The Group of Treatment Resistant Schizophrenias. Heterogeneity in Treatment Resistant Schizophrenia (TRS)

Abstract

Schizophrenia is composed of a heterogeneous group of patient segments. Our current notion of the heterogeneity in schizophrenia is based on patients presenting with diverse disease symptom phenotypes, risk factors, structural and functional neuropathology, and a mixed range of expressed response to treatment. It is important for clinicians to recognize the various clinical presentations of resistance to treatment in schizophrenia and to understand how heterogeneity across treatment resistant patient segments may potentially inform new strategies for the development of effective treatments for Treatment Resistant Schizophrenia (TRS). The heterogeneity of schizophrenia may be reduced by parsing patient segments based on whether patients demonstrate an adequate or inadequate response to treatment. In our current concept of TRS, TRS is defined as non-response to at least two adequate trials of antipsychotic medication and is estimated to affect about 30% of all patients with schizophrenia. In this narrative review, the author discusses that the demonstration of inadequate response to antipsychotic drugs (APDs) may infer that some TRS patients may be suffering from a non-dopamine pathophysiology since D2 receptor antagonist-based treatment is ineffective. Preliminary neurobiological findings may further support the pathophysiologic distinction of TRS from that of general schizophrenia. Investigation of the basis for heterogeneity in TRS through the systematic investigation of relevant "clusters" of similarly at risk individuals may hopefully bring us closer to realize a precision medicine approach for developing effective therapies for TRS patient segments.

Keywords: antipsychotic drug; clozapine; dopamine; first-episode schizophrenia (FES); magnetic resonance spectroscopy (MRS); positron emission tomography–PET; schizophrenia; treatment resistant.

Figure 1

Heterogeneity in the trajectory of response to APD treatment over the illness course of schizophrenia. This schematic drawing illustrates that some patient segments may demonstrate APD responsiveness throughout their illness, others demonstrate resistance to treatment only after an initial period of treatment responsiveness, and others still may be found to respond poorly to APD treatment since their first episode of psychosis.

Figure 2

A continuum of cumulative factors (Fn), as suggested by the above bulleted factors, may additively contribute (i.e., Factor Loading) to compromise response to treatment in schizophrenia. TRS may be considered a consequence of diminished likelihood to respond favorably to treatment in the face of such overwhelming factors. Despite these associations, there may be no clearly defined predictors of TRS.