Treatment-resistant schizophrenia (TRS) is defined by persistent positive symptoms despite trials with at least two different antipsychotics at adequate dose and duration, with confirmed adherence. While clozapine is the only approved treatment for TRS, many patients do not respond or refuse it. Delays in initiating clozapine and reliance on less effective therapies are common. TRS is biologically heterogeneous, involving mechanisms like dopamine supersensitivity or glutamatergic dysfunction. Pseudoresistance, often due to nonadherence or pharmacokinetic issues, can also complicate diagnosis and delay effective care.

TRS places a substantial burden on patients, caregivers, and the healthcare system, including higher costs, stigma, and functional impairment. Despite this, research funding remains limited and access to specialized care is lacking. Nonpharmacologic adjuncts like electroconvulsive therapy and cognitive behavioral therapy for psychosis may offer additional support, though evidence is limited. Earlier recognition, improved adherence strategies, and comprehensive care models may improve long-term outcomes. More research is needed to identify biomarkers and develop targeted therapies that address the complex nature of TRS. 

Reference: Kane JM, Agid O, Baldwin ML, et al. Clinical Guidance on the Identification and Management of Treatment-Resistant Schizophrenia. J Clin Psychiatry. 2019;80(2):18com12123. doi: 10.4088/JCP.18com12123.