Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis.

Background: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder.
Methods: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation.
Findings: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented.
Interpretation: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores.
Funding: German Research Foundation (grant number: 428509362).
Competing Interests: Declaration of interests RAM has received speaker or consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and co-directs a company that designs digital resources to support treatment of mental illness. JMK has been a consultant or advisor for, or has received honoraria from, Alkermes, Allergan, LB Pharmaceuticals, H Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson & Johnson, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Reviva, Roche, Sumitomo Dainippon, Sunovion, Takeda, Teva, and UpToDate, and is a shareholder in LB Pharmaceuticals and Vanguard Research Group. CA has been a consultant to, or has received honoraria or grants from, Acadia, Abbot, Ambrosetti, AMGEN, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Forum, Gedeon Richter, Janssen Cilag, Lundbeck, Merck, Otsuka, Pfizer, Roche, Servier, Shire, Schering Plough, Sunovion, and Takeda. WWF has received consulting fees from Boehringer Ingelheim, Angelini, Richter, and Recordati, and grant support from Lundbeck and Otsuka. PF received paid speakership from Otsuka, Recordati, Richter, Rovi, and Janssen, and is a member of advisory boards of Richter, Rovi, and Janssen. AH has received paid speakerships from AbbVie, Janssen, Otsuka, Rercordati, and Lundbeck. He was member of Rovi, Recordati, Otsuka, Lundbeck, and Janssen advisory boards. SRM has received consulting fees from Boehringer-Ingelheim, H. Lundbeck, Otsuka, Takeda, Teva, Roche, Genentech, Targacept, Forum, AbbVie, Allergan, and Neurocrine. He has received research support from Boehringer-Ingelheim, Takeda, and Neurocrine. NS has been a consultant or advisor to, or has received honoraria, from Alkermes, Lundbeck, Otsuka, Otsuka Canada, and Teva. WGH has received consulting fees or sat on paid advisory boards for In Silico Biosciences, Translational Life Sciences, Newron, Otsuka, and AbbVie. RWB is a data and safety monitoring board member for Merck, Newron, and Roche; on the advisory board for Acadia, Boehringer Ingelheim, Karuna, Neurocrine, and Roche; and consultant for Boehringer Ingelheim. MD is an employee of Minerva Neurosciences. MW He has received advisory board, speaker's, or consultant fees from, and owns stock, with Acadia, Dexcel, Janssen, Lundbeck, Minerva, Pfizer, Roche, and Teva. OH was a part-time employee of H. Lundbeck, and has received investigator-initiated research funding from, or participated in, advisory or speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, and Viatris/Mylan. Neither he nor his family have holdings/a financial stake in any pharmaceutical company. He has a patent for the use of dopaminergic imaging. CUC has been a consultant or advisor to, or has received honoraria from, AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Cardio Diagnostics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a data safety monitoring board for Lundbeck, Relmada, Reviva, Rovi, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantics. In the past 3 years, SL has received honoraria as a consultant, adviser, or lecturer from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitsubishi. All other authors declare no competing interests.
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