An iterative approach was adopted to develop criteria for treatment resistance in schizophrenia. Initially, a systematic review of definitions of treatment resistant schizophrenia used in clinical trials was conducted. A literature search of PubMed, PsycINFO, and Embase from January 1980 to January 2016 was undertaken using the search string: “(randomized or random or randomly) and (resistant or refractory or clozapine) and (schizophrenia)”. Titles and abstracts were reviewed to initially determine eligibility. The reference lists of each relevant paper were also searched, as were reference lists of relevant review papers, to further identify potential studies. Studies were included if they were randomized controlled trials of a pharmacological intervention in adults with treatment resistant schizophrenia. Studies were excluded if they were naturalistic, or purely of biomarkers such as neuroimaging measures, studies of adjuvant treatments or non-pharmacological interventions, studies of childhood onset or late onset schizophrenia.
The data extracted were: the prerequisites for previous antipsychotic treatment (requirements of different antipsychotics, minimum treatment duration, dose); the specified severity of symptoms; and whether there was a stipulation for resistance to be prospectively demonstrated. Additionally, whether criteria were operationalized or not was recorded. To be considered as operationalized, the study had to report criteria that met the following characteristics: 1) The use of a validated rating scale to determine symptom severity; 2) A specification of minimum symptom duration; and 3) A definition of adequate treatment that specified minimum dose, duration, and number of previous antipsychotics.
Subsequently, a working group - consisting of expert researchers and clinicians, scientists from the pharmaceutical industry and other specialists with experience and expertise in the area of schizophrenia - was identified by the co-chairs of the Treatment Response and Resistance in Psychosis working group (OH, JMK, CUC). This was augmented by attendees at TRRIP meetings held at international conferences in the field. Members of the final working group included researchers who had published recently in the field and researchers who attended the inaugural TRRIP meeting at the Schizophrenia International Research Society Biennial meeting in 2014. The working group mapped out the key criteria and operationalized them.
Second, members of the TRRIP working group were contacted and invited to take part in an on-line survey to identify key areas of agreement and disagreement. The survey was developed by the TRRIP co-chairs and modified with input from TRRIP work group members. In its final version (see Appendix 1), the survey was conducted using SurveyMonkey (www.surveymonkey.com ). 48 researchers and clinicians were invited by email to take part in the survey. Over the 30-day collection period, 29 responses (60%), covering 13 countries, were received to the on-line survey; 3 (10%) responses were incomplete. See supplementary information for a summary of the responses to individual items. These responses were synthesized and refined during subsequent discussions amongst the whole group to derive the consensus recommendations for both minimum and optimum criteria.
Third, the working group met to consider and revise criteria for which there was a lack of consensus. The revised criteria were circulated to the TRRIP working group members, and presented as part of an open workshop at an international meeting in the field for further discussion, input and refinement. Finally, consensus was reached regarding this publication through review by all authors.
The data extracted were: the prerequisites for previous antipsychotic treatment (requirements of different antipsychotics, minimum treatment duration, dose); the specified severity of symptoms; and whether there was a stipulation for resistance to be prospectively demonstrated. Additionally, whether criteria were operationalized or not was recorded. To be considered as operationalized, the study had to report criteria that met the following characteristics: 1) The use of a validated rating scale to determine symptom severity; 2) A specification of minimum symptom duration; and 3) A definition of adequate treatment that specified minimum dose, duration, and number of previous antipsychotics.
Subsequently, a working group - consisting of expert researchers and clinicians, scientists from the pharmaceutical industry and other specialists with experience and expertise in the area of schizophrenia - was identified by the co-chairs of the Treatment Response and Resistance in Psychosis working group (OH, JMK, CUC). This was augmented by attendees at TRRIP meetings held at international conferences in the field. Members of the final working group included researchers who had published recently in the field and researchers who attended the inaugural TRRIP meeting at the Schizophrenia International Research Society Biennial meeting in 2014. The working group mapped out the key criteria and operationalized them.
Second, members of the TRRIP working group were contacted and invited to take part in an on-line survey to identify key areas of agreement and disagreement. The survey was developed by the TRRIP co-chairs and modified with input from TRRIP work group members. In its final version (see Appendix 1), the survey was conducted using SurveyMonkey (
Third, the working group met to consider and revise criteria for which there was a lack of consensus. The revised criteria were circulated to the TRRIP working group members, and presented as part of an open workshop at an international meeting in the field for further discussion, input and refinement. Finally, consensus was reached regarding this publication through review by all authors.
