23,24 Starting in the late 1970s and 1980s, the diagnostic systems (Diagnostic and Statistical Manual of Mental Disorders [DSM]

and International Classification of Diseases [ICD]) have been continually revised to reflect a more narrow definition of schizophrenia with psychosis as a central feature. Interestingly this corresponds to the period when antipsychotic drugs have fully penetrated daily clinical practice. No wonder, therefore, that treatment success and treatment refractoriness were defined as a function of these drugs’ ability to suppress psychotic symptoms. During most of the 1990s, the focus of schizophrenia research and treatment has moved from psychosis towards enduring negative symptoms,25,26 cognitive Inhibitors,research,lifescience,medical impairment,27-31 Inhibitors,research,lifescience,medical and recently, quality of life32,33 and social reintegration.34-36

Interestingly, the more recent definition of TRS has raised the bar to include the persistence of moderate -to-severe positive and negative symptoms together with the persistence of other symptoms such as cognitive, social, and occupational impairments and behavioral problems.37,38 This definition, in addition to the expectation that the novel antipsychotics will distinguish themselves from the classic ones and among themselves, has changed treatment expectations and redefined treatment outcome to encompass these domains. Some of the difficulty associated Inhibitors,research,lifescience,medical with the definition of TRS derives from the confusion between illness severity, chronicity, and illness sequels. Using the broadest definition of TRS would imply that any persistence of any symptom, or abnormal behavior or sequel, would qualify for treatment Inhibitors,research,lifescience,medical refractoriness. For example, an adolescent who before the first psychotic episode had been socially and vocationally successful, but who has not returned to the Inhibitors,research,lifescience,medical previous level of functioning despite adequate and extensive treatment, could be considered as suffering from TRS. In summary, because of the syndromal nature of schizophrenia, and the heterogeneous

response to treatment, classifying a patient or a cohort as TRS has little and descriptive or empirical value. For example, patients can be defined as suffering from TRS for the purpose of enrolment into an intervention trial, or for the purposes of deciding the level of disability compensations and support need with activities of daily living (ADLs). Hence, depending on the purpose of the definition, the criteria for TRS must reflect the specific domain(s) of refractoriness, its severity, and previous treatment attempts. Mechanisms of TRS Since it became clear that a significant proportion of patients do not respond to AZD6738 mw available treatments, clinicians and investigators attempted to predict nonresponse to treatment as early as possible and explain the mechanisms of TRS. However, this attempt has been fraught with both scientific and conceptual difficulties.