Measuring Outcomes in Schizophrenia and Examining Their Clinical Application

Stefan Leucht, MD

Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany

Rating scales can be used in both research and clinical practice to assess baseline symptoms and track treatment response in patients with schizophrenia. Once patients achieve response, clinicians should aim for resolution of symptoms, remission, and recovery. Remission indicates that patients are mostly symptom-free, while recovery focuses on patients’ social and vocational functioning. However, these definitions often vary in schizophrenia research. In addition, the clinical application of research study results is often limited by clinicians’ lack of understanding of how numeric rating scale results translate into patients’ clinical status. By examining the ways that response, resolution, remission, and recovery are measured by various scales, clinicians can better understand how to apply rating scale results to their treatment of patients with schizophrenia.

Response

Response is measured in many treatment studies by a percentage reduction from baseline scores on validated rating scales like the PANSS1 and BPRS.2 Rating scales can be useful for measuring response in clinical practice if clinicians know how to interpret their results in practical terms. For example, what does a PANSS total score of 90 or a ≥ 20% reduction of the BPRS score mean from a clinical perspective? These questions can be answered by linking scores on these rating scales to results of CGI scales.2

AV 1. Linking CGI Ratings With BPRS/PANSS Scores (00:37)

Data from Leucht et al4,5,7 and Levine et al6

Clinicians can assess patients’ illness severity and improvement by using a CGI scale, which provides descriptions like “markedly ill” or “much improved” instead of numerical scores. The CGI-S question rates the current severity of illness, while the CGI-I question tracks patients’ overall improvement from baseline. While CGI results are more readily understood, scales like the BPRS and PANSS have the advantage of established psychometric properties. However, the CGI-SCH,3 a CGI scale specific for schizophrenia, has acceptable psychometric properties and covers the full range of symptoms common in schizophrenia, although this refined scale tends to be underused.

The CGI-S and CGI-I ratings can be linked to BPRS or PANSS percentage reduction in total scores to provide more meaningful clinical application (AV 1).4–7 For example, the CGI-S rating of “mildly ill” has been shown to correspond to BPRS total scores of 30–36 and PANSS scores of 55–62, while “markedly ill” corresponds to BPRS scores of 52–55 and PANSS scores of 88–96.4–7 BPRS/PANSS score reductions of 44% to 58% were associated with the CGI-I rating of “much improved” while lower reductions in the 20% to 30% range were associated with being “minimally improved.”5,6 These results suggest that a 50% reduction in scores may be a more appropriate cutoff for defining response in patients with acute, nonrefractory schizophrenia rather than lower cutoffs like a 20% or 25% reduction, which represent only minimal improvement (but are widely used in schizophrenia studies).4,5 However, in treatment-resistant patients, a 25% cutoff may be useful because even small improvements can be clinically significant.4,5

The problem with using too low a response cutoff is that trial results vary depending on the chosen cutoff marker.8 When randomized controlled trials are analyzed using different response cutoffs, the statistical significance of the results changes.8 Another problem is choosing a cutoff post hoc because this then manipulates the results.8 Instead, researchers should select the response cutoff a priori based on clinical relevance (eg, “much improved”).

One reason for choosing low response cutoffs in studies is the widely-held belief that low response cutoffs are more sensitive than higher cutoffs for detecting differences between active agents and placebo.8 Moncrieff and Kirsch9 have shown that, for depression trials, the most sensitive response cutoff may be the one that maximally separates the normal distribution curves of drug and placebo. The point of maximum separation depends on the study population, a separation that may be around 50% HDRS reduction in major depression trials or around 20% PANSS/BPRS reduction in patients with chronic schizophrenia, explaining why this cutoff is used so often. However, in an analysis8 of amisulpride studies, lower cutoffs were not more sensitive to differences between the drug and the comparator, except in studies of patients with chronic, treatment-refractory schizophrenia.

To solve these problems with determining appropriate cutoffs, researchers could present PANSS/BPRS responder rates in a table as well as the number of patients in remission. A similar table could also be used to present the overall distribution of CGI-S and CGI-I response rates for drug and placebo results. These tables would show the distribution of results and make them easier to compare than current study results.

Resolution and Remission

Remission involves maintaining a state without clinically important symptoms over a certain period of time. Resolution, or symptomatic remission, occurs when patients achieve the symptom severity criterion but not the time criterion.10 A consensus definition of remission created by the Remission in Schizophrenia Working Group (RSWG) links remission to DSM-IV-TR11 symptoms of schizophrenia by matching the items to widely used ratings scales, such as the PANSS, BPRS, or combination of the SANS and SAPS.12 The symptoms must all have a rating scale severity score of mild or less for at least 6 months for the patient’s illness to be considered in remission.12 Because the time criterion of 6 months poses a problem for clinical trials that need to be sufficiently long and require frequent measurements, 3 months may be a more balanced time criterion.

More

AV 2. Discussing Outcomes With a Patient With Schizophrenia (03:13)

Between 45% to 70% of patients have been shown to fulfill RSWG remission criteria at some point during their respective follow-up periods, which range from 6 months to 5 years.13 Another study14 that validated the RSWG remission criteria tracked 145 patients who met RSWG symptom remission criteria at baseline and 172 patients who did not for a median of 3 years. Of the remitted patients at baseline, 35% lost remission status during follow-up while 31% of nonremitters at baseline achieved remission. In both remission groups, remission status was associated with improved functioning compared with nonremission status.

Using the RSWG remission criteria in studies could improve researchers’ and clinicians’ ability to make cross-study comparisons.15 However, the disadvantage of the remission criteria is that they do not indicate the amount of change. For example, if study participants are only mildly ill at baseline, many patients may achieve remission at endpoint. However, response rates indicate the amount of change and show patients’ improvement since baseline, which is why studies should include results according to both remission criteria and percentage reductions in total rating scale scores.

Recovery

The ultimate goal of treatment of schizophrenia is recovery, which focuses on patients regaining social and occupational functioning (AV 2). Although no consensus definition exists for recovery,16 several criteria have been proposed that include symptom stabilization and functional improvement over a specified time.17

AV 3. Schizophrenia Outpatients Health Outcomes (SOHO) Study Results of Recovery in Patients With Schizophrenia (N=6,642) (00:36)

Data from Novick et al19

Jääskeläinen and colleagues18 defined recovery in schizophrenia as having improvements in both clinical and social domains, with improvements in at least 1 of the domains persisting for at least 2 years and current symptoms of no greater severity than mild. Using these criteria, they conducted a meta-analysis of 50 studies (N = 8,994) and found a median recovery rate of 13.5%. Another study19 found a similar 13% rate for patients achieving functional remission during a 3-year naturalistic follow-up and a 4% recovery rate using stringent criteria that also measured quality of life (AV 3). Although the recovery rates are not high, these results show that recovery from schizophrenia is achievable. As pharmacologic and psychosocial treatments continue to improve, clinicians should have more options to individualize therapy for their patients with schizophrenia.

Conclusion

The treatment goals of response, resolution, remission, and recovery have different meanings in schizophrenia studies and to clinicians. The rating scale cutoffs used to define response vary from study to study and may not provide much useful information for clinical application. However, linking rating scale results to CGI scores and establishing a consistent cutoff for improvement (≥ 50% reduction) can provide clinically meaningful terms and data from which to base treatment decisions. Researchers may use a simple table to display PANSS/BPRS change rates from baseline to endpoint in 25% increments as well as remission rates, and a similar table could show how many study participants met the various degrees of improvement and severity of the CGI.

The RSWG consensus remission criteria are beginning to be applied in many studies and should make remission results easy to compare. Finally, although no consensus definition of recovery has been reached, the concept reflects a return to social and occupational functioning and is the ultimate goal of schizophrenia treatment. Measuring improvement from baseline throughout treatment will help clinicians and patients define and reach their target goals.

Clinical Points

  • Understand rating scale results in clinically meaningful terms and use scales to track patients’ improvement
  • Apply RSWG remission criteria to your patients with schizophrenia
  • Strive for regaining your patients’ social and vocational functioning as the ultimate goal of treatment

Abbreviations

BPRS = Brief Psychiatric Rating Scale
CGI = Clinical Global Impression scale
CGI-SCH = Clinical Global Impression-Schizophrenia Scale
DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
HDRS = Hamilton Depression Rating Scale
PANSS = Positive and Negative Syndrome Scale
QoL = Quality of Life
RSWG = Remission in Schizophrenia Working Group
SANS = Scale for the Assessment of Negative Symptoms
SAPS = Scale for the Assessment of Positive Symptoms

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