top of page

Day # 19: Treatment-Resistant Schizophrenia

I have great news to share with all of you. This website has only been around for a few weeks at the time of writing this post and I just received news that Bullet Psych was added to the Top 50 Psychiatry Blogs and Top 100 Psychology Blogs on the internet. Thanks to all of you who continue to visit the site. I hope it is providing value to you.

Now that we have discussed antipsychotic medications it will be helpful to take one day to give an introduction to treatment-resistant schizophrenia. After this lesson, we will take one day to discuss some specifics about clozapine.

Today's Content Level: Intermediate; Advanced

Definition of Treatment-Resistant Schizophrenia

•Antipsychotic medication is first-line treatment for schizophrenia and other psychotic spectrum disorders. Many patients will have substantial improvement in psychotic symptoms. In the case where patients do not respond, it is helpful to have a framework for these cases.

•There have been many attempts to define treatment-resistance. In 2017 an international panel of experts formed the Treatment Response and Resistance in Psychosis (TRRIP) work group and published the following definition. 1

Minimal TRRIP criteria:

  • Must have DSM-V diagnosis of schizophrenia.

  • Must have at least moderate symptom severity (>3) using a standardized scale (PANSS or BPRS).

  • Must have at least moderate functional impairment using validated scale (Social and Occupational Functioning Assessment Scale).

  • Inadequate response to at least two antipsychotic trials of ≥6 weeks at therapeutic dose with adherence ≥80% of prescribed doses.

Optimal TRRIP criteria:

  • Symptom reduction <20% over six weeks using standardized scale (PANSS or BPRS)

  • +/- One of the two antipsychotics should ideally be a long-acting injectable.

  • Antipsychotic adherence should be confirmed by ≥2 plasma levels.

•Prevalence is difficult to ascertain due to lack of consensus criteria prior to 2017. However, it is more common than we may realize. Some studies have shown: ~50% failed to respond with one trial of antipsychotic medication 2, only 16.6% who failed the first antipsychotic responded to the second trial 3, and one cohort study showed that at 10 year follow up ~23% met treatment-resistance criteria 4.


•The treatment of choice for treatment-resistant schizophrenia is clozapine, which has superior efficacy in this population compared with other antipsychotics 5.

•As we will discuss in more detail tomorrow, clozapine can cause significant adverse effects and has complicated management implications. Because of this there are a number of steps that should be taken prior to a clozapine trial.

  • Assess for other causes of residual symptoms. AKA = "pseudo-resistance".

  • Optimize nonpharmacologic treatment.

  • Optimize current antipsychotic drug treatment.

Other causes of residual symptoms ("pseudo-resistance"): Potential confounding factors include re-evaluating the primary diagnosis (is this really schizophrenia?), considering other co-ocurring conditions (medical illness, substance use, etc.), are residual symptoms actually side effects of medications (akathisia, sedation, insomnia, parkinsonism, etc.).

Optimize nonpharm interventions: Full Bullet Psych article on this topic here. Some options include CBT, DBT, family psychoeducational interventions, social skills training, crisis intervention, case management, and assertive community treatment.

Optimize current antipsychotics: First off, non-adherence to antipsychotic drugs is often overlooked yet is a common reason for "non responders". As discussed yesterday, the main outcome of the NICE trial was not continuing with treatment. Some options include arranging for supervised medication intake, checking blood levels, and trialing a long-acting injectable. Also ensure that it truly was an adequate trial for at least six weeks at the maximally tolerated dose. If switching medications, consider very small increased benefit of olanzapine, asenapine, and risperidone.

•If these steps do not lead to symptom remission, and the patient has had at least two antipsychotic trials of ≥ 6 weeks at adequate plasma levels of drugs then clearly the next recommend step is to proceed to a clozapine trial.

•Tomorrow we will discuss clozapine in detail.

•If the patient fails a 24-week trial of clozapine they are often termed to have "clozapine-resistant schizophrenia". Treatment in this population is difficult and deserves an article for a different day, but some options include ECT augmentation, TMS, SGA (often aripiprazole), and lamotrigine. Studies are mixed in terms of effectiveness.


I hope you learned something from today's article. This is an advanced topic and deserves more of your attention than just this overview. I highly encourage reading the original research and articles referenced in this post as well as other lit reviews that you find. Tune back in tomorrow for a discussion on clozapine and our last post for this current theme (Intro to Psychotic Spectrum Disorders).

Resources for today's post include:

And the articles referenced in the main text

See our full list of book recommendations

If you enjoy this content and would like to support the website then consider donating

Bullet Psych is an Amazon Associate and we receive a small commission if you use our links for the purchase of our recommended resources.

1,352 views1 comment

Recent Posts

See All

1 Comment

That's really great news! I'm glad your efforts are being recognized!

bottom of page