Real-World Patterns of Utilization and Costs Associated with Second-Generation Oral Antipsychotic Medication for the Treatment of Bipolar Disorder: A Literature Review

Figures & data

Figure 1 Search Results and Study Selection.

Note: Articles retrieved from other sources refer to papers identified from bibliographic review of relevant published systematic reviews. PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.⁵⁷

Abbreviation: NHS EED, National Health Service Economic Evaluation Database.

Table 1 SGA Dosing

Study	Data Source [Study Period] Sample	Dose Findings Reported	Dose, mg [Current Recommended Range]
			Aripiprazole [10–30mg]	Olanzapine [5–20mg]	Quetiapine [400–800mg]	Risperidone [1–6mg]	Ziprasidone [80–160mg]
Al Jurdi et al, 2008^Citation17	STEP-BD study [1998–2005] n=3615 (67.6% BD-I)	Mean daily dose, overall sample	15.99	9.2	224.79	1.37	90.16
Brooks et al, 2011^Citation18	STEP-BD study [1998–2005] n=1958 (72% BD-I)	Mean daily dose, SGA monotherapy	16	10	269	2	92
Gianfrancesco et al, 2008^Citation19	Commercial claims [1999–2004] n=8750 Tx episodes* (70% M/M)	Mean daily dose in any 3-month segment (M/M group), minimum/maximum	13/16.4	9.0/9.7	172.8/239.7	1.7/2.0	76.8/88.7
Jing et al, 2009^Citation21 and Kim et al, 2009^Citation23	Commercial claims [2003–2006] n=6162 (BD) **	Mean daily dose, starting/maximum	11.2/12.4	9.3/10.2	147/169.8	1.6/1.8	90.3/100.2
Jing et al, 2011^Citation20	Medicaid claims [2003–2008] n=22,479 (BD)	Mean daily dose, starting/maximum	11.8/13.7	8.2/9.6	149/194	1.4/1.7	80.4/94.4
Kim et al, 2011^Citation22	Commercial claims [2003–2006] n=7169 (BD)	Mean daily dose, starting/maximum	11.8/13.4	7.8/8.7	140.3/172.2	1.6	83.2/95.5
Rascati et al, 2011^Citation24	Medicaid claims [2002–2008] n=2446 (BD)	Mean daily dose for patients with clinically recommended doses	16	13	450	3	126

Notes: Current recommended ranges listed are sourced from product package inserts. *A treatment episode was defined as period consisting of ≥2 sequential antipsychotic prescriptions. **This is one dataset that was published in two different analyses.

Abbreviations: BD, bipolar disorder; BD-I, bipolar I disorder; M/M, manic/mixed; SGA, second-generation antipsychotic; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder; Tx, treatment.

Table 2 Adherence with SGAs and BD Medications (Multiple Classes Including SGAs)

Study	Data Source [Study Period]	Sample	Adherence Findings
Bagalman et al, 2010^Citation29	Commercial claims [2001–2004]	n=1258 (BD) Employed patients receiving psychotropic medication(30.6% index oral SGA)	At 1 year, mean MPR was 0.58. Only 35.3% of employees were adherent (MPR ≥0.8) with their BD medication after 1 year.
Baldessarini et al, 2008^Citation35	Cross-sectional study [2001–2005]	n=429 (79.0% BD-I) Patients recruited by their prescribing physician for a survey(61.3% receiving an antipsychotic)	Self-report of missing ≥1 dose of BD medication was 33.8% over a 10-day recall period.
Chen et al, 2013^Citation30	Commercial, Medicare, and Medicaid claims [2005]	n=16,807 (BD-I) Patients newly initiating SGA monotherapy	At 1 year, mean MPR was 0.19 (overall). Adherence (MPR ≥0.8) was 8.3% to index SGA after 1 year.
Gianfrancesco et al, 2008^Citation19	Commercial claims [1999–2004]	n=8750 treatment episodes* (70% M/M) Patients receiving SGA or FGA monotherapy (95% SGA)	In any 3-month period, mean MPR ranged from 0.8 to 1.02 (M/M cohort) over the 15-month evaluation period.
Gianfrancesco et al, 2008^Citation32	Commercial claims [1999–2004]	n=8770 treatment episodes* (70% M/M) Patients receiving SGA or FGA monotherapy (95% SGA)	In any 3-month period, mean MPR ranged from 0.87 to 0.96 (M/M cohort) over the 15-month evaluation period.
Gianfrancesco et al, 2008^Citation33	Commercial claims [1999–2005]	n=5531 treatment episodes* (69% M/M) Patients initiated on quetiapine or risperidone, alone and in various MS+ADT combinations	Over a 150-day period, mean MPR was 0.94 (quetiapine) and 0.91 (risperidone) in the monotherapy groups and ranged from 0.86 to 1.00 in the combination treatment groups.
Hassan and Lage, 2009^Citation40	Commercial claims [2000–2006]	n=1973 (BD) Hospital discharges with an SGA/FGA prescription(98% SGA)	At 1 year, mean MPR was 0.4565. The proportion of patients with MPR ≥0.75 was 26.76%.
Lage and Hassan, 2009^Citation39	Commercial claims [2000–2006]	n=7769 (BD) Patients with ≥1 SGA/FGA claim(95% SGA)	At 1 year, mean MPR was 0.417. The proportion of patients with MPR ≥0.75 was 21.3%.
Lang et al, 2011^Citation31	Medicaid claims [2004–2006]	n=9410 (BD-I) Patients with ≥1 SGA/FGA claim(83.1% oral SGA)	Among patients receiving oral SGA, mean MPR was 0.63 and only 38.9% were adherent (MPR ≥0.8) at 1 year.
Perlis et al, 2010^Citation34	Prospective longitudinal cohort study [1998–2005]	n=3640 (BD) Patients receiving ≥1 psychotropic medication	Across all study visits, 46.4% of patients reported adherence with BD medication.
Qiu et al, 2009^Citation25	Medicaid claims [2000–2005]	n=838 (BD) Patients receiving monotherapy with olanzapine, risperidone, or quetiapine	Adherence with index SGA, as measured by CMA and CMG, was similar across treatment groups at 1 year. CMA ranged from 70% to 76% and CMG ranged from 35% to 38%.
Rascati et al, 2011^Citation24	Medicaid claims [2002–2008]	n=2446 (BD) Patients initially prescribed SGA therapy	At 1 year, 58% of patients prescribed a clinically recommended dose of an index SGA were adherent (MPR ≥0.8).
Seabury et al, 2014^Citation36	Medicaid claims [2001–2008]	n=170,596 (BD) Patients newly initiated on SGA therapy	At 1 year, the mean proportion of days covered over 12 months for patients with BD was 72%.

Notes: *A treatment episode was defined as period consisting of ≥2 sequential antipsychotic prescriptions. CMA calculated as the sum of days’ supply of all SGA prescriptions in the 12-month treatment period after the index date divided by total days between the date of the first fill to the date of last refill. CMG was calculated as the ratio of total days without treatment divided by total days between the first fill and last refill date.

Abbreviations: ADT, antidepressant therapy; BD, bipolar disorder; BD-I, bipolar I disorder; CMA, cumulative medication acquisition; CMG, cumulative medication gap; FGA, first-generation antipsychotic (also known as typical antipsychotics); M/M, manic/mixed; MPR, medication possession ratio; MS, traditional mood stabilizer medication; SGA, second-generation antipsychotic.

Table 3 Factors Associated with Suboptimal Adherence with SGA Regimen in Analyses of Health Care Claims

Patient Characteristic		Factors Associated with Suboptimal Adherence to SGA Regimen
		Commercial Claims, BD (predominately M/M)		Medicaid Claims, BD-I	Medicaid Claims, BD
		Gianfrancesco et al., 2008^Citation19	Gianfrancesco et al., 2009^Citation33	Lang et al., 2011^Citation31	Rascati et al., 2011^Citation24
Sociodemographic Characteristics	Age (younger, ≤30 years)			●
	Age (older, range not specified)	●	●		●
	Race (African American vs. Caucasian)				●
Clinical Characteristics	History of suicide attempt				●
	Current (or history) of comorbid substance use disorder	●		●
	Baseline psychiatric hospitalization			●
Treatment-Related Characteristics	Newly initiated SGA			●
	Higher SGA dose (olanzapine, risperidone)	●
	Baseline antidepressant use			●
	Prior or concomitant use of mood stabilizers	●			●
	Concomitant use of SGA with other psychotropic medication		●
	Hyperprolactinemia as a pre-existing antipsychotic-related side effect	●

Abbreviations: BD, bipolar disorder; BD-I, bipolar I disorder; M/M, manic/mixed symptoms; SGA, second-generation antipsychotic.

Table 4 Persistence with Oral SGAs or BD Medication

Study	Data Source [Study Period]	Sample	Persistence Findings
Bagalman et al, 2010^Citation29	Commercial claims [2001–2004]	n=1258 (BD) Employed patients receiving psychotropic medication (30.6% index oral SGA)	At 1 year, mean persistence with BD medication was 0.77 (overall, measure for persistence was not defined). Adherent (vs MPR <0.8) patients had greater persistence at 1 year (0.99 vs 0.64).
Chen et al, 2013^Citation30	Commercial, Medicare, and Medicaid claims [2005]	n=16,807 (BD-I) Patients newly initiating SGA monotherapy	At 1 year, 10.5% of patients were persistent to SGA therapy (no gaps >15 days between refills and no continuous concomitant treatment with another SGA ≥30 days).
Lang et al, 2011^Citation31	Medicaid claims [2004–2006]	n=9410 (BD-I) Patients with ≥1 SGA/FGA claim (83.1% oral SGA)	At 1 year, mean persistence was 0.84 (±0.26) (defined as the number of days between the first and last day receiving an oral SGA divided by the number of days remaining in the period after the first oral SGA was dispensed).
Rascati et al, 2011^Citation24	Medicaid claims [2002–2008]	n=2446 (BD) Patients initially prescribed SGA therapy	At 1 year, 18% of patients prescribed SGA at clinically recommended doses were persistent (no gap >30 days between SGA refills). The median time-to-SGA-nonpersistence was 96 days with modest variation depending on the index SGA (range: 72 for olanzapine to 117 days for ziprasidone).

Abbreviations: BD, bipolar disorder; BD-I, bipolar I disorder; FGA, first-generation antipsychotic (also known as typical antipsychotics); MPR, medication possession ratio; SGA, second-generation antipsychotic.

Table 5 Duration of Therapy and Treatment Gaps with SGAs

Study	Data Source [Study Period]	Sample	Treatment Gap and/or Duration of Therapy Findings
Bagalman et al, 2010^Citation29	Commercial claims [2001–2004]	n=1258 (BD) Employed patients receiving psychotropic medication (30.6% index oral SGA)	Over 1 year, adherent patients (vs MPR <0.8) had more gaps in therapy (3.62 vs 2.60), but these gaps occurred for shorter durations (15.57 vs 58.89 days).
Chen et al, 2013^Citation30	Commercial, Medicare, and Medicaid claims [2005]	n=16,807 (BD-I) Patients newly initiating SGA monotherapy	Average time to first non-compliance was approximately 90 days (defined as gaps between index SGA refills >15 days but <30 days and no evidence of adding or switching to another SGA medication). Over 1 year, most patients (63.4%) discontinued initial SGA therapy (gap of ≥30 days for index SGA with no evidence of antipsychotic augmentation or switch). The average time to discontinuation was 66 days. Many (69.7%) did not restart any type of antipsychotic therapy during the remainder of the 1-year follow-up period; one-third resumed antipsychotic therapy after 3 to 6 months.
Kim et al, 2011^Citation22	Commercial claims [2003–2006]	n=7169 (BD) Patients with ≥1 SGA claim	Over 1 year, rates of discontinuation (>15 days’ gap in coverage) were high (67% [ziprasidone] to 83% [aripiprazole]). Fewer than 5% of patients completed a full year of follow-up taking their index SGA medication. The duration of therapy with SGA was comparable across all treatment groups (median of 30 days across all index SGA treatment groups).
Lang et al, 2011^Citation31	Medicaid claims [2004–2006]	n=9410 (BD-I) Patients with ≥1 SGA/FGA claim (83.1% oral SGA)	The mean maximum consecutive gap in treatment was 49.3 days for the oral SGA group over a 1-year period.
Gianfrancesco et al, 2008^Citation19	Commercial claims [1999–2004]	n=8750 treatment episodes* (70% M/M) Patients receiving SGA or FGA monotherapy (95% SGA)	In the M/M cohort, treatment duration ranged from 7.6 months (aripiprazole) to 9.6 months (risperidone). For all risperidone- or quetiapine-treated individuals, higher doses were associated with longer duration of treatment among patients with predominantly M/M symptoms.
Gianfrancesco et al, 2009^Citation33	Commercial claims [1999–2005]	n=5531 treatment episodes* (69% M/M) Patients initiated on quetiapine or risperidone, alone and in various MS/ADT combinations	Mean treatment duration for both quetiapine and risperidone monotherapy was 12.4 months. The mean treatment duration for combination therapies (ADT and/or MS) with quetiapine or risperidone ranged from 11.1 to 13.3 months. Comparisons of MPRs for quetiapine/risperidone combinations vs monotherapy showed no clear relationship to treatment duration.
Pilhatsch et al, 2018^Citation37	Prospective study [NR – 100-day periods]	n=241 Outpatients recruited from a university mood clinic and private practice. (50% SGA)	Patients took drugs on 84.4% of days. Irregular daily dosing was frequently reported, mostly due to single-day omissions (64.7% of analysis period) or patients’ self-directed dosage changes (86.7% of analysis periods). Drug holidays (missing ≥3 consecutive days of medication) were found in 35.8% of analysis periods.

Note: *Treatment episode was defined as period consisting of ≥2 sequential antipsychotic prescriptions.

Abbreviations: ADT, antidepressant therapy; BD, bipolar disorder; FGA, first-generation antipsychotic (also known as typical antipsychotics); M/M, manic/mixed; MPR, medication possession ratio; MS, traditional mood stabilizers; NR, not reported; SGA, second-generation antipsychotic.

Table 6 Prevalence of Combination Treatment

Study	Data Source [Study Period] Sample	SGA Combination Treatment (Use of ≥2 SGAs Concurrently)	Combination Treatment (Use of ≥2 Psychotropics Concurrently)	Notes
Aparasu et al, 2009^Citation53	Cross-sectional study [2003–3004] N=2860 (multiple diagnoses)	10.3%	–	Proportion of treatment visits for BD in which concurrent SGA use was documented
Baldessarini et al, 2008^Citation54	Commercial claims [2001–2005] N=7406 (55.4% BD-I)	–	48% to 49% (SGA + any psychotropic)	Range for initial and final treatment over 1 year
Baldessarini et al, 2008^Citation35	Cross-sectional study [2005] N=429 (79.0% BD-I)	–	76.2% (any combination ≥2 psychotropics) 20.0% (>3 psychotropics) 11.2% (antipsychotic + MS)	Combination treatment reported at study baseline
Brooks et al, 2011^Citation18	STEP-BD study [1998–2005] n=1958 (72% BD-I)	8.3%	–	Calculated (162/1958 [patients prescribed >1 SGA/patients prescribed ≥1 SGA during the study])
Chen et al, 2013^Citation30	Commercial, Medicare and Medicaid claims [2002–2008] N=16,807 (BD-I)	1% (baseline) 4.2% (during the study)	–
Goldberg et al, 2009^Citation38	STEP-BD study [1998–2005] n=4035 (66% BD-I)	–	38% (SGA + ≥3 any psychotropic)	Study refers to the use of ≥4 psychotropic medications as a “complex regimen”
Guo et al, 2008^Citation55	Commercial claims [1998–2002] N=67,862 (BD)	–	25.3% (SGA +MS)
Jing et al, 2011^Citation20	Medicaid claims [2003–2008] n=22,479 (BD)	4% to 6%	59% to 68% (SGA + ADT) 17% to 31% (SGA +MS)	Rates varied by individual SGA treatment group
Kim et al, 2011^Citation22	Commercial claims [2003–2006] n=7169 (BD)	–	67.6% to 77.9% (SGA + MS)	Rates varied by individual SGA treatment group
Lang et al, 2011^Citation31	Medicaid claims [2004–2006] n=9410 (BD-I)	–	78% (SGA + ADT) 68% (SGA + MS) 53.6% (SGA + anxiolytic)	Data reported for the oral SGA treatment group only
Qiu et al, 2009^Citation25	Medicaid claims [2000–2005] N=838 (BD)	2% to 5%	–	Rates of SGA augmentation over the 1-year evaluation period
Qiu et al, 2010^Citation56	Medicaid claims [2000–2005] N=3328 (BD)	–	43.4% (SGA + MS)
Rascati et al, 2011^Citation24	Medicaid claims [2002–2008] n=2446 (BD)	–	57% (SGA + MS)
Tohen et al, 2017^Citation26	Commercial claims [2012–2014] n=3329 (BD)	6.7% to 23%	5% to 7.7% (SGA + MS)	Rates varied by individual SGA treatment group

Abbreviations: ADT, antidepressant therapy (any); BD, bipolar disorder; BD-I, bipolar I disorder; MS, mood stabilizer therapy; SGA, second-generation antipsychotic; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder.

Table 7 Utilization Patterns with SGAs Associated with Increased HCRU or Costs

Study	Data Source [Study Period]	Sample	HCRU/Cost Findings
Bagalman et al, 2010^Citation29	Commercial claims from the MarketScan research database [2001–2004]	n=1258 Employees with BD who had ≥1 claim for mood stabilizer or SGA therapy (oral SGA was the index BD medication for 30.6% of the sample)	Employees receiving BD medication who had a MPR <0.8 had incrementally higher adjusted indirect costs over 1 year for increased claims due to absence from work (+$1156), short-term disability (+$427), and workers’ compensation (+$541) compared to those with those who were adherent (MPR ≥0.8).
Brooks et al, 2011^Citation18	STEP-BD study [1998–2005]	n=1958 Longitudinal cohort of BD patients (72% BD-I) who were prescribed ≥1 SGA medication	Over 21 months, patients receiving ≥2 SGA concurrently reported greater use of medical and mental health related HCRU compared to those receiving SGA monotherapy. BD-I patients receiving ≥2 SGAs had 80% more general medical HCRU (3.6 v. 2.0) and more than twice the mental health-related HCRU (6.4 vs 2.1) than patients taking SGA monotherapy.
Gianfrancesco et al, 2008^Citation32	Commercial claims from the PharMetrics database [1999–2004]	n=8770 treatment episodes* (70% predominately manic/mixed symptoms) Patients with BD or manic disorder receiving SGA or FGA monotherapy, evaluated in 3-month segments	The risk of acute mental health care (hospitalization or ER visit) at the end of treatment was reduced by 2.6% in the M/M cohort for each additional month of antipsychotic treatment. In M/M individuals, a 1-point increase in MPR (over 3 months) was associated with a $192 to $686 quarterly reduction in total expenditures and a $112 to $583 quarterly reduction in outpatient mental health care over subsequent quarters of treatment.
Hassan and Lage, 2009^Citation40	Commercial claims from the PharMetrics database [2000–2006]	n=1973 BD patients who received outpatient antipsychotic prescription within 2 weeks of hospital discharge	Discharged patients prescribed antipsychotics who had higher MPR, had lower risk of rehospitalization over 1 year. Patients who achieved MPR ≥0.75 had significantly decreased odds of rehospitalization for any cause (OR=0.730), and significantly decreased odds of mental health-related rehospitalization (OR=0.759).
Lage and Hassan, 2009^Citation39	Commercial claims from the PharMetrics database [2000–2006]	n=7769 BD patients with ≥1 claim for antipsychotic medication	Over 1 year, higher antipsychotic MPR was associated with lower risk of hospitalization and ER visit. Patients who achieved MPR ≥0.75 had significantly lower odds of all-cause hospitalization (OR=0.85) and those with MPR ≥0.8 had a significant reduction in the odds of a psychiatric-related hospitalization (OR=0.82).
Lang et al, 2011^Citation31	Medicaid claims from the MarketScan research database [2004–2006]	n=9410 Patients with BD-I who received ≥1 antipsychotic prescription for oral or injectable SGA or FGA	Over 1 year of follow-up, patients with suboptimal adherence (vs MPR ≥0.8) had higher rates of acute HCRU (ER visits and hospitalizations). ER visits, all-cause: 72.5% vs 57.4%ER visits, psychiatric: 30.0% vs 23.5%Hospitalization, all-cause: 38.8% vs 33.5%Hospitalization, psychiatric: 35.5% vs 30.9%

Notes: *Treatment episode was defined as period consisting of ≥2 sequential antipsychotic prescriptions.

Abbreviations: BD, bipolar disorder; BD-I, bipolar I disorder; ER, emergency room; FGA, first-generation antipsychotic (also known as typical antipsychotics; HCRU, health care resource use; MPR, medication possession ratio; OR, odds ratio; SGA, second-generation antipsychotic; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder.

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