Clozapine Optimization: A Delphi Consensus Guideline From the Treatment Response and Resistance in Psychosis Working Group
Authors: Wagner Elias , Siskind Dan , Falkai Peter , Howes Oliver , Correll Christoph , Lee Jimmy , Honer William G , Kane John M , Fernandez-Egea Emilio , Barnes Thomas R E , Hasan Alkomiet ,   TRRIP Working Group, Agid Ofer , Arango Celso , Baandrup Lone , Barnes Thomas R E , de Bartolomeis Andrea , van Beveren Nico J M , Birnbaum Michael L , Bitter István , Breier Alain , Buchanan Robert W , Carpenter William T , Castle David J , Chen Eric , Citrome Leslie , Cotter David , Correll Christoph U , Crespo-Facorro Benedicto , Davidson Michael , Drake Richard J , Dollfus Sonia , Dursun Serdar , Ebdrup Bjørn H , Emsley Robin , Fernandez-Egea Emilio , Elkis Helio , Falkai Peter , Fleischhacker Wolfgang , Freudenreich Oliver , Gadelha Ary , Gaebel Wolfgang , Glenthøj Birte Y , Goff Donald C , Graff-Guerrero Ariel , Hallak Jaime E C , Hasan Alkomiet , Honer William G , Homan Philip , Howes Oliver , Kahn Rene S , Kaiser Stefan , Kane John , Kennedy James , Kinon Bruce , Kim Euitae , Lawrie Stephen M , Lee Jimmy , Leucht Stefan , Leweke Markus , Libiger Jan , Loebel Antony , MacCabe James H , Marder Stephen R , McCutcheon Rob , Melle Ingrid , Meltzer Herbert , Mucci Armida , Naber Dieter , Nakajima Shinchiro , Nielsen Jimmi , O’Brien Oisin , Ojagbemi Akin , Pantelis Christos , Peuskens Joseph , Potkin Steve , Marques Tiago Reis , Raedler Thomas , Remington Gary , Rossell Susan L , Rubio-Lorente Jose , Sachs Gabriele , Siskind Dan , Siu Cynthia O , Sommer Iris E , Kwon Jun Soo , Suzuki Takefumi , Suvisaari Jaana , Takeuchi Hiroyoshi , Tandon Rajiv , Taylor David , Thomas Neil , Tiihonen Jari , Uchida Hiroyuki , Üçok Alp , Umbricht Daniel , Venkatasubramanian Ganesan , Wagner Elias , Walters James T R , Wang Chuan-Yue , Weiller Emmanuelle , Weiser Mark 
Published: March 2023

Abstract

Background and Hypothesis
There is limited evidence to guide the approaches to clozapine treatment. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for the optimization of clozapine monotherapy.

Study Design
We conducted an online Delphi survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group comprising experts from twenty-nine countries. The threshold criterion for a consensus recommendation was ≥ 75% agreement (“agree” and “strongly agree” responses) on a question. Agreement of ≥ 50% but &lt; 75% in a second or third Delphi round was deemed to provide guidance.

Study Results
Forty-nine (first round), 32 (second round), and 48 (third round) of the 91 current TRRIP members participated. Expert recommendations at ≥ 75% comprised second-line treatment with clozapine in cases of persistent positive symptoms with co-occurring extrapyramidal symptoms, tardive dyskinesia, or suicidality/aggression. There was considerable disagreement on myocarditis screening parameters. The management of somatic and neuropsychiatric adverse drug reactions warrants further research for more evidence-based recommendations. Rechallenge with clozapine was recommended for eosinophilia, sinus tachycardia and fever and guidance (agreement ≥ 50%) was reached for pneumonia and thrombocytopenia.

Conclusions
Given the limited evidence available, this consensus-based series of recommendations and guidance statements supports clinical decision-making to optimize clozapine monotherapy and provides guidance for future research in treatment-resistant schizophrenia.