Managing Mania: A Clinical Conundrum

Cyclical mood changes, oscillatingfrom severe depression touncontrolled mania, are thedefining traits of bipolar illness, butother diseases or causes also are connectedwith mania. Characterized byseverely elevated and potentially dangerousmood and uncontrolled energy(Table 1), mania can be difficult to treat.The exhilarating high experienced bysome patients while in a manic stateproduces ambivalence about acceptingtreatment. The lack of an ideal agent totreat mania is another barrier.Treatment, however, is crucial.

Although many patients associatemania with increased creativity, its frequentend point is persistent agitationand poor impulse control. The sense ofwell-being mania patients experience isentirely false and ultimately is thepatient's undoing. Mania, like all otherserious psychiatric disorders, is a debilitatingdisorder adversely affecting relationships,health, jobs, and rational decisionmaking. Hypomania, a less severevariant of mania, differs from mania onlyin the magnitude of the loss of control.Also, mania can present with mixedmoods, meaning that elements ofeuphoria and depression are present.

Diagnosis

In the absence of a preexisting diagnosisof bipolar illness, and even whenbipolar illness has been diagnosed, cliniciansshould look for underlying causesof mania. Multiple sclerosis and corticalor limbic brain lesions can producemania, as can treatment with systemiccorticosteroids and ^L-dopa. Substanceabuse can, too. Initiation of antidepressantsor benzodiazepines can sometimesprecipitate mania, especially inbipolar patients.

Anxiety, attention-deficit/hyperactivitydisorder, and substance abuse arecommon comorbidities in patients withbipolar illness,¹ and selecting treatmentcan be a clinical conundrum. Whenmania is associated with underlyingmedical conditions or drug treatment,treatment of the conditions or cessationof drug therapy is prudent.

In patients with preexisting diagnosesof bipolar disorder, mania often followsnonadherence to maintenance medication.If the patient is taking lithium orantiepileptic drugs for mood stabilization,serum levels should be tested. Ifthe levels are subtherapeutic, improvedpatient adherence or close medicationsupervision to attain therapeutic levelsmay resolve the mania. If adherence isgood but serum levels are on the lowend of the therapeutic range, increasingthe dose and subsequently elevatingthe levels closer to the upper end of thetherapeutic range may resolve themania.

During the diagnostic process anduntil patients are stabilized, close supervisionis essential to ensure thatpatients do not act impulsively on ideason which they lack insight.

Determining a Course of Treatment

To keep patients and others safe,treatment often requires hospitalization.The primary goal is alleviatingimpulsivity, agitation, and aggression.Although several guidelines are available^2-4 that approach acute manicepisodes slightly differently, overallguidelines are similar. If mania is lessthan severe, monotherapy with a mood-stabilizing agent may be sufficient.Lithium, the cornerstone of treatment,remains the preferred agent, but it haslimitations?a high number of nonresponders,several significant drug interactions,a narrow therapeutic window,and side effects such as tremor,hypothyroidism, and skin complications.⁵ Fortunately, alternatives areavailable.

When mania is severe, most expertsrecommend a mood stabilizer with anatypical antipsychotic to start.^2-4Prescribers must weigh relative risksand benefits of various drug combinations.If the patient has a history ofmania, they often will prescribe whatworked for a previous episode of maniaor a drug that the patient prefers if possible(and avoid using what did not workor what the patient eschews).

Prescribers often select monotherapybased on the patient's presentation.Antidepressants should be tapered toavoid withdrawal syndromes and shouldbe discontinued as treatment for maniabegins, because they can contribute toor sustain the manic period. Appropriatemonotherapy for euphoria includes lithium,^2-4 valproate,^6-8 aripiprazole, quetiapine,risperidone, and ziprasidone.^9-11Monotherapy for mixed moods includesvalproate rather than lithium, aripiprazole,risperidone, and ziprasidone.

Lamotrigine is not used for acutemania because of its long titrationschedule.¹² Although olanzapine andcarbamazepine^2,3,13-17 also can be usedin euphoric or mixed moods, they areassociated with more adverse effectsthan the others. High-potency benzodiazepinesoften are used for as-neededrelief of agitation, insomnia, or anxiety.^2,3

Patients who fail to respond orrespond incompletely to monotherapygenerally step up to a 2-drug regimenconsisting of a mood stabilizer and lithium,2 concurrent mood stabilizers, or amood stabilizer and an atypical antipsychotic(but never 2 concurrent atypicalantipsychotics).^18-25 If mania continues,carbamazepine, oxcarbazepine,^26,27gabapentin (especially if the mania iscomorbid with panic disorder, socialphobia, or pain syndrome),^28-30 or topiramate³¹can be added to the 2-drug treatment.When multiple drugs are necessary,clinicians should strive to minimizeside effects and promote adherence.

In the small minority of patients whodo not respond^32,33 or in those who arepregnant,³⁴ electroconvulsive therapycan be considered. Clozapine also representsan option for treatment-resistantpatients, as does a 3-drug regimenthat employs lithium, an anticonvulsant,and an antipsychotic.^2-4

Smoking is an important factor that isoften overlooked in patients with mentalillness. People with mental illness aremore likely to smoke than those withoutmental illness. The results of a recentstudy indicate that 30.3% of the cigarettessold in the United States in 2001-2002 were purchased by the 7.1% of thepopulation that has mental illness.³⁵

Smoking induces CYP 1A2 activityand hence reduces plasma levels ofdrugs metabolized by this enzyme(Table 2). Many drugs targeting mentalillness are CYP 1A2 substrates. Patientswho smoke often need higher doses ofclozapine or olanzapine.

End Note

Pharmacists should ensure that prescribingclinicians optimize doses andattain appropriate serum levels if theselevels can be measured. Achieving therapeuticblood levels of mood stabilizershas been tied to faster remission.^36,37Most of these agents either have manufacturer-recommended dosing titrationrequirements or take days to work.Several researchers are studying oralloading of antiepileptic drugs in anattempt to reach therapeutic levelsfaster in patients with mania or seizuredisorders.^37-41

Regardless, up to two thirds ofpatients will require same-class, multi-class,adjunctive, or augmentationpolypharmacy for adequate control.^42,43Understanding the rationale for theselegitimate types of polypharmacy isimperative. Finally, acute mania may bea single episode, but for others it maybe the beginning of a chronic conditionrequiring lifelong monitoring and treatment.

Ms. Wick is a senior clinical researchpharmacist at the National CancerInstitute, National Institutes ofHealth, Bethesda, Md. The viewsexpressed are those of the authorand not those of any governmentagency.

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