Prevalence and clinical features associated with bipolar disorder polypharmacy: a systematic review

Figures & data

Figure 1 Adapted PRISMA 2009 flow diagram.

Table 1 Essential cross-sectional evidence

Author	Aim/hypothesis	Sample size	Main results	Conclusions	Limitations	Quality score and differentiation
Goldberg et al^Citation3	To investigate the prevalence rates of complex polypharmacy (defined as more than four medications for BD) and clinical features associated with different mood episode phases of BD, primarily depression, prior to entering the STEP- BD naturalistic study.^Citation10	N=4,025 outpatients (BD-I, n=2,666; BD-II =1,048; BD-NOS =285; cyclothymic disorder or schizoaffective bipolar disorder =36).	Use of three or more medications at once occurred in 40% of the sample; 18% of the cases received complex polypharmacy, especially if they had ever taken SGAs, had at least six lifetime depressive episode, attempted suicide, and above-average annual income.	Complex polypharmacy occurred in approximately one in five individuals with BD. Use of lithium or proven mood-stabilizer anticonvulsants was associated with lower odds or polypharmacy. Higher income was associated with antidepressant and SGA use, higher rates of polypharmacy, and greater depressive burden.	Post hoc analysis, lack of control group, limited number of drugs, lack of additional stratifications for different classes of antidepressants or lithium blood levels or potential confounders (eg, concomitant psychotherapy or environmental stressors).	I =1 II =2 III =0 IV =0 V =2 VI =0 VII =2 VIII =2 IX =2 Total =11 Overall quality = good.

Abbreviations: BD, bipolar disorder; NOS, not otherwise specified; SGA, second-generation antipsychotic; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder.

Table 2 Essential retrospective studies

Author	Aim/hypothesis	Sample size	Main results	Conclusions	Limitations	Quality score and differentiation
Sachs et al^Citation23	To chart-review the personality traits associated with the practice of current (≥4 drugs) and/or lifetime polypharmacy (≥11) in BD.	The study included a total of 89 consecutively selected records of treatment seeking patients with a history of refractory BD (F:M =48:41).	According to the NEO Five Factor Personality Inventory,^Citation67 the patients with lower scores on “openness” had significantly more current psychotropic medication use compared to those cases with higher openness scores (3.7±1.9 vs 2.8±1.8; P≤0.05). Similarly, the patients with lower extraversion (21.8±8.9 vs 25.4±7.6, P≤0.05) and lower conscientiousness (21.9±8.2 vs 27.9±8.2, P≤0.05) had the highest lifetime medication use.	Low levels of openness, extraversion, and conscientiousness may be associated with higher rates polypharmacy. Further research should examine whether the duration of exposure to ineffective medication is correlated to reluctance to discontinue ineffective agents.	Small sample size and selection bias. Lack of additional stratification for in vs outpatient cases, type, and mood state of BD.	I =0 II =2 III =2 IV =2 V =2 VI =0 VII =0 VIII =0 IX =0 Total =8 Overall quality = moderate.
Weinstock et al^Citation27	To chart-review the rates of complex polypharmacy (≥4 psychotropic and nonpsychotropic drugs at once) in BD-I cases.	The sample included a total of 230 BD-I inpatients across different mood episode polarity were.	Overall, complex polypharmacy was documented in 82 (36%) of the cases. Patients reported taking an average of 3.31±1.46 psychotropic and 5.94±3.78 nonpsychotropic medications. Those cases receiving complex polypharmacy were significantly more likely to be women and to be prescribed with antidepressants, benzodiazepines, and stimulants, even after controlling for mood episode polarity. Lithium was prescribed as part of polypharmacy in 13% of the cases.	Data highlighted the high medication burden experienced by patients with BD, especially those BD-I inpatients who are acutely symptomatic.	Relatively small sample size and selection bias.	I =0 II =2 III =2 IV =2 V =2VI =2 VII =0 VIII =2 IX =1 Total =13 Overall quality = good.
Hung et al^Citation28	The Taiwanese Nationwide Psychiatric Inpatient Medical Claims (2000–2007) were used to examine prescription for mood stabilizers, antipsychotics, and antidepressants among recently discharged patients with BD. Operative definition of polypharmacy was two or more psychotropic medications.	Out of 5,449 BD patients, 5,155 (95%) were BD-I. Among them, n=2,923 (57%) presented with a manic episode, 1,076 (21%) depressed episode, 768 (15%) mixed episode, and 370 (7%) unspecified episode.	For 3,853 (71%) patients, prescriptions involved between-class polypharmacy, and for 941 (17%), prescriptions contained within-class polypharmacy.	Mood stabilizers accounted for a majority of polypharmacy among hospitalized patients, which rates were particularly high in case of between-class prescriptions. As prompted out by the authors themselves, this is contrast to the usual finding reported by studies carried on outpatient samples of BD, especially BD-II women, whereas antidepressants are often prescription in the context of polypharmacy.	Almost only BD-I manic inpatients were included. Permissive criterion for polypharmacy (yet accurate distinction between within- and between- class polypharmacy prescriptions).	I =1 II =2 III =2 IV =2 V =2 VI =0 VII =0 VIII =0 IX =0 Total =9 Overall quality = moderate.
Baek et al^Citation29	To retrospectively assess the pattern of pharmacotherapy by episode type in Korean BD patients and rates of concordance with varying international standard treatment guidelines.	The sample included BD-I cases (n=990; of whom, n=480 being currently manic inpatients, n=113 being depressive inpatients, and n=397 being outpatients) and BD-II cases (total n=457, of whom depressive inpatients were n=190 and outpatients were n=267).	The overall concordance rate of prescriptions for manic inpatients to the guidelines was higher and relatively more consistent (43.8%–48.7%) compared to that for depressive inpatients (18.6%–46.9%).	Polypharmacy was a common reason of nonconcordance toward varying treatment guidelines for BD, especially for those BD-II depressed patients receiving SGA(s) too.	Retrospective design of the study; partial control for potential confounding factors.	I =1 II =2 III =1 IV =2 V =0 VI =0 VII =1 VIII =2 IX =1 Total =10 Overall quality = good.

Abbreviations: BD, bipolar disorder; NOS, not otherwise specified; F, female; M, male; SGA, second-generation antipsychotic.

Table 3 Essential prospective studies

Author	Aim/hypothesis	Sample size	Main results	Conclusions	Limitations	Quality score and differentiation
Haeberle et al^Citation25	To longitudinally follow European inpatients with a diagnosis of bipolar depression over a 15-year follow-up period (1994–2009).	A total 2,246 inpatients, both sex and age 18 or older were included in the present study.	Antidepressants were the most frequently prescribed class of drugs given in combination. Olanzapine plus fluoxetine combination was found to be prescribed only in very few patients, as it was the case for bupropion (which may reflect a differential prescription trend compared to North America within the period at study). Quetiapine was found to be the second most frequently prescribed substance for bipolar depression during the period of 2006–2009.	Overall, the present study showed that multiple combinations of psychotropic drugs is routinely prescribed in the clinical routine, including antidepressant, despite their controversial role in bipolar depression. The trend of second- generation antipsychotic combinations was also steadily increasing over the time within the covered period of time. Only 337 (15%) patients received monotherapy at time of assessment, with virtually none of them being medication free at time of hospitalization. Finally, lithium was the less common drug used in combination with any other class of substance (n=741 or 33% of the cases).	Permissive operative definition of polypharmacy (two or more class of psychotropic substances). Lack of additional demographic or clinical stratifications, including BD type.	I =1 II =2 III =1 IV =2 V =0 VI =0 VII =1 VIII =2 IX =1 Total =10 Overall quality = good.
Bauer et al^Citation34	To prospectively document the naturalistic prescription trends of BD patients in the USA, Germany, Canada, and elsewhere.	Data on 450 cases of BD were collected over a period of approximately 6 months. BD-I cases were n=272 (60%), BD-II n=157 (35%), and BD-NOS =17 (5%).	Polypharmacy (namely the concomitant use of at least two psychotropic medications of either the same or different classes) was recorded in up to 75% of the cases. Specifically, sustained polypharmacy regarded 353 (78.4%) of patients for at least ≥50% of days. Overall mean follow-up was 222 days.	Overall, most of the patients received mood-stabilizer drugs. Yet, though most patients were receiving polypharmacy, there were no predominant drug regimens even among those taking stable combinations. Most patients with stable combinations took a relatively small number of drugs daily.	No stratification was documented for current mood phase of BD.	I =1 II =2 III =2 IV =2 V =1 VI =1 VII =0 VIII =2 IX =0 Total =11 Overall quality = good.
Bauer et al^Citation51	To analyze the regularity in daily dosage of antidepressants taken by BD patients and factors associated with irregularity.	The sample included 144 BD patients: BD-I, n=67; BD-II, n=65; and BD-NOS, n=10. Females were n=108 (or 75% of the sample). Polypharmacy was defined as the use of two or more psychotropic drugs at once. Regularity was measured using the ApnEn, which is the tendency that values within a time series remain the same on the incremental comparisons.^Citation76	Total number of psychotropic medications was significantly associated with irregularity (P=0.005), as it was “pill burden” (P=0.005), and depression (P=0.015), Neither the percentage of days missing doses nor the drug holidays were associated with any demographic of clinical factors.	Irregularity in daily dosage is common, despite a low percentage of days missing. Daily irregularity in drug dosage may be more dependent on the individual rather than on a specific drug.	Relatively small sample size and relatively short follow-up (100 days). Permissive criterion of polypharmacy.	I =1 II =2 III =1 IV =1 V =1 VI =1 VII =0 VIII =1 IX =1 Total =9 Overall quality = moderate.

Abbreviations: BD, bipolar disorder; NOS, not otherwise specified; ApnEn, approximate entropy.

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