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Abstract
Treatment-resistant schizophrenia (TRS), the persistence of positive symptoms despite ≥2 trials of adequate dose and duration of antipsychotic medication with documented adherence, is a serious clinical problem with heterogeneous presentations. TRS can vary in its onset (at the first episode of psychosis or upon relapse), in its severity, and in the response to subsequent therapeutic interventions (i.e., clozapine, electroconvulsive therapy). The heterogeneity of TRS indicates that the underlying neurobiology of TRS may differ not only from treatment-responsive schizophrenia but also among patients with TRS. Several hypotheses have been proposed for the neurobiological mechanisms underlying TRS, including dopamine supersensitivity, hyperdopaminergic and normodopaminergic subtypes, glutamate dysregulation, inflammation and oxidative stress, and serotonin dysregulation. Research supporting these hypotheses is limited in part by variations in the criteria used to define TRS, as well as by the biological and clinical heterogeneity of TRS. Clinical trial designs for new treatments should be informed by this heterogeneity, and further clinical research is needed to more clearly understand the underlying neurobiology of TRS and to optimize treatment for patients with TRS.
Highlights
Treatment-resistant schizophrenia (TRS) has been defined as the persistence of symptoms despite ≥2 trials of antipsychotic medications of adequate dose and duration with documented adherence.[1,2] TRS occurs in up to 34% of patients with schizophrenia.[3–5] persistent symptoms may be negative or cognitive,[1] persistence of positive symptoms is generally one of the defining features of TRS.[6]
Later onset of treatment resistance may be preceded by relapses,[8–10] which in part may result from medication nonadherence or discontinuation.[2]
The goal of this review is to examine advances in our understanding of the underlying neurobiology of TRS as it relates to positive symptoms, that is, symptoms that were not responsive to antipsychotic treatment from illness onset or that were previously, but are no longer, responsive to antipsychotic treatment
Summary
Treatment-resistant schizophrenia (TRS) has been defined as the persistence of symptoms despite ≥2 trials of antipsychotic medications of adequate dose and duration with documented adherence.[1,2] TRS occurs in up to 34% of patients with schizophrenia.[3–5] persistent symptoms may be negative or cognitive,[1] persistence of positive symptoms is generally one of the defining features of TRS.[6]. Treatment-resistant schizophrenia (TRS) has been defined as the persistence of symptoms despite ≥2 trials of antipsychotic medications of adequate dose and duration with documented adherence.[1,2]. The failure of serial antipsychotic medication trials is not sufficient to define TRS, as other potential causes of persistent symptoms need to be excluded as well (Table 1). It is critical to differentiate true TRS from pseudo-resistance (i.e., when a patient appears resistant, but treatment is inadequate rather than ineffective).[8,11]. TRS results from lack of response to adequate exposure to medication with no confounding factors (Table 1), whereas pseudo-resistance may occur as a result of medication nonadherence, insufficient plasma levels of a medication, inadequate dosage or duration of treatment, misdiagnosis, adverse events of a treatment masking a response, or the presence of confounding psychiatric or medical comorbidities.[8,11,12] It is critical to differentiate true TRS from pseudo-resistance (i.e., when a patient appears resistant, but treatment is inadequate rather than ineffective).[8,11] TRS results from lack of response to adequate exposure to medication with no confounding factors (Table 1), whereas pseudo-resistance may occur as a result of medication nonadherence, insufficient plasma levels of a medication, inadequate dosage or duration of treatment, misdiagnosis, adverse events of a treatment masking a response, or the presence of confounding psychiatric or medical comorbidities.[8,11,12]
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