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APA Practice Guideline for Schizophrenia: Risperidone Equivalents

To the Editor: Clinicians seek guidance regarding conversion factors that will allow them to compare novel neuroleptics to existing conventional agents in milligram equivalents. Recently published APA guidelines indicate that a 1–2-mg dose of risperidone equals a 2-mg dose of haloperidol (1), suggesting that haloperidol may require doses twice as high as those of risperidone. However, several lines of investigation support equivalent dosing.

Positron emission tomography findings indicate that risperidone and haloperidol are approximately equivalent in terms of dopamine 2 (D₂) occupancy. Specifically, mean D₂ occupancies for risperidone and haloperidol at 2 mg are 66.3% and 66.7%, respectively (2, 3). While it might be argued that risperidone's shared serotonin-dopamine antagonism prevents a comparison based simply on D₂ occupancy, there is no evidence to date to suggest that risperidone is different from conventional neuroleptics such as haloperidol in terms of the need to achieve at least 60%–70% D₂ occupancy for antipsychotic response (2-5). This is in contrast to clozapine, which clearly demonstrates its therapeutic effect at levels of D₂ occupancy below 60% (5, 6).

Comparative data between risperidone and haloperidol, when flexible dosing is employed, provide further support for dose equivalence. In a recent double-blind study of first-episode psychosis (7), individuals were randomly assigned to 4 mg/day of either haloperidol or risperidone. Thereafter, doses of each could be titrated by 2 mg, on the basis of clinical response and side effects, to a maximum of 16 mg/day or a minimum of 2 mg/day. Results indicated that dosing changes over the 6-week trial were comparable for both compounds; at endpoint, the final doses for risperidone and haloperidol were 6.1 mg/day and 5.6 mg/day, respectively.

Comparative data between risperidone and haloperidol, when flexible dosing is employed, provide further support for dose equivalence. In a recent double-blind study of first-episode psychosis (7), individuals were randomly assigned to 4 mg/day of either haloperidol or risperidone. Thereafter, doses of each could be titrated by 2 mg, on the basis of clinical response and side effects, to a maximum of 16 mg/day or a minimum of 2 mg/day. Results indicated that dosing changes over the 6-week trial were comparable for both compounds; at endpoint, the final doses for risperidone and haloperidol were 6.1 mg/day and 5.6 mg/day, respectively.

Evidence involving patients with chronic schizophrenia, although more indirect, also suggests equivalent dosing. Unfortunately, in controlled trials directly comparing risperidone to haloperidol, lower doses of risperidone (i.e., 1–16 mg/day) have been compared to haloperidol doses of 10–20 mg/day (8-10). This has made it virtually impossible to establish whether these two compounds may be equipotent. However, other reports involving neuroleptics in lower doses, including a meta-analysis of 22 randomized, controlled trials, have indicated that for a compound such as haloperidol, the optimal daily dose range is between 3 and 8 mg (11-13). This closely parallels the multiple fixed-dose studies with risperidone indicating that 4–8 mg/day appears to represent the optimal dose range for a similar patient population (8-10).

The recommendation that risperidone and haloperidol be considered equal in terms of dosing must be made with the caveat that these compounds are not necessarily clinically equivalent. Specific advantages have been linked to risperidone's concomitant 5-hydroxytryptamine antagonism, such as diminished extrapyramidal side effects and improvement in negative symptoms (8–10). At the same time, though, the recommendation means that the results of studies comparing these agents must be revisited and that future investigations must employ comparable doses of each.

REFERENCES

1. American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. Am J Psychiatry 1997; 154(April suppl)
2. Kapur S, Remington G, Zipursky RB, Wilson AA, Houle S: The D2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study. Life Sci 1995; 57:103–107[Medline]
3. Kapur S, Remington G, Jones C, Wilson A, Da Silva J, Houle S, Zipursky R: High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study. Am J Psychiatry 1996; 153:948–950 [Abstract/Free Full Text]
4. Nordström A-L, Farde L, Wiesel F-A, Forslund K, Pauli S, Halldin C, Uppfeldt G: Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry 1993; 33:227–235[Medline]
5. Farde L, Nordström A-L, Wiesel F-A, Pauli S, Halldin C, Sedvall G: Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Arch Gen Psychiatry 1992; 49:538–544[Abstract]
6. Nordström A-L, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G: D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 1995; 152:1444–1449[Abstract/Free Full Text]
7. Emsley RA, McCreadie R, Livingston M, De Smedt G, Lemmons P: Risperidone in the treatment of first-episode patients with schizophreniform disorder (abstract). Eur Neuropsycho­pharmacol 1995; 5:350
8. Chouinard G, Jones B, Remington G, Bloom D, Addington D, MacEwan GW, Labelle A, Beauclair L, Arnott W: A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993; 13:25–40[Medline]
9. Marder SR, Meibach RC: Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151:825–835[Abstract/Free Full Text]
10. Peuskens J, Risperidone Study Group: Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Br J Psychiatry 1995; 166:712–726[Abstract/Free Full Text]
11. McEvoy JP, Hogarty GE, Steingard S: Optimal dosing of neuroleptic in acute schizophrenia. Arch Gen Psychiatry 1991; 48:739–745[Abstract]
12. Bolini P, Pampallona S, Orza MJ, Adams ME, Chalmers TC: Antipsychotic drugs: is more worse? A meta-analysis of the published randomized control trials. Psychol Med 1994; 24:307–316[Medline]
13. Stone CK, Garver DL, Griffith J, Hirschowitz J, Bennett J: Further evidence of a dose-response threshold for haloperidol in psychosis. Am J Psychiatry 1995; 152:1210–1212[Abstract/Free Full Text]

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