.

Much is yet to be understood about the best therapeutic approaches for treatment-resistant schizophrenia.

Some experts believe that TRS may be a true subtype of schizophrenia, with different pathological markers, which warrant 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 primary treatment of choice for TRS.

Clozapine is the only medication with proven efficacy against treatment-resistant schizophrenia.

Medication is just one component of successful treatment, however.

Candace Kotkin-De Carvalho, a licensed clinical social worker from Morris Plains, New Jersey, explains that TRS can also see success when treated with a multidisciplinary approach involving medication, psychotherapy, and alternative interventions.

“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 elderly patients 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.

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Managing clozapine-treatment-resistant schizophrenia

Approximately 40% to 70% of clozapine-treated people with schizophrenia don’t respond to the medication. When clozapine is ineffective, experts may refer to this as ultra-treatment-resistant schizophrenia, although this isn’t an official DSM diagnosis.

In order to manage ultra-treatment-resistant schizophrenia, clinicians may try an augmented approach, which involves using clozapine in conjunction with other pharmacological agents like brexpiprazole or aripiprazole, as well as supportive psychotherapy approaches.

Among these approaches may be:

In a small 2019 study of 10 treatment-resistant schizophrenia and schizoaffective disorder cases, researchers noted that pimavanserin, an antipsychotic medication used in Parkinson’s disease, saw success when clozapine was ineffective.

The exact causes of treatment-resistant schizophrenia are unknown, but research suggests that a number of structural and functional brain alterations can exist between treatment-resistant schizophrenia and treatment-responsive schizophrenia.

Differences noted in TRS include:

  • greater reduction of gray matter, particularly in frontal regions of the brain
  • decreased thickness of the dorsolateral prefrontal cortex
  • 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 than treatment-responsive cases. For this reason, many researchers are reluctant to indicate neurobiology is the only underlying cause of TRS.

Other factors may increase the chances of TRS. A 2019 study of more than 1,000 people found treatment resistance was more likely with:

  • early age onset of psychosis
  • poor levels of functioning prior to symptom development

An earlier study from 2007 suggests that TRS may be related to the extent of neuronal damage present in some schizophrenia cases.

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 treatment-resistant schizophrenia.

Clozapine, an antipsychotic medication proven effective in some TRS cases, may be your doctor’s next recommendation.

Schizophrenia is a lifelong condition, and while clozapine or other medications may help alleviate symptoms, successful treatment often involves a dynamic approach, including social and functional supports, as well as behavioral therapy approaches.