When Clozapine Isn’t Enough: Expert Consensus on Next Steps in Schizophrenia Care

Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS), yet up to 60% of patients show only partial or no response. What comes next has long been unclear. To address this gap, the international Treatment Response and Resistance in Psychosis (TRRIP) Working Group surveyed leading experts and developed consensus recommendations, published in Schizophrenia Bulletin (Wagner et al., 2020).

Key recommendations:

• First step: Always ensure therapeutic plasma levels (≥350 ng/ml) before declaring clozapine resistance.

• Positive symptoms: If symptoms persist, options include adding amisulpride or oral aripiprazole, or considering ECT.

• Negative symptoms: Augmentation with antidepressants (particularly escitalopram/citalopram) gained consensus.

• Mixed symptoms: Similar to positive—antipsychotic combination or ECT.

• Suicidality: Augmentation with antidepressants (citalopram, escitalopram, fluoxetine), mood stabilizers (lithium, lamotrigine), or ECT.

• Aggression: Combine with an antipsychotic or mood stabilizer; ECT may also be considered.

• Psychosocial care: Cognitive-behavioral therapy (CBT) and psychosocial interventions were recommended across domains, despite modest trial evidence.

• Avoid discontinuation: Experts strongly advised against stopping clozapine, even in the face of nonresponse, due to poor outcomes after withdrawal.

Safety considerations: Agranulocytosis and myocarditis remain the most concerning risks, yet overall clozapine safety was rated favorably by experienced clinicians when carefully monitored.

Why this matters: In the absence of strong randomized trial data, these consensus guidelines provide a pragmatic roadmap for clinicians navigating one of psychiatry’s toughest challenges. The message is clear: don’t give up on clozapine too soon, optimize dosing, and tailor augmentation carefully to symptom domains.

📖 Full article: Schizophrenia Bulletin, 2020 https://academic.oup.com/schizophreniabulletin/article-abstract/46/6/1459/5838770?redirectedFrom=fulltext&login=false