Bipolar Disorder: Treating Both Ends of the Spectrum
At the time of writing, Dr. Striker was a psychiatry pharmacy resident at the Louis Stokes Cleveland Department of Veterans Affairs Medical Center (VAMC), a pharmacist at Huron Hospital, and a relief pharmacist with Target Pharmacy. Dr. Fuller is a clinical pharmacy specialist in psychiatry at the Louis Stokes Cleveland VAMC, a clinical pharmacy specialist in psychiatry with Lexi-Comp Inc, an associate clinical professor of psychiatry at Case Western Reserve University, and an adjunct associate professor of clinical pharmacy at the University of Toledo.
Bipolar spectrum disorder is arange of mental illness thatincludes a continuum of depression,euthymia, hypomania, and mania.Patients may experience 1 or a mix ofthese presentations, with or without psychoticfeatures. It is estimated that theincidence of bipolar spectrum disorder is3.7% to 3.9% in the United States.1,2
Bipolar spectrum disorder comprises 2main diagnoses, Bipolar I (BDI) andBipolar II (BDII) disorders. A diagnosis ofBDI disorder is made when mania is presentfor at least 1 week or is severeenough to require hospitalization, whereasBDII disorder is associated with hypomanialasting at least 4 days and notrequiring hospitalization.
Both classifications of bipolar disordermay include periods of depression,which are associated with the majority ofthe morbidity and mortality seen in bipolardisorder.
The distinction between BDI and BDIIdisorders is the presence of hypomaniaor mania.
Other symptoms of bipolar maniainclude inflated self-esteem or grandiosity,decreased need for sleep, rapidspeech or increased talkativeness, racingthoughts or experiencing a flight of ideas,distractibility, increased goal-directedactivity, and increased activity in riskybehaviors (eg, spending sprees, badinvestments, risky sexual behavior).3Currently, treatment guidelines existonly for the management of BDI.Literature regarding the treatment of BDIIis not strong enough to support the formationof treatment guidelines. Becausethe distinction between mania and hypomaniacan be difficult to assess, in practicepatients with BDI and BDII typicallyare treated in a similar fashion. The treatmentof BDI manic episodes will be discussedfurther.Medication-approval History
For decades, lithium has been thecornerstone of pharmacotherapy forthe treatment of bipolar spectrum disorders.Although it has been used formood stabilization since the late 1800s,it was not approved for the treatment ofbipolar mania until 1970. It remains thegold standard of therapy for bipolarspectrum disorder (both acute andmaintenance).
It was not until 1995 that divalproexwas approved for the acute treatment ofmania. In current practice, divalproex isused for the maintenance treatment ofbipolar spectrum disorder, although itcarries FDA approval only for the treatmentof acute manic episodes.
After the approval of divalproex, manyother antiepileptic medications began tosee use in the treatment of acute maniaand the maintenance of bipolar disorder.Carbamazepine ER (Equetro) was approvedfor use in bipolar mania in 2004and lamotrigine for bipolar maintenancein 2003. Oxcarbazepine (Trileptal) also isconsidered an option for bipolar disorderas an off-label therapy.
Recently, the atypical antipsychotics(olanzapine, risperidone, aripiprazole,quetiapine, and ziprasidone) have gainedindications for acute and maintenancetreatment of bipolar disorder as well.Quetiapine and olanzapine/fluoxetinecurrently are the only agents approvedfor the treatment of bipolar depression.Treatment GuidelinesThree different sets of guidelines existfor the treatment of BDI. They are fromthe American Psychiatric Association,the Expert Consensus Guideline Series,and the Texas Implementation ofMedication Algorithms (TIMA).4-6 Currently,the TIMA guidelines are the mostup-to-date. They were published in 2005,and the other 2 bodies are in the processof updating their guidelines.
For this reason, there are differencesin the recommendations, based on thepool of published data available at thetime the guidelines were prepared.
In general, first-line agents recommendedin the TIMA guidelines includelithium, divalproex, aripiprazole, quetiapine,risperidone, and ziprasidone. Alternatefirst-line agents are olanzapine andcarbamazepine. If one of the first-lineagents is unsuccessful, the next option istypically changing to another of the previouslymentioned agents and then movingon to a 2-drug combination, changingto oxcarbazepine, adding a typical antipsychotic,or employing electroconvulsivetherapy.
Patients who experience psychoticfeatures during a manic episode typicallyare placed on an antipsychotic agent inaddition to a mood stabilizer.Choosing an Agent
Although the guidelines support theuse of many different agents for the firstlinetreatment of bipolar spectrum disorders,in the practice setting choosing apharmacologic agent is individualized,based on patient-specific factors.
Prior to the initiation of an agent, it isvital that a detailed medication history beobtained to assess priormedication trials. When possible,it is best to inquire notonly about the agent(s) usedbut also about the dose thatwas taken and the durationof therapy.
Adherence to therapy alsoshould be assessed, becausepatients may report that amedication has been ineffectiveafter a short trial with asubtherapeutic dose of medication,or they may discontinue treatmentafter feeling better.
Patient-specific factors that impactpharmacologic selection include thepatient?s medication history, medical andpsychiatric comorbidities, concurrentdrug therapy, potential medication sideeffects and drug?drug interactions, andthe prescriber?s experience.The Pharmacist?s Role
In the treatment of bipolar spectrumdisorder, pharmacists can be involved inmedication management in a variety ofways. Pharmacists working on inpatientunits or in outpatient clinics may beinvolved in obtaining a medication history,patient education, drug selection, andproviding drug information to the treatmentteam. Pharmacists have an opportunityto use their unique training inpatient counseling and in obtaining adetailed medication history.
Pharmacists also may be involved inthe monitoring of medications. Themajority of the medications used to treatbipolar spectrum disorder require continuedmonitoring for effectiveness andsafety.
Agents such as lithium, divalproex, andcarbamazepine can be monitored in theblood. Lithium has a well-defined therapeuticrange (0.5-1.5 mEq/L), and assessingserum levels of divalproex (50-125?/mL) is helpful in evaluating efficacy andtoxicity. Although carbamazepine levelsoften are obtained, these serum levelshave not correlated with efficacy for themanagement of bipolar disorder.
In addition to therapeutic drug levels,agents also require monitoring for sideeffects such blood dyscrasias,weight gain, and electrolyteabnormalities. In addition,lithium therapy necessitatesmonitoring of thyroid function,the ability of the kidneyto concentrate urine, and glucoseregulation. Moreover, abaseline electrocardiogram isrecommended for thosepatients who are older than40 years or those with preexistingcardiovascular disease(Table 1).
Therapeutic drug levels are not used inatypical antipsychotic therapy. As a class,these medications require extensivemonitoring of potential metabolic sideeffects. These effects include weightgain, dyslipidemia (primarily increasedtriglycerides), and glucose dysregulationindependent of weight gain. TheAmerican Diabetes Association hasranked the ability of the various atypicalantipsychotics for their likelihood of producingmetabolic side effects and hasdeveloped guidelines for monitoringthem (Table 2).7
One of the most valuable roles anypharmacist can play is that of patienteducator. Community pharmacists comeinto contact with patients more frequentlythan inpatient pharmacists andmany outpatient providers and are readilyaccessible to the public. Pharmacistscan educate patients on side effects andrequired monitoring, and they can reinforcethe need for continuing adherenceto medications and follow-up withproviders.References
1. Hirschfeld RM, Calabrese JR, Weissman MM, et al. Screening for bipolar disorder in the community. J Clin Psychiatry. 2003;64:53-59.
2. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: APA; 2000.
4. Suppes T, Dennehy EB, Hirschfeld RM, et al. The Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870-886.
5. Keck PE, Perlis RH, Otto MW, Carpenter D, Ross R, Docherty JP. The expert consensus guideline series: treatment of bipolar disorder 2004. Postgrad Med. 2004 Dec; Spec No:1-116.
6. American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder (rev). Am J Psychiatry. 2002;159(4 suppl):1-50.
7. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus Development Conference on Atypical Antipsychotic Drugs and Obesity and Diabetes. J Clin Psychiatry. 2004;65:267-272.