A number of people with schizophrenia do not respond to any antipsychotic medication, a condition known as treatment resistance. The exact percentage is unknown since definitions of treatment resistant schizophrenia (TRS) vary widely and people respond differently to antipsychotic medications. It is estimated that approximately 30% of patients with schizophrenia do not respond to dopamine-blocking antipsychotics and of those, only half find symptom relief by the only alternative medication, clozapine. As a result, those with TRS typically experience poorer clinical outcomes. However, recent research is beginning to unravel the biological basis for non-response and may assist in the development of effective medications for this population.

The International Treatment Response and Resistance in Psychosis (TRRIP) working group was convened to provide an operational definition of treatment resistance that could be used across research and clinical settings. According to a consensus of the group, the following must occur in order for an individual to be identified as treatment resistant:

There are differing opinions as to whether the clinical course of TRS is a stable, specific type of schizophrenia or the result of a neurodegenerative process of the illness. However, a recent longitudinal (10 years) study of first episode psychosis found that the vast majority (80%) of treatment resistant patients were resistant from the early presentation of their illness. Predictors of TRS include a younger age of onset, longer duration of untreated psychosis, and prominent negative symptoms such as blunted affect or social isolation.

Evidence from TRS imaging and genetic studies point to dysregulation of several neurotransmitters including dopamine and glutamate. In addition, brain imaging demonstrates increased cortical atrophy in treatment non-responders compared with responders.

While clozapine is the only antipsychotic to show symptom reduction in patients with TRS and earlier initiation of clozapine is shown to improve outcomes in this population it is significantly underutilized by clinicians. For the approximately 50% of treatment resistant patients who do not respond to clozapine (ultra-treatment resistant), unfortunately there are limited efficacious treatment strategies. More research is needed to understand treatment resistance in schizophrenia and develop new strategies to improve symptoms for this population.