Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care, Boston, USA, and Korea Health Industry Development Institute, Seoul, Korea
Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care, Boston, USA
London School of Economics and Political Science, London, UK
Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care, Boston, USA
Correspondence: Dr Sylvia Park, Korea Health Industry Development Institute, 57-1Noryangjin-Dong, Dongjak-GU, Seoul 156-800, Republic of Korea. E-mail: sylviap{at}khidi.or.kr
Declaration of interest None. Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To examine the effects of switching antipsychotics on antiparkinsonian medication use among individuals with schizophrenia in UK general practices.
Method We included those switched from typical to atypical antipsychotics (n=209) or from one typical antipsychotic to another (n=261) from 1994 to 1998.
Results Antiparkinsonian drug prescribing dropped by 9.2% after switching to atypical antipsychotics (P<0.0001). Switching to olanzapine decreased the rate by 19.2% (P<0.0001), but switching to risperidone had no impact. After switching from one typical antipsychotic to another, antiparkinsonian drug prescribing increased by 12.9% (P<0.0001).
Conclusions Reduction in antiparkinsonian medication use after switching to atypical antipsychotics was substantial in community practice but not as large as in randomised controlled trials. The rate of reduction varied according to the type of medication.
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INTRODUCTION |
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METHOD |
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Study group
We studied 6356 individuals from 266 general practices who had been
diagnosed with schizophrenia and prescribed antipsychotics between 1992 and
2000. Schizophrenia diagnoses were derived from the records of out-patient
contacts with general practitioners. We focused on those who had been switched
from typical to atypical antipsychotics (TA group) or from typical to
different typical antipsychotics (TT group) between 1994 and 1998, and who
were present in the database for at least 2 years before and after the switch.
Only those who were diagnosed with schizophrenia at least 2 years before the
switch were evaluated. We defined the TA group as those who had been
prescribed typical antipsychotics before the switch, completely stopped
typical antipsychotics and subsequently switched to atypical antipsychotics,
with no typical antipsychotic use for at least 2 years after the switch. The
TT group included patients who were prescribed one typical antipsychotic (e.g.
chlorpromazine) and then switched to a different typical antipsychotic (e.g.
haloperidol), and who never received an atypical antipsychotic. The analysis
included 209 in the TA group and 261 in the TT group.
Because risperidone and olanzapine were the most commonly prescribed (87%) atypical antipsychotics after the switch in the TA group, we also focused on those within that group who had been switched from typical antipsychotics to either of these two atypical antipsychotics. Using the same inclusion criteria as above, we defined the risperidone, TAR (or olanzapine, TAO) recipients as those who had been prescribed typical antipsychotics with no atypical antipsychotics before the switch, and then switched to either risperidone or olanzapine between 1994 and 1998, with no typical antipsychotic or other atypical antipsychotics for at least 2 years after the switch. Thus, 87 risperidone and 78 olanzapine recipients were studied.
Outcome measures
First we examined the antipsychotic prescribing rates yearly between 1992
and 2000, calculated as the number with schizophrenia prescribed
antipsychotics divided by the number of all those with schizophrenia each
year, adjusted for age (39, 40-64,
65 years) and gender. Then we
examined the annual percentage of those prescribed either typical or atypical
antipsychotics among those prescribed antipsychotics.
We measured rates of prescribing for antiparkinsonian drugs quarterly for 2 years before and after the switch, by switching group. We regarded prescribing of antiparkinsonian drugs (including benztropine, biperidine, orphenadrine, procyclidine and trihexyphenidyl) as indication of treatment of extrapyramidal symptoms. This has frequently been used in previous studies (Tran et al, 1999; Costa e Silva et al, 2001; Inada et al, 2001; Bobes et al, 2003; Montes et al, 2003), and the use of antiparkinsonian medication is highly correlated with clinical indices of extrapyramidal symptoms (Costa e Silva et al, 2001; Inada et al, 2001; Bobes et al, 2003; Montes et al, 2003). The antiparkinsonian drug prescribing rate was calculated as the number of individuals during an observation period who were prescribed an antiparkinsonian drug divided by the number in each switching group. We adjusted gender and age to the combined study population at the time of switching. Because individuals switched at different times, the quarter when the switch occurred was treated as the start of the follow-up period (point 0).
We also examined the mean daily dose of antiparkinsonian drugs prescribed for 2 years before and after switching. We analysed only tablets and capsules, which accounted for 98% of all antiparkinsonian drug prescriptions. Daily dose was estimated by dividing total dose by duration of antiparkinsonian medication use before and after the switch. Only the TA and TT groups were investigated because of the small sample sizes for the two subgroups.
Statistical analyses
We conducted interrupted time series analyses to estimate changes in the
rates of prescribing of antiparkinsonian drugs after drug switching,
controlling for the trend before the switch
(SAS Institute,
2000a; Wagner et
al, 2002). Our models included the trend in the rate of
antiparkinsonian drug prescribing before the switch, and changes in the trend
and level of antiparkinsonian drug prescribing after switching. The switch
point quarter (point 0) was excluded from analyses because it was not clear
whether the outcome in that quarter resulted from antipsychotics used before
or after switching. We used t-tests to compare the mean daily dose of
antiparkinsonian drugs before and after the switch
(SAS Institute,
2000b).
We used SAS Version 8.2 for all statistical analyses. All statistical analyses were performed separately for each group.
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RESULTS |
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Individuals in the TT and the TA groups were equally likely to be co-prescribed other medications when prescribed antipsychotics prior to switching, including both psychoactive drugs (54.0% v. 52.6%) and other non-psychoactive drugs (75.9% v. 76.1%). There were also no significant differences in baseline rates of use of psychoactive and non-psychoactive medicines among those switched to risperidone v. olanzapine.
Overall use of antipsychotics
The adjusted average rate of antipsychotic prescribing between 1992 and
2000 was 80%, with a range of 78-82%. Of those prescribed antipsychotics, 47%
were prescribed atypical antipsychotics in 2000, increasing from 3% in 1992.
The percentage of those prescribed typical antipsychotics declined from 99% in
1992 to 70% in 2000.
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The mean daily doses of antiparkinsonian medication, calculated in benztropine equivalents, were not different before and after switching in either group (TA group: 1.87 mg/day before, 1.75 mg/day after, t= -0.74, d.f.=181, P=0.462; TT group: 1.97 mg/day before, 1.86 mg/day after, t= -0.77, d.f.=248, P=0.441).
Figure 2 presents antiparkinsonian drug prescribing rates before and after switching from typical antipsychotics to risperidone or olanzapine. Average daily prescribed doses of risperidone and olanzapine were 6.4 mg (s.d. 5.4 mg) and 12.2 mg (s.d.=6.2 mg) respectively, which were in the optimal dose range (Tran et al, 1997). There were no changes either in the level or in the trend of antiparkinsonian drug prescribing rate associated with the switch to risperidone. The switch to olanzapine caused a sudden drop in the rate of use of antiparkinsonian medication by 19.2% (t= -7.13, d.f.=1, P<0.0001) and a gradual decline by 1.5% per quarter thereafter (t= -3.84, d.f.=1, P=0.002).
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DISCUSSION |
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The reduction in use of antiparkinsonian medication was not evenly distributed among different atypical antipsychotics. Switching from typical agents to olanzapine resulted in an abrupt decrease in the use of antiparkinsonian medication, whereas switching to risperidone caused no change in rate. Previous studies have reported the superiority of olanzapine over risperidone in reducing extrapyramidal symptoms (Tran et al, 1997; Montes et al, 2003; Soholm & Lublin, 2003). Because of the difference in baseline trends in use of antiparkinsonian medication in our study, it is necessary to be cautious regarding comparison of the effectiveness of olanzapine and risperidone in reducing extrapyramidal symptoms (Fig. 2). Specifically, physicians may have been more likely to prescribe olanzapine for those with a higher prevalence of extrapyramidal symptoms since this drug was launched with clinical data supporting its advantage over risperidone in lowering the risk of these symptoms (Tran et al, 1997). Nevertheless, olanzapine may have a lower risk of extrapyramidal symptoms than risperidone based on the large differences in the observed rates of reduction in use of antiparkinsonian agents between those initiated on olanzapine and risperidone.
Switching to atypical antipsychotics did not change the average daily dose of antiparkinsonian drugs among those prescribed these medications. This implies that switching to atypical antipsychotics may not have mitigated the severity of extrapyramidal symptoms among those continuing to receive antiparkinsonian medications despite the overall reductions in the rate of antiparkinsonian drug use. Those with milder extrapyramidal symptoms may be more likely to have discontinued antiparkinsonian therapy after switching to atypical antipsychotics. For example, among individuals in the TA group who received lower than the median daily dose of antiparkinsonian agents before switching to atypical antipsychotics, 42% discontinued antiparkinsonian medication after the switch, compared with a discontinuation rate of 27% among those in the group who received higher than the median daily dose of antiparkinsonian drugs before switching. However, for some it is possible that the antiparkinsonian medication was simply neglected, leading to no change in dose.
Comparison with clinical trials
In this study, the effect of switching to olanzapine on the treatment of
extrapyramidal symptoms was not as large as in clinical trials
(Costa e Silva et al,
2001). Moreover, the daily dose of antiparkinsonian medication did
not decrease after switching to atypical antipsychotics in the community,
which contrasts with findings from previous clinical studies that daily doses
of antiparkinsonian medication were lower in those using atypical
antipsychotics than those using typical antipsychotics
(Tran et al, 1999;
Costa e Silva et al,
2001; Inada et al,
2001).
These differences might result from differences in study design. Participants in the clinical trials were typically younger and the observation periods were shorter than ours. Typical antipsychotics only included haloperidol, a high-potency antipsychotic with a high risk of extrapyramidal symptoms, which accounted for less than 10% of typical antipsychotic use in our study.
Another possible explanation for the differences is the poor adherence of those in the community compared with those in the controlled environments of clinical trials. In addition, physician prescribing in community settings might be more susceptible to other factors such as patient demand, pharmaceutical marketing and resulting physicians' perceptions of benefits and risks of specific medications.
Limitations
As the design of this observational study did not include randomisation,
groups might have differed in demographic characteristics, severity and
duration of disease, or treatment course. For example, those switching within
typical antipsychotics were older and more likely to be female than those
switching from typical to atypical antipsychotics. The use of low-potency
typical antipsychotics with a low incidence of extrapyramidal symptoms was
higher in the TT group (27%) than in the TA group (19%) before switching.
Thus, it is difficult to compare the effect of switching between groups, even
though age and gender were adjusted for in our analyses. Nevertheless, our
results are valid within groups since we observed the same individuals over 4
years.
Those who switched medications might also have been different from those who remained on the same treatment. In additional analyses of those who received new prescriptions for antipsychotics and did not switch therapy, rates of antiparkinsonian drug prescribing were 10% lower among new atypical antipsychotic users compared with rates observed after switching to atypical antipsychotics, whereas the rates in new recipients of typical antipsychotics were not different from rates observed before switching to atypical antipsychotics. Those who had been switched seemed more likely to be prescribed antiparkinsonian drugs than those who had not been switched, even though they commonly used atypical antipsychotics.
In addition, switching might have resulted from several factors, including side-effects or lack of efficacy. Our data do not permit evaluation of the reasons for switching, which might differ between patient groups. For example, the prescribing of high-potency typical antipsychotics (e.g. haloperidol) with a high incidence of extrapyramidal symptoms increased after switching between two typical antipsychotic agents (from 36% before switching to 42% after switching). Some of this switching between typical antipsychotics is likely to have been caused by reasons other than extrapyramidal symptoms. Therefore, we cannot infer the appropriateness of switching based only on the change in the rate of antiparkinsonian prescribing.
Our results from those who switched antipsychotics in primary care might not be generalisable to all people with schizophrenia. However, the well-integrated healthcare delivery system in the UK might enable general practitioners to collaborate with specialists and follow their recommendations. Of those who switched antipsychotics in this study, 14% had been referred to specialists during the 6-month period before switching, whereas only 5% had been referred between 6 months and 1 year before switching. This suggests that some switches in this study might have reflected specialists' recommendations.
We measured antiparkinsonian drug prescribing to assess the effect of switching on treatment of extrapyramidal symptoms. Although antiparkinsonian drug prescribing has been used in previous studies to assess extrapyramidal symptoms (Tran et al, 1999; Costa e Silva et al, 2001; Inada et al, 2001; Bobes et al, 2003; Montes et al, 2003), it is only a marker and cannot accurately reflect their incidence. Moreover, our data did not permit us to ascertain whether clinical tests of extrapyramidal symptoms were performed before prescription of antiparkinsonian drugs. Their prescription might also have been influenced by practice variables or environmental factors. The results of this study should be interpreted in the light of these limitations.
Our study recorded prescribing, not dispensing. Drugs recorded might not have been dispensed or taken by patients. This should also be considered in the interpretation of results.
Finally, we cannot exclude the possibility that some individuals might have been prescribed antiparkinsonian medications because they had Parkinson's disease, not because they had extrapyramidal symptoms caused by antipsychotics. However, we do not have data on the prevalence of Parkinson's disease in the study population.
Implications
This study investigated changes in the use of antiparkinsonian medication
after switching antipsychotics. We found that the magnitude of the effects of
switching from typical to atypical antipsychotics on reducing antiparkinsonian
medication use was considerable in community practices, but not as large as
the effects observed in clinical trials. The effects of switching
antipsychotics on antiparkinsonian medication use also varied substantially
between risperidone and olanzapine. The differences between specific atypical
agents as well as between typical and atypical antipsychotics should be
considered in treatment decisions and policies concerning antipsychotic use
(Tamminga, 2003). Several US
Medicaid programmes require individuals to undergo a trial of use of the
lowest-cost atypical antipsychotic before approval of more expensive agents,
which may not lead to optimum control of extrapyramidal symptoms
(Soumerai, 2004). Further
research is needed on the relationship between extra-pyramidal symptoms and
treatment adherence and the quality of life of those with schizophrenia, as
well as on clinical outcomes of cost containment policies that restrict access
to specific antipsychotic agents.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Bobes, J., Gibert, J., Ciudad, A., et al (2003) Safety and effectiveness of olanzapine versus conventional antipsychotics in the acute treatment of first-episode schizophrenic inpatients. Progress in Neuropsychopharmacology and Biological Psychiatry, 27, 473 -481.[CrossRef][Medline]
Bouchard, R. H., Merette, C., Pourcher, E., et al (2000) Longitudinal comparative study of risperidone and conventional neuroleptics for treating patients with schizophrenia. Journal of Clinical Psychopharmacology, 20, 295 -304.[CrossRef][Medline]
Buckley, P. F., Miller, A., Chiles, J. A., et al ((1999) Implementing effectiveness research and improving care for schizophrenia in real-world settings. American Journal of Managed Care, 5, SP47 -56.[Medline]
Coley, K. C., Carter, C. S., DaPos, S. V., et al (1999) Effectiveness of antipsychotic therapy in a naturalistic setting: a comparison between risperidone, perphenazine, and haloperidol. Journal of Clinical Psychiatry, 60, 850 -856.[Medline]
Costa e Silva, J. A., Alvarez, N., Mazzotti, G., et al (2001) Olanzapine as alternative therapy for patients with haloperidol-induced extrapyramidal symptoms: results of a multicenter, collaborative trial in Latin America. Journal of Clinical Psychopharmacology, 21, 375 -381.[CrossRef][Medline]
Freedman, R. (2003) Schizophrenia.
New England Journal of Medicine,
349, 1738
-1749.
Inada, T., Yagi, G. & Miura, S. (2001) Extrapyramidal symptom profiles in Japanese patients with schizophrenia treated with olanzapine or haloperidol. Schizophrenia Research, 57, 227 -238.
Knapp, M. (1997) Costs of schizophrenia. British Journal of Psychiatry, 171, 509 -518.[Abstract]
Lang, F. H., Johnstone, E. C. & Murray, G. D. (1997) Service provision for people with schizophrenia. II. Role of the general practitioner. British Journal of Psychiatry, 171, 165 -168.[Abstract]
Lindstrom, E. & Bingefors, K. (2000) Patient compliance with drug therapy in schizophrenia. Economic and clinical issues. Pharmacoeconomics, 18, 106 -124.[Medline]
Montes, J. M., Ciudad, A., Gascon, J., et al (2003) Safety, effectiveness, and quality of life of olanzapine in first-episode schizophrenia: a naturalistic study. Progress in Neuropsychopharmacology and Biological Psychiatry, 27, 667 -674.[CrossRef][Medline]
Ritchie, C. W., Chiu, E., Harrigan, S., et al (2003) The impact upon extra-pyramidal side effects, clinical symptoms and quality of life of a switch from conventional to atypical antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia. International Journal of Geriatric Psychiatry, 18, 432 -440.[CrossRef][Medline]
SAS Institute (2000a) SAS/ETS User's Guide, Version 8. Cary, NC: SAS Institute.
SAS Institute (2000b) SAS/STAT User's Guide, Version 8. Cary, NC: SAS Institute.
Soholm, B. & Lublin, H. (2003) Long-term effectiveness of risperidone and olanzapine in resistant or intolerant schizophrenic patients. A minor study. Acta Psychiatrica Scandinavica, 107, 344 -350.[CrossRef][Medline]
Soumerai, S. B. (2004) Benefits and risks of
increasing restrictions on access to costly drugs in Medicaid.
Health Affairs, 23, 135
-146.
Tamminga, C. (2003) Similarities and differences among antipsychotics. Journal of Clinical Psychiatry, 64, 7 -10.
Tran, P. V., Hamilton, S. H., Kuntz, A. J., et al (1997) Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. Journal of Clinical Psychopharmacology, 17, 407 -418.[CrossRef][Medline]
Tran, P. V., Tollefson, G. D., Sanger, T. M., et al (1999) Olanzapine versus haloperidol in the treatment of schizoaffective disorder: Acute and long-term therapy. British Journal of Psychiatry, 174, 15 -22.[Abstract]
Wagner, A. K., Soumerai, S. B., Zhang, F., et al (2002) Segmented regression analysis of interrupted time series studies in medication use research. Journal of Clinical Pharmacy and Therapeutics, 27, 299 -309.[CrossRef][Medline]
Walley, T. & Mantgani, A. (1997) The UK General Practice Research Database. Lancet, 350, 1097 -1099.[CrossRef][Medline]
Received for publication June 16, 2004. Revision received December 1, 2004. Accepted for publication December 9, 2004.
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