Systematic literature review on patterns of pharmacological treatment and adherence among patients with bipolar disorder type I in the USA

Figures & data

Table 1 Search terms used

Publication database^*	Search terms used^
MEDLINE^	((bipolar AND disorder) OR mania OR manic) AND (“Therapeutics” [Mesh]) AND (cross sectional OR prospective OR retrospective OR longitudinal OR cohort OR transversal OR database OR chart review OR medical records OR claim OR survey OR registry OR naturalistic OR health record)
EMBASE	‘bipolar disorder’/exp AND ‘therapy’/exp AND (‘cross-sectional study’/exp OR ‘prospective study’/exp OR ‘retrospective study’/exp OR ‘longitudinal study’/exp OR ‘cohort analysis’/exp OR ‘data base’/exp OR ‘medical record review’/exp OR ‘administrative claims (health care)’/exp OR ‘disease registry’/exp OR ‘health care survey’/exp OR ‘electronic medical record’/exp OR naturalistic:ab,ti) AND [18-10-2006]/sd NOT [18-10-2016]/sd AND [english]/lim AND [embase]/lim AND ([article]/lim OR [article in press]/lim OR [conference abstract]/lim OR [conference paper]/lim OR [short survey]/lim)

Notes: ^*Search date: October 4, 2016.

^ All MEDLINE searches were limited to a 10-year period (2006–2016).

Figure 1 PRISMA flow diagram.

Table 2 Studies evaluating patterns of care

Study	Source of data [period]	Population	Results
Treatment prevalence outcomes: treatment rates
Blanco et al^Citation35/NESARC-III	National USA survey addressing BD-I prevalence according to DSM-5 [2012–2013]. Diagnostic screening used AUDADIS-5	n=36,309 adults (person-level response rate of 84%)	Treatment rates of 46% (12-month) and 72.4% (lifetime) among all patients with BD-I
Merikangas et al^Citation36/NCS-R	National USA population-based cross-sectional survey (National Comorbidity Survey Replication) [2001–2003]. BD-I diagnosis according to DSM-IV. Diagnostic screening used CIDI	n=9,282 respondents aged ≥18 years	Patients with BD-I – 12-month treatment rates were 67.3%; lifetime treatment rates were 89.2%
Sajatovic et al^Citation41	VA National Psychosis Registry*; VA pharmacy benefits management strategic health care group and outpatient visits [2003]	73,964 BD patients; mean age=52.3 years	44.6% received treatment with AP medications
Patterns of treatment: medications used outcome: medications used among the sample
Alexander et al^Citation32	IMS Health National Disease and Therapeutic Index (nationally representative USA data) describing outpatient antipsychotic use [1995–2008]	Approximately 4,800 office-based, patient-care physicians, data for patient visits where an FGA or SGA drug was reported	BD – treatment visits increase (1995–1996 vs 2007–2008): total SGA/FGA in BD visits (thousands): 297/1,199 vs 9,112/383; thus, SGA accounted for 19.8% vs 96% of BD visits
Baldessarini et al^Citation15	USA national MarketScan^® research databases used to quantify utilization rates for psychotropic drug classes in persons with ICD-9 BD [2002–2003]	n=7,760 BD patients (69.2% with BD-I)	Baseline: 60.1% of BD patients prescribed initial psychotropic monotherapy (10.7% with AP, where 10.1% are SGA), lithium (7.5%), and divalproex (8.3%) BD-I – midpoint of the 2-year study: 43.3% monotherapy Patients with BD-I receiving monotherapy: lithium (13%), antipsychotics (10.9%), anticonvulsants (7.6%), and antidepressants (57.9%) Patients with BD-I receiving ≥2 drugs: lithium (9.4%), anticonvulsants (15.2%), and AP (18.1%)
Baldessarini et al^Citation33	Survey including 131 randomly selected prescribing psychiatrists and their adult BD patients in five geographic regions in USA [2005]	n=1,321 patients with BD approached/429 (32.5% of them responded)/among these 429 patients: 79% with BD-I (n=339)	Psychiatrists considered patients’ state: 52.7% clinically euthymic and in maintenance treatment when surveyed; 18% depressed; 10.7% hypomanic; 5.6% manic – of whom 37.5% were hospitalized Drugs used: 76.2% received ≥2 psychotropic drugs, mean of 2.5 (±1.1) medicines/person Most commonly drugs used: 61.3% APs; 56.2% MSs other than lithium; 50.1% antidepressants
Baldessarini et al^Citation14	Proprietary research database containing eligibility information and pharmacy and medical claims data from a large commercial USA health plan (concentration in the South and Midwest) [2000–2004]	n=7,406 BD patients ≥17 years (55.4% BD-I)	Among all patients, 67% with initial monotherapy prescription and 33% with a prescription for two or more major psychotropic drugs (anticonvulsants with mood-stabilizing or antimanic effects, lithium, antipsychotics, or antidepressants) Initial monotherapy: 24.2% any MS (6.4% lithium, 11.3% valproate); 10.6% any antipsychotic (6.1% olanzapine, 1.8% risperidone, 1.7% quetiapine, 0.3% aripiprazole, and 0.3% ziprasidone) Initial polytherapy: 61.6% any mood stabilizer (49.3% anticonvulsant, most frequently: 34.3% carbamazepine or oxcarbazepine and 15.8% lithium); 50% any antipsychotic (21.2% olanzapine, 14.3% quetiapine, 12.9% risperidone, 2.2% ziprasidone, and 1.9% aripiprazole) At one year: 31% monotherapy; 32% received two or more primary psychotropics; 37% had no evidence of receiving a primary mood-altering agent in the preceding 90 days At final treatment: 49.9% any MS (38.4% anticonvulsant and 14.5% lithium); 29.8% any AP (10.6% quetiapine, 10.4% olanzapine, 6.7% risperidone, 2.3% aripiprazole, and 0.2% ziprasidone)
Bates et al^Citation34	Self-report, web-based survey from USA patients aged 18–65 years who reported a diagnosis of BD and current use of psychotropic medication [2008]	n=1,052 patients with high risk of BD according to the CIDI-bipolar disorder score ≥7	Drug usage: 47% SGA; 83.3% MS
Bauer et al^Citation16	Administrative claims records from the VA Data Center (drawing from all VA medical centers across the USA) [2003–2010]	n=27,727 BD (79.8% BD-I) patients receiving one or more 30-day outpatient prescription as a first intentional trial of SGA or other common antimanic agents	Drug prescriptions: 43.2% only SGA; 27.9% only valproate; 14.1% only lithium; 7.7% SGA/valproate; 3.6% SGA/lithium; 3.4% carbamazepine or oxcarbazepine
Chen et al^Citation20	Three MarketScan research databases: Commercial Claims and Encounters Database, “Medicare”: Medicare supplemental and coordination of benefits database, and multistate Medicaid database [2002–2008]	n=16,807 patients with BD-I (34.7% from commercial/Medicare and 65.3% from Medicaid) aged ≥18 years who newly initiated an oral SGA	Baseline: 35.7% using mood stabilizers Most frequently used index SGA: quetiapine (31.5%), olanzapine (28.7%), risperidone (20.5%), aripiprazole (9.7%), ziprasidone (5.6%), and paliperidone (0.1%). Index polytherapy in only 3.8%. Similar drug use patterns between commercial/Medicare and Medicaid patients
Citrome et al^Citation21	Retrospective cohort using adult OptumInsight commercial data set** [2008–2011]	n=6,115 BD patients	Most commonly used antipsychotics: quetiapine (39.5%), aripiprazole (37.2%), risperidone (11%), olanzapine (7.9%), and ziprasidone (4.2%)
Depp et al^Citation22	Medicaid beneficiaries receiving service in the San Diego county public mental health system (merged data from the encounter-based management information system of San Diego county’s adult and older adult mental health services and the California’s department of health care services) [2001–2004]	n=2,427 adult BD patients (n=1,473 were continuously enrolled)	Drug usage in 2004: 77% MS or AP (among these, 20% MS monotherapy; 36% AP monotherapy; 44% MS+AP) AP used: 96% SGA; MS: 35% lithium, 13% valproate/carbamazepine, and 53% lamotrigine, topiramate, or gabapentine. Antidepressants used by 62% of patients Significant trend for decreased use of MS monotherapy (25%–20%); increase in the use of AP monotherapy (32%–36%)
Dusetzina et al^Citation24	Retrospective, repeated cross-sectional study based on MarketScan Commercial Claims and Encounters inpatient, outpatient, and pharmacy claims databases, representing enrollees in commercial health insurance plans sponsored by over 100 large- or medium-sized USA based employers [2007]	n=16,641 children and adolescents aged 0–17 years (35% BD-I)	Treated prevalence (BD): 0.26%/63.5% receiving one or more psychotropic drug (among these, 60.2% were receiving two or more drugs) BD-I – psychotropic drugs use: 33.4% SGA; 28.8% anticonvulsants; 25% antidepressants; 7.4% lithium BD – AP use: aripiprazole (32.8%), quetiapine (28.5%), risperidone (25.9%), ziprasidone (8.1%), and olanzapine (4.6%)
Lage and Hassan^Citation27	Extracted data for individuals with bipolar disorder from the PharMetrics database*** [2000–2006]	n=7,769 BD patients	SGAs prescribed: quetiapine (45.7%), olanzapine (33.9%), risperidone (28.2%), aripiprazole (18.3%), ziprasidone (7.2%), fluoxetine/olanzapine (4.3%), and clozapine (0.08%) Mean days prescribed for any SGA: 175.08 days (12-month study period)
Lang et al^Citation28	Retrospective cohort analysis of Medicaid patients [2004–2006]	n=9,410 patients aged ≥18 years, had medical claims indicating BD-I, and filled one or more prescription for antipsychotic medication	Drug usage: 81.2% only oral SGA; 9.6% oral FGA and SGA; 2.4% received oral FGA only; 2.3% LAI SGA; 4.4% LAI FGA Overall concomitant drug usage: 68.6% with anticonvulsants or mood stabilizers; 76.4% concomitant antidepressants
Hooshmand et al^Citation39	BD outpatients referred to the Stanford University Bipolar Disorder Clinic [2000–2011]	n=597 patients were included (40.7% with BD-I)	BD-I: medication usage (2000–2005 vs 2006–2011): lamotrigine (17% vs 30.6%), valproate (37.4% vs 22.2%), quetiapine (10% vs 22.2%), aripiprazole (3.5% vs 20.8%), olanzapine (24.6% vs 11.1%), and risperidone (14% vs 6.9%). No data presented for lithium BD: lithium (27.6% vs 22.7%)
Seabury et al^Citation31	Claim-level data on inpatient, outpatient, long-term care, and pharmacy claims from the Medicaid Analytic eXtract (MAX) files [2001–2008]	n=170,596 BD patients from 24 states, newly prescribed an SGA, aged 18–64 years	Index SGA used: quetiapine (40%), risperidone (30%), aripiprazole (11%), olanzapine (10%), and ziprasidone (8%)
Patterns of treatment: outcomes: clinical practice guidelines adherence–concordance
Burns et al^Citation18	Medicaid and Medicare administrative data, nationally representative cohort [2004–2007]	n=1,431 adults, dual beneficiaries, with diagnosed BD-I	Measures of pharmacotherapy quality derived from clinical practice guidelines (two VA guidelines) and FDA indications Average percentage of beneficiaries with recommended antimanic medication available each month=72%; mean percentage receiving antidepressant monotherapy (a contraindicated strategy) for ≥7 days=17%
Busch et al^Citation19	Retrospective private insurance administrative data	Patients with BD-I aged 18–64: n=431 from 1991, n=598 from 1994, and n=600 from 1999	Medication and psychotherapy quality indicators based on APA guidelines published in 1994 Percentage of patients receiving one or more prescription for lithium, valproic acid, or carbamazepine: 68% (1991), 64% (1994), and 77% (1999), corresponding to an increase after guideline publication The prevalence of receiving any psychotherapy declined from 94% (1991) to 89% (1994) and 69% (1999)
Dennehy et al^Citation37	STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) patients observed over 2 years as part of the standard-of-care pathway prospective study [1999–2002]	n=964 patients (68.7% with BD-I) who experienced a new major depressive, manic, hypomanic, or mixed episode	Guideline concordance defined as concordance with choice of medication, and concordance with medication and dosage range according to APA, VA, and expert consensus guidelines, and Texas Implementation of Medication Algorithms guidelines Overall concordance with guidelines: depressive episodes (83.4% concordant by medication type and dose); hypomanic/manic episodes (81.9% concordant by medication type and dose); mixed episodes (81.8% concordant by medication type and dose)
Dusetzina et al^Citation23	Retrospective, repeated cross-sectional study based on MarketScan [2005–2007]	Children (n=412; aged 6–17 years) with BD-I	Guideline-recommended therapy: only 20% of the children. Among children receiving care from a psychiatrist (51% of the children), this percentage rises to 68%
Freeland et al^Citation38	Retrospective chart review of patients discharged from a 100-bed inpatient psychiatric hospital in South Carolina [2007–2010]	n=294 patients with BD depression	58% were prescribed evidence-based medications (one of the following: quetiapine, lithium, and olanzapine–fluoxetine combination) upon discharge
Huang et al^Citation26	Humana Medicare advantage beneficiaries [2008–2010]	n=2,338 beneficiaries with BD diagnosis	The rate of guideline-concordant bipolar care (defined as receipt of a mood stabilizer and/or antipsychotic) =48.1% (54% for those aged <65 years and 40% for those aged ≥65 years)
Merikangas et al^Citation36/NCS-R	National USA population-based cross-sectional survey (National Comorbidity Survey Replication) [2001–2003]. BD-I diagnosis according to DSM-IV. Diagnostic screening used CIDI	n=9,282 respondents aged ≥18 years	Patients with BD-I: appropriate medication (in patients receiving 12-month treatment) was reported by 41.6% of patients with BD-I treated by psychiatrists Mood stabilizers, anticonvulsants, and antipsychotics were classified as appropriate medications, while antidepressants and other psychotropic medications in the absence of antimanic agents were classified as inappropriate

Notes:

* VA National Psychosis Registry – consists of records for all patients who received a diagnosis of psychosis during inpatient stays and outpatient visits and received VA Services.

** OptumInsight commercial data set – represents a geographically diverse, national health plan, including >20 million members.

*** PharMetrics database – contains information on 55 million commercially insured individuals.

Abbreviations: AP, antipsychotic; APA, American Psychological Association; AUDADIS-5, Alcohol and Use Disorder and Associated Disabilities Interview Schedule-5; BD, bipolar disorder; BD-I, BD type I; CIDI, Composite International Diagnostic Interview; DSM, Diagnostic and Statistical Manual of Mental Disorders; FDA, US Food and Drug Administration; FGA, first-generation antipsychotic; IMS, Intercontinental Marketing Services; LAI, long-acting injectable; MPR, medication possession rate; MS, mood stabilizer; SGA, second-generation antipsychotic; VA, Veterans Affairs.

Table 3 Studies included regarding adherence and persistence

Study	Source of data [period]	Population	Results
Adherence and persistence outcome: adherence and persistence
Baldessarini et al^Citation14	Proprietary research database containing eligibility information and pharmacy and medical claims data from a large commercial USA health plan (concentration in the South and Midwest) [2000–2004]	n=7,406 BD patients aged ≥17 years (55.4% BD-I)	2,197 patients with MS monotherapy prescription: only 28% considered adherent (MPR – percentage of the past 365 days with apparent access to an initial mood stabilizer – ≥80%) Factors independently associated with MS adherence: older age, lack of substance abuse, treatment by a psychiatrist (vs primary care physician), and lower illness complexity
Bates et al^Citation34	Data collected via a self-report, web-based survey from USA patients aged 18–65 years who reported a diagnosis of BD and current use of psychotropic medication [2008]	1,052 patients with high risk of BD according to the CIDI-BD score ≥7	Nonadherent: 49.5% of patients Adherencea positively associated with college degree, higher satisfaction with antipsychotic medication scale score, and monotherapy treatment. Adherence negatively associated with alcohol use, higher burden of symptoms (24-item Behavior and Symptom Identification Scale), and higher side effect burden (Liverpool University Neuroleptic Side-effect Rating Scale)
Berger et al^Citation17	Truven MarketScan^® Commercial Claims and Encounters Database (a health insurance claims database) and the Truven MarketScan Hospital Drug Database (admission-level database) [2001–2008]	n=84 BD patients receiving SGAs (aripiprazole, quetiapine, or ziprasidone) at hospital discharge	During the 6-month period of follow-up, mean MPR=37.3%, suggesting a poor adherence in BD patients discharged on SGA
Burns et al^Citation18	Analysis of Medicaid and Medicare administrative data, nationally representative cohort [2004–2007]	n=1,431 adults, dual beneficiaries, with diagnosed BD-I	Average percentage of beneficiaries with MPRb ≥80%=62%
Chen et al^Citation20	Three MarketScan research databases: Commercial Claims and Encounters Database (“commercial”), Medicare supplemental and coordination of benefits database (“Medicare”), and multistate Medicaid database [2002–2008]	n=16,807 patients (34.7% from commercial/Medicare and 65.3% from Medicaid database) aged ≥18 years with BD-I who newly initiated an oral SGA	Adherence generally poor (8.3%; mean MPR=0.19) Mean MPR and adherence by SGA: quetiapine (0.23/10.4%), aripiprazole (0.18/5.9%), risperidone (0.17/6.8%), and olanzapine (0.16/6.8%) Average time to first noncompliance (gap between refills between 15 and 30 days): aripiprazole (102 days), quetiapine (90 days), olanzapine (87 days), and risperidone (84 days)
Hassan et al^Citation25	Claims data from a Medicaid database [1999–2001]	n=620 BD patients receiving SGA; n=205 receiving FGA	Mean MPR: quetiapine (71%), risperidone (68%), olanzapine (68%), and FGA (46%) Mean persistence (days treatment until discontinuation or switching for another medication): quetiapine (219.8), olanzapine (200.9), risperidone (194.8), and FGA (179.2)
Lage and Hassan^Citation27	Extracted data from the PharMetrics database* [2000–2006]	n=7,769 BD patients	Mean MPR for antipsychotics: 41.7% (MPR ≥80% was present in only 15.82% of the patients) Mean days prescribed for any SGA: 175.08 days (12-month study period)
Lang et al^Citation28	Retrospective cohort analysis of Medicaid patients [2004–2006, 1-year follow-up]	n=9,410 patients with BD-I aged ≥18 years, and filled one or more prescription for antipsychotic medication	MPR ≥80% (mean MPRb): 38.9% (63%) oral SGA monotherapy; 46.3% (66%) oral FGA and SGA; 42.7% (57%) oral FGA monotherapy; 52.9% (74%) LAI SGA; 51.6% (70%) LAI FGA; overall rate of 40.6% (63%) Mean persistencec in patients: 0.84 oral SGA monotherapy; 0.90 oral FGA and SGA; 0.79 oral FGA monotherapy; 0.94 LAI SGA; 0.93 LAI FGA; overall mean persistence of 0.85 Factors significantly related to nonadherence (MPR <80%, adjusted analysis): new starts (vs continuing users), age <45 (vs ≥45 years), baseline substance abuse diagnosis, and baseline psychiatric hospitalization Factors significantly related to adherence (adjusted analysis): baseline MS use, baseline other psychosis diagnosis, baseline anticonvulsant use, baseline anticholinergic use, and LAI SGA (vs oral FGA)
Perlis et al^Citation40 Outcome: poor adherence	Prospective data from two cohorts of individuals from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study [1999–2005]	n=3,640 BD patients	Poor adherence (≥25% of milligrams for each medication missed in the past week) reported on 12.8% of visits (average). Nonadherence on ≥20% visits: 23.9% patients; adherence at all visits: 46.4% patients Poor adherence – significantly associated clinical features: alcohol use disorder (OR=1.35), anxiety disorder (OR=1.33), rapid cycling in the lifetime (OR=1.23), and earlier onset of illness (OR=0.8 for each 10-year increase)
Rascati et al^Citation29	Retrospective analysis of claims data for Medicaid patients from eight states (claims extracted from the Texas Medicaid Vendor Drug, Texas Medicaid Medical Services, and MarketScan databases) [2002–2008]	n=2,446 BD patients	Patients with clinically recommended doses: 58% considered adherent (MPRb). Adherence rates per drug: ziprasidone (62%), aripiprazole (60%), olanzapine (58%), quetiapine (55%), and risperidone (58%) Median time to non-persistenced: 96 days (117 days for ziprasidone; 93 days for aripiprazole; 72 days for olanzapine; 112 days for quetiapine; and 95 days for risperidone) 12-month persistence rates (whole cohort)=18% (no relevant differences among different antipsychotics). Gap between refills >30 days
Sajatovic et al^Citation41	VA National Psychosis Registry;** VA pharmacy benefits management strategic health care group [2003]	73,964 BD patients	Mean MPR for individuals receiving SGAs: 75% (84% clozapine, 75% risperidone, 75% olanzapine, 77% quetiapine, 77% ziprasidone, and 79% aripiprazole) Persistence – median SGA treatment duration=240 days Factors associated with nonadherence: younger age, minority ethnicity, comorbid substance abuse, and homelessness
Sajatovic et al^Citation30	VA National Psychosis Registry;** VA pharmacy benefits management strategic health care group [2003]	44,637 BD patients receiving lithium and anticonvulsants	Mean MPR for individuals receiving lithium or anticonvulsants: 77% (79% lithium, 80% carbamazepine, 76% valproate, and 81% lamotrigine) Persistence – median MS treatment duration=270 days
Adherence and persistence outcome: other outcomes
Baldessarini et al^Citation15 Outcome: time to discontinuation of index drug; time to augmentation	USA national MarketScan research database was used to quantify utilization rates for psychotropic drug classes in patients with ICD-9 BD [2002–2003]	n=7,760 BD patients (69.2% with BD-I)	Median time to discontinuation of the initial drug (weeks): lithium (58.3), divalproex (36.1), and SGAs (29.1) Median time to augmentation (adding one or more drugs, weeks): lithium (39.1), divalproex (14.9), and SGAs (10.6)
Adherence and persistence outcome: factors related to medication adherence and nonadherence
Baldessarini et al^Citation33	Survey including 131 randomly selected prescribing psychiatrists and their adult BD patients in five geographic regions in the USA [2005]	n=429 (32.5%) BD patients (79% BD-I)	Prominent AE associated with treatment nonadherence (n=145): weight gain (58.5%), excessive sedation (54.2%), and physical awkwardness or tremor (33.1%) Multivariate models identified nine factors independently, ranked by significance: alcohol dependence (OR=4.89); younger age (OR=1.03), greater number of affective symptoms (OR=1.1), not being in full remission (OR=4.12), side effect as a major source of patient frustration (OR=1.9); cognitive impairment (OR=2.59), “anticholinergic side effects” (OR=3.84), comorbid obsessive–compulsive disorder (OR=7.24), and recent mania or hypomania (OR=2.77)
Sajatovic et al^Citation41	VA National Psychosis Registry**; VA pharmacy benefits management strategic health care group [2003]	73,964 BD patients	Factors associated with nonadherence: younger age, minority ethnicity, comorbid substance abuse and homelessness.

Notes:

a Medication adherence – assessed via the Morisky Medication Adherence Scale, with scores ≥2 considered nonadherent.

b MPR – defined as ratio between number of days’ supply for all index medication fills during the study period and the number of days between index and end date of the last index medication dispensed during the study period.

c Persistence – defined as the number of days between the first and last day receiving an antipsychotic divided by the number of days remaining in the period after the first antipsychotic was dispensed.

d Non-persistence – defined as duration of therapy from initiation of the index medication until discontinuation.

* PharMetrics database – contains information on 55 million commercially insured individuals.

** VA National Psychosis Registry – consists of records for all patients who received a diagnosis of psychosis during inpatient stays and outpatient visits and received VA Services.

Abbreviations: AE, adverse effect; BD, bipolar disorder; BD-I, BD type I; CIDI, Composite International Diagnostic Interview; FGA, first-generation antipsychotic; ICD-9, International Classification of Diseases, Ninth Revision; LAI, long-acting injectable; MPR, medication possession rate; MS, mood stabilizer; OR, odds ratio; SGA, second-generation antipsychotic; VA, Veterans Affairs.

Table 4 Main results of the SLR

Topic	Specific topic	Main results
Treatment prevalence	12-month treatment rate	• 46%^Citation35 and 67.3% in patients with BD-I^Citation36
		• 44.6%^Citation41 and 50.7%^Citation36 in BD as a whole (BD-I, BD-II, or subthreshold BD)
	Lifetime treatment prevalence	• 72.4% of patients^Citation35
Patterns of pharmacological treatment	Polypharmacy rates	• 88.7%^Citation16 to 96.2%^Citation20 start as monotherapy
		• Up to 70% receive polytherapy after 1 year^Citation14,Citation15
		• Overall, polytherapy in 68.6% of patients^Citation28
	Most common medications	• Between patients receiving antipsychotics, 93.1%–100% receive SGAs^Citation14,Citation22,Citation28,Citation32,Citation39,Citation41
		• SGA and MS as preferred first-line therapy^Citation16
		• Quetiapine has been the most commonly used SGA in nearly all studies – between 35 and 45% of patients receiving atypical antipsychotics^Citation14,Citation21,Citation27,Citation31
		• Other common drugs: olanzapine and aripiprazole^Citation14,Citation21,Citation27,Citation39
	Concordance with clinical practice guidelines	• Appropriate in 41.572% of patients^Citation18,Citation26,Citation36
Adherence to pharmacological therapy	Measured by number of missed doses in previous days/adherence scales	• 45%–50% of patients considered adherent^Citation34,Citation40
	Ratio between the days of medication supply and the total period of observation within the study	• Rates of MPR ≥80%: 8.3%–54.1% (median of 28%)^Citation30,Citation41
		• Mean MPR: 19%–77% (median of 47.1%)^Citation30,Citation41
	Ratio between the days of medication supply and the period between the first and the last day of medication supply	• MPR ≥80%: in 58%–62% of patients^Citation18,Citation29
		• Mean MPR of 68%–71% for different SGAs^Citation25

Abbreviations: BD, bipolar disorder; BD-I, BD type I; BD-II, BD type II; MS, mood stabilizer; MPR, medication possession ratio; SGA, second-generation antipsychotic; SLR, systematic literature review.

Table 5 Factors associated with nonadherence to pharmacological treatment in BD*^/**/BD-I^¶

Study/BD population*	Factors studied
	Younger age	Minority ethnicity	Comorbid psychiatric condition	Gender	Marital status	Specific therapy (specific oral SGA or specific MS)	Medication adverse events	Higher illness complexity	Education (lower level)	Polytherapy
Antipsychotics
Sajatovic et al^Citation41/BD*	(+)	(+)	(+) for SUD	(−)	(−)	(−)	NR	NR	NR	NR
Hassan et al^Citation25/BD*	NR	NR	NR	NR	NR	(−)	NR	NR	NR	NR
Baldessarini et al^Citation33/BD**	(+)	NR	(+) for SUD (+) for OCD	NR	NR	NR	(+)	NR	NR	NR
Bates et al^Citation34/BD*	NR	NR	(+) for SUD	NR	NR	NR	(+)	(+)	(+)	(+)
Perlis et al^Citation40/BD**	(+)	(+)	(+) for SUD (+) for anxiety	(−)	(+) for not married	NR	(−)	NR	(−)	(+)
Lang et al^Citation28/BD-I^¶	(+)	NR	(+) for SUD	NR	NR	NR	NR	NR	NR	NR
Rascati et al^Citation29/BD*	(+)	(+)	(+) SUD (−) for anxiety	(−)	NR	(−)	NR	NR	NR	(−)
Chen et al^Citation20/BD-I^¶	NR	NR	NR	NR	NR	(−)	NR	NR	NR	NR
Mood stabilizers
Sajatovic et al^Citation30/BD*	(+)	(+)	(+)	(−)	(+) for not married	NR	NR	NR	NR	NR
Baldessarini et al^Citation14/BD**	(+)	NR	(−)	NR	NR	NR	NR	(+)	NR	NR

Notes: (+): factor associated with higher nonadherence; (−): factor not associated with adherence; NR: not reported (factor not studied in that publication).

* BD: bipolar disorder as a whole (includes BD-I but no data separately reported for this population); ^¶BD-I: data reported specifically for BD-I;

** BD: bipolar disorder as a whole, but study population predominantly composed of BD-I patients.

Abbreviations: BD, bipolar disorder; BD-I, BD type I; MS, mood stabilizer; NR, not reported; OCD, obsessive–compulsive disorder; SGA, second-generation antipsychotic; SUD, substance use disorder.

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