Martha Sajatovic, MD

Slideshows

Treatment nonadherence in psychiatric patients contributes to increased suicide rates, illness exacerbation, hospitalization, and mortality. This Special Report countdown highlights the psychiatrist’s role in addressing barriers to treatment in a number of scenarios.

Treatment Adherence: Strategies and Best Practices

The World Health Organization defines adherence as “the extent to which a person’s behavior-taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care professional.” Suboptimal adherence is pervasive among individuals with chronic health conditions, including psychiatric disorders, and nearly always contributes to worse outcomes.

Much time, effort, and resources have been devoted to developing psychotropic drugs that are safe and effective, and that improve health outcomes. However, drugs don’t work if patients don’t take them. Rates of poor adherence can exceed 60% among patients with schizophrenia. Moreover, poor adherence is associated with relapse, hospitalizations, and high financial costs. Among patients with bipolar disorder, rates of nonadherence are estimated at 20% to 60%, and they are similarly associated with more relapse, higher costs and, in worst-case scenarios, suicide.

Approximately 30% of patients stop taking antidepressants after 1 month and 45% to 60% after 3 months. Poor adherence to evidence-based medication treatment is a problem that crosses psychiatric diagnoses and types of psychotropic medications. Fortunately, an emerging literature on the topic of adherence enhancement provides input on how clinicians might address adherence with their patients.

The articles in this 2-part Special Report spotlight the issue of poor adherence, particularly 

, and take on some of the multiple areas where interventions may be possible. In part 1, one article focuses on 

. A key emphasis is that changing adherence is a process that takes time and effort to master. The other article addresses the 

importance of culture as a factor in adherence

. Effective adherence enhancement is never “one size fits all,” and culture-specific factors need to be targeted to move the adherence dial.

In part 2, coming in the September issue, one article addresses 

-an approach that appears effective in other health conditions and may also translate to psychiatric disorders. While one might argue that good health is its own “reward,” compensating individuals for positive health behaviors is likely to be a win-win situation for patients, payers, and care systems. The issue of motivation as it affects medication adherence is the focus of 

 focuses on the benefits of partnering with primary care providers. Collaborative care can be an effective way to target suboptimal adherence, particularly given the multi-morbidities experienced by many patients with mental health disorders.

I am a Professor of Psychiatry and of Neurology at Case Western Reserve University School of Medicine in Cleveland, Ohio.

 I am a researcher, educator, and clinician and have devoted myself to the study and treatment of traditionally hard-to-treat populations with CNS disorders for the past 3 decades.

Relevant to the topic of the Special Report on treatment adherence in this issue, my interest in adherence began in 2003, when I was the recipient of a National Institute of Mental Health career development research grant (K-award). The K-award allowed me to focus on this topic and learn research methods, including those borrowed from the field of medical anthropology. Approaching the topic of suboptimal treatment adherence from the perspective of a person with a health condition can be an important way to understand adherence behavior.

Understanding why a person does or does not take medication is valuable in being able to apply methods of intervention that consider benefits versus burdens of treatment. In addition, the K-award mechanism is a wonderful opportunity to learn new skills that can make one a better and more competitive researcher. Collaborations and relationships that were established during my own K-award definitely amped up my grant-writing skills by orders of magnitude!

Since 2009, I have had an academic appointment in the Department of Neurology at University Hospitals of Cleveland and have been conducting research in brain disorders that affect behavior, such as epilepsy, stroke, and dementia. I run a health services center called the Neurological and Behavioral Outcomes Center. This has allowed me to interact with a whole new range of colleagues and reminds me how very closely the disciplines of psychiatry and neurology are intertwined. More recently, I have been involved in global brain health research with colleagues in Uganda and in Tanzania.

Dr. Sajatovic is Professor of Psychiatry and of Neurology at the Case Western Reserve University School of Medicine, University Hospitals Case Medical Center in Cleveland, OH.

Dr. Sajatovic reports no conflicts of interest concerning the subject matter of this Special Report. 

Articles

The articles in this 2-part Special Report spotlight the issue of poor adherence, particularly medication adherence, and take on some of the multiple areas where interventions may be possible.

Introduction: Problems of Poor Adherence

Click here to download a PDF of this slideshow.

Clinicians need to consider and manage multiple medical and cognitive comorbidities when working with the elderly population. This slideshow provides an overview of key points relevant to geriatric bipolar disorder as it relates to comorbidity.

5 Key Issues About Comorbidity in Geriatric Bipolar Disorder

The world’s elderly population is growing at an unprecedented pace, and it is expected that within the next 50 years the number of individuals aged 60 or older 

 The health care community has to prepare for sharply ramped-up service needs for older adults, including those with chronic mental conditions, such as bipolar disorder (BD). Elderly patients may represent up to 25% of the population with BD.

 This article provides an overview of key issues relevant to geriatric BD, including epidemiology, assessment, medical and psychiatric comorbidity, and treatment.

Epidemiologic studies suggest that 0.5% to 1% of elderly people have type I or II BD.

 summarizes the key epidemiologic points on BD in elderly patients. Similar to what is seen in late-life schizophrenia, BD in the geriatric population is only one-third as common as in younger populations.

 In both younger and geriatric persons, BD may be misdiagnosed or underdetected.

Older patients with BD are a group with variable evolutionary pathways. The great majority of elderly persons with BD have illness onset in early adulthood and have aged with BD. A smaller subgroup, 5% to 10%, are aged 50 or older at the time of a first definitive manic or hypomanic episode.

 While there is no “official” cutoff, it is agreed that age 50 is a reasonable defining threshold for lateonset BD.

 Since there are higher rates of familial transmission in early-onset cases and late-onset cases are usually more associated with neurological comorbidity, it is possible that early-onset BD and the lateonset variant are different illnesses. Clinical presentation and course of illness in later life also vary. Older patients may have more severe depressive episodes and less severe manic episodes than younger patients.

The epidemiology and clinical presentation of geriatric BD must be interpreted cautiously, since most study samples are cross-sectional and are probably survivor cohorts. The individuals in these samples may be healthier or more resilient than the general population of people with BD. Longitudinal analyses that include mortality data are needed to arrive at a more definitive understanding of course and presentation of BD across the life span.

Recognition and accurate diagnosis of late-life BD can be challenging. Assessment of mood symptoms in elderly patients should start with a careful history taken from the patient and collaborative sources. Evaluation should focus on mood, anxiety, and cognitive and neuropsychiatric symptoms as well as on assessment for comorbidities, use of new medications or herbal/alternative supplements, and adherence to prescribed medications.

Pop Quiz: Disturbances, Disorientation, and Delirium

The differential diagnosis of acute mania is often complicated by comorbidities, such as medical illness. It is therefore important to differentiate between idiopathic late-onset BD and secondary mania due to medical causes. Several medical conditions have been associated with mania, including CNS disorders (vascular dementia, encephalitis, neurosyphilis, HIV encephalopathy, strokes, Huntington disease, multiple sclerosis, traumatic brain injury), tumors (right temporal lobe, orbitofrontal, hypothalamic), and systemic diseases (systemic lupus erythematosus, hyperthyroidism, vitamin B12 deficiency). Substances that can induce mania include stimulants, cocaine, sympathomimetics, corticosteroids, TCAs, thyroid replacement therapies, hydralazine, and levodopa.

Mania in the elderly should also be differentiated from delirium or dementia. Sudden cognitive disturbances, disorientation, and cloudiness of consciousness are more suggestive of delirium than mania. Impulsivity, disinhibition, and irritability are more common in moderate and severe dementia but could also be related to underlying mood symptoms. Familiarity with the typical symptom patterns of individual patients, the chronology of presenting symptoms supported by physical and neurological examination, and laboratory and imaging investigations can help clarify the presenting picture and guide treatment.

Laboratory tests and imaging studies can help rule out mania due to medical causes. A recommended basic workup typically includes a complete blood cell count; electrolytes profile; liver, kidney, and thyroid function tests; vitamin B12 and folate levels; urinalysis; urine drug screen; and ECG. The clinical picture and relevant differential diagnosis should dictate the need for other assessments. Imaging studies (head CT or MRI) are indicated in all cases of new-onset mania to rule out vascular and other intracranial pathology. If the clinical presentation is suggestive of brain neoplasm, encephalitis, multiple sclerosis, or vasculitis, a brain MRI scan is preferred.

Medical, cognitive, and psychiatric comorbidity

 summarizes key points about comorbidity in geriatric BD. Physical illnesses are common in the elderly, with an average of 3 or 4 medical conditions. This population is particularly vulnerable to metabolic syndrome (up to 50%), hypertension (45% to 69%), diabetes mellitus (18% to 31%), and cardiovascular disease (9% to 49%).

 Cardiovascular comorbidity partially explains the increased rates of cerebrovascular disease in late-life BD, and vascular events may be etiologically involved in late-onset BD. Cardiovascular and other medical conditions probably arise from a combination of factors, including biological stressors inherent to BD (eg, inflammation, oxidative stress), lifestyle (eg, dietary habits, physical activity, substance use), and psychotropic medication exposure (eg, antipsychotics, mood stabilizers).

Although patients with BD die on average 10 years earlier than persons in the general population because of medical comorbidities, rates of medical comorbidity may not be higher in late-life BD patients than in geriatric controls.

 As noted earlier, geriatric BD studies should be interpreted cautiously because they may represent a comparatively healthy survivor cohort. Given the high prevalence of medical comorbidity in late-life BD, it is important to regularly monitor for medical adverse effects and levels of psychotropic drugs such as lithium, valproate, and carbamazepine. Medications can reach toxic levels because of declining renal and hepatic functioning with aging and medical comorbidity and because of drug interactions (eg, use of diuretics and lithium).

Cognitive dysfunction affects many older BD patients, and it is often associated with functional disability. Although impairment exists in multiple domains, including attention, executive function, processing speed, working memory, and verbal memory, it is unclear whether dysfunction is comparatively more severe in older BD patients. As with medical comorbidity, cognitive dysfunction has a number of causes in BD, including inflammatory and oxidative processes. Medications with higher anticholinergic burden may be a contributing factor (eg, certain antipsychotics), as may be substance use and cardiovascular disease.

Effective therapies, including cholinesterase inhibitors, have not yet been found for cognitive dysfunction in BD. Epidemiological evidence suggests that lithium users experience lower rates of dementia than do other BD patients.

 Whether lithium can treat or prevent BDrelated cognitive decline remains unclear, and further research is needed.

Psychiatric comorbidities are less common in geriatric BD patients than in younger adults with BD. The most prevalent comorbidities are substance use (up to 9% to 29%, mostly alcohol use) and anxiety disorders (up to 22%).

Age-specific treatment guidelines are lacking. Other than an ongoing large-scale randomized controlled trial (RCT) that has not yet been published, no large-scale prospective study has been conducted in geriatric BD patients. The current literature consists largely of uncontrolled, retrospective, open-label, or secondary analysis of large mixed-age population studies with a wide range of reported outcomes.

Clinicians could start by using treatments with both RCT evidence in adults and some data in older adults, followed by medication with evidence of fewer risks. Conclusions and treatment recommendations based on the extant literature must be tempered with the consideration that all are based on suboptimal data sources.

Treatment of late-life bipolar depression

. Lithium, lamotrigine, quetiapine, lurasidone, and some mood stabilizer/antidepressant combinations may be helpful in bipolar depression, but geriatric-specific data on their use are limited. A few small studies reported efficacy of lithium and valproate in later-life bipolar depression-lamotrigine and adjunctive aripiprazole may also be helpful.

Electroconvulsive therapy (ECT) is well tolerated and effective in the elderly, and findings indicate that it is an effective treatment for bipolar depression.

 Other neurostimulation techniques, such as transcranial magnetic stimulation, may potentially be useful, but more research in geriatric patients is needed.

A treatment algorithm for geriatric bipolar depression might be to start with lithium or lamotrigine, then move to agents such as quetiapine, lurasidone, valproate, and adjunctive aripiprazole. If response to these agents is poor, ECT could be tried, with cautious surveillance for cognitive dysfunction.

. Lithium has long been used in acute mania. Delirium, cognitive impairment, ataxia, tremors, renal dysfunction, hypothyroidism, rash, weight gain, and peripheral edema have been reported with use of lithium in geriatric patients.

 Concerns about tolerability and drug-drug interactions (eg, with diuretics, angiotensin-converting enzyme inhibitors, NSAIDs) and the availability of other treatment options have contributed to fewer lithium prescriptions for the elderly.

However, up to 40% of patients have been found to primarily respond to lithium.

 Moreover, lithium discontinuation was responsible for symptomatic mood relapse in 50% of geriatric responders.

 With regular laboratory monitoring (serum levels less than 0.8 mmol/L, and lower if possible) and clinical neurotoxicity assessment, lithium can often be safely used in older adults.

Divalproex has also been used for acute mania in older adults.

 GI problems, sedation, weight gain, and metabolic syndrome are the most common adverse effects.

 Rare adverse effects include thrombocytopenia, pancreatitis, fatal hepatotoxicity, and encephalopathy.

 Aspirin, digoxin, warfarin, phenytoin, and lamotrigine affect divalproex clearance.

Although many atypical antipsychotics have RCT evidence for mania, the data for geriatric use are limited. Quetiapine data pooled from RCTs in adults showed efficacy.

 A small uncontrolled trial of asenapine also showed efficacy in the older adult population.

 The benefits of antipsychotics need to be carefully weighed with the potential risks, including weight gain, metabolic syndrome, QTc prolongation, somnolence, and extrapyramidal symptoms.

Lithium, valproate, and quetiapine could be considered as initial choices in late-life mania. Given that depression may be especially burdensome in late-life BD, agents that are potentially helpful for both mania and depression may also be preferred, such as lurasidone and aripiprazole.

. There are few geriatric-specific data for preventing mood relapse in geriatric BD. Lamotrigine and lithium may be best at preventing depression and mania, respectively, while secondary analysis of a large NIH study showed that 80% of elderly patients recovered with a stepped-care pharmacotherapy approach.

 While patients on average took 2.05 psychoactive medications, 42% of those who achieved symptomatic remission were receiving lithium monotherapy.

Lithium monotherapy can be recommended for late-life BD maintenance for individuals who are able to tolerate lithium. For those who are unable to tolerate or who do not respond to lithium, lamotrigine, valproate, and quetiapine can be considered. Lurasidone and aripiprazole may also be helpful in preventing mania and/or depression, although more data on geriatric maintenance are needed. The use of adjunctive antidepressants is controversial, although older adults with depression may be less prone to manic switching.

Although cognitive-behavioral therapy, interpersonal therapy, social rhythm therapy, and psychoeducation can be useful adjuncts in BD, there is almost no literature regarding psychosocial interventions in late-life BD. While some older patients with BD could improve with behavioral interventions promoting treatment adherence, more research is necessary.

Despite the rapidly growing elderly population, there is limited evidence to guide treatment of geriatric patients with BD. Existing data suggest that standard medications may be useful; lower doses are preferred, and clinicians need to consider and manage multiple medical and cognitive comorbidities.

Dr Rej is Geriatric Psychiatry Fellow at the University of Toronto, and Lead of the JGH Geri-PARTy Research Group at the Jewish General Hospital in Montreal. Dr Al Jurdi is Deputy Executive at the Mental Health Care Line at the Michael E. DeBakey Veterans Affairs Medical Center and Associate Professor in the Menninger Department of Psychiatry and Behavioral Sciences at the Baylor College of Medicine in Houston. Dr Sajatovic is Professor of Psychiatry and of Neurology at the Case Western Reserve University School of Medicine, University Hospitals Case Medical Center in Cleveland. Drs Rej and Al Jurdi report no conflicts of interest concerning the subject matter of this article. Dr Sajatovic reports that she has received research grants from the CDC, Janssen, Merck, Ortho-McNeil-Janssen, the NIH, Pfizer, Reinberger Foundation, Reuter Foundation, and Woodruff Foundation; she is a consultant for Amgen, Bracket, Otsuka, Pfizer, ProPhase; she receives royalties from Johns Hopkins University Press, Oxford Press, Springer Press, UpToDate, Lexicomp; and she has consulted on CME activities for the American Physician Institute and MCM Education.

http://www.un.org/esa/population/publications/worldageing19502050/pdf/80chapterii.pdf

 Sajatovic M, Gyulai L, Calabrese JR, et al. Maintenance treatment outcomes in older patients with bipolar I disorder. 

 Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. 

 Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication [published correction appears in Arch Gen Psychiatry. 2005;62:768]. 

 UnÃ¼tzer J, Simon G, Pabiniak C, et al. The treated prevalence of bipolar disorder in a large staff-model HMO. 

 Depp CA, Jeste DV. Bipolar disorder in older adults: a critical review. 

 Sajatovic M, Kessing LV. Bipolar disorder in the elderly. In: Yatham LN, Maj M, eds. 

Bipolar Disorder: Clinical and Neurobiological Foundations

. West Sussex, UK: John Wiley & Sons, Inc; 2010.

 Lala SV, Sajatovic M. Medical and psychiatric comorbidities among elderly individuals with bipolar disorder: a literature review. 

 Westman J, HÃ¤llgren J, Wahlbeck K, et al. Cardiovascular mortality in bipolar disorder: a population-based cohort study in Sweden. 

 Mauer S, Vergne D, Ghaemi SN. Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. 

 Dols A, Rhebergen D, Beekman A, et al. Psychiatric and medical comorbidities: results from a bipolar elderly cohort study. 

 McFarland BH, Miller MR, Straumfjord AA. Valproate use in the older manic patient. 

 Sajatovic M, Gildengers A, Al Jurdi RK, et al. Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report [published correction appears in Bipolar Disord. 2011;13:581]. 

 Sajatovic M, Coconcea N, Ignacio RV, et al. Aripiprazole therapy in 20 older adults with bipolar disorder: a 12-week, open-label trial. 

 Hausner L, Damian M, Sartorius A, FrÃ¶lich L. Efficacy and cognitive side effects of electroconvulsive therapy (ECT) in depressed elderly inpatients with coexisting mild cognitive impairment or dementia. 

 Sackeim HA, Prudic J. Length of the ECT course in bipolar and unipolar depression. 

 Young RC, Schulberg HC, Gildengers AG, et al. Conceptual and methodological issues in designing a randomized, controlled treatment trial for geriatric bipolar disorder: GERI-BD. 

 Shulman KI, Rochon P, Sykora K, et al. Changing prescription patterns for lithium and valproic acid in old age: shifting practice without evidence. 

 Grof P. Sixty years of lithium responders. 

 Fahy S, Lawlor BA. Discontinuation of lithium augmentation in an elderly cohort. 

 Goldberg JF, Sacks MH, Kocsis JH. Low-dose lithium augmentation of divalproex in geriatric mania. 

Drug Information Handbook for Mental Health

 Bowden CL. Lamotrigine in the treatment of bipolar disorder [published correction appears in Expert Opin Pharmacother. 2002;3:1683]. 

 Sajatovic M, Calabrese JR, Mullen J. Quetiapine for the treatment of bipolar mania in older adults. 

 Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. 

 Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study.

 Sajatovic M, Dines P, Fuentes-Casiano E, et al. Asenapine in the treatment of older adults with bipolar disorder. 

 Al Jurdi RK, Marangell LB, Petersen NJ, et al. Prescription patterns of psychotropic medications in elderly compared with younger participants who achieved a “recovered” status in the systematic treatment enhancement program for bipolar disorder. 

Key issues about geriatric bipolar disorder-epidemiology, assessment, medical and psychiatric comorbidity, and treatment-are the focus. 

Managing Late-Life Bipolar Disorder: Current Issues and Clinical Tips

The Art of Psychopharmacology, David S. Janowsky, MD

Hypnotics: How Effective Are They for Insomnia?, Malcolm H. Lader, MD, PhD, LLB

Antidepressants: Brand Name or Generic?, James W. Jefferson, MD

Antipsychotic Combination Strategies in Bipolar Disorder, David J. Muzina, MD and Martha Sajatovic, MD

Optimal management of bipolar disorder (BD) includes the careful selection and regular ingestion of appropriate medication to stabilize mood. Unfortunately, between 40% and 50% of patients with BD in routine clinical settings take breaks or forget to take their medication or even discontinue the drug altogether.

 Treatment nonadherence is associated with mood relapse, hospitalization, and suicide.

Adequate adherence can be defined as the taking of the minimum amount of medication required to achieve acceptable control of symptoms and to prevent relapse to an extent that is mutually agreed on by the patient and the clinician. This definition underscores the need for a collaborative treatment approach that takes into account the nature and severity of the illness, associated comorbidities, the patient’s response to medication (including adverse effects and perceived benefits), and patient preference.

One of the challenges in addressing the issue of nonadherence is that there are a variety of ways to measure adherence, all of which have limitations (

). Various studies have defined a working concept of what constitutes clinically relevant nonadherence, including serum drug levels (for drugs in which serum levels might be typically monitored), categorical stratification (ie, missing a specific percentage of prescribed medication), medication refill frequencies, and combined/composite definitions.

Recognizing that adherence is rarely an all-or-nothing phenomenon, some groups have defined adherence categories within a range. For example, patients who are adherent take 80% or more of the prescribed medication; partially adherent patients take 51% to 79% of a prescribed medication; and those who are nonadherent take 50% or less of a prescribed drug.

 Such categorization allows for comparison of medication prescription filling across various medication classes, 

including medication combination therapies, among groups of individuals in a health care network. Whether any one specific compound or class of compounds (either as monotherapy or in combination) might be generally associated with relatively greater adherence among patients with BD has yet to be determined.

In recent years, the pharmacopeia for BD therapy has expanded substantially to include not only traditional mood-stabilizing compounds (such as lithium and anticonvulsants) but also the atypical antipsychotics. The latter have been associated with antimanic, antidepressant, and mood-stabilizing properties.

Randomized, placebo-controlled trials, which demonstrated the efficacy of atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole), led to their approval for the management of acute bipolar mania with or without psychotic features. The differences in antimanic efficacy among these agents are likely to be small.

There does not appear to be a “class effect” with atypical antipsychotics in the management of acute bipolar depression. The combination of olanzapine and fluoxetine but not olanzapine monotherapy, demonstrated sufficient efficacy to be named the first FDA-approved treatment for patients with acute bipolar depression.

 Quetiapine monotherapy demonstrated efficacy in managing acute bipolar depression; aripiprazole monotherapy did not.

Olanzapine and aripiprazole monotherapies are approved by the FDA for maintenance treatment of patients with BD. In addition, FDA approval of quetiapine in combination with lithium or divalproex as maintenance therapy for patients with BD was recently granted on the basis of controlled data.

Adherence with atypical antipsychotic drugs

Antipsychotics have become an integral component of drug therapy across all phases of BD. More than 90% of acutely manic patients are treated with antipsychotics, and antipsychotics in combination with mood stabilizers are prescribed for 47% to 90% of patients for acute and maintenance treatment.

 Continuation of antipsychotic medications in the outpatient setting is very common: these medications are prescribed for 60% to 89% of affected patients for 6 months or longer.

 Given the expanding role of atypical antipsychotics in the treatment of patients with all phases of BD, exploration of adherence to these medications is critical.

examined claims data for 825 patients with BD who were started on a regimen of antipsychotic monotherapy (risperidone, olanzapine, quetiapine, or typical antipsychotic). A Medicaid database was used during a 3-year period.

 Medication adherence was measured using the medication possession ratio: (MPR = number of days’ supply of medication that was actually received/number of days’ supply of medication that should have been dispensed per prescription). Adherence to antipsychotic therapy was also measured by the total number of days from the start of treatment to any therapy modification.

The overall rate of adherence measured by the MPR was significantly higher among patients treated with an atypical antipsychotic than with a typical antipsychotic (

 There were no significant differences in MPRs among patients treated with 1 of the 3 studied atypical antipsychotics (MPR range, 0.68 to 0.71). There were no significant differences in persistence with antipsychotic therapy between groups during the initial 250 days of therapy; however, after the first 250 days of treatment, patients who started on a regimen of typical antipsychotics were 5.2 times more likely to modify therapy than were patients who started on a regimen of risperidone (

 suggest that typical antipsychotics might be associated with lower adherence and a greater probability that patients would switch therapy than with atypical antipsychotics, not all reports have found treatment adherence differences between typical and atypical antipsychotics in bipolar populations. Sajatovic and colleagues

 found that adherence was highest only with the atypical antipsychotic clozapine. Patients who take this drug need long-term hematological monitoring, which may enhance adherence. A 2006 retrospective claims-based study by Gianfrancesco and colleagues

 evaluated treatment adherence among 15,224 patients with BP who were treated with typical and atypical antipsychotics-risperidone, olanzapine, quetiapine, and ziprasidone. Medication adherence was measured using the MPR as well as treatment duration. Greater adherence intensity was achieved with the majority of the atypical antipsychotics.

Several patient characteristics were positively associated with adherence intensity in this study, including male gender, prior mental health expenditure, switch from another antipsychotic, more frequent physician contact, and greater use of other psychotropics.

 Reduced adherence was observed among older patients and those with bipolar depression, previous use of a higher number of different psychotropic drugs, substance abuse/dependence, more managed forms of health coverage, and longer treatment duration.

 also found significant differences in treatment duration between each of the antipsychotic groups. Quetiapine and risperidone, but not olanzapine and ziprasidone, had significantly longer treatment durations than did the typical antipsychotics (

 < .001). Both quetiapine and risperidone also had significantly longer treatment durations than did olanzapine and ziprasidone.

In short, adherence may be somewhat better with atypical antipsychotics than with typical antipsychotics, although this finding is not consistently noted in the literature. Patient-specific and treatment-related variables also play a key role in adherence outcomes. Atypical antipsychotic therapy coupled with relatively intensive staff involvement, as occurs in clozapine-treated populations, may enhance treatment adherence. Finally, adherence rates as measured by MPRs for lithium and the anticonvulsants valproate, carbamazepine, and lamotrigine (MPR range, 0.76 to 0.81) do not differ markedly from those seen with antipsychotic drugs.

The role of combination therapy in treatment adherence

The choice between monotherapy and combination therapy is dictated largely by clinical impression and individualized treatment planning. In many cases, clinical experience-supported by evidence-based treatment guidelines-suggests that early or initial combinations of mood-stabilizing medications (including atypical antipsychotics) may enhance effectiveness beyond that provided by monotherapy. However, multiple medications or complex treatment regimens may promote nonadherence.

 examined the association between antipsychotic combination therapy and treatment adherence in persons with BD. Using a retrospective claims-based study design among commercially insured individuals with this disorder, the investigators assessed and compared adherence to quetiapine or risperidone monotherapy with these drugs in combination with traditional mood stabilizers and antidepressants. Adherence was measured using MPRs and treatment duration; additional stratification of data was based on predominant bipolar symptoms (manic or mixed, depressed, or unspecified). Treatment episodes from more than 5200 patients with BD were examined.

Among persons with predominantly manic or mixed symptoms, adherence intensity was reduced when an antipsychotic was prescribed with any combination of lithium, an anticonvulsant, and an antidepressant. Adherence to the atypical antipsychotic was better when only 1 other medication was coprescribed; adherence was lowest when all 3 of the other medication types were used. Adherence was lower in those taking risperidone or quetiapine and an anticonvulsant than in those taking lithium and an atypical antipsychotic. The combination of quetiapine with lithium or with lithium and an anticonvulsant was associated with significantly shorter treatment durations than was quetiapine monotherapy. The type of combination therapy for risperidone did not significantly affect treatment duration.

Among individuals with predominant symptoms of depression, any combination of therapy with quetiapine reduced adherence intensity, although the smallest reduction occurred when this drug was combined with an antidepressant. Reduced adherence with risperidone-as reflected by lower MPRs-was observed only with strategies that combined 2 or more other psychotropic medications. Among the predominantly depressed patients with BD, none of the combination strategies with risperidone or quetiapine had a significant effect on adherence.

Other investigators have found evidence that suggests that among some patients with BD, adherence is greater with combination therapies than with monotherapy. Adherence with antipsychotic medications has also been studied in a large cohort of veterans with BD using the Veterans Affairs National Psychosis Registry.

 The study used the MPR to categorize patients as fully adherent, partially adherent, and nonadherent. About 95% of the patients were taking an atypical antipsychotic, and 81.2% were taking a single antipsychotic. Nearly 50% of these patients were either partially adherent (21.2%) or nonadherent (26.9%). The nonadherent patients were significantly more likely to be younger, members of a minority, known substance abusers, or homeless. Interestingly, the mean MPR for individuals who took 2 antipsychotics was higher than MPRs for those taking single antipsychotics (

These findings are strikingly comparable to those from a similar study that examined adherence with lithium and anticonvulsant therapy among patients with BD. Nearly 50% of the study participants were only partially adherent or nonadherent, yet better overall adherence was observed among patients who received 2 mood-stabilizing drugs than among those who were given a single drug.

 Unfortunately, case-registry methodology does not address the question of whether combination therapy actually promotes treatment adherence in bipolar populations, or whether improved adherence with combination therapy is simply due to the fact that clinicians might be more likely to prescribe medication treatments more intensively to adherent individuals.

In contrast to conventional clinical wisdom, which posits that polytherapy promotes nonadherence, recent data on combination therapy in bipolar populations does not support a consistent position that adherence is either generally hurt or helped by combination treatment. As Gianfrancesco and colleagues

 showed, adherence may deteriorate when medication regimens become very large or cumbersome (3 or more drugs). It is possible, however, that appropriately aggressive use of medication combinations that reduce symptoms and enhance quality of life may have beneficial effects on treatment adherence.

Adherence to medications to treat BD is a complex and multifaceted issue that is affected by patient-specific factors as well as by medication choice, drug response, and provider or treatment-setting factors. Atypical antipsychotic drugs are used for both acute and maintenance treatment in patients with BD and nonadherence is common, as is the case with all psychotropics in psychiatric populations.

While recent data suggest that atypical antipsychotics may help promote adherence for some individuals with BD, psychosocial interventions-such as long-term and intensive involvement with mental health clinicians-are important in optimizing adherence outcomes. For example, weight gain or metabolic disturbances associated with atypical antipsychotics may be of such concern that some individuals may refuse to take these medications. Psychoeducation that focuses on goals and expectations of treatment and close monitoring of adverse effects are critical in preventing and minimizing problems in medication therapy that may ultimately lead to treatment nonadherence or discontinuation.

Combination therapies are widely used in clinical settings, yet there has not been extensive research on key outcome domains, such as adherence or quality of life for many commonly used bipolar treatment polytherapies. Polytherapy does not necessarily promote nonadherence. However, combination treatments may exacerbate medication adverse effects and/or create new adverse effects that would not occur with monotherapy.These issues need to be proactively addressed to optimize future symptom response and adherence outcomes.

Finally, given the frequency with which combination therapy is prescribed in clinical settings, there is a critical need for research that comprehensively evaluates outcomes in bipolar populations. As with bipolar mania and bipolar depression monotherapy trials, it is unlikely that atypicals are equivalent and indistinguishable. Differences between the various popular combinations should be explored using rigorous and systematic methods.

Dr Muzina is director of the Center for Mood Disorders Treatment and Research in the department of psychiatry at the Cleveland Clinic in Cleveland. Dr Sajatovic is professor of psychiatry at Case Western Reserve University School of Medicine in Cleveland and director of geropsychiatry at University Hospitals Case Medical Center in Cleveland. Dr Muzina reports that he is on the speakers’ bureau for AstraZeneca, Bristol-Myers Squibb, Pfizer, Sepracor, and Wyeth; and that he is a member of the scientific advisory board for AstraZeneca. Dr Sajatovic reports that she has received research funding from AstraZeneca, GlaxoSmithKline, and the NIMH; and she is a consultant for GlaxoSmithKline, Cognition Group, and AstraZeneca.

Aripiprazole (Abilify)
  Carbamazepine (Carbatrol, Tegretol, others)
  Clozapine (Clozaril)
  Divalproex (Epival, Depakote)
  Fluoxetine (Prozac, Sarafem)
  Lamotrigine (Lamictal)
  Lithium (Eskalith, Lithane, Lithobid)
  Olanzapine (Zyprexa)
  Quetiapine (Seroquel)
  Risperidone (Risperdal)
  Valproate/Valproic acid (Depakote, others)
  Ziprasidone (Geodon)


 Lingam R, Scott J. Treatment non-adherence in affective disorders. 

 Perlick DA, Rosenheck RA, Kaczynski R, Kozma L. Medication non-adherence in bipolar disorder: a patient-centered review of research findings. 

 Scott J, Pope M. Self-reported adherence to treatment with mood stabilizers, plasma levels, and psychiatric hospitalization. 

 Colom F, Vieta E. Treatment adherence in bipolar patients. 

 MÃ¼ller-Oerlinghausen B, MÃ¼ser-Causemann B, Volk J. Suicides and parasuicides in a high-risk patient group on and off lithium long-term medication. 

 Scott J, Pope M. Non-adherence with mood stabilizers: prevalence and predictors. 

 Sajatovic M, Davies M, Hrouda DR. Enhancement of treatment adherence among patients with bipolar disorder. 

 Sajatovic M, Valenstein M, Blow F, et al. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. 

 Muzina DJ, Kemp DE, Gao K, et al. Atypical antipsychotics in bipolar depression: applying emerging evidence to clinical practice. 

 Muzina DJ, Kemp DE, Gao K, Calabrese JR. Mood stabilizers. In: Tasman A, Kay J, Lieberman J, et al, eds. 

 West Sussex, England: John Wiley & Sons, Ltd; 2008:2202-2222.


 Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. 

 Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. 

 Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. 

 Thase ME, Macfadden W, Weisler RH, et al; BOLDER II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). 

 Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. 

 Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). 

 Tohen M, Zhang F, Taylor CC, et al. A meta-analysis of the use of typical antipsychotic agents in bipolar disorder. 

 Keck PE, McElroy SL, Strakowski SM, et al. Factors associated with maintenance antipsychotic treatment of patients with bipolar disorder. 

 Ozerdem A, Tunca Z, Kaya N. The relatively good prognosis of bipolar disorders in a Turkish bipolar clinic. 

 Verdoux H, Gonzales B, Takei N, Bourgeois M. A survey of prescribing practice of antipsychotic maintenance treatment for manic-depressive outpatients. 

 Hassan M, Madhavan SS, Kalsekar ID, et al. Comparing adherence to and persistence with antipsychotic therapy among patients with bipolar disorder. 

 Sajatovic M, Valenstein M, Blow FC, et al. Treatment adherence with antipsychotic medications in bipolar disorder. 

 Gianfrancesco FD, Rajagopalan K, Sajatovic M, Wang RH. Treatment adherence among patients with bipolar or manic disorder taking atypical and typical antipsychotics. 

 Kingsbury SJ, Yi D, Simpson GM. Psychopharmacology: rational and irrational polypharmacy. 

 Burton SC. Strategies for improving adherence to second-generation antipsychotics in patients with schizophrenia by increasing ease of use. 

Gianfrancesco FD, Rajagopalan K, Sajatovic M, Wang RH. Treatment adherence among patients with bipolar or manic disorder taking atypical and typical antipsychotics. 

 2006;67:222-232.
Perlick DA, Rosenheck RA, Kaczynski R, Kozma L. Medication non-adherence in bipolar disorder: a patient-centered review of research findings. 

Optimal management of bipolar disorder (BD) includes the careful selection and regular ingestion of appropriate medication to stabilize mood. Unfortunately, between 40% and 50% of patients with BD in routine clinical settings take breaks or forget to take their medication or even discontinue the drug altogether.1-3 Treatment nonadherence is associated with mood relapse, hospitalization, and suicide.4,5

Author | Martha Sajatovic, MD

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