Managing Mania: A Clinical Conundrum

APRIL 01, 2007
Jeannette Yeznach Wick, RPh, MBA, FASCP

Cyclical mood changes, oscillating from severe depression to uncontrolled mania, are the defining traits of bipolar illness, but other diseases or causes also are connected with mania. Characterized by severely elevated and potentially dangerous mood and uncontrolled energy (Table 1), mania can be difficult to treat. The exhilarating high experienced by some patients while in a manic state produces ambivalence about accepting treatment. The lack of an ideal agent to treat mania is another barrier. Treatment, however, is crucial.

Although many patients associate mania with increased creativity, its frequent end point is persistent agitation and poor impulse control. The sense of well-being mania patients experience is entirely false and ultimately is the patient's undoing. Mania, like all other serious psychiatric disorders, is a debilitating disorder adversely affecting relationships, health, jobs, and rational decision making. Hypomania, a less severe variant of mania, differs from mania only in the magnitude of the loss of control. Also, mania can present with mixed moods, meaning that elements of euphoria and depression are present.


In the absence of a preexisting diagnosis of bipolar illness, and even when bipolar illness has been diagnosed, clinicians should look for underlying causes of mania. Multiple sclerosis and cortical or limbic brain lesions can produce mania, as can treatment with systemic corticosteroids and L-dopa. Substance abuse can, too. Initiation of antidepressants or benzodiazepines can sometimes precipitate mania, especially in bipolar patients.

Anxiety, attention-deficit/hyperactivity disorder, and substance abuse are common comorbidities in patients with bipolar illness,1 and selecting treatment can be a clinical conundrum. When mania is associated with underlying medical conditions or drug treatment, treatment of the conditions or cessation of drug therapy is prudent.

In patients with preexisting diagnoses of bipolar disorder, mania often follows nonadherence to maintenance medication. If the patient is taking lithium or antiepileptic drugs for mood stabilization, serum levels should be tested. If the levels are subtherapeutic, improved patient adherence or close medication supervision to attain therapeutic levels may resolve the mania. If adherence is good but serum levels are on the low end of the therapeutic range, increasing the dose and subsequently elevating the levels closer to the upper end of the therapeutic range may resolve the mania.

During the diagnostic process and until patients are stabilized, close supervision is essential to ensure that patients do not act impulsively on ideas on which they lack insight.

Determining a Course of Treatment

To keep patients and others safe, treatment often requires hospitalization. The primary goal is alleviating impulsivity, agitation, and aggression. Although several guidelines are available2-4 that approach acute manic episodes slightly differently, overall guidelines are similar. If mania is less than severe, monotherapy with a mood-stabilizing agent may be sufficient. Lithium, the cornerstone of treatment, remains the preferred agent, but it has limitations?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 are available.

When mania is severe, most experts recommend a mood stabilizer with an atypical antipsychotic to start.2-4 Prescribers must weigh relative risks and benefits of various drug combinations. If the patient has a history of mania, they often will prescribe what worked for a previous episode of mania or a drug that the patient prefers if possible (and avoid using what did not work or what the patient eschews).

Prescribers often select monotherapy based on the patient's presentation. Antidepressants should be tapered to avoid withdrawal syndromes and should be discontinued as treatment for mania begins, because they can contribute to or sustain the manic period. Appropriate monotherapy for euphoria includes lithium,2-4 valproate,6-8 aripiprazole, quetiapine, risperidone, and ziprasidone.9-11 Monotherapy for mixed moods includes valproate rather than lithium, aripiprazole, risperidone, and ziprasidone.

Lamotrigine is not used for acute mania because of its long titration schedule.12 Although olanzapine and carbamazepine2,3,13-17 also can be used in euphoric or mixed moods, they are associated with more adverse effects than the others. High-potency benzodiazepines often are used for as-needed relief of agitation, insomnia, or anxiety.2,3

Patients who fail to respond or respond incompletely to monotherapy generally step up to a 2-drug regimen consisting of a mood stabilizer and lithium, 2 concurrent mood stabilizers, or a mood stabilizer and an atypical antipsychotic (but never 2 concurrent atypical antipsychotics).18-25 If mania continues, carbamazepine, oxcarbazepine,26,27 gabapentin (especially if the mania is comorbid with panic disorder, social phobia, or pain syndrome),28-30 or topiramate31 can be added to the 2-drug treatment. When multiple drugs are necessary, clinicians should strive to minimize side effects and promote adherence.

In the small minority of patients who do not respond32,33 or in those who are pregnant,34 electroconvulsive therapy can be considered. Clozapine also represents an option for treatment-resistant patients, as does a 3-drug regimen that employs lithium, an anticonvulsant, and an antipsychotic.2-4

Smoking is an important factor that is often overlooked in patients with mental illness. People with mental illness are more likely to smoke than those without mental illness. The results of a recent study indicate that 30.3% of the cigarettes sold in the United States in 2001- 2002 were purchased by the 7.1% of the population that has mental illness.35

Smoking induces CYP 1A2 activity and hence reduces plasma levels of drugs metabolized by this enzyme (Table 2). Many drugs targeting mental illness are CYP 1A2 substrates. Patients who smoke often need higher doses of clozapine or olanzapine.

End Note

Pharmacists should ensure that prescribing clinicians optimize doses and attain appropriate serum levels if these levels can be measured. Achieving therapeutic blood levels of mood stabilizers has been tied to faster remission.36,37 Most of these agents either have manufacturer-recommended dosing titration requirements or take days to work. Several researchers are studying oral loading of antiepileptic drugs in an attempt to reach therapeutic levels faster in patients with mania or seizure disorders.37-41

Regardless, up to two thirds of patients will require same-class, multi-class, adjunctive, or augmentation polypharmacy for adequate control.42,43 Understanding the rationale for these legitimate types of polypharmacy is imperative. Finally, acute mania may be a single episode, but for others it may be the beginning of a chronic condition requiring lifelong monitoring and treatment.

Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Md. The views expressed are those of the author and not those of any government agency.


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