Antipsychotic Combination Strategies in Bipolar Disorder:Strategies to Maximize Treatment Adherence


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

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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

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.6

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 (Table). 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.3,7

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.8 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.

The role of antipsychotic drugs

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.9,10

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.11

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.12 Quetiapine monotherapy demonstrated efficacy in managing acute bipolar depression; aripiprazole monotherapy did not.13-15

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.16

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.17,18 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.18-20 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.

Hassan and colleagues21 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.21 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 (P < .05).21 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 (P < .001).

While Hassan and colleagues21 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 colleagues22 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 colleagues23 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.23 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.

Gianfrancesco and colleagues23 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 (P < .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.8

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.24,25

Gianfrancesco and colleagues26 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.22 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 (P < .0001).

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.8 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 colleagues26 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.

Conclusions and clinical implications

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.


Drugs Mentioned in This Article

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)


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Evidence-Based References

Gianfrancesco FD, Rajagopalan K, Sajatovic M, Wang RH. Treatment adherence among patients with bipolar or manic disorder taking atypical and typical antipsychotics. J Clin Psychiatry. 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. Clin Approaches Bipolar Disord. 2004;3:56-54.

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