Treatment-resistant schizophrenia occurs when initial antipsychotics haven’t improved your schizophrenia symptoms. Options, such as Clozapine, may help you manage your condition.

Antipsychotic medications help many people manage symptoms of schizophrenia, such as hallucinations and delusions.

But sometimes, symptoms don’t respond to these first-line treatment approaches. This is known as treatment-resistant schizophrenia (TRS).

While it may take time and some trial and error, you may still see improvement in symptoms with other treatments for schizophrenia.

Schizophrenia affects 1 in 300 people worldwide. Most doctors recommend antipsychotic medications as a first-line treatment approach. But, up to 34% of people with schizophrenia are resistant to treatment.

TRS is when you try two or more first-line schizophrenia medicines, each for at least 6 weeks at the correct dose, and still don’t see improvement in your symptoms.

It can make managing schizophrenia a challenge and make it harder to recover functional and social skills.

Treatment resistance can occur from the first episode of schizophrenia, or it may occur later in the course of your condition.

According to 2021 research, many patients experience primary or secondary treatment resistance:

  • Primary TRS: is present from the beginning of treatment
  • Secondary TRS: you may initially respond to antipsychotics but become resistant over time

Relapses also increase your risk of future treatment resistance.

Treating schizophrenia can involve finding what works best for you. But if you don’t see improvement in your symptoms after trying at least two other antipsychotic drugs, there may be other options.


Clozapine is an FDA-approved atypical antipsychotic medication for treatment-resistant schizophrenia. It’s the only medication that’s been shown to be effective in treating TRS.

A 2017 study found that patients who began taking clozapine earlier than 2.8 years from the start of TRS had an 82% response rate. Those who started treatment after 2.8 years of TRS had a 31% response rate.


Several recent studies suggest clozapine is superior to other antipsychotics in:

  • improving total and positive (but not negative) symptoms
  • decreasing relapse
  • preventing hospitalization
  • reducing the risk of suicide and the mortality rate

Side effects and complications

Because clozapine can cause serious health complications, doctors prescribe it only after other medications haven’t been effective. They also require you to have regular blood work while you’re taking clozapine.

Potential complications of clozapine include:

  • seizures
  • cardiovascular and respiratory problems
  • agranulocytosis, a severe form of neutropenia, which involves having low levels of white blood cells
  • myocarditis, inflammation of the heart muscle
  • increased mortality in older people with dementia-related psychosis

Side effects are also common with clozapine, but many subside weeks or months after starting the medication. Side effects may include:

  • excessive salivation
  • constipation
  • sedation
  • tachycardia, a faster than average heart rate
  • urinary retention
  • sexual dysfunction

To help manage side effects, your doctor may start you on a low dosage of medication and gradually increase it.

Other treatments

Although there’s little research on the effects of other treatments for TRS, many people with schizophrenia benefit from combining medication with psychotherapy and other steps to improve their overall health and well-being.

These may include:

  • cognitive behavioral therapy (CBT) can help you understand and manage symptoms, and improve life and social skills
  • regular physical activity
  • healthy sleep habits
  • social engagement
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When you have TRS, you continue to experience symptoms of schizophrenia. This typically includes positive symptoms, which are changes in thoughts or behavior, or things that are “added” to your experiences. They include:

  • delusions
  • hallucinations
  • disorganized thoughts and behavior

But you may also experience negative symptoms, and they may be more severe. Negative symptoms are things that impact your abilities. These may include:

  • Blunted affect: diminished emotional expression
  • Anhedonia: inability to experience joy or pleasure
  • Alogia: reduction in speech
  • Avolition: complete lack of motivation
  • Social withdrawal: decreased interest in forming social connections

It’s not exactly clear what causes resistance to antipsychotic treatment. But 2021 research suggests several factors may increase the risk of TRS:

  • being male with a family history of psychosis
  • longer duration of illness or untreated psychosis
  • more severe negative symptoms
  • poor levels of functioning prior to developing symptoms
  • structural and functional brain alterations

If you continue to have schizophrenia symptoms after taking at least two antipsychotic medications, talk with your doctor. They will evaluate your symptoms and treatment plan to determine if you have treatment-resistant schizophrenia.

Your doctor may recommend clozapine, an antipsychotic medication that can be effective for some people with TRS. They may also suggest additional treatments, such as cognitive behavioral therapy, and lifestyle tips.

Together, you can find the best combination of treatment and support to help you manage your condition and the impact it has on your life.