Group Proposes Consensus Criteria for ‘Treatment-Resistant’ Psychosis

What does it mean to say a patient with schizophrenia is “treatment resistant”?

Stephen Marder, M.D.

Prescribers may recognize treatment resistance when they see it, but there has been no standardized definition.

That’s why an international group of more than 50 experts on schizophrenia and treatment resistance this month issued “consensus criteria,” which focus on symptom duration and severity, functional impairment, and prior treatment for determining when schizophrenia is treatment resistant.

“This consensus definition of treatment resistance addresses a problem that affects both research and clinical care,” Stephen Marder, M.D., one of the members of the Treatment Response and Resistance in Psychosis (TRRIP) working group, told Psychiatric News. “That is, researchers who study treatment resistance have used widely varying criteria for defining clinical populations. This has made it very difficult to compare the results from different studies. The lack of a consensus about the meaning of the term treatment resistance also affects clinicians since it makes it difficult to interpret the relevance of treatment studies to a particular patient.”

The TRRIP working group was conceived by Oliver Howes, M.R.C.Psych., of the Imperial College of London, and Christoph Correll, M.D., and John Kane, M.D., of the Zucker Hillside Hospital. “The three of us felt that it was time to develop a consensus around how we should define treatment resistance and publish something that will help investigators develop a common framework for conducting clinical research,” Kane told Psychiatric News. “We knew we needed to engage a lot of experts from around the world to develop a true consensus.”

The group performed a systematic review of definitions of treatment-resistant schizophrenia used in randomized antipsychotic clinical trials and found that in half of the trials there was no defined, operationalized criteria for what constituted “resistance” at all; that is, patients were often enrolled in the trials based largely on clinical judgment, Kane told Psychiatric News.

John Kane, M.D.

In the other 50 percent, the criteria differed widely, particularly in the domains of symptom severity, prior treatment duration, and antipsychotic dosage thresholds. Only two studies used the same criteria.

To address this variation, the working group sought to develop a consensus on several domains crucial to defining treatment resistance, with minimum and optimal criteria for each domain.

Forty-eight researchers and clinicians who were members of the TRRIP working group were invited by email to participate in an online survey to identify key areas of agreement and disagreement. The survey was developed by Kane, Correll, and Howes with modifications suggested by the TRRIP members.

Over the 30-day collection period, 29 responses (60 percent), from researchers in three countries, were received. These responses were synthesized and refined during subsequent discussions among the whole group to derive the consensus recommendations for both minimum and optimum criteria.

Some of the domains and their optimal criteria for determining treatment resistance include the following:

• Assessment: Patients should be deemed to be treatment resistant only after evaluation of treatment using a standardized rating scale, such as the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, or the Scale for the Assessment of Positive Symptoms.

• Symptom severity and change: Patients should be deemed to be treatment resistant if symptoms are at least moderately severe, as defined on a standardized rating scale such as the PANSS. They should experience less than 20 percent symptom reduction, also using a standardized rating scale, during a prospective trail or observation of six or more weeks.

• Functioning: Treatment-resistant patients should be determined to have at least moderate functional impairment, measured using a validated scale, such as the Social and Occupational Functioning Scale.

• Past treatment: Treatment-resistant patients should have experienced at least two past unsuccessful treatment episodes with different antipsychotic drugs that were taken a duration of at least six weeks at a therapeutic dosage for both trials.

• Dosage: Treatment-resistant patients should have been treated with a dose of medication equivalent to at least 600 mg of chlorpromazine per day.

• Adherence: Treatment-resistant patients should have taken at least 80 percent of prescribed doses, verified by at least two sources (pill counts, dispensing chart reviews, or patient/caregiver report). Antipsychotic plasma levels should be monitored on at least one occasion.

The group noted that the proposed criteria for determining treatment resistance in patients with schizophrenia are not meant to govern clinical practice. Rather, they wrote, “it is intended that these criteria provide benchmarks to aid study design and reporting as well as research on the neurobiology of more homogeneously defined subgroups and the development of novel treatment strategies.”

Kane emphasized that better, more standardized research protocols will likely lead to improvements in clinical care.

“The management of treatment resistance remains a real clinical challenge,” he said. “I think we need to focus a lot more of our research energy on how we can better serve those patients who don’t respond adequately to the medications we have.” ■