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Meta-Analysis
. 2009 Oct 7;2009(4):CD007474.
doi: 10.1002/14651858.CD007474.pub2.

Risperidone dose for schizophrenia

Chunbo Li  1 , Jun Xia, Jijun Wang
Affiliations
Meta-Analysis

Risperidone dose for schizophrenia

Chunbo Li et al. Cochrane Database Syst Rev. .

Abstract

Background: Risperidone is a widely used antipsychotic drug for people with schizophrenia. It is important to get a balance between gaining the most positive effects for the least negative outcomes. The optimal dose of risperidone is the focus of this review.

Objectives: To determine risperidone dose response relationships for schizophrenia and schizophrenia-like psychoses.

Search strategy: We searched the Cochrane Schizophrenia Groups Trials Register (July 2008) for all relevant references.

Selection criteria: All relevant randomised controlled clinical trials (RCTs).

Data collection and analysis: Two review authors independently extracted data and resolved disagreement by discussion with a third member of the team. When insufficient data were provided, we contacted the study authors. For homogenous dichotomous data we calculated fixed-effect relative risk (RR) and 95% confidence intervals (CI) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (MD).

Main results: A consistent finding when risperidone ultra low doses (<2 mg/day) were compared with other doses (short-term data) was that more people left early because of insufficient response (n=456, 1 RCT, RR when compared with standard-low (>==4-<6 mg/day) 12.48 CI 1.43 to 4.30). The insufficient response for this low dose is reflected in measures of mental state. When low doses (>==2-<4 mg/day) are used and compared with standard-higher doses (>==6-<10 mg/day) and the high dose range (>==10 mg/day), more people left early because of insufficient response (>==4-<6 mg/day: n=173, 2 RCTs, RR 4.05 CI 1.09 to 15.07; >==10 mg/day: n=173, 2 RCTs, RR 1.92 CI 1.36 to 2.70). For the outcome of 'no clinically important improvement' results favour standard-higher doses (n=272, 2 RCTs, RR 2.26 CI 0.81 to 6.34). When low doses are compared with other higher doses, we found no differences in terms of cardiovascular, CNS, endocrine or gastrointestinal adverse effects. Unspecified EPS were more frequent with the higher doses (>==10 mg: n=262, 2 RCTs, RR 0.45 CI 0.24 to 0.84). One trial did find that endpoint scores on PANSS significantly favoured a low dose when compared with >==4-6 mg/day (n=124, 1 RCT, MD -12.40 CI -17.01 to -7.79). When >==4-<6 mg/day is compared with high doses, less people left early (n=677, 1 RCT, RR leaving any reason 0.74 CI 0.54 to 1.00; n=677, 1 RCT, RR due to adverse effects 0.56 CI 0.32 to 0.97). >==4-<6 mg/day was no worse than >==6-<10 mg/day for 'no clinically important improvement' (n=39, 1 RCT, RR on CGI-I 0.79 CI 0.29 to 2.17). People allocated >==4-<6 mg/day had more movement disorders than those on a low dose (n=124 1 RCT, RR 2.28 CI 1.67 to 3.11). When >==6-<10 mg/day is compared with standard-lower doses and a high dose range, there is no significant difference in terms of proportions leaving early. >==6-<10 mg/day is better than a low dose for 'no clinical important improvement' (n=172, 2 RCTs, RR 0.76 CI 0.61 to 0.94). Overall >==6-<10 mg/day caused less problems especially in EPS when compared with >==10mg/day (n=261, 2 RCTs, RR unspecified EPS 0.56 CI 0.31 to 0.99). When a high dose was compared with a low dose less people left early (n=70, 1 RCT, RR 0.43 CI 0.26 to 0.71) but not when compared with a standard-lower dose (n=677, 1 RCT, RR leaving due to adverse event 1.78 CI 1.03 to 3.09). >==10 mg/day was better than a low dose in terms of 'no clinical important improvement' (n=257, 2 RCTs, RR 0.64 CI 0.50 to 0.82), but worse than a standard-higher dose (>==6-<10 mg/day: n=255, 2 RCTs, RR 1.22 CI 1.00 to 1.51). >==10 mg/day caused more unspecified EPS adverse effects and any drug for adverse events when compared with a standard-higher dose and with a low dose.

Authors' conclusions: There is still lack of strong evidence for an optimal dose for clinical practice. The quality of trials suggests that an over estimate of effect is likely and we think this is most probably for the mid-range doses. One such dose (standard-lower dose range, 4-<6 mg/day) does seem optimal for clinical response and adverse effects. Weak evidence suggests that low doses (>==2-<4 mg/day) may be of value for people in their first episode of illness. High doses (>==10 mg/day) did not confer any advantage over any other dose ranges and caused more adverse effects, especially for movement disorders. Ultra low dose (<2 mg/day) seemed useless. We advise the use of dosages from low dose to standard-lower dose for different kinds of individual patients. Future trials should focus on specific populations, e.g. those in their first episode, with acute exacerbation, in relapse or refractory to treatment, and should also test the optimal dose of risperidone over a longer period of time and in the community.

PubMed Disclaimer

Conflict of interest statement

None known.

Figures

1
1
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
4
4
5
5
1.1
1.1. Analysis
Comparison 1 ULTRA LOW DOSE (<2 mg/day) versus ANY DOSE ‐ short term, Outcome 1 Leaving the study early: 1. Various reasons ‐ when compared with standard‐low dose (≧4‐<6 mg/day).
1.2
1.2. Analysis
Comparison 1 ULTRA LOW DOSE (<2 mg/day) versus ANY DOSE ‐ short term, Outcome 2 Leaving the study early: 2. Various reasons ‐ when compared with standard‐higher dose (≧6‐<10 mg/day).
1.3
1.3. Analysis
Comparison 1 ULTRA LOW DOSE (<2 mg/day) versus ANY DOSE ‐ short term, Outcome 3 Leaving the study early: 3. Various reasons ‐ when compared with high dose (≧10 mg).
1.4
1.4. Analysis
Comparison 1 ULTRA LOW DOSE (<2 mg/day) versus ANY DOSE ‐ short term, Outcome 4 Mental state: 1. No clinically important improvement ‐ as measured by PANSS.
1.5
1.5. Analysis
Comparison 1 ULTRA LOW DOSE (<2 mg/day) versus ANY DOSE ‐ short term, Outcome 5 Mental state: 2. Average change score ‐ PANSS (larger decline is better).
1.6
1.6. Analysis
Comparison 1 ULTRA LOW DOSE (<2 mg/day) versus ANY DOSE ‐ short term, Outcome 6 Adverse effects ‐ when compared with standard‐low dose (≧4‐<6 mg/day).
2.1
2.1. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 1 Leaving the study early: 1. Any reason ‐ when compared with standard‐lower dose (≧4‐<6 mg/day).
2.2
2.2. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 2 Leaving the study early: 2. Various reasons ‐ when compared with standard‐higher dose (≧6‐<10 mg/day).
2.3
2.3. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 3 Leaving the study early: 3. Various reasons ‐ when compared with high dose ( ≧10 mg).
2.4
2.4. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 4 Global state: 1. No clinically important improvement.
2.5
2.5. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 5 Global state: 2. Average endpoint score.
2.6
2.6. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 6 Mental state: 1. No clinically important improvement.
2.7
2.7. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 7 Mental state: 2. Average endpoint score ‐ various scales.
2.11
2.11. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 11 Adverse effects: 1. Cardiovascular.
2.12
2.12. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 12 Adverse effects: 2. CNS.
2.13
2.13. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 13 Adverse effects: 3. Endocrine ‐ sweating ‐ versus low dose (≧2‐<4 mg/day).
2.14
2.14. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 14 Adverse effects: 4. Gastrointestinal.
2.15
2.15. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 15 Adverse effects: 5a. Movement disorders ‐ specific symptoms.
2.17
2.17. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 17 Adverse effects: 6. Respiratory.
2.18
2.18. Analysis
Comparison 2 LOW DOSE (≧2‐<4 mg/day) versus ANY DOSE ‐ short term, Outcome 18 Adverse effects: 7a. Others ‐ specific problems.
3.1
3.1. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 1 Leaving the study early: 1. Various reasons ‐ when compared with ultra low dose (<2 mg/day).
3.2
3.2. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 2 Leaving the study early: 2. Treatment deviations ‐ when compared with low dose (≧2‐<4 mg/day).
3.3
3.3. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 3 Leaving the study early: 3. Various reasons ‐ when compared with standard‐higher dose (≧6‐<10 mg/day).
3.4
3.4. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 4 Leaving the study early: 4. When compared with high dose ( ≧10 mg).
3.5
3.5. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 5 Global state: No clinically important improvement.
3.6
3.6. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 6 Mental state: 1. No clinically important improvement.
3.7
3.7. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 7 Mental state: 2. Average endpoint score ‐ various scales.
3.8
3.8. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 8 Mental state: 3. Average change score ‐ various scales.
3.9
3.9. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 9 Mental state: 4. Average percentage change ‐ when compared with versus low dose (≧2‐<4 mg/day) ‐ total (PANSS, low=poor).
3.13
3.13. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 13 Cognitive function: No clinically important improvement.
3.14
3.14. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 14 Adverse effects: 1. Any reason.
3.15
3.15. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 15 Adverse effects: 2. Cardiovascular.
3.16
3.16. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 16 Adverse effects: 3. CNS.
3.17
3.17. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 17 Adverse effects: 4. Endocrine.
3.18
3.18. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 18 Adverse effects: 5. Gastrointestinal.
3.19
3.19. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 19 Adverse effects: 6. Movement disorders ‐ specific symptoms.
3.20
3.20. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 20 Adverse effects: 7. Others ‐ specific problems.
3.21
3.21. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 21 Adverse effects: 8. Global tolerance of treatment (high=poor).
3.22
3.22. Analysis
Comparison 3 STANDARD‐LOWER DOSE (≧4‐<6 mg/day) versus ANY DOSE ‐ short term, Outcome 22 Adverse effects: 9. Global tolerance of treatment (high=poor).
4.1
4.1. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 1 Leaving the study early: 1. When compared with ultra low dose (<2 mg/day).
4.2
4.2. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 2 Leaving the study early: 2. When compared with low dose (≧2‐<4 mg/day).
4.3
4.3. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 3 Leaving the study early: 3. When compared with standard‐lower dose (≧4‐<6 mg/day).
4.4
4.4. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 4 Leaving the study early: 4. When compared with high dose ( ≧10 mg/day).
4.5
4.5. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 5 Global state: 1. No clinically important improvement.
4.6
4.6. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 6 Global state: 2. Average endpoint score.
4.7
4.7. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 7 Mental state: 1. No clinically important improvement.
4.8
4.8. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 8 Mental state: 2. Average endpoint score.
4.9
4.9. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 9 Mental state: 3. Average endpoint score change.
4.11
4.11. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 11 Cognitive function: No clinically important improvement.
4.12
4.12. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 12 Adverse effects: 1. Any reason.
4.13
4.13. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 13 Adverse effects: 2. Cardiovascular.
4.14
4.14. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 14 Adverse effects: 3. CNS.
4.15
4.15. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 15 Adverse effects: 4. Gastrointestinal.
4.16
4.16. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 16 Adverse effects: 5. Movement disorders ‐ specific symptoms.
4.17
4.17. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 17 Adverse effects: 6. Respiratory.
4.18
4.18. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 18 Adverse effects: 7. Others ‐ specific problems.
4.19
4.19. Analysis
Comparison 4 STANDARD‐HIGHER DOSE (≧6‐<10 mg/day) versus ANY DOSE ‐ short term, Outcome 19 Adverse effects: 8. Global tolerance of treatment (high=poor).
5.1
5.1. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 1 Leaving the study early: 1. When compared with ultra low dose (<2 mg/day).
5.2
5.2. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 2 Leaving the study early: 2. When compared with low dose (≧2‐<4 mg/day).
5.3
5.3. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 3 Leaving the study early: 3. When compared with standard‐lower dose (≧4‐<6 mg/day).
5.4
5.4. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 4 Leaving the study early: 4. When compared with standard‐higher dose (≧6‐<10 mg/day).
5.5
5.5. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 5 Global state: 1. No clinically important improvement.
5.6
5.6. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 6 Global state: 2. Average endpoint score.
5.7
5.7. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 7 Mental state: 1. No clinically important improvement.
5.8
5.8. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 8 Mental state: 2. Average endpoint score.
5.9
5.9. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 9 Mental state: 3. Average endpoint score change.
5.11
5.11. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 11 Adverse effects: 1. Cardiovascular.
5.12
5.12. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 12 Adverse effects: 2. CNS.
5.13
5.13. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 13 Adverse effects: 3. Gastrointestinal.
5.14
5.14. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 14 Adverse effects: 4. Movement disorders ‐ specific symptoms.
5.15
5.15. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 15 Adverse effects: 5. Respiratory.
5.16
5.16. Analysis
Comparison 5 HIGH DOSE (≧10 mg/day) versus ANY DOSE ‐ short term, Outcome 16 Adverse effects: 6. Others ‐ specific problems.
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Update of

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References

References to studies included in this review

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Lane 2001 {published data only}
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References to studies excluded from this review

Alvarez 2006 {published data only}
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Bouchard 1998 {published data only}
    1. Bouchard RH. A comparative longitudinal study of risperidone versus classic neuroleptic drugs in the treatment of schizophrenia: 24 Months observation [Etude comparative longitudinale de la risperidone versus les neuroleptiques classiques dans le traitemante de la schizophrenie: 24 mois d'observation]. Encephale 2002;28(5 II):31‐2. - PubMed
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Brecher 1998 {published data only}
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Eerdekens 2004 {published data only}
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Emsley 1999 {published data only}
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Harrigan 2004 {published data only}
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Kopala 2003 {published data only}
    1. Kopala L, Rabinowitz J, Davidson M. Extra‐pyramidal signs and symptoms (eps) in recent onset schizophrenia: a comparison of risperidone and haloperidol. European Neuropsychopharmacology 2003;13(4):S338.
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Lacro 2001 {published data only}
    1. Lacro J. Antipsychotic treatment in late life schizophrenia. CRISP database (https://www‐commons.cit.nih.gov/crisp/index.html) (accessed 19th February 2001). [CRISP: Grant Number ‐ 5R29MH56938‐04]
Meltzer 2008 {published data only}
    1. Meltzer H, Peters P, Elkis H, Ruschel S, Rosenthal M, Mills R. Co‐therapy with pimavanserin and risperidone 2 mg provides an improved clinical profile. Schizophrenia Research 2008;98:16.
Potkin 2006 {published data only}
    1. Potkin SG, Gharabawi GM, Greenspan AJ, Mahmoud R, Kosik‐Gonzalez C, Rupnow MFT, Bossie CA, Davidson M, Burtea V, Zhu Y, Trivedi JK. A double‐blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization. Schizophrenia Research 2006;85(1‐3):254‐65. - PubMed
Wang 2002 {published data only}
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Xin 2001 {published data only}
    1. Xin X‐F, Du B‐C, Zeng Z‐X. A controlled clinical study of risperidone and low dose of clozapine in treating schizophrenia. Herald of Medicine 2001;20(8):501‐2.
Zhong 2005 {published data only}
    1. Zhong K, Harvey P, Brecher M, Sweitzer D. A randomized double ‐ blind study of quetiapine and risperidone in the treatment of schizophrenia. Schizophrenia Bulletin 2005;31:508.

References to studies awaiting assessment

Chen 2001e {published data only}
    1. Chen FB, Yu HY, Liu GY, Zhang SY, Gao ZQ. Plasma drug level of risperidone and its clinical significance. Chinese New Drugs Journal 2001;10(6):450‐3.
Merlo 2002 {published data only}
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References to ongoing studies

Lieberman 2001a {published data only}
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