Using Treatment Response to Subtype Schizophrenia
Using Treatment Response to Subtype Schizophrenia
Ironically, our proposal comes at the same time the field is embracing a broader definition of schizophrenia, one that incorporates multiple symptom domains. Further, this shift parallels an increased focus on functional vs clinical recovery, with evidence already available suggesting that features other than positive symptoms play a greater role in functional outcomes.
We hold to our reasoning, however, based on several lines of thinking. Antipsychotics quickly established themselves as the cornerstone of treatment in schizophrenia because psychosis is central to this illness. Treatment-resistant schizophrenia is first and foremost about poorly controlled positive symptoms; the crux of definitions is persistence of positive symptoms in the face of adequate antipsychotic trials. On this point, thinking regarding antipsychotics seems to have drifted in the last several decades, perhaps fuelled by the hope (and claims) that these drugs would be "antischizophrenic" rather than merely antipsychotics. In fact, their impact on these other symptom domains is modest at best. The approach of developing an antipsychotic with broad spectrum symptom improvement continues although we are witnessing a shift to symptom-specific drugs that constitute add-on strategies to existing antipsychotic treatment.
It is important that the 3 subgroups proposed here are relatively discreet and, ideally, trait rather than state dependent. Our own work, which follows individuals from the earliest stages of treatment, has established that treatment resistance can be observed from the illness' onset. Unlike relapses, associated with psychotic exacerbation and transient in nature, treatment-resistant schizophrenia appears stable and poorly responsive to treatments other than clozapine. It is also of note that clozapine does not appear unique outside of this subpopulation. Although it is often continued in the third group (Schizophrenia-Clozapine Resistant), this may be a decision of convenience; it takes considerable effort to move patients to clozapine, and it is a drug routinely identified as the treatment of "last resort." This said, current evidence has failed to establish any treatment as consistently effective in this sample.
There are practical challenges to the approach we propose. Many individuals are not willing to start clozapine or may not tolerate it, making an adequate clinical trial impossible. Criteria for treatment-resistant schizophrenia and clozapine resistance exist, but aspects remain vaguely defined (eg, previous antipsychotic effectiveness; level of functioning). Similarly, there is a need to clearly establish treatment response. We argue that it be operationalized and at a threshold exceeding partial, suboptimal response; to this end, we support the argument for a 50% Brief Psychiatric Rating Scale (BPRS)/Positive and Negative Syndrome Scale (PANSS) reduction, which translates to a score of 2 on Clinical Global Impression-Global Improvement (ie, CGI-I, much improved). In very ill patients, there is the possibility that they could demonstrate response, but still remain quite symptomatic. One means of addressing this would be to couple the CGI-I and CGI-Severity (CGI-S) scores, and identify those who are at particular threshold in terms of severity (eg, ≥4—moderately ill) as Schizophrenia-Clozapine Eligible. Such a strategy would also provide a threshold for establishing candidacy for clozapine when background information regarding treatment response cannot be easily obtained, or in the case of individuals who meet criteria for clozapine but, for whatever reason, do not undertake or complete an adequate trial. The CGI in particular is conducive to busy clinical settings demanding a brief, simple measurement tool. Although such scales address more immediate drug response, over the longer term remission criteria can also be implemented.
Schizophrenia represents a lifelong illness, and treatment response/remission can wax and wane. This must be distinguished from response per se; numerous factors can contribute to what appears as evolving treatment resistance or attenuated response, such as poor adherence and substance abuse. There is evidence that multiple relapses have biological consequences and are associated with diminished response across episodes. Alternatively, it has been hypothesized that schizophrenia is characterized by different trajectories, evident in the earliest stages of psychosis, an idea in keeping with the conceptualization of schizophrenia as a heterogeneous group of disorders.
Challenges in Subtyping Schizophrenia Based on Treatment Response
Ironically, our proposal comes at the same time the field is embracing a broader definition of schizophrenia, one that incorporates multiple symptom domains. Further, this shift parallels an increased focus on functional vs clinical recovery, with evidence already available suggesting that features other than positive symptoms play a greater role in functional outcomes.
We hold to our reasoning, however, based on several lines of thinking. Antipsychotics quickly established themselves as the cornerstone of treatment in schizophrenia because psychosis is central to this illness. Treatment-resistant schizophrenia is first and foremost about poorly controlled positive symptoms; the crux of definitions is persistence of positive symptoms in the face of adequate antipsychotic trials. On this point, thinking regarding antipsychotics seems to have drifted in the last several decades, perhaps fuelled by the hope (and claims) that these drugs would be "antischizophrenic" rather than merely antipsychotics. In fact, their impact on these other symptom domains is modest at best. The approach of developing an antipsychotic with broad spectrum symptom improvement continues although we are witnessing a shift to symptom-specific drugs that constitute add-on strategies to existing antipsychotic treatment.
It is important that the 3 subgroups proposed here are relatively discreet and, ideally, trait rather than state dependent. Our own work, which follows individuals from the earliest stages of treatment, has established that treatment resistance can be observed from the illness' onset. Unlike relapses, associated with psychotic exacerbation and transient in nature, treatment-resistant schizophrenia appears stable and poorly responsive to treatments other than clozapine. It is also of note that clozapine does not appear unique outside of this subpopulation. Although it is often continued in the third group (Schizophrenia-Clozapine Resistant), this may be a decision of convenience; it takes considerable effort to move patients to clozapine, and it is a drug routinely identified as the treatment of "last resort." This said, current evidence has failed to establish any treatment as consistently effective in this sample.
There are practical challenges to the approach we propose. Many individuals are not willing to start clozapine or may not tolerate it, making an adequate clinical trial impossible. Criteria for treatment-resistant schizophrenia and clozapine resistance exist, but aspects remain vaguely defined (eg, previous antipsychotic effectiveness; level of functioning). Similarly, there is a need to clearly establish treatment response. We argue that it be operationalized and at a threshold exceeding partial, suboptimal response; to this end, we support the argument for a 50% Brief Psychiatric Rating Scale (BPRS)/Positive and Negative Syndrome Scale (PANSS) reduction, which translates to a score of 2 on Clinical Global Impression-Global Improvement (ie, CGI-I, much improved). In very ill patients, there is the possibility that they could demonstrate response, but still remain quite symptomatic. One means of addressing this would be to couple the CGI-I and CGI-Severity (CGI-S) scores, and identify those who are at particular threshold in terms of severity (eg, ≥4—moderately ill) as Schizophrenia-Clozapine Eligible. Such a strategy would also provide a threshold for establishing candidacy for clozapine when background information regarding treatment response cannot be easily obtained, or in the case of individuals who meet criteria for clozapine but, for whatever reason, do not undertake or complete an adequate trial. The CGI in particular is conducive to busy clinical settings demanding a brief, simple measurement tool. Although such scales address more immediate drug response, over the longer term remission criteria can also be implemented.
Schizophrenia represents a lifelong illness, and treatment response/remission can wax and wane. This must be distinguished from response per se; numerous factors can contribute to what appears as evolving treatment resistance or attenuated response, such as poor adherence and substance abuse. There is evidence that multiple relapses have biological consequences and are associated with diminished response across episodes. Alternatively, it has been hypothesized that schizophrenia is characterized by different trajectories, evident in the earliest stages of psychosis, an idea in keeping with the conceptualization of schizophrenia as a heterogeneous group of disorders.
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