Treatment-resistant schizophrenia therapy reference (2026)

TRS therapy in 2026 organises around several components.

Clozapine: the most-evidenced therapy specifically for TRS, defined as failure to respond adequately to at least two adequate trials of different antipsychotics. Despite substantial evidence, clozapine remains underutilised due to required hematological monitoring (for agranulocytosis), metabolic monitoring, and historic provider concerns. Modern integrated clozapine pathways with structured monitoring infrastructure are formalising in major health systems.

Augmentation strategies for partial clozapine response: addition of another antipsychotic (with caution given side effect burden), mood stabiliser augmentation, ECT augmentation in selected patients.

Long-acting injectable antipsychotics: aripiprazole, paliperidone, risperidone, olanzapine, and others provide adherence-supported options that are often particularly meaningful in TRS where adherence challenges are common.

Electroconvulsive therapy (ECT): an option for selected patients with severe symptoms despite clozapine optimisation.

Non-pharmacological interventions: cognitive remediation, social skills training, supported employment, family-based interventions, peer support, and structured wraparound care all contribute to TRS outcomes.

Emerging mechanism tier: KarXT (xanomeline-trospium) muscarinic mechanism class is approved for schizophrenia broadly (September 2024) and is being explored in TRS settings via post-approval research. GlyT1 (glycine transporter 1) inhibitor programs and novel GABA-modulator programs are in late-stage trials. Whether any of these provides meaningful benefit beyond clozapine is the central question.

The care-pathway and infrastructure question matters. TRS care benefits from specialised clinics with clozapine-monitoring infrastructure, integrated wraparound care, and capacity for the broad range of psychosocial interventions. Access to such clinics remains uneven.