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.
Highlights
The author discusses that the demonstration of inadequate response to antipsychotic drugs (APDs) may infer that some Treatment Resistant Schizophrenia (TRS) patients may be suffering from a non-dopamine pathophysiology since D2 receptor antagonist-based treatment is ineffective
This elevated glutamate signal is seen in first-episode schizophrenia (FES) nonremitters as compared to remitters to APD treatment [32]. These results provide further evidence to suggest that Primary TRS unlike treatment responsive schizophrenia may be a category of schizophrenia characterized more by a hyperglutamatergic than a hyper-dopaminergic pathology
A significant challenge to developing a new and effective treatment for TRS is the heterogeneity in the patient segments that make up what we refer to as The Group of Treatment Resistant Schizophrenias
Summary
Heterogeneity in response to antipsychotic drug (APD) treatment is seen across the course of schizophrenia. This algorithm apparently identified Primary TRS patients whose failure to respond to non-clozapine APDs suggests that the symptoms of their first episode psychosis may not be mediated by an increase in dopaminergic activity nor at least improved by blocking the effects of a hyperdopaminergic state After these 2 APD failures, the overwhelming majority of the non-responding patients (75%) when treated with clozapine demonstrated an adequate treatment response, suggesting that clozapine may be mediating a treatment response through a mechanism beyond limited D2 receptor antagonism that may involve a nondopamine pathophysiology. Ultra-TRS may reflect a schizophrenia disease state in which dopaminergic, glutamatergic, and perhaps much of the receptor pharmacology of available APDs have a greatly diminished influence on psychosis expression
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