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Antipsychotic Combination Strategies in Bipolar Disord
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Antipsychotic Combination Strategies in Bipolar Disorder:
Strategies to Maximize Treatment Adherence
April 14, 2009 | Bipolar Disorder [1], Mania [2], Alcohol Abuse [3]
By David J. Muzina, MD [4] and Martha Sajatovic, MD [5]
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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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.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,
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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).
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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
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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
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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.
References:
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
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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.
Source URL:
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egies-maximize-treatment-adherence
Links:
[1] http://www.psychiatrictimes.com/bipolar-disorder
[2] http://www.psychiatrictimes.com/mania
[3] http://www.psychiatrictimes.com/alcohol-abuse
[4] http://www.psychiatrictimes.com/authors/david-j-muzina-md
[5] http://www.psychiatrictimes.com/authors/martha-sajatovic-md
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