Psychotropic Polypharmacy for the Treatment of Bipolar Disorder in Taiwan Galen Chin-Lun Hung, M.D., Sc.M. Shu-Yu Yang, Ph.D. Yuefan Chen, Sc.M. Shih-Ku Lin, M.D.

Objective: Psychotropic polypharmacy in the treatment of bipolar disorder has proliferated. Yet evidence about the prevalence and predictors of different combinations of polypharmacy in inpatient settings is scarce. Methods: The Nationwide Psychiatric Inpatient Medical Claims (2000–2007) in Taiwan were used to examine prescriptions for mood stabilizers, antipsychotics, and antidepressants among recently discharged patients with bipolar disorder (N55,449; 51% women, mean6SD age536.86 12.4). Results: A total of 71% of prescriptions involved betweenclass polypharmacy, and 17% involved within-class polypharmacy. Patients older than 50 and patients at medical centers (>500 beds) were less likely to receive polypharmacy. Lower prescribed doses predicted polypharmacy. Receiving polypharmacy was not associated with a higher rate of readmission within one year. Conclusions: There was Dr. Hung, Dr. Yang, and Dr. Lin are with Taipei City Psychiatric Center, Taipei City Hospital, Taipei City, Taiwan. Dr. Yang is also with the Graduate Institute of Clinical Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City, Taiwan. Dr. Lin is also with the Department of Psychiatry, Taipei Medical University, Taipei City. Ms. Chen is with the Department of General Pediatrics, Boston Children’s Hospital, and was with the Department of Social and Behavioral Science, Harvard School of Public Health, both in Boston, when this report was written. Send correspondence to Dr. Lin (e-mail: [email protected]).

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substantial use of various forms of polypharmacy in the treatment of inpatients with bipolar disorder. Randomized studies should be used to compare the cost-effectiveness of common psychotropic combinations and monotherapy to treat bipolar disorder. (Psychiatric Services 65:125–128, 2014; doi: 10.1176/appi. ps.201200529)

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ince the U.S. Food and Drug Administration approved use of olanzapine to treat bipolar disorder in March 2000 (1), pharmacological options regarding bipolar disorder have proliferated. Although such availability may improve treatment outcome, it also increases the chance of psychotropic polypharmacy (2,3), which raises concerns about whether treatment is safe, tolerable, and costeffective (3,4). Combining medications with different pharmacodynamic properties, such as antipsychotics and lithium or valproate, may augment therapeutic effect for persistent mania, yet available data are not sufficient to support its superior efficacy (5). Consequently, current practice guidelines mostly reserve polypharmacy for a later stage of treatment, making its proliferation unjustified (5–7). Despite a scarcity of evidence to support its use, polypharmacy is common in treating bipolar disorder in naturalistic settings. Among outpatient visits, 33% to 61% of prescriptions may entail polypharmacy in various forms, most commonly a combination of antidepressants and other psychotropics (2,8,9). Using a national sample of

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office-based U.S. psychiatric visits, Mojtabai and Olfson (10) demonstrated that the chance of polypharmacy is greater for bipolar disorder than for other common psychiatric diagnoses. Polypharmacy for inpatient regimens aimed at relieving an acute episode would be substantially different from outpatient prescriptions, which represent the maintenance phase of treatment. However, to date, only piecemeal data are available to illustrate the patterns of polypharmacy among hospitalized patients with bipolar disorder (11). Previous studies have documented factors that predict psychotropic polypharmacy, including patient demographic characteristics, disease severity, comorbid psychiatric disorders, treatment setting, and prescribed dose (10,12). These predictors have not been comprehensively examined among patients with bipolar disorder. Specifically, the association of prescribed dose and polypharmacy warrants clinical attention. Medications indicated for bipolar disorder, such as anticonvulsants and antidepressants, have extensive drug-drug interactions, which pose significant safety concerns when prescribed in combination and at a higher dose. In this study, we used medical claims from a nationwide data set from Taiwan to examine the patterns and predictors of polypharmacy among patients with bipolar disorder immediately after discharge from a psychiatric hospital. We examined whether polypharmacy served as a prognostic indicator by its association with readmission rate within one year. Such descriptive 125

Table 1

Predictors of between-class and within-class polypharmacy among recently discharged inpatients with bipolar disorder in Taiwan (N55,449), 2000–2007 Between class Predictora Sex Men (reference) Women Age (M6SD) #30 31–40 41–50 .50 (reference) Psychiatric diagnoses 1 .1 (reference) Outpatient clinic setting Medical center (reference) Regional hospital District hospital Hospitalization (M6SD days) Average daily dose (M6SD)b

N

% OR 95% CI

2,676 2,752

49 51 1.01

1,956 1,389 1,157 947

p

OR 95% CI

.491

36 1.30 1.09–1.56 26 1.30 1.07–1.57 21 1.33 1.09–1.62 17

.004 1.28 1.03–1.58 .007 1.10 .87–1.38 .006 1.19 .94–1.51

.024 .416 .138

4,717 732

87 1.04 13

.652 1.29 1.03–1.61

.027

1,981 2,058 1,291

36 38 1.17 1.01–1.35 24 1.31 1.10–1.57

.035 1.14 .003 1.06

.97–1.35 .86–1.29

.110 .597

.011 1.00 1.00–1.00

.009

.76.9

.87–1.25

1.00 1.00–1.00 .50

.44–.57

.837

,.001

.95

p

.82–1.10

30.3646.9

.89–1.15

Within class

.57

.47–.70

,.001

a

Data for some patients are missing for some predictors. Because there are no reference groups for hospitalization and average daily dose, the comparison indicates the effects on polypharmacy of each increase of one unit. b The average daily dose for the prescription was calculated by adding the daily doses of each medication and dividing by the number of medications prescribed. The daily dose of each medication was calculated by dividing the prescribed daily dose by the defined daily dose, which represents the amount assumed to be the average maintenance daily dose of a medication for an adult. Each unit increase of average daily dose halved the odds of both between-class polypharmacy and within-class polypharmacy.

data would help highlight specific issues for facilitating guideline-concordant practice or for examining in future research.

Methods We used the nationwide psychiatric inpatient medical claims in Taiwan’s National Health Insurance Research Database, 2000 to 2007, for all patients with a diagnosis of bipolar disorder (ICD-9-CM codes 296.0– 296.16, 296.4–296.81, and 296.89) who had been hospitalized during the study period. Patients with a primary diagnosis of bipolar disorder at admission were enrolled, and patients with a concurrent diagnosis of schizophrenia (ICD-9-CM code 295) were excluded. We examined the patients’ first outpatient prescription after discharge from their first psychiatric hospitalization for mood stabilizers, antipsychotics, or antidepressants. [A complete list of medications identi126

fied in the claims data is available online as a data supplement to this report.] Consequently, for each patient, only one prescription (which could contain more than one medication) was documented. For each prescription, we determined if betweenclass polypharmacy and within-class polypharmacy were present. Betweenclass polypharmacy referred to the prescription of two or more classes of medication, and within-class polypharmacy referred to the prescription of two or more medications in the same class. Multivariable regression analysis was applied to examine potential predictors of both between-class polypharmacy and within-class polypharmacy, including sex, age, number of psychiatric diagnoses, outpatient clinic setting, hospitalization length, and prescribed dose. Outpatient clinic setting was categorized into medical centers (.500 beds, N518), regional hospitals PSYCHIATRIC SERVICES

(250–500 beds, N574), and district hospitals (,250 beds, N5249). The daily dose of each medication was defined by dividing the prescribed daily dose (PDD) by the defined daily dose (DDD), which represented the average maintenance daily dose of a medication for an adult (13). We then obtained, for each prescription, an average daily dose of medication by adding up the PDD:DDD ratio for each drug and dividing by the number of drugs contained. Last, logistic regression was used to examine the oneyear readmission rate as a function of polypharmacy. A p value of ,.01 was considered to be statistically significant. Statistical analyses were performed with the SAS software, version 9.1 for Windows.

Results Our study sample consisted of 5,449 Chinese patients with bipolar disorder (51% women; mean6SD age536.86 12.4). A total of 5,155 (95%) were diagnosed as having bipolar I disorder. Among them, 2,923 (57%) presented with a manic episode; 1,076 (21%), depressed episode, 786 (15%), mixed episode; and 370 (7%), unspecified episode. Of our study patients, 4,331 (80%) received mood stabilizers, 4,031 (74%) received antipsychotics, and 1,192 (22%) received antidepressants. For 3,853 (71%) patients, prescriptions involved between-class polypharmacy, and for 941 (17%), prescriptions contained within-class polypharmacy. The combination of mood stabilizer and antipsychotic was the most common type of between-class polypharmacy (N52,825, 52%), followed by mood stabilizer, antipsychotic, and antidepressant (N5456, 8%), mood stabilizer and antidepressant (N5324, 6%), and antidepressant and antipsychotic (N5248, 5%). Polypharmacy with mood stabilizers (N5623, 11%) was the most frequently prescribed type of within-class polypharmacy, followed by antipsychotics (N5296, 5%) and antidepressants (N568, 1%). The daily dose for each medication was .626.29 for mood stabilizers, .776.02 for antipsychotics, and 1.246.82 for antidepressants. These data indicated that doses of mood stabilizers and antipsychotics were, on

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average, lower than the recommended dose, and doses of antidepressants were more likely to be higher than recommended. The average daily dose per prescription was .76.9. Multivariable regression analysis showed that patients older than 50 years and those who were treated at medical centers had a lower likelihood of receiving between-class polypharmacy. Each unit increase of average daily dose halved the odds of both between-class polypharmacy (odds ratio [OR]5.50, p,.001) and withinclass polypharmacy (OR5.57, p,.001) (Table 1). Finally, neither betweenclass polypharmacy nor within-class polypharmacy was associated with a higher rate of readmission within one year.

Discussion Our findings suggest that over 70% of psychotropic regimens among recently discharged patients with bipolar disorder involved between-class polypharmacy. Within-class polypharmacy was present in nearly 20% of prescriptions. Notably, a lower prescribed dose was strongly associated with the chance of polypharmacy. The strength of our study lies in its illustration of various types of polypharmacy among a nationally representative sample consisting mostly of inpatients with bipolar I disorder. Hospitalized patients are likely to have a more solid diagnosis of bipolar disorder, but the psychotropic regimen is specifically used to relieve an acute mood episode. Meanwhile, our data require cautious interpretation, given that they may not be generalizable to patients with bipolar disorder other than bipolar I or to patients who have not been hospitalized. In our findings, mood stabilizers accounted for a majority of polypharmacy among hospitalized patients, in contrast to outpatient regimens, in which antidepressants are the most frequently used medications for polypharmacy with another psychotropic (2,8). This finding is concordant with the clinical states of our study population. Over 70% of our patients suffered from an exacerbation of a manic or mixed episode, whereas many outpatients may be dealing with unresolved depression (2). Consistent PSYCHIATRIC SERVICES

with the report from Biancosino and colleagues (12), our data suggest that older patients are less likely to receive polypharmacy. One possible explanation is that the prescription of polypharmacy for the elderly is prevented by comorbid general medical illnesses or intolerable side effects. In addition, receiving treatment at a medical center is a protective factor for polypharmacy. As shown in the Systematic Treatment Enhancement Program for Bipolar Disorder studies, academic teaching hospitals are more likely to provide guideline-concordant care and may, therefore, be more reserved in prescribing polypharmacy (14). Furthermore, receiving polypharmacy did not predict a higher risk of readmission within one year, indicating that patients treated with polypharmacy do not necessarily have a more severe course of disease. Future research is needed to determine if severity of disease predicts polypharmacy or if polypharmacy brings substantial long-term benefits. The association between underdosing and polypharmacy calls for special notice. The most common mode of psychiatric polypharmacy is the “addon” strategy to boost or accelerate therapeutic effect (11,15), the tradeoff being potentially complex drugdrug interactions, intolerable side effects, higher cost, and decreased adherence (10). In our findings, polypharmacy was accompanied by the underdosing of mood stabilizers and antipsychotics, indicating the importance of considering whether to raise a single medication to its full therapeutic dose before proceeding to polypharmacy. Such an approach would also be more concordant with guideline recommendations. In contrast, higher-than-recommended prescribed doses of antidepressants warrant caution because of their undetermined efficacy for bipolar depression and the associated risk of triggering hypomania and escalation of cycling (2).

Conclusions This study suggested that there is substantial use of various forms of polypharmacy in the treatment of inpatients with bipolar disorder. We suggest that randomized studies be used to compare the cost-effectiveness

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of common psychotropic combinations and monotherapy to treat bipolar disorder. Acknowledgments and disclosures This research was supported by grants (9900162-049) from Taipei City Hospital, Taipei, Taiwan. This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and managed by the National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health, or the National Health Research Institutes. The authors report no competing interests.

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Collaborating Centre for Drug Statistic Methodology, 2003 14. Dennehy EB, Bauer MS, Perlis RH, et al: Concordance with treatment guidelines for bipolar disorder: data from the systematic treatment enhancement program for bipolar disorder. Psychopharmacology Bulletin 40:72–84, 2007 15. Preskorn SH, Lacey RL: Polypharmacy: when is it rational? Journal of Psychiatric Practice 13:97–105, 2007

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Psychotropic polypharmacy for the treatment of bipolar disorder in Taiwan.

Psychotropic polypharmacy in the treatment of bipolar disorder has proliferated. Yet evidence about the prevalence and predictors of different combina...
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