Subtyping Schizophrenia by Treatment Response: Antipsychotic Development and the Central Role of Positive Symptoms

Abstract

We have recently proposed a model for subtyping schizophrenia based on antipsychotic (AP) treatment response. Evidence suggests that APs, both old and new, are comparable in terms of efficacy; however, one AP, clozapine, is uniquely effective in one subgroup of patients (that is, those with treatment-resistant schizophrenia [TRS]). This permits us to subdivide schizophrenia into 3 specific groups: AP responsive, clozapine responsive, and clozapine resistant. Here, we integrate this model with current criteria related to TRS and ultraresistant schizophrenia, the latter referred to in our model as clozapine resistant. We suggest several modifications to existing criteria, in line with current evidence and practice patterns, particularly emphasizing the need to focus on positive symptoms. While APs can favourably impact numerous dimensions related to schizophrenia, it is their effect on positive symptoms that distinguishes them from other psychotropics. Further, it is positive symptoms that are central to AP and clozapine resistance, and it is these people that place the greatest demands on acute and long-term inpatient resources. In moving AP development forward, we advocate specifically focusing on positive symptoms and capitalizing on the evidence we have of 3 subtypes of psychosis (that is, positive symptoms) based on treatment response, implicating 3 distinguishable forms of underlying pathophysiology. Conversely, pooling these groups risks obfuscating potentially identifiable differences. Such a position does not challenge the importance of dopamine D2 receptor blockade, but rather highlights the need to better isolate those other subgroups that require something more or entirely different.

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

“…As such, they extend previous recommendations (e.g. (82; 83)) to reflect a wide body of opinion, and have been refined to be applicable to a variety of settings. Nevertheless, a limitation is that they may not reflect practice or opinion in all locations.…”

Combination of Electroconvulsive Therapy and Clozapine in Treatment-Resistant Schizophrenia

“…However, the remission rate was still limited and the response to ECT was not consistent with individual patients. In this study, the PANSS total score after acute ECT decreased to a statistically insignificant level compared with the non-ECT group, but it was not reached below the cut-off score for treatment-resistance [ 10 , 53 ].…”

“…Clozapine is known to be the most effective drug for treatment-resistant schizophrenia (TRS), a clinical-based concept with various operating criteria [ 10 ], but 40% to 70% of patients with TRS do not respond to clozapine [ 11 - 14 ], so called clozapineresistance [ 15 ]. To overcome clozapine-resistance, a number of adjunctive approaches including pharmacological and non-pharmacological options have been attempted, but the results have been only modest or equivocal [ 16 - 20 ], except ECT augmentation with high response rates [ 21 , 22 ].…”

Antipsychotic prescribing patterns on admission to and at discharge from a tertiary care program for treatment-resistant psychosis

“…A significant proportion of individuals with psychosis will fail to attain an adequate clinical response. Such patients may be referred to as having refractory or treatment-resistant psychosis (TRP) [ 1 ] (although see [ 2 ]). Consensus diagnostic criteria for TRP have historically remained elusive [ 3 ], although there is an implicit agreement among researchers and clinicians that treatment resistance requires the continued persistence of symptoms despite at least two antipsychotic trials of adequate dose and duration [ 4 ].…”