The diagnosis of treatment resistant schizophrenia generally follows two not always consistent lines of thinking: one is based on research strategies, the other one on every day clinical practice. Both require a failure to respond to at least two (sometimes three) treatment attempts of adequate duration with an adequate dose of an antipsychotic.

In research, one needs to define clearly operationalized criteria which can be applied and reproduced in different settings. Response data are usually operationalized using rating scales scores. Under routine treatment conditions physicians often have to rely upon poor drug response histories or less than perfect chart notes. A more general view of the patient's condition, often including social functioning and quality of life, will then be amalgamated for the clinical diagnosis of treatment resistant schizophrenia.

Once the diagnosis has been established, alternative treatment strategies can be discussed. The treatment option which is substantiated by the largest research base is clozapine.

If a trial with clozapine is unsuccessful, various alternatives are currently discussed. These range from adding another antipsychotic, mood stabilizers, benzodiazepines, serotonin antagonists, serotonin reuptake-inhibitors, glutamatergic drugs to dopaminergic agents and electroconvulsive therapy. None of these have proved unequivocally efficacious in sufficiently large patient samples. There is some evidence, that treatment resistant patients need more time until they show a positive response. Although this evidence is tentative, for practical matters last resort trials will be extended anyway since very little treatment options remain after these have failed.