Treatment-Resistant Schizophrenia – New Definitions for Research and Clinical Use

By Bartosz Janikowski, M.D., Vice President, Medical & Scientific Affairs, Worldwide Clinical Trials,

Treatment-resistant schizophrenia, antipsychotic

Treatment-resistant schizophrenia is a phenomenon that most clinicians and researchers try to combat in their daily practices. Treatment-resistant schizophrenics are patients who are repeatedly admitted to hospitals or require frequent visits to specialists or, as study subjects, are often excluded from participation in efficacy and safety studies of new antipsychotic medications. That said, the research community faced various definitions of treatment-resistance and response to schizophrenia treatments and was also often not looking specifically into the issue of the adequate adherence to treatments provided sometimes resulting in confusion between treatment resistance and potential resistance to treatment.

Treatment Response and Resistance in Psychosis (TRRIP) Working Group: Unifying Guidelines for Clinical Use

An expert working group –Treatment Response and Resistance in Psychosis (TRRIP) Working Group — attempted developing and unifying guidelines for defining treatment response and resistance in patients with schizophrenia, as well as defining what the adequate treatment definition might be. Consensus guidelines were published online recently in the American Journal of Psychiatry. [1]

The TRIPP group provided systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia, focused on used definitions of treatment resistance, and developed consensus-operationalized criteria via:

  • multiphase, mixed methods approach
  • identification of key criteria via an online survey

There were 2808 potentially relevant studies identified by the TRIPP group, of which 42 met inclusion criteria. Of those, 21 studies (50%) did not provide operationalized criteria for treatment-resistant schizophrenia. In the remaining studies, criteria varied with respect to:

  • symptom severity
  • prior treatment duration
  • antipsychotic dosage thresholds

There were only two studies (5%) that utilized the same criteria.

The TRRIP group identified three main elements that define the concept of treatment-resistant schizophrenia:

  1. confirmed diagnosis of schizophrenia
  2. adequate pharmacologic treatment
  3. persistence of significant symptoms despite adequate treatment

Consensus Criteria for Assessment and Definition of Treatment-Resistant Schizophrenia  

Minimum and optimal consensus criteria for assessment and definition of treatment-resistant schizophrenia were agreed by applying several aspects:

  • current symptoms of a minimum duration and severity as assessed by standardized psychometric tool
  • moderate or worse functional impairment measured using a validated scale
  • prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage
  • systematic monitoring of adherence and meeting of minimum adherence criteria
  • ideally, at least one prospective treatment trial
  • criteria that separate responsive from treatment-resistant patients

Definition of and Criteria for Adequate Treatment Response

Reduction of <20% will correspond to a clinically insignificant reduction in symptoms according to the group.

For defining adequate treatment response, the guidelines recommend the following:

  • each antipsychotic treatment last at least 6 weeks (which might differ from 4 weeks of treatment that is still followed by some local standards and guidelines)
  • medication be administered at a therapeutic dose deemed “adequate”

The minimum number of different antipsychotic treatment episodes is two, therefore the minimum duration of treatment required is 12 weeks. The guidelines also recommend that at least one treatment episode utilize a long-acting injectable antipsychotic for at least 4 months before regarding the case as one of treatment resistance.

Criteria for establishing a group of patients with adequate treatment response include the following:

  • symptoms assessed as being no more than mild in severity
  • response sustained for at least 12 weeks
  • impairment assessed as mild or better on a standard scale.

It is yet to be seen if these TRRIP recommendations will translate to standard clinical or research practice; however the work reflects importance of the issue that requires close attention in any antipsychotic research.

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

Oliver D. Howes, M.R.C.Psych., Ph.D., Rob McCutcheon, M.R.C.Psych., Ofer Agid, M.D., Andrea de Bartolomeis, M.D., Ph.D., Nico J.M. van Beveren, M.D., Ph.D., Michael L. Birnbaum, M.D., Michael A.P. Bloomfield, M.R.C.Psych., Ph.D., Rodrigo A. Bressan, M.D., Ph.D., Robert W. Buchanan, M.D., William T. Carpenter, M.D., David J. Castle, F.R.C.Psych., Leslie Citrome, M.D., M.P.H., Zafiris J. Daskalakis, M.D., Ph.D., Michael Davidson, M.D., Richard J. Drake, M.R.C.Psych., Ph.D., Serdar Dursun, Ph.D., F.R.C.P.C., Bjørn H. Ebdrup, M.D., Ph.D., Helio Elkis, M.D., Ph.D., Peter Falkai, M.D., Ph.D., W. Wolfgang Fleischacker, M.D., Ary Gadelha, M.D., Ph.D., Fiona Gaughran, M.D., F.R.C.Psych., Birte Y. Glenthøj, M.D., Dr.Med.Sci., Ariel Graff-Guerrero, M.D., Ph.D., Jaime E.C. Hallak, M.D., Ph.D., William G. Honer, M.D., F.R.C.P.C., James Kennedy, M.D., Ph.D., Bruce J. Kinon, M.D., Stephen M. Lawrie, M.D., F.R.C.Psych., Jimmy Lee, M.B.B.S., M.Med., F. Markus Leweke, M.D., James H. MacCabe, F.R.C.Psych., Carolyn B. McNabb, P.G.Dip.Sci., M.H.Sc., Herbert Meltzer, M.D., Hans-Jürgen Möller, M.D., Shinchiro Nakajima, M.D., Ph.D., Christos Pantelis, M.D., M.R.C.Psych., Tiago Reis Marques, M.D., Ph.D., Gary Remington, M.D., Ph.D., Susan L. Rossell, Ph.D., Bruce R. Russell, Ph.D., Cynthia O. Siu, Ph.D., Takefumi Suzuki, M.D., Ph.D., Iris E. Sommer, M.D., Ph.D., David Taylor, Ph.D., Neil Thomas, D.Clin.Psy., Alp Üçok, M.D., Daniel Umbricht, M.D., James T.R. Walters, M.R.C.Psych., Ph.D., John Kane, M.D., Christoph U. Correll, M.D.

J Psychiatry. Published online December 6, 2016.