Charles M. Beasley, Jr and Roy Tamura: What We Know and Do Not Know by Conventional Statistical Standards About Whether a Drug Does or Does Not Cause a Specific Side Effect (Adverse Drug Reaction)


Daniel Kanofsky's Comments on Beasley and Tamura Essay



        The authors state: "all interested parties should clearly understand the virtual impossibility of 'proving' by a conventional gold standard what is or is not an ADR associated with a drug."

        I want to elaborate a bit on a mentioned complication of this quest. Drug-drug interactions have been reported in cases of adverse drug reactions as possible contributing actors (Kanofsky,Woesner, Harris et al. 2011). Focusing only on clozapine, valproate has been implicated as a possible contributing factor in “clozapine induced acute renal failure” (CIARF) and clozapine induced myocarditis (Kanofsky,Woesner, Harris et al. 2011; Woesner and Kanofsky 2015; Nielsen, Manu and Kane 2015; Ronaldson, Fitzgerald and McNeil 2015; Kanofsky and Woesner 2017). Our group used a Fisher's Exact test on the set of all reported CIARF cases which at that time was only eight. The analysis suggested co-treatment with antibiotics may exacerbate CIARF (Kanofsky, Woesner, Harris et al. 2012). A definitive statement would require many more reported cases.

        In keeping with these thoughts, these serious but rare inflammatory responses to clozapine which include clozapine induced pancreatitis, colitis and pericarditis should lead to termination of clozapine but since clozapine can be a very effective antipsychotic drug when no other antipsychotic is effective the highly clinically relevant question emerges: is clozapine rechallenge safe and meaningful (Nielsen, Manu, Kane and Correll 2015)? Few cases of rechallenge have been reported. This lack of statistical power makes overarching conclusions impossible. Under these circumstances what can guide clinical decision making? Nielsen et al. respond: "As these low numbers illustrate, it is highly important that any patient who experienced a serious/potentially life threatening ADR with clozapine who is later rechallenged is reflected in the literature, so that we can learn more about under which circumstances clozapine rechallenge is or is not safe."

        Our group has expanded on this recommendation. We believe there is a need for a clozapine rechallenge case file or special registries. A case file or registry could encourage a greater and more accessible flow of information and expedite learning under what conditions a clozapine rechallenge can be safely conducted (Kanofsky and Woesner 2017). Clozapine is the only psychiatric medication in this country that is currently dispensed using a national registry - the Risk Evaluation and Mitigation Strategy (REMS). The REMS program has the potential to become an ideal resource to locate American-based clozapine rechallenge cases. We hope this opportunity will be realized.



Kanofsky JD, Woesner ME. Clozapine-valproate adverse drug reactions and the need for a clozapine rechallenge case file. Prim Care Companion CNS Disord. 2017; 19(1) .

Kanofsky JD,Woesner ME, Harris AZ, Kelleher JP, Gittens K, Jerschow E. A case of acute renal failure in a patient recently treated with clozapine and a review of previously reported cases. Prim Care Companion CNS Disord. 2011; 13(3).

Kanofsky JD, Woesner ME, Harris AZ, Kelleher JP, Gittens K, Jerschow E. Antibiotic treatment may exacerbate clozapine induced renal failure. Intern Med J. 2012; 42(11):1272.  

Nielsen J, Manu P, Kane JM, Correll CU. Dr. Nielsen and colleagues reply. J Clin Psychiatry. 2015; 76(12):1694-5.

Ronaldson KJ, Fitzgerald PB, McNeil JJ. Clozapine-induced myocarditis, a widely overlooked adverse reaction. Acta Psychiatr Scand. 2015; 132:231-40.

Woesner ME, Kanofsky JD. Revisiting the discussion: termination of clozapine treatment due to renal failure. J Clin Psychiatry. 2015; 76(12):1694.


April 16, 2020