Objective: To examine the use and economic cost of antiparkinsonian agents during the medication management of patients diagnosed with schizophrenic disorders in a naturalistic healthcare setting. Design: Cross-sectional retrospective analysis of 1-year (1999) administrative data from a large managed care organization.
Patients and Methods: Patients were 1938 adults who were treated for a schizophrenic disorder. Monthly per patient utilization rate and cost of antiparkinsonian agents, and the proportion of the total psychiatric medication costs attributed to the antiparkinsonian agents, were compared across antipsychotic medications (typical, atypical, olanzapine, risperidone), age, sex, and diagnostic subtype.
Results: About one third (39%) of the patients were treated with typical antipsychotics only, and half of them (51%) received antiparkinsonian agents. Those treated with atypical antipsychotics only (41%) were considerably less likely to receive antiparkinsonian agents (25%), and the rate of use differed by atypical type such that risperidone-treated patients were more likely to receive antiparkinsonian agents than those treated with olanzapine. Lower utilization rates of antiparkinsonian agents were also found among patients age 75 years or older, and among those diagnosed with a schizoaffective disorder. Average monthly per patient cost of antiparkinsonian agents was $3.0, constituting 2.6% of the monthly expenditure on all psychiatric medications.
Conclusions: Adjunctive use of antiparkinsonian agents differs widely among patients who are treated with typical or atypical antipsychotic drugs, and differs between types of atypical antipsychotics. The choice of atypical antipsychotics that have a lower liability for extrapyramidal symptoms may assist in optimizing the long-term functional outcomes of schizophrenia patients.
(Am J Manag Care. 2003;9:20-24)
Typical antipsychotics are associated with treatment- emergent extrapyramidal symptoms (EPS)1 such as akathisia, muscle spasms (dystonia), and symptoms resembling Parkinson's disease. Extrapyramidal symptoms are distressing to patients2 and also are linked to later development of tardive dyskinesia.3 Antiparkinsonian agents (APAs) are customarily used to counteract EPS4 in order to facilitate patients' adherence to their antipsychotic regimens.5 Unfortunately, in addition to their beneficial effect, APAs tend to cause other adverse side effects such as cognitive impairment,6-8 impaired alertness, and decreased cardiac function.9
Unlike typical antipsychotics, atypical antipsychotics are much less likely to cause EPS. Randomized clinical trials have demonstrated that atypical antipsychotics differ in their liability for EPS.10-13 However, randomized clinical trials may not reflect patient heterogeneity or prescription practices in everyday clinical settings. Additionally, there is little information regarding the patient characteristics associated with the use of APAs.14 The primary objective of this retrospective, cross-sectional study was to examine the naturalistic use and economic cost of APAs during the medication management of schizophrenia in a managed care setting.
In accordance with prior research findings, we expected to find lower utilization rates of APAs among patients receiving atypical antipsychotics;10-13 among the elderly;15 among women;16 and among patients diagnosed with a schizoaffective disorder as opposed to schizophrenia. Prior research found EPS to be dose related,17 and patients with schizophrenia, who require higher doses of antipsychotics,17 demonstrate greater susceptibility to EPS.3,18 Because APAs are inexpensive, we also expected their cost to constitute only a small fraction of the patients' total psychiatric medication costs, even among patient groups that use APAs most frequently.
SUBJECTS AND METHODS
Administrative claims data from a US private managed care organization (Constella Health Strategies, Durham, NC) were used to identify the study participants. This database annually covers approximately 20 million members of several preferred provider organizations and health maintenance organizations in 22 states.
International Classification of Diseases, 9th Revision, Clinical Modification
Anonymous medical claims and patient eligibility data were used to identify enrollees diagnosed with schizophrenia or schizoaffective disorder ([ICD-9-CM] codes 295.0-295.65, 285.8-295.95, and 295.7-295.75). Patients were included if they were (1) 18-99 years old as of December 31, 1998; (2) eligible for medical and pharmacy benefits for at least 1 day during 1999; and (3) filled at least 1 prescription for an antipsychotic medication during 1999. A total of 1938 enrollees met the above criteria.
Dependent Measures: Utilization and Cost of Antiparkinsonian Agents
Antiparkinsonian agents were defined as amantadine, benztropine, biperiden, bromocriptine, carbidopa/levodopa, procyclidine, selegiline, and triihexphenidyl.19 Use of APAs was defined by (1) the number of patients receiving at least 1 APA, (2) the number of APAs used per patient per month, (3) the number of days any APA was supplied per patient per month, and (4) the number of patients using each APA. Cost in US dollars of APAs was defined by (1) the average cost of APAs received per patient per month and (2) the percentage of the total monthly psychiatric medication costs attributed to APAs. Psychiatric medications were defined as antipsychotics, mood stabilizers, antidepressants, antianxiety agents, anticonvulsants, APAs, sleep agents, and other anti-EPS drugs. Cost calculations represent actual cost as billed by the managed care pharmacy.
Independent Variables: Patient Group Categories
The dependent measures were identified for all patients and categorized by type of antipsychotic (typical, atypical); by age (18-41, 42-64, 65-75, or >75 years); by sex; and by diagnostic subtype (schizophrenia, schizoaffective disorder). Further comparisons on the independent measures were made between patients receiving olanzapine versus risperidone. Age was not used as a continuous variable because we anticipated a nonlinear relationship between age and the use of APAs, with lower utilization rates among elderly patients (age >75 years). Antipsychotics were categorized according to the patients' first antipsychotic prescription in 1999. The group receiving a single atypical antipsychotic was primarily comprised of patients receiving olanzapine or risperidone, but also included a few patients on quetiapine or clozapine. Patients receiving quetiapine or clozapine were not studied separately because of the small sample size. Patients who received multiple agents (typical antipsychotics, atypical antipsychotics, mood stabilizers) in any combination were not studied due to difficulties involved with interpreting the results. Length of treatment with antipsychotic medication was calculated as the number of days the medication was supplied per patient per month, using the number of days supplied divided by months of follow-up in 1999.
Chi-square tests were used to compare the groups for categorical variables. Student tests or 1-way analysis of variance with posttests (Tukey) was used to compare groups for continuous variables. Computations were performed by using SAS software, version 8.1.20
Most patients (83%, 1616/1938) were less than 65 years of age, with a mean age of 49 years (SD = 14 years). They were divided approximately equally by type of antipsychotic received (43% [824/1938] received typical agents; 44% [851/1938] received atypical agents), sex (57% [1106/1938] were women), and diagnostic subtype (56% [1088/1938] had a diagnosis of schizophrenia). Patients were supplied with antipsychotic medications for an average of 273.9 days (SD = 242.1 days) in 1999. Antipsychotics were supplied per patient per month for comparable durations among the medication groups, the age groups, and between men and women. (> .05). However, patients diagnosed with schizoaffective disorder were supplied with antipsychotics for a significantly longer time than patients with schizophrenia (33.3 days [SD = 25.0 days] vs 27.7 days [SD 19.4 days]; = .02).
Most Frequently Used Antiparkinsonian Agents.
Most patients received benztropine (82.8%, 601/726), followed by trihexyphenidyl (13.1%, 95/726) and amantadine (6.3%, 46/726). These percentages exceed 100% because some patients used more than 1 APA.
Rate of Use and Cost of Antiparkinsonian Agents
Table 1 presents the rate, pattern, and cost of APA use for all patients and by antipsychotic type, age group, sex, and diagnostic subtype.
About a third of all patients received at least 1 APA at an average cost of $3.0 per patient month, constituting 2.6% of the average monthly expenditure on all psychiatric drugs.
Typical vs Atypical Antipsychotic Agents.
About a third of the patients (39%, 764/1938) were treated with a single typical antipsychotic agent. As seen in Table 1, half of them (51.2%) received APAs. Compared with patients receiving a single atypical antipsychotic agent (n = 791), those receiving a single typical antipsychotic agent were twice as likely to receive APAs and to receive a significantly larger number of APAs, for a significantly longer duration and for a higher cost.
Age and Sex Differences.
Patients age 75 years or older were significantly less likely to receive APAs, and received significantly fewer APAs than their younger counterparts. Compared with patients younger than age 65 years, those older than age 65 years accrued lower psychiatric drug costs. Compared with men, women did not receive significantly fewer APAs, nor did they differ on rates of use or cost of APAs.
Compared with patients diagnosed with a schizoaffective disorder, patients with schizophrenia were significantly more likely to receive APAs, to receive more APAs, and to receive them for a longer duration.
Olanzapine vs Risperidone.
Table 2 demonstrates that compared with olanzapine-treated patients (n = 347), those receiving risperidone (n = 404) were 1.43 times more likely to receive at least 1 APA. Risperidonetreated patients received a significantly larger number of APAs, and they were prescribed APAs for a significantly longer duration. The APA costs associated with the 2 agents were not significantly different. However, the average monthly per patient costs for psychiatric drugs were significantly higher for olanzapine. Olanzapine and risperidone were supplied in doses typically prescribed for patients with schizophrenia (mean and median doses were 13.0 mg/day and 10.5 mg/day for olanzapine, and 4.1 mg/day and 3.3 mg/day for risperidone).
Despite the advent of atypical antipsychotics, more than a third (39%) of the patients with schizophrenia at a large managed care setting were treated with typical antipsychotics only, and half of them received APAs. Although the use of typical antipsychotics with adjunctive APAs offers an inexpensive treatment option, the long-term implications of the link between EPS and increased likelihood of later development of tardive diskinesia4 should enter the treatment decision process. Although APAs help minimize EPS, these agents may introduce other adverse events such as decreased alertness, cognitive impairment, and cardiac dysfunction.6-9 Such side effects may undermine treatment adherence, treatment response, and relapse prevention, and may further jeopardize patients' already compromised cognitive functioning.21 Moreover, patients with schizophrenia often are treated with polypharmacy,14 and the addition of APAs to a complex medication regimen may further increase the likelihood of adverse drug interactions.
Consistent with randomized clinical trials,10-13 findings from this naturalistic study demonstrated that atypical antipsychotics differ in their liability for EPS. Compared with olanzapine-treated patients, those treated with risperidone were significantly more likely to receive APAs, to receive more APAs, and to receive them for a longer duration. As hypothesized, we also found that elderly patients and patients diagnosed with schizoaffective disorder were prescribed fewer APAs. Contrary to expectation,16 women did not receive fewer APAs than men, suggesting that future research will be needed to assess sex-based differences in the risk for EPS and the use of APAs.
As expected, the cost of APAs was found to be low even among patient groups that used APAs most frequently. Despite the appeal of short-term savings in medication acquisition cost, clinicians and clinical decision makers need to recognize the long-term implications of such treatment practices. Increased use of atypical antipsychotics with lower EPS liability may lead to better adherence, less disability, and improved long-term outcomes-all of which may ultimately result in total cost savings.
The current findings need to be interpreted in the context of their limitations. First, we used APAs as a marker for EPS experienced by the patient. However, APAs are unlikely to be used for treatment of any condition other than EPS in patients with schizophrenia who are receiving antipsychotics.17 Second, the current findings do not address the dose of the respective antipsychotics, although EPS liability is often dose related.17 Third, the findings may not generalize to other healthcare settings. The use of the managed care database offers, however, a source of unbiased information about the treatment of a large number of patients from across the United States.
The use of typical antipsychotics with adjunctive APAs may offer short-term savings in the cost of psychotropic medications. However, these immediate savings may, in turn, translate into high long-term costs, both economically and personally. Use of atypical antipsychotics with a lower EPS liability may assist healthcare providers in optimizing the long-term functional outcomes of schizophrenia patients. This will need to be demonstrated, however, in future longitudinal, naturalistic studies across healthcare systems.
The authors thank Anne Ogostalick, PharmD, for her assistance with the literature review and Robert Fowler for his assistance with the statistical analyses.
From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Ind (HAS, JSK); Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Ind (HAS, JSK); and Constella Health Strategies, Durham, NC (DL, MH).
This study was funded by Eli Lilly and Company, Indianapolis, Ind.
Presented as an abstract at the American Psychiatric Nurses Association, Dallas, Tex, October 5-8, 2002.
Address correspondence to: Haya Ascher-Svanum, PhD, Lilly Research Laboratories, Eli Lilly and Company, Corporate Center DC 4025, Indianapolis, IN 46285. E-mail: firstname.lastname@example.org.
Int Clin Psychopharmacol.
1. Casey DE. Motor and mental aspects of EPS. 1995;10:105-114.
2. Hansen L. A critical review of akathisia, and its possible association with suicidal behavior. Hum Psychopharmacol. 2001;16:495-505.
Am J Psychiatry.
3. Woerner MG, Alvir JM, Saltz BL, Loeberman JA, Kane JM. Prospective study of tardive dyskinesia in the elderly: rates and risk factors. 1998;155:1521-1528.
4. Lehaman AF, Steinwachs DM. At issue: translating research into practice: the schizophrenia Patients Outcomes Research Team (PORT) treatment recommendations. Schizophr Bull. 1998;24:1-10.
Acta Psychiatr Scand.
5. Fleischhacker WW, Meise U, Gunther V et al. Compliance with antipsychotic drug treatment: influence of side effects. 1994;89:11-25.
6. Fayen M, Goldman MB, Moulthrop MA, Luchins DJ. Differential memory function with dopaminergic versus anticholinergic treatment of drug-induced extrapyramidal symptoms. Am J Psychiatry. 1988;145:483-486.
Arch Gen Psychiatry.
7. Spohn HE, Coyne L, Lacoursiere R, Mazur D, Hays K. Relation of neuroleptic dose and tardive dyskinesia to attention, information-processing, and psychophysiology in medicated schizophrenics. 1985;42:849-859.
8. Zachariah E, Kumari V, Das M, et al. Procyclidine administration disrupts cognitive functions in healthy subjects: implications for schizophrenia. Biol Psychiatry. 2001;49:120S.
9. Galea A, Kumari V, Zachariah E, et al. The effect of procyclidine on the critical flicker fusion threshold in healthy human subjects: implications for schizophrenia. 2001; 49:170S.
10. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol. 1997;17:407-418.
Arch Gen Psychiatry.
11. Purdon SE, Jones BD, Stip E, et al. Neuropsychological change in the early phase of schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for Research in Schizophrenia. 2000;57:249-258.
12. Volavka J, Czobor P, Sheitman B, et al. Clozapine, olanzapine, risperidone, and haloperidol in treatment-resistant patients with schizophrenia and schizoaffective disorder. Am J Psychiatry. 2002;159:255-262.
13. Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. 1999;35:51-68.
14. Buchanan RW, Kreyenbuhl J, Zito J, Lehman A. Relationship of the use of adjunctive pharmacological agents to symptoms and level of function in schizophrenia. Am J Psychiatry. 2002;159:1035-1043.
15. Waddington JL. Tardive dyskinesia in schizophrenia and other disorders: Associations with ageing, cognitive dysfunction and structural brain pathology in relation to neurologic exposure. 1987;2:11-22.
16. Smith JM, Dunn DD. Sex differences in the prevalence of severe tardive dyskinesia. Am J Psychiatry. 1979;136:1080-1082.
17. Schillevoort I, De Boer A, Hering RM, et al. Risk of extrapyramidal syndromes with haloperidol, risperidone, or olanzapine. 2001;35:1517-1522.
18. Marsden CD, Jenner P. The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med. 1980;10:55-72.
Mosby's 2002 Nursing Drug Reference.
19. Skidmore-Roth L. 2nd ed. St. Louis, Mo: Mosby, Inc; 2002.
20. SAS Institute. SAS/STAT User's Guide. Vols 1, 2, and 3. Version 8. Cary, NC: SAS Institute, Inc; 2000.
J Psychiatry Neurosci.
21. Addington J, Addington D. Cognitive functioning in firstepisode schizophrenia. 2002;27:188-192.