Minimum Effective Doses for Atypical Antipsychotics Updated

Kenneth Bender

March 12, 2014

Recommendations for the minimum effective dose for second-generation antipsychotics, also known as atypical antipsychotics, have been updated.

The minimum effective dose, the threshold at which an agent proves more efficacious than placebo, was determined for 13 second-generation antipsychotics and was used to calculate their dosing equivalents relative to the standard neuroleptic antipsychotics chlorpromazine and haloperidol (Haldol, Ortho-McNeil-Janssen Pharmaceuticals, Inc) and to the early second-generation agents olanzapine (Zyprexa, Eli Lilly and Company) and risperidone (Risperdal, Janssen Pharmaceuticals, Inc).

Expanding upon a method reported in 2003 for estimating dose equivalents across drug development programs, the researchers reassessed the initial dose determinations for 5 second-generation agents and analyzed data for 8 additional agents subsequently introduced.

The investigators reported the following minimum effective daily doses/olanzapine equivalents: aripiprazole (Abilify, Otsuka Pharmaceutical Co, Ltd), 10 mg/1.33; asenapine (Saphris, Merck & Co, Inc), 10 mg/1.33; clozapine, 300 mg/40; haloperidol, 4 mg/0.53; iloperidone (Fanapt, Novartis Pharmaceuticals Corporation), 8 mg/1.07; lurasidone (Latuda, Sunovion Pharmaceuticals, Inc), 40 mg/5.33; olanzapine 7.5 mg/1; paliperidone (Invega, Janssen Pharmaceuticals, Inc), 3 mg/0.4; quetiapine (Seroquel, AstraZeneca Pharmaceuticals LP), 150 mg/20; risperidone, 2 mg/0.27; sertindole (Serdolect, H. Lundbeck A/S), 12 mg/1.60; and ziprasidone (Geodon, Pfizer Inc), 40 mg/5.33.

John Davis, MD, Psychiatric Institute, University of Illinois at Chicago, and colleagues in the United States and Europe began with the method described by Scott Woods, MD, in 2003, and, as they explained, "we operationalized the selection process, updated the original findings, and expanded them by systematically searching more recent literature and by including 13 second-generation antipsychotics."

The researchers indicated that these estimated dose equivalents should be useful to clinicians considering switching agents and to clinical researchers seeking to design fair drug-drug comparison trials, as well as in conducting cost-benefit analyses and developing treatment guidelines.

The study was published in the March issue of Schizophrenia Bulletin.

No Study Missed

The primary criterion for determining minimum effective antipsychotic dose was the lowest dose found to be statistically significantly superior to placebo in 1 double-blind, randomized control trial (RCT) on standardized measures such as the Positive and Negative Syndrome Scale (PANSS) total score or the Brief Psychiatric Rating Scale (BPRS) total score. The researchers also used meta- analysis to ascertain whether the greater statistical power would reveal lower doses that were more efficacious than placebo.

To test the sensitivity of their own methodology, a second RCT was sought in which the dose proved efficacious.

"In essence, this is in keeping with a rule for the registration of a compound by the Food and Drug Administration (FDA)," the researchers write. "If a dose was supported by only one trial, the next higher dose that was effective in another trial qualified for the secondary criterion."

Seventy-three studies were included in this analysis; studies in "special populations" were excluded. This exclusion precludes the association of the estimated minimum effective doses to adolescent, elderly, and first-episode patients, as well as those with predominately negative symptoms, treatment resistance, and those on stable, relapse-prevention regimens.

A draft of the report was provided to the respective drug manufacturers with a request for any additional unpublished data that could be relevant to the assessment. "Most manufacturers replied," Dr. Davis and colleagues indicated, "which increased our confidence that no study was missed."

Dose determinations were necessarily made with consideration of the varied number, size, and design of available studies. The determination of the aripiprazole minimum effective daily dose of 10 mg, for example, was based on 7 fixed-dose, placebo-controlled studies and differed from the 15 mg that had been determined by Dr. Woods from the 5 studies that were available at that time.

There were 12 studies on quetiapine immediate release and 3 on the extended-release dosage form, which examined daily doses between 75 mg and 800 mg. The researchers found that the 75-mg dose had been ineffective; and although in a single study, the 150-mg dose separated from placebo, meeting the primary criterion, the dose of 250 mg met the criterion of the sensitivity analysis.

Dr. Davis and colleagues acknowledged that, as the quetiapine data illustrate, the antipsychotic dose determinations are estimations for clinical circumstances.

"Overall determining dose response for quetiapine is not straightforward," they indicated, "as higher doses did not separate from placebo in several studies, including quetiapine 800 mg/d arms."

The efforts to incorporate calculated effect size also proved problematic, because placebo response and dropout rates appear to have increased over the decades and reduced effect size. The researchers encountered studies in which "even well-established drugs such as haloperidol and olanzapine do not separate from placebo."

Schizophr Bull. 2014;40:314-326. Abstract

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