Psychotropic Polypharmacy for the Treatment of Bipolar Disorder in Taiwan
Abstract
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 (N=5,449; 51% women, mean±SD age=36.8±12.4).
Results
A total of 71% of prescriptions involved between-class 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 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.
Since 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 cost-effective (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 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 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 identified 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 between-class polypharmacy and within-class polypharmacy were present. Between-class 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, N=18), regional hospitals (250–500 beds, N=74), and district hospitals (<250 beds, N=249). 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 one-year 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; mean±SD age=36.8±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 (N=2,825, 52%), followed by mood stabilizer, antipsychotic, and antidepressant (N=456, 8%), mood stabilizer and antidepressant (N=324, 6%), and antidepressant and antipsychotic (N=248, 5%). Polypharmacy with mood stabilizers (N=623, 11%) was the most frequently prescribed type of within-class polypharmacy, followed by antipsychotics (N=296, 5%) and antidepressants (N=68, 1%). The daily dose for each medication was .62±.29 for mood stabilizers, .77±.02 for antipsychotics, and 1.24±.82 for antidepressants. These data indicated that doses of mood stabilizers and antipsychotics were, on 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 .7±.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]=.50, p<.001) and within-class polypharmacy (OR=.57, p<.001) (Table 1). Finally, neither between-class polypharmacy nor within-class polypharmacy was associated with a higher rate of readmission within one year.
Between class | Within class | |||||||
---|---|---|---|---|---|---|---|---|
Predictora | N | % | OR | 95% CI | p | OR | 95% CI | p |
Sex | ||||||||
Men (reference) | 2,676 | 49 | ||||||
Women | 2,752 | 51 | 1.01 | .89–1.15 | .837 | .95 | .82–1.10 | .491 |
Age (M±SD) | ||||||||
≤30 | 1,956 | 36 | 1.30 | 1.09–1.56 | .004 | 1.28 | 1.03–1.58 | .024 |
31–40 | 1,389 | 26 | 1.30 | 1.07–1.57 | .007 | 1.10 | .87–1.38 | .416 |
41–50 | 1,157 | 21 | 1.33 | 1.09–1.62 | .006 | 1.19 | .94–1.51 | .138 |
>50 (reference) | 947 | 17 | ||||||
Psychiatric diagnoses | ||||||||
1 | 4,717 | 87 | 1.04 | .87–1.25 | .652 | 1.29 | 1.03–1.61 | .027 |
>1 (reference) | 732 | 13 | ||||||
Outpatient clinic setting | ||||||||
Medical center (reference) | 1,981 | 36 | ||||||
Regional hospital | 2,058 | 38 | 1.17 | 1.01–1.35 | .035 | 1.14 | .97–1.35 | .110 |
District hospital | 1,291 | 24 | 1.31 | 1.10–1.57 | .003 | 1.06 | .86–1.29 | .597 |
Hospitalization (M±SD days) | 30.3±46.9 | 1.00 | 1.00–1.00 | .011 | 1.00 | 1.00–1.00 | .009 | |
Average daily dose (M±SD)b | .7±.9 | .50 | .44–.57 | <.001 | .57 | .47–.70 | <.001 |
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 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 “add-on” strategy to boost or accelerate therapeutic effect (11,15), the trade-off being potentially complex drug-drug 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 of common psychotropic combinations and monotherapy to treat bipolar disorder.
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