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Letters to the Editor   |    
Adequate Dosing for Second-Generation Antipsychotics in Establishing Treatment Resistance in Schizophrenia
Jimmy Lee, M.B.B.S, M.Med.; Gary Remington, M.D., Ph.D.
Am J Psychiatry 2014;171:118-119. doi:10.1176/appi.ajp.2013.13070965
View Author and Article Information

Dr. Lee has served as a consultant for Roche and is currently supported by the Singapore Ministry of Health’s National Medical Research Council under its Transition Award (grant NMRC/TA/002/2012). Dr. Remington has received research support, consulting fees, or speaker’s fees from the Canadian Diabetes Association, the Canadian Institutes of Health Research, Hoffman-La Roche, Laboratorios Farmacéuticos Rovi, Medicure, Neurocrine Biosciences, Novartis Canada, Research Hospital Fund–Canada Foundation for Innovation, and the Schizophrenia Society of Ontario.

From the Department of General Psychiatry 1 and Research Division, Institute of Mental Health, Singapore; the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; and the Department of Psychiatry, University of Toronto.

Copyright © 2014 by the American Psychiatric Association

Accepted November , 2013.

To the Editor: Treatment resistance in schizophrenia requires evidence of two previous failed antipsychotic trials of 6 weeks at a dose of 600 mg in chlorpromazine equivalents (1), while the original criteria for clozapine’s role in treatment resistance stipulated a dose of 1,000 mg in chlorpromazine equivalents (2).

Second-generation antipsychotics have largely supplanted their first-generation counterparts in the last decade, and studies have attempted to derive chlorpromazine equivalents for these agents either through expert consensus or calculation methods. This calls into question the impact of these different approaches on studies employing chlorpromazine equivalents.

The estimated doses of five commonly prescribed second-generation antipsychotics, using four widely used methods, are listed in Table 1. Immediately apparent is the wide variation in calculated doses for any given second-generation antipsychotics; for example, at 600 mg of chlorpromazine equivalents, doses of risperidone vary between 6 mg and 12 mg and doses of aripiprazole vary between 24 mg and 45 mg. These differences are amplified at 1,000 mg of chlorpromazine equivalents.

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TABLE 1.Computed Doses of Antipsychotics at 600 and 1,000 mg Chlorpromazine Equivalents From Consensus and Calculation Methods
Table Footer Note

a Recommended dose range for treatment of an acute episode (3).

Table Footer Note

b Doses obtained and approximated from haloperidol, 10 mg for 600 mg of chlorpromazine equivalents and 20 mg for 1,000 mg of chlorpromazine equivalents, from guideline 5A of Kane et al. (4).

Table Footer Note

c Doses computed from dose equivalency ratio versus chlorpromazine (5).

Table Footer Note

d Doses calculated from table provided in Woods (6).

Table Footer Note

e Doses calculated from power transformation for chlorpromazine equivalent (7).

Table Footer Note

f Median (interquartile range) maximum doses (5).

At 1,000 mg of chlorpromazine equivalents, calculated doses for the second-generation antipsychotics uniformly exceed the maximum dosages currently recommended for these agents (3). Even at 600 mg of chlorpromazine equivalents, values frequently lie outside the recommended dosage range. As importantly, the calculated doses differ markedly based on the method employed.

This variance raises practical considerations, for example, in declaring a failed second-generation antipsychotics trial in the process of defining treatment-resistant schizophrenia. The wide variation challenges the validity of using chlorpromazine equivalents to compare across antipsychotics. The reported near-maximal effective dose of chlorpromazine was 400–450 mg, not 600–1,000 mg, and there appears to be little evidence to support high doses in treatment-resistant schizophrenia (4). In addition, the high doses calculated raise serious safety concerns and fly in the face of regulatory dosing recommendations. Accordingly, adopting chlorpromazine equivalents may not be appropriate for evaluating an adequate dosage for specific second-generation antipsychotics, and we suggest that a more appropriate means to confirm a failed clinical trial is suboptimal response at the maximum recommended dosage range for a specific second-generation antipsychotics, as per product monograph.

Conley  RR;  Kelly  DL:  Management of treatment resistance in schizophrenia.  Biol Psychiatry 2001; 50:898–911
[CrossRef] | [PubMed]
 
Kane  J;  Honigfeld  G;  Singer  J;  Meltzer  H:  Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine.  Arch Gen Psychiatry 1988; 45:789–796
[CrossRef] | [PubMed]
 
Buchanan  RW;  Kreyenbuhl  J;  Kelly  DL;  Noel  JM;  Boggs  DL;  Fischer  BA;  Himelhoch  S;  Fang  B;  Peterson  E;  Aquino  PR;  Keller  W; Schizophrenia Patient Outcomes Research Team (PORT):  The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements.  Schizophr Bull 2010; 36:71–93
[CrossRef] | [PubMed]
 
Kane  JM;  Leucht  S;  Carpenter  D;  Docherty  JP; Expert Consensus Panel for Optimizing Pharmacologic Treatment of Psychotic Disorders:  The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary.  J Clin Psychiatry 2003; 64(suppl 12):5–19
[CrossRef] | [PubMed]
 
Gardner  DM;  Murphy  AL;  O’Donnell  H;  Centorrino  F;  Baldessarini  RJ:  International consensus study of antipsychotic dosing.  Am J Psychiatry 2010; 167:686–693
[CrossRef] | [PubMed]
 
Woods  SW:  Chlorpromazine equivalent doses for the newer atypical antipsychotics.  J Clin Psychiatry 2003; 64:663–667
[CrossRef] | [PubMed]
 
Andreasen  NC;  Pressler  M;  Nopoulos  P;  Miller  D;  Ho  BC:  Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs.  Biol Psychiatry 2010; 67:255–262
[CrossRef] | [PubMed]
 
Davis  JM;  Chen  N:  Dose response and dose equivalence of antipsychotics.  J Clin Psychopharmacol 2004; 24:192–208
[CrossRef] | [PubMed]
 
References Container
Anchor for Jump
TABLE 1.Computed Doses of Antipsychotics at 600 and 1,000 mg Chlorpromazine Equivalents From Consensus and Calculation Methods
Table Footer Note

a Recommended dose range for treatment of an acute episode (3).

Table Footer Note

b Doses obtained and approximated from haloperidol, 10 mg for 600 mg of chlorpromazine equivalents and 20 mg for 1,000 mg of chlorpromazine equivalents, from guideline 5A of Kane et al. (4).

Table Footer Note

c Doses computed from dose equivalency ratio versus chlorpromazine (5).

Table Footer Note

d Doses calculated from table provided in Woods (6).

Table Footer Note

e Doses calculated from power transformation for chlorpromazine equivalent (7).

Table Footer Note

f Median (interquartile range) maximum doses (5).

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References

Conley  RR;  Kelly  DL:  Management of treatment resistance in schizophrenia.  Biol Psychiatry 2001; 50:898–911
[CrossRef] | [PubMed]
 
Kane  J;  Honigfeld  G;  Singer  J;  Meltzer  H:  Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine.  Arch Gen Psychiatry 1988; 45:789–796
[CrossRef] | [PubMed]
 
Buchanan  RW;  Kreyenbuhl  J;  Kelly  DL;  Noel  JM;  Boggs  DL;  Fischer  BA;  Himelhoch  S;  Fang  B;  Peterson  E;  Aquino  PR;  Keller  W; Schizophrenia Patient Outcomes Research Team (PORT):  The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements.  Schizophr Bull 2010; 36:71–93
[CrossRef] | [PubMed]
 
Kane  JM;  Leucht  S;  Carpenter  D;  Docherty  JP; Expert Consensus Panel for Optimizing Pharmacologic Treatment of Psychotic Disorders:  The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary.  J Clin Psychiatry 2003; 64(suppl 12):5–19
[CrossRef] | [PubMed]
 
Gardner  DM;  Murphy  AL;  O’Donnell  H;  Centorrino  F;  Baldessarini  RJ:  International consensus study of antipsychotic dosing.  Am J Psychiatry 2010; 167:686–693
[CrossRef] | [PubMed]
 
Woods  SW:  Chlorpromazine equivalent doses for the newer atypical antipsychotics.  J Clin Psychiatry 2003; 64:663–667
[CrossRef] | [PubMed]
 
Andreasen  NC;  Pressler  M;  Nopoulos  P;  Miller  D;  Ho  BC:  Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs.  Biol Psychiatry 2010; 67:255–262
[CrossRef] | [PubMed]
 
Davis  JM;  Chen  N:  Dose response and dose equivalence of antipsychotics.  J Clin Psychopharmacol 2004; 24:192–208
[CrossRef] | [PubMed]
 
References Container
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