Abstract
BackgroundSchizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes.MethodA systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics).ResultsNineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons.ConclusionsTentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.
Highlights
Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant
First described in the 1988 Kane et al criteria [6], a consistent minimum requirement for a diagnosis of treatment-resistance is two periods of treatment with different antipsychotics at adequate dose, each for at least 4 weeks, without at least a 20% reduction in symptoms. This is reflected in guidelines for clozapine prescription [7, 8]: a 2014 review of clozapine prescription trends concludes that clozapine has consistently remained the gold standard for treatment-resistant schizophrenia, with all evidence-based guidelines recommending prescription “after failure of two adequate trials of two different antipsychotic agents” [9]
Recent variations have progressed from exclusively considering persistent positive symptoms to incorporating persistent negative and cognitive symptoms [10, 11]; positive symptoms remain a central focus as the main target of antipsychotics and the primary outcome in the early clozapine trials which defined treatment-resistance
Summary
Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. First described in the 1988 Kane et al criteria [6], a consistent minimum requirement for a diagnosis of treatment-resistance is two periods of treatment with different antipsychotics at adequate dose (variously defined), each for at least 4 weeks, without at least a 20% reduction in symptoms. This is reflected in guidelines for clozapine prescription [7, 8]: a 2014 review of clozapine prescription trends concludes that clozapine has consistently remained the gold standard for treatment-resistant schizophrenia, with all evidence-based guidelines recommending prescription “after failure of two adequate trials of two different antipsychotic agents” [9]. That the dopamine hypothesis may not apply to treatment-resistant schizophrenia [17], where symptoms are instead driven by non-dopaminergic abnormalities, perhaps involving the glutamate system [18,19,20]
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