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Promoting treatment adherence in patients with bipolar disorder
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Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,1 which adds to the burden of illness and worsens prognosis.
Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.
This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.
What is adherence?
As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.
Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.2 Research on adherence in BD can be difficult to interpret because results may be influenced by:
- selection bias (patients who are adherent and insightful are more likely to consent to research)
- complications caused by polypharmacy and comorbidity
- investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
- patients’ compliance with the adherence-enhancing interventions.2
Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).3-7
Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.2
Table 1
Tools for measuring adherence to medications
| Components/characteristics | Advantages | Disadvantages |
|---|---|---|
| Rating of Medication Influences3 | ||
| 19 items. Subscales: Reasons for adherence (prevention, influence of others, medication affinity), reasons for nonadherence (denial, dysphoria, logistical problems, label rejection, family influence, negative therapeutic alliance) | Valid, reliable. Correlates with other scales (DAI) | Developed on a population including only patients with schizophrenia treated with antipsychotics. Requires a trained rater |
| Drug Attitude Inventory4 | ||
| 30 items. Reflects patients’ attitudes about medication | Self-rated. High internal consistency. Accurately discriminates between adherent and nonadherent patients | Developed on a population including only patients with schizophrenia |
| Lithium Attitudes Questionnaire5 | ||
| 19 items. Areas of assessment: opposition to continue lithium, therapeutic effectiveness of lithium not accepted, difficulty with pill-taking routine, denial of illness severity, subcultural attitudes opposed to drug treatment, dissatisfaction with factual knowledge of lithium | Self-rated. Developed on patients with BD attending a lithium clinic. Good test/retest reliability for most items | The questionnaire is fairly long; shorter versions were adapted from original version |
| Medication Adherence Rating Scale6 | ||
| 10 items that assess medication adherence behavior, attitudes toward taking medication, negative side effects, attitudes toward psychotropic medication, measures adherence in past week | Self-rated. Validated on patients with various diagnoses, including BD. Correlates well with DAI, MAQ, and mood stabilizer drug levels (lithium and carbamazepine) | Validation methods may be limited by the other measures (for example, medication levels can be influenced by metabolism) |
| Brief Adherence Rating Scale7 | ||
| 3 items. Number of pills prescribed daily, days with no medication taken, and days with medication taken less than prescribed. Nonadherence defined as <70% of doses taken. Measures adherence in past month | Clinician–rated. Short. Good correlation with electronic medication monitoring. High internal reliability. Good test/retest reliability. Greater adherence on BARS correlates with lower psychotic symptom scores. Sensitive and specific in identifying nonadherence | Validation study only on patients with schizophrenia and schizoaffective disorder taking antipsychotics |
| BARS: Brief Adherence Rating Scale; BD: bipolar disorder; DAI: Drug Attitude Inventory; MAQ: Medication Adherence Questionnaire | ||
BD adherence studies
Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.2 Scott and Pope8 evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.
In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.9 Jónsdóttir et al10 looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.
In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al11 defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.
Strakowski12 followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic13 found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini14 found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.
What affects adherence?
Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.1,15
Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.16,17
Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.16 Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.17 Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.17
Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.18
Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.17 Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.19
A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.20 A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.21 Rosa et al9 found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.
Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.15 Marriage has a beneficial affect on adherence.15 A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.22
Adherence and BD course
Treatment adherence decreases the suicide rate among BD patients. Angst et al23 evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.15
Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al24 showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.
Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).
As emerging studies document morphologic brain changes associated with bipolar disorder (BD), researchers have been relating these changes to the duration and progression of illness. A longer duration of illness is associated with a smaller total gray matter volume on brain MRI of BD patients compared with unipolar patients and normal controls.a Brain MRI analysis of grey and white matter in elderly patients with longstanding BD who underwent neuropsychological testing to rule out dementia showed a decreased concentration of grey matter in the anterior limbic areas as well as reduced fiber tract coherence in the corpus callosum when compared with normal controls.b
Additionally, microstructural brain changes have been associated with acute mood states, in particular bipolar depression.c Lithium, valproate, olanzapine, and clozapine are neuroprotective in cultures of human-derived neuroblastoma cells, by enhancing the cells’ proliferation and survival.d
Source:
a. Frey BN, Zunta-Soares GB, Caetano SC, et al. Illness duration and total brain gray matter in bipolar disorder: evidence for neurodegeneration? European Neuropsychopharm. 2008;18:717-722.
b. Haller S, Xekardaki A, Delaloye C, et al. Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder. J Psychiatry Neurosci. 2011;36(1):100140.
c. Zanetti MV, Jackowski MP, Versace A, et al. State-dependent microstructural white matter changes in bipolar I depression. Eur Arch Psychiatry Clin Neurosci. 2009;259(6):316-328.
d. Aubry J, Schwald M, Ballmann E, et al. Early effects of mood stabilizers on the Akt/GSK-3ß signaling pathway and on cell survival and proliferation. Psychopharmacology. 2009;205:419-429.
Increasing adherence
Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,25 most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.25 Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.
Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.26 Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.27 Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.15
Although antidepressant use in BD is controversial, Sajatovic17 found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.1
Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.28 In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al31 found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.
Miklowitz32 reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.
In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.33 Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis30 of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.
Table 2
FDA-approved medications for adult bipolar disorder
| Bipolar disorder indication | Medications |
|---|---|
| Acute treatment of mania/mixed episodes | Aripiprazole,a,b asenapine,a carbamazepine extended release,a divalproex sodium,a lithium,a quetiapine,a risperidone,a-c ziprasidonea,b |
| Depressive episodes | Olanzapine/fluoxetine,a quetiapinea |
| Maintenance treatment | Aripiprazole (as monotherapy and as adjunct to lithium or divalproex sodium),a,b asenapine,d lamotrigine,a lithium,a olanzapine,a-c quetiapine (as adjunct to lithium or divalproex sodium),a risperidone,e ziprasidone (as adjunct to lithium or divalproex sodium)a |
| apill form bintramuscular for acute agitation cdisintegrating tablet dsublingual tablet elong-acting injectable | |
Table 3
Psychosocial interventions for bipolar disorder
| Intervention | Description | Results in bipolar disorder | Optimal stage of illness for intervention |
|---|---|---|---|
| Individual and family psycho-education28,29 | Strategies to educate the patient about the illness, medications, side effects, and relapse prevention | Decreases relapse, (particularly manic episodes) and hospitalizations. Increases adherence | Manic episodes |
| Cognitive-behavioral therapy28-30 | Focuses on understanding patient’s perceptions of illness and treatment. Equates resistance with exploring, rather than challenging resistance to take medication. Identifies and modifies negative automatic thoughts about medication. Motivation techniques useful in comorbid substance use | Decreases clinical symptoms. Increases adherence, quality of life, and social functioning | Depressive episodes |
| IPSRT28,29 | Uses motivational interviewing and CBT techniques to stabilize daily routines and resolve interpersonal problems | Prevents relapse | Depressive episodes |
| Family-focused therapy28,29 | A combination of psychoeducation, communication, and problem-solving skills training | Reduces mood symptoms, number of depressive relapses, and time depressed. Increases adherence | Depressive episodes |
| IPSRT: interpersonal and social rhythm therapy | |||
Related Resource
- Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.
Drug Brand Names
- Aripiprazole • Abilify
- Asenapine • Saphris
- Bupropion • Wellbutrin
- Carbamazepine • Carbatrol, Tegretol
- Carbamazepine extended- release • Equetro
- Clozapine • Clozaril
- Divalproex • Depakote, Depakote ER
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Lamotrigine • Lamictal
- Lithium • Eskalith, Lithobid
- Mirtazapine • Remeron
- Olanzapine • Zyprexa
- Olanzapine/fluoxetine • Symbyax
- Paroxetine • Paxil
- Quetiapine • Seroquel, Seroquel XR
- Risperidone • Risperdal
- Risperidone long-acting injectable • Risperdal Consta
- Selegiline • Eldepryl, Emsam
- Valproate • Depacon
- Venlafaxine • Effexor
- Ziprasidone • Geodon
Disclosures
Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.
Dr. Sheehan and Ms. Johns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Buckley PF, Foster AE, Patel NC, et al. Adherence to mental health treatment. New York, NY: Oxford University Press; 2009;1-10:53-69.
2. Velligan D, Sajatovic M, Valenstein M, et al. Methodological challenges in psychiatric treatment adherence research. Clin Schizophr Relat Psychoses. 2010;4(1):74-91.
3. Weiden P, Rapkin B, Mott T, et al. Rating of Medication Influences (ROMI) scale in schizophrenia. Schizophr Bull. 1994;20:297-310.
4. Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med. 1983;13(1):177-183.
5. Harvey NS. The development and descriptive use of the Lithium Attitudes Questionnaire. J Affect Disord. 1991;22(4):211-219.
6. Thompson K, Kulkarni J, Sergejew AA. Reliability and validity of a new Medication Adherence Rating Scale (MARS). Schizophr Res. 2000;42:241-247.
7. Byerly MJ, Nazonezny PA, Rush AJ. The Brief Adherence Rating Scale (BARS) validated against electronic monitoring in assessing the antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. Schizophr Res. 2008;100(1-3):60-69.
8. Scott J, Pope M. Non-adherence with mood stabilizers: prevalence and predictors. J Clin Psychiatry. 2002;63:384-390.
9. Rosa AR, Marco M, Fachel JM, et al. Correlation between drug treatment adherence and lithium treatment attitudes and knowledge in bipolar patients. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:217-224.
10. Jónsdóttir H, Opjordsmoen S, Birkenaes A, et al. Medication adherence in outpatients with severe mental disorders, relation between self-reports and serum level. J Clin Psychopharmacol. 2010;30:169-175.
11. DelBello M, Hanserman D, Adler CM, et al. Twelve-month outcome of adolescents with bipolar disorder following first hospitalization for a manic or mixed episode. Am J Psychiatry. 2007;164:582-590.
12. Strakowski SM, Tsai SY, DelBello MP, et al. Outcome following a first manic episode: cross national US and Taiwan comparison. Bipolar Disord. 2007;9:820-827.
13. Sajatovic M, Valenstein M, Blow F, et al. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. Psychiatr Serv. 2007;58:855-863.
14. Baldessarini RJ, Perry R, Pike J. Factors associated with treatment nonadherence among US bipolar patients. Hum Psychopharmacol. 2008;23:95-105.
15. Berk L, Hallam KT, Colom F, et al. Enhancing medication adherence in patients with bipolar disorder. Hum Psychopharmacol. 2010;25(1):1-16.
16. Johnson FR, Ozdemir S, Manjunath R, et al. Factors that affect adherence to bipolar disorder treatments: a stated-preference approach. Med Care. 2007;45(6):545-552.
17. Sajatovic M, Jenkins JH, Cassidy KA, et al. Medication treatment perceptions, concerns and expectations among depressed individuals with type I bipolar disorder. J Affect Disord. 2009;115(3):360-366.
18. Depp CA, Cain AE, Palmer BW, et al. Assessment of medication management ability in middle-aged and older adults with bipolar disorder. J Clin Psychopharmacol. 2008;28(2):225-229.
19. Gaudiano BA, Miller IW. Patients’ expectancies the alliance in pharmacotherapy, and treatment outcomes in bipolar disorder. J Consult Clin Psychol. 2006;74(4):671-676.
20. Copeland LA, Zeber JE, Salloum IM, et al. Treatment adherence and illness insight in veterans with bipolar disorder. J Nerv Ment Dis. 2008;196(1):16-21.
21. Yen CF, Chen CS, Ko CH, et al. Relationships between insight and medication adherence in outpatients with schizophrenia and bipolar disorder: prospective study. Psychiatry Clin Neurosci. 2005;59(4):403-409.
22. Drotar D, Greenley RN, Demeter CA, et al. Adherence to pharmacological treatment for juvenile bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):831-839.
23. Angst J, Angst F, Gerber-Werder R, et al. Suicide in 406 mood-disorder patients with and without long–term medication: a 40 to 44 years’ follow-up. Arch Suicide Res. 2005;9:279-300.
24. Lopez-Jaramillo C, Lopera-Vasquez J, Aurora G, et al. Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence. Bipolar Disord. 2010;12:557-567.
25. Minirth FB, Neal V. Assessment of patient preference and side effects in patients switched from divalproex sodium delayed release to divalproex sodium extended release. J Clin Psychopharmacol. 2005;25:99-101.
26. Han C, Lee MS, Pae CU, et al. Usefulness of long-acting injectable risperidone during 12-month maintenance therapy of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1219-1223.
27. McIntyre RS, Cohen M, Zhao J, et al. Asenapine for long term treatment of bipolar disorder: a double blind 40-week extension study. J Affect Disord. 2010;126:358-365.
28. Velligan DI, Weiden PJ, Sajatovic M, et al. Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from expert consensus guidelines. J Psychiatr Pract. 2010;16(5):306-324.
29. Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am J Psychiatry. 2008;165(11):1408-1419.
30. Szentagotai A, David D. The efficacy of cognitive-behavioral therapy in bipolar disorder: a quantitative meta-analysis. J Clin Psychiatry. 2010;71(1):66-72.
31. Even C, Thuile J, Stern K, et al. Psychoeducation for patients with bipolar disorder receiving lithium: short and long term impact on locus of control and knowledge about lithium. J Affect Disord. 2010;123:299-302.
32. Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: A 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry. 2007;64:419-426.
33. Bauer MS, McBride L, Williford WO, et al. Collaborative care for bipolar disorder, part II. Impact on clinical outcome, function and costs. Psychiatr Serv. 2006;57:937-945.
Discuss this article at www.facebook.com/CurrentPsychiatry
Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,1 which adds to the burden of illness and worsens prognosis.
Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.
This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.
What is adherence?
As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.
Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.2 Research on adherence in BD can be difficult to interpret because results may be influenced by:
- selection bias (patients who are adherent and insightful are more likely to consent to research)
- complications caused by polypharmacy and comorbidity
- investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
- patients’ compliance with the adherence-enhancing interventions.2
Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).3-7
Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.2
Table 1
Tools for measuring adherence to medications
| Components/characteristics | Advantages | Disadvantages |
|---|---|---|
| Rating of Medication Influences3 | ||
| 19 items. Subscales: Reasons for adherence (prevention, influence of others, medication affinity), reasons for nonadherence (denial, dysphoria, logistical problems, label rejection, family influence, negative therapeutic alliance) | Valid, reliable. Correlates with other scales (DAI) | Developed on a population including only patients with schizophrenia treated with antipsychotics. Requires a trained rater |
| Drug Attitude Inventory4 | ||
| 30 items. Reflects patients’ attitudes about medication | Self-rated. High internal consistency. Accurately discriminates between adherent and nonadherent patients | Developed on a population including only patients with schizophrenia |
| Lithium Attitudes Questionnaire5 | ||
| 19 items. Areas of assessment: opposition to continue lithium, therapeutic effectiveness of lithium not accepted, difficulty with pill-taking routine, denial of illness severity, subcultural attitudes opposed to drug treatment, dissatisfaction with factual knowledge of lithium | Self-rated. Developed on patients with BD attending a lithium clinic. Good test/retest reliability for most items | The questionnaire is fairly long; shorter versions were adapted from original version |
| Medication Adherence Rating Scale6 | ||
| 10 items that assess medication adherence behavior, attitudes toward taking medication, negative side effects, attitudes toward psychotropic medication, measures adherence in past week | Self-rated. Validated on patients with various diagnoses, including BD. Correlates well with DAI, MAQ, and mood stabilizer drug levels (lithium and carbamazepine) | Validation methods may be limited by the other measures (for example, medication levels can be influenced by metabolism) |
| Brief Adherence Rating Scale7 | ||
| 3 items. Number of pills prescribed daily, days with no medication taken, and days with medication taken less than prescribed. Nonadherence defined as <70% of doses taken. Measures adherence in past month | Clinician–rated. Short. Good correlation with electronic medication monitoring. High internal reliability. Good test/retest reliability. Greater adherence on BARS correlates with lower psychotic symptom scores. Sensitive and specific in identifying nonadherence | Validation study only on patients with schizophrenia and schizoaffective disorder taking antipsychotics |
| BARS: Brief Adherence Rating Scale; BD: bipolar disorder; DAI: Drug Attitude Inventory; MAQ: Medication Adherence Questionnaire | ||
BD adherence studies
Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.2 Scott and Pope8 evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.
In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.9 Jónsdóttir et al10 looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.
In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al11 defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.
Strakowski12 followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic13 found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini14 found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.
What affects adherence?
Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.1,15
Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.16,17
Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.16 Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.17 Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.17
Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.18
Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.17 Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.19
A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.20 A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.21 Rosa et al9 found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.
Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.15 Marriage has a beneficial affect on adherence.15 A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.22
Adherence and BD course
Treatment adherence decreases the suicide rate among BD patients. Angst et al23 evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.15
Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al24 showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.
Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).
As emerging studies document morphologic brain changes associated with bipolar disorder (BD), researchers have been relating these changes to the duration and progression of illness. A longer duration of illness is associated with a smaller total gray matter volume on brain MRI of BD patients compared with unipolar patients and normal controls.a Brain MRI analysis of grey and white matter in elderly patients with longstanding BD who underwent neuropsychological testing to rule out dementia showed a decreased concentration of grey matter in the anterior limbic areas as well as reduced fiber tract coherence in the corpus callosum when compared with normal controls.b
Additionally, microstructural brain changes have been associated with acute mood states, in particular bipolar depression.c Lithium, valproate, olanzapine, and clozapine are neuroprotective in cultures of human-derived neuroblastoma cells, by enhancing the cells’ proliferation and survival.d
Source:
a. Frey BN, Zunta-Soares GB, Caetano SC, et al. Illness duration and total brain gray matter in bipolar disorder: evidence for neurodegeneration? European Neuropsychopharm. 2008;18:717-722.
b. Haller S, Xekardaki A, Delaloye C, et al. Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder. J Psychiatry Neurosci. 2011;36(1):100140.
c. Zanetti MV, Jackowski MP, Versace A, et al. State-dependent microstructural white matter changes in bipolar I depression. Eur Arch Psychiatry Clin Neurosci. 2009;259(6):316-328.
d. Aubry J, Schwald M, Ballmann E, et al. Early effects of mood stabilizers on the Akt/GSK-3ß signaling pathway and on cell survival and proliferation. Psychopharmacology. 2009;205:419-429.
Increasing adherence
Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,25 most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.25 Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.
Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.26 Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.27 Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.15
Although antidepressant use in BD is controversial, Sajatovic17 found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.1
Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.28 In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al31 found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.
Miklowitz32 reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.
In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.33 Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis30 of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.
Table 2
FDA-approved medications for adult bipolar disorder
| Bipolar disorder indication | Medications |
|---|---|
| Acute treatment of mania/mixed episodes | Aripiprazole,a,b asenapine,a carbamazepine extended release,a divalproex sodium,a lithium,a quetiapine,a risperidone,a-c ziprasidonea,b |
| Depressive episodes | Olanzapine/fluoxetine,a quetiapinea |
| Maintenance treatment | Aripiprazole (as monotherapy and as adjunct to lithium or divalproex sodium),a,b asenapine,d lamotrigine,a lithium,a olanzapine,a-c quetiapine (as adjunct to lithium or divalproex sodium),a risperidone,e ziprasidone (as adjunct to lithium or divalproex sodium)a |
| apill form bintramuscular for acute agitation cdisintegrating tablet dsublingual tablet elong-acting injectable | |
Table 3
Psychosocial interventions for bipolar disorder
| Intervention | Description | Results in bipolar disorder | Optimal stage of illness for intervention |
|---|---|---|---|
| Individual and family psycho-education28,29 | Strategies to educate the patient about the illness, medications, side effects, and relapse prevention | Decreases relapse, (particularly manic episodes) and hospitalizations. Increases adherence | Manic episodes |
| Cognitive-behavioral therapy28-30 | Focuses on understanding patient’s perceptions of illness and treatment. Equates resistance with exploring, rather than challenging resistance to take medication. Identifies and modifies negative automatic thoughts about medication. Motivation techniques useful in comorbid substance use | Decreases clinical symptoms. Increases adherence, quality of life, and social functioning | Depressive episodes |
| IPSRT28,29 | Uses motivational interviewing and CBT techniques to stabilize daily routines and resolve interpersonal problems | Prevents relapse | Depressive episodes |
| Family-focused therapy28,29 | A combination of psychoeducation, communication, and problem-solving skills training | Reduces mood symptoms, number of depressive relapses, and time depressed. Increases adherence | Depressive episodes |
| IPSRT: interpersonal and social rhythm therapy | |||
Related Resource
- Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.
Drug Brand Names
- Aripiprazole • Abilify
- Asenapine • Saphris
- Bupropion • Wellbutrin
- Carbamazepine • Carbatrol, Tegretol
- Carbamazepine extended- release • Equetro
- Clozapine • Clozaril
- Divalproex • Depakote, Depakote ER
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Lamotrigine • Lamictal
- Lithium • Eskalith, Lithobid
- Mirtazapine • Remeron
- Olanzapine • Zyprexa
- Olanzapine/fluoxetine • Symbyax
- Paroxetine • Paxil
- Quetiapine • Seroquel, Seroquel XR
- Risperidone • Risperdal
- Risperidone long-acting injectable • Risperdal Consta
- Selegiline • Eldepryl, Emsam
- Valproate • Depacon
- Venlafaxine • Effexor
- Ziprasidone • Geodon
Disclosures
Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.
Dr. Sheehan and Ms. Johns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
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Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,1 which adds to the burden of illness and worsens prognosis.
Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.
This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.
What is adherence?
As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.
Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.2 Research on adherence in BD can be difficult to interpret because results may be influenced by:
- selection bias (patients who are adherent and insightful are more likely to consent to research)
- complications caused by polypharmacy and comorbidity
- investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
- patients’ compliance with the adherence-enhancing interventions.2
Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).3-7
Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.2
Table 1
Tools for measuring adherence to medications
| Components/characteristics | Advantages | Disadvantages |
|---|---|---|
| Rating of Medication Influences3 | ||
| 19 items. Subscales: Reasons for adherence (prevention, influence of others, medication affinity), reasons for nonadherence (denial, dysphoria, logistical problems, label rejection, family influence, negative therapeutic alliance) | Valid, reliable. Correlates with other scales (DAI) | Developed on a population including only patients with schizophrenia treated with antipsychotics. Requires a trained rater |
| Drug Attitude Inventory4 | ||
| 30 items. Reflects patients’ attitudes about medication | Self-rated. High internal consistency. Accurately discriminates between adherent and nonadherent patients | Developed on a population including only patients with schizophrenia |
| Lithium Attitudes Questionnaire5 | ||
| 19 items. Areas of assessment: opposition to continue lithium, therapeutic effectiveness of lithium not accepted, difficulty with pill-taking routine, denial of illness severity, subcultural attitudes opposed to drug treatment, dissatisfaction with factual knowledge of lithium | Self-rated. Developed on patients with BD attending a lithium clinic. Good test/retest reliability for most items | The questionnaire is fairly long; shorter versions were adapted from original version |
| Medication Adherence Rating Scale6 | ||
| 10 items that assess medication adherence behavior, attitudes toward taking medication, negative side effects, attitudes toward psychotropic medication, measures adherence in past week | Self-rated. Validated on patients with various diagnoses, including BD. Correlates well with DAI, MAQ, and mood stabilizer drug levels (lithium and carbamazepine) | Validation methods may be limited by the other measures (for example, medication levels can be influenced by metabolism) |
| Brief Adherence Rating Scale7 | ||
| 3 items. Number of pills prescribed daily, days with no medication taken, and days with medication taken less than prescribed. Nonadherence defined as <70% of doses taken. Measures adherence in past month | Clinician–rated. Short. Good correlation with electronic medication monitoring. High internal reliability. Good test/retest reliability. Greater adherence on BARS correlates with lower psychotic symptom scores. Sensitive and specific in identifying nonadherence | Validation study only on patients with schizophrenia and schizoaffective disorder taking antipsychotics |
| BARS: Brief Adherence Rating Scale; BD: bipolar disorder; DAI: Drug Attitude Inventory; MAQ: Medication Adherence Questionnaire | ||
BD adherence studies
Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.2 Scott and Pope8 evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.
In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.9 Jónsdóttir et al10 looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.
In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al11 defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.
Strakowski12 followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic13 found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini14 found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.
What affects adherence?
Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.1,15
Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.16,17
Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.16 Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.17 Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.17
Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.18
Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.17 Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.19
A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.20 A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.21 Rosa et al9 found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.
Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.15 Marriage has a beneficial affect on adherence.15 A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.22
Adherence and BD course
Treatment adherence decreases the suicide rate among BD patients. Angst et al23 evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.15
Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al24 showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.
Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).
As emerging studies document morphologic brain changes associated with bipolar disorder (BD), researchers have been relating these changes to the duration and progression of illness. A longer duration of illness is associated with a smaller total gray matter volume on brain MRI of BD patients compared with unipolar patients and normal controls.a Brain MRI analysis of grey and white matter in elderly patients with longstanding BD who underwent neuropsychological testing to rule out dementia showed a decreased concentration of grey matter in the anterior limbic areas as well as reduced fiber tract coherence in the corpus callosum when compared with normal controls.b
Additionally, microstructural brain changes have been associated with acute mood states, in particular bipolar depression.c Lithium, valproate, olanzapine, and clozapine are neuroprotective in cultures of human-derived neuroblastoma cells, by enhancing the cells’ proliferation and survival.d
Source:
a. Frey BN, Zunta-Soares GB, Caetano SC, et al. Illness duration and total brain gray matter in bipolar disorder: evidence for neurodegeneration? European Neuropsychopharm. 2008;18:717-722.
b. Haller S, Xekardaki A, Delaloye C, et al. Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder. J Psychiatry Neurosci. 2011;36(1):100140.
c. Zanetti MV, Jackowski MP, Versace A, et al. State-dependent microstructural white matter changes in bipolar I depression. Eur Arch Psychiatry Clin Neurosci. 2009;259(6):316-328.
d. Aubry J, Schwald M, Ballmann E, et al. Early effects of mood stabilizers on the Akt/GSK-3ß signaling pathway and on cell survival and proliferation. Psychopharmacology. 2009;205:419-429.
Increasing adherence
Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,25 most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.25 Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.
Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.26 Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.27 Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.15
Although antidepressant use in BD is controversial, Sajatovic17 found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.1
Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.28 In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al31 found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.
Miklowitz32 reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.
In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.33 Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis30 of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.
Table 2
FDA-approved medications for adult bipolar disorder
| Bipolar disorder indication | Medications |
|---|---|
| Acute treatment of mania/mixed episodes | Aripiprazole,a,b asenapine,a carbamazepine extended release,a divalproex sodium,a lithium,a quetiapine,a risperidone,a-c ziprasidonea,b |
| Depressive episodes | Olanzapine/fluoxetine,a quetiapinea |
| Maintenance treatment | Aripiprazole (as monotherapy and as adjunct to lithium or divalproex sodium),a,b asenapine,d lamotrigine,a lithium,a olanzapine,a-c quetiapine (as adjunct to lithium or divalproex sodium),a risperidone,e ziprasidone (as adjunct to lithium or divalproex sodium)a |
| apill form bintramuscular for acute agitation cdisintegrating tablet dsublingual tablet elong-acting injectable | |
Table 3
Psychosocial interventions for bipolar disorder
| Intervention | Description | Results in bipolar disorder | Optimal stage of illness for intervention |
|---|---|---|---|
| Individual and family psycho-education28,29 | Strategies to educate the patient about the illness, medications, side effects, and relapse prevention | Decreases relapse, (particularly manic episodes) and hospitalizations. Increases adherence | Manic episodes |
| Cognitive-behavioral therapy28-30 | Focuses on understanding patient’s perceptions of illness and treatment. Equates resistance with exploring, rather than challenging resistance to take medication. Identifies and modifies negative automatic thoughts about medication. Motivation techniques useful in comorbid substance use | Decreases clinical symptoms. Increases adherence, quality of life, and social functioning | Depressive episodes |
| IPSRT28,29 | Uses motivational interviewing and CBT techniques to stabilize daily routines and resolve interpersonal problems | Prevents relapse | Depressive episodes |
| Family-focused therapy28,29 | A combination of psychoeducation, communication, and problem-solving skills training | Reduces mood symptoms, number of depressive relapses, and time depressed. Increases adherence | Depressive episodes |
| IPSRT: interpersonal and social rhythm therapy | |||
Related Resource
- Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.
Drug Brand Names
- Aripiprazole • Abilify
- Asenapine • Saphris
- Bupropion • Wellbutrin
- Carbamazepine • Carbatrol, Tegretol
- Carbamazepine extended- release • Equetro
- Clozapine • Clozaril
- Divalproex • Depakote, Depakote ER
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Lamotrigine • Lamictal
- Lithium • Eskalith, Lithobid
- Mirtazapine • Remeron
- Olanzapine • Zyprexa
- Olanzapine/fluoxetine • Symbyax
- Paroxetine • Paxil
- Quetiapine • Seroquel, Seroquel XR
- Risperidone • Risperdal
- Risperidone long-acting injectable • Risperdal Consta
- Selegiline • Eldepryl, Emsam
- Valproate • Depacon
- Venlafaxine • Effexor
- Ziprasidone • Geodon
Disclosures
Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.
Dr. Sheehan and Ms. Johns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Buckley PF, Foster AE, Patel NC, et al. Adherence to mental health treatment. New York, NY: Oxford University Press; 2009;1-10:53-69.
2. Velligan D, Sajatovic M, Valenstein M, et al. Methodological challenges in psychiatric treatment adherence research. Clin Schizophr Relat Psychoses. 2010;4(1):74-91.
3. Weiden P, Rapkin B, Mott T, et al. Rating of Medication Influences (ROMI) scale in schizophrenia. Schizophr Bull. 1994;20:297-310.
4. Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med. 1983;13(1):177-183.
5. Harvey NS. The development and descriptive use of the Lithium Attitudes Questionnaire. J Affect Disord. 1991;22(4):211-219.
6. Thompson K, Kulkarni J, Sergejew AA. Reliability and validity of a new Medication Adherence Rating Scale (MARS). Schizophr Res. 2000;42:241-247.
7. Byerly MJ, Nazonezny PA, Rush AJ. The Brief Adherence Rating Scale (BARS) validated against electronic monitoring in assessing the antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. Schizophr Res. 2008;100(1-3):60-69.
8. Scott J, Pope M. Non-adherence with mood stabilizers: prevalence and predictors. J Clin Psychiatry. 2002;63:384-390.
9. Rosa AR, Marco M, Fachel JM, et al. Correlation between drug treatment adherence and lithium treatment attitudes and knowledge in bipolar patients. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:217-224.
10. Jónsdóttir H, Opjordsmoen S, Birkenaes A, et al. Medication adherence in outpatients with severe mental disorders, relation between self-reports and serum level. J Clin Psychopharmacol. 2010;30:169-175.
11. DelBello M, Hanserman D, Adler CM, et al. Twelve-month outcome of adolescents with bipolar disorder following first hospitalization for a manic or mixed episode. Am J Psychiatry. 2007;164:582-590.
12. Strakowski SM, Tsai SY, DelBello MP, et al. Outcome following a first manic episode: cross national US and Taiwan comparison. Bipolar Disord. 2007;9:820-827.
13. Sajatovic M, Valenstein M, Blow F, et al. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. Psychiatr Serv. 2007;58:855-863.
14. Baldessarini RJ, Perry R, Pike J. Factors associated with treatment nonadherence among US bipolar patients. Hum Psychopharmacol. 2008;23:95-105.
15. Berk L, Hallam KT, Colom F, et al. Enhancing medication adherence in patients with bipolar disorder. Hum Psychopharmacol. 2010;25(1):1-16.
16. Johnson FR, Ozdemir S, Manjunath R, et al. Factors that affect adherence to bipolar disorder treatments: a stated-preference approach. Med Care. 2007;45(6):545-552.
17. Sajatovic M, Jenkins JH, Cassidy KA, et al. Medication treatment perceptions, concerns and expectations among depressed individuals with type I bipolar disorder. J Affect Disord. 2009;115(3):360-366.
18. Depp CA, Cain AE, Palmer BW, et al. Assessment of medication management ability in middle-aged and older adults with bipolar disorder. J Clin Psychopharmacol. 2008;28(2):225-229.
19. Gaudiano BA, Miller IW. Patients’ expectancies the alliance in pharmacotherapy, and treatment outcomes in bipolar disorder. J Consult Clin Psychol. 2006;74(4):671-676.
20. Copeland LA, Zeber JE, Salloum IM, et al. Treatment adherence and illness insight in veterans with bipolar disorder. J Nerv Ment Dis. 2008;196(1):16-21.
21. Yen CF, Chen CS, Ko CH, et al. Relationships between insight and medication adherence in outpatients with schizophrenia and bipolar disorder: prospective study. Psychiatry Clin Neurosci. 2005;59(4):403-409.
22. Drotar D, Greenley RN, Demeter CA, et al. Adherence to pharmacological treatment for juvenile bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):831-839.
23. Angst J, Angst F, Gerber-Werder R, et al. Suicide in 406 mood-disorder patients with and without long–term medication: a 40 to 44 years’ follow-up. Arch Suicide Res. 2005;9:279-300.
24. Lopez-Jaramillo C, Lopera-Vasquez J, Aurora G, et al. Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence. Bipolar Disord. 2010;12:557-567.
25. Minirth FB, Neal V. Assessment of patient preference and side effects in patients switched from divalproex sodium delayed release to divalproex sodium extended release. J Clin Psychopharmacol. 2005;25:99-101.
26. Han C, Lee MS, Pae CU, et al. Usefulness of long-acting injectable risperidone during 12-month maintenance therapy of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1219-1223.
27. McIntyre RS, Cohen M, Zhao J, et al. Asenapine for long term treatment of bipolar disorder: a double blind 40-week extension study. J Affect Disord. 2010;126:358-365.
28. Velligan DI, Weiden PJ, Sajatovic M, et al. Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from expert consensus guidelines. J Psychiatr Pract. 2010;16(5):306-324.
29. Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am J Psychiatry. 2008;165(11):1408-1419.
30. Szentagotai A, David D. The efficacy of cognitive-behavioral therapy in bipolar disorder: a quantitative meta-analysis. J Clin Psychiatry. 2010;71(1):66-72.
31. Even C, Thuile J, Stern K, et al. Psychoeducation for patients with bipolar disorder receiving lithium: short and long term impact on locus of control and knowledge about lithium. J Affect Disord. 2010;123:299-302.
32. Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: A 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry. 2007;64:419-426.
33. Bauer MS, McBride L, Williford WO, et al. Collaborative care for bipolar disorder, part II. Impact on clinical outcome, function and costs. Psychiatr Serv. 2006;57:937-945.
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13. Sajatovic M, Valenstein M, Blow F, et al. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. Psychiatr Serv. 2007;58:855-863.
14. Baldessarini RJ, Perry R, Pike J. Factors associated with treatment nonadherence among US bipolar patients. Hum Psychopharmacol. 2008;23:95-105.
15. Berk L, Hallam KT, Colom F, et al. Enhancing medication adherence in patients with bipolar disorder. Hum Psychopharmacol. 2010;25(1):1-16.
16. Johnson FR, Ozdemir S, Manjunath R, et al. Factors that affect adherence to bipolar disorder treatments: a stated-preference approach. Med Care. 2007;45(6):545-552.
17. Sajatovic M, Jenkins JH, Cassidy KA, et al. Medication treatment perceptions, concerns and expectations among depressed individuals with type I bipolar disorder. J Affect Disord. 2009;115(3):360-366.
18. Depp CA, Cain AE, Palmer BW, et al. Assessment of medication management ability in middle-aged and older adults with bipolar disorder. J Clin Psychopharmacol. 2008;28(2):225-229.
19. Gaudiano BA, Miller IW. Patients’ expectancies the alliance in pharmacotherapy, and treatment outcomes in bipolar disorder. J Consult Clin Psychol. 2006;74(4):671-676.
20. Copeland LA, Zeber JE, Salloum IM, et al. Treatment adherence and illness insight in veterans with bipolar disorder. J Nerv Ment Dis. 2008;196(1):16-21.
21. Yen CF, Chen CS, Ko CH, et al. Relationships between insight and medication adherence in outpatients with schizophrenia and bipolar disorder: prospective study. Psychiatry Clin Neurosci. 2005;59(4):403-409.
22. Drotar D, Greenley RN, Demeter CA, et al. Adherence to pharmacological treatment for juvenile bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):831-839.
23. Angst J, Angst F, Gerber-Werder R, et al. Suicide in 406 mood-disorder patients with and without long–term medication: a 40 to 44 years’ follow-up. Arch Suicide Res. 2005;9:279-300.
24. Lopez-Jaramillo C, Lopera-Vasquez J, Aurora G, et al. Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence. Bipolar Disord. 2010;12:557-567.
25. Minirth FB, Neal V. Assessment of patient preference and side effects in patients switched from divalproex sodium delayed release to divalproex sodium extended release. J Clin Psychopharmacol. 2005;25:99-101.
26. Han C, Lee MS, Pae CU, et al. Usefulness of long-acting injectable risperidone during 12-month maintenance therapy of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1219-1223.
27. McIntyre RS, Cohen M, Zhao J, et al. Asenapine for long term treatment of bipolar disorder: a double blind 40-week extension study. J Affect Disord. 2010;126:358-365.
28. Velligan DI, Weiden PJ, Sajatovic M, et al. Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from expert consensus guidelines. J Psychiatr Pract. 2010;16(5):306-324.
29. Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am J Psychiatry. 2008;165(11):1408-1419.
30. Szentagotai A, David D. The efficacy of cognitive-behavioral therapy in bipolar disorder: a quantitative meta-analysis. J Clin Psychiatry. 2010;71(1):66-72.
31. Even C, Thuile J, Stern K, et al. Psychoeducation for patients with bipolar disorder receiving lithium: short and long term impact on locus of control and knowledge about lithium. J Affect Disord. 2010;123:299-302.
32. Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: A 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry. 2007;64:419-426.
33. Bauer MS, McBride L, Williford WO, et al. Collaborative care for bipolar disorder, part II. Impact on clinical outcome, function and costs. Psychiatr Serv. 2006;57:937-945.