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Tips on Choosing an Antipsychotic for Schizophrenia

The Carlat Psychiatry Blog, Volume , Number ,

Which antipsychotics should we consider selecting as the first-line and second-line treatments, and what should we base this decision on? Dr. Aziz addresses this in a past article from The Carlat Psychiatry Report. Here’s some of his advice:


  1. Tolerability instead of efficacy should be considered when selecting a first-line treatment. “If it’s not tolerable, switch to an option with a different side effect profile”.
  2. Tolerability and efficacy should be the main determinants when choosing a proper second-line treatment, after 4 weeks of an inadequate response to the first-line treatment.
  3. Move to clozapine quickly for treatment-resistant cases, defined as a failure to respond to 2 or more antipsychotics.

Antipsychotic Selection in Schizophrenia:

First-Line Treatments. 

  • “Aripiprazole, risperidone, ziprasidone, and cariprazine are good starting places”. 
  • Particularly, aripiprazole and, if cost is not an issue, cariprazine “stand out for their mild benefits in negative symptoms and favorable long term side effect profiles”. However, aripiprazole-treated patients are more likely to experience akathisia.

Second-Line Treatments. 

  • “Options include an alternate second-generation antipsychotic, risperidone if not already tried, olanzapine, or a first-generation antipsychotic”. 
  • If efficacy is the main concern, then olanzapine is a great choice, however, it may negatively impact metabolism (Osser DN et al, Harv Rev Psychiatry 2013;21(1):18–40). 

Treatment-Resistant Cases. 

  • Once a patient is considered treatment-resistant, clozapine must be started early because the chances of “responding to clozapine drops by 8%-11% with every failed antipsychotic trial”, and if it’s started 3 years after the first episode, then its potential efficacy diminishes from 82% to 32% (John AP et al, Can J Psychiatry 2018;63(8):526–531; Yoshimura B et al, Psych Res 2017;250:65–70). 
  • While clozapine may produce some treacherous side effects including “neutropenia, seizures, cardiotoxicity, and small bowel obstruction”, a meta-analysis showed that “the mortality rate was 44% lower with clozapine than other antipsychotics” (Vermeulen JM et al, Schizophr Bull 2019;45(2):315–329).

Helpful Resources:

  • The Harvard South Shore Psychopharmacology Algorithm Project. A flowchart that helps guide your decision-making process.
  • Jonathan Meyers’ The Clozapine Handbook (2019). “A useful guide to managing clozapine’s side effects”.
  • CATIE trial. A study that evaluated the effectiveness of second-generation antipsychotics v.s. Each other and perphenazine (Lieberman JA and Stroup TS, Am J Psychiatry 2011;168(8):770–775).
  • “Seven Clozapine Tips”. A recent podcast we did containing imperative information about clozapine treatment.

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