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.
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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17. Weisler RH, Keck PE Jr, Swann AC, Cutler AJ, Ketter TA, Kalali AH. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2005;66:323-330.
18. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry. 2002;59:62-69.
19. Namjoshi MA, Risser R, Shi L, Tohen M, Breier A. Quality of life assessment in patients with bipolar disorder treated with olanzapine added to lithium or valproic acid. J Affect Disord. 2004;81:223-229.
20. Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry. 2002;159:1146-1154.
21. Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A. Mood stabilizers plus risperidone or placebo in the treatment of acute mania: international, double-blind, randomised controlled trial. Br J Psychiatry. 2003;182:141-147.
22. Bowden CL, Myers JE, Grossman F, Xie Y. Risperidone in combination with mood stabilizers: a 10-week continuation phase study in bipolar I disorder. J Clin Psychiatry. 2004;65:707-714.
23. DelBello MP, Schwiers ML, Rosenberg HL, Strakowski SM. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry. 2002;41:1216-1223.
24. Yatham LN, Paulsson B, Mullen J, Vagero AM. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol. 2004;24:599-606.
25. Sachs G, Chengappa KN, Suppes T, et al. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 2004;6:213-223.
26. Emrich HM, Dose M, von Zerssen D. The use of sodium valproate, carbamazepine and oxcarbazepine in patients with affective disorders. J Affect Disord. 1985;8:243-250.
27. Wagner KD, Kowatch RA, Emslie GJ, et al. A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry. 2006;163:1179-1186.
28. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 2000;20:467-471.
29. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19:341-348.
30. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837-1842.
31. Bahk WM, Shin YC, Woo JM, et al. Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:115-121.
32. Ciapparelli A, Dell'Osso L, Tundo A, et al. Electroconvulsive therapy in medication-non-responsive patients with mixed mania and bipolar depression. J Clin Psychiatry. 2001;62:552-555.
33. Small JG, Klapper MH, Kellams JJ, et al. Electroconvulsive treatment compared with lithium in the management of manic states. Arch Gen Psychiatry. 1988;45:727-732.
34. Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry. 1994;45:444-450.
35. Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA. Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry. 2004;61:1107-1115.
36. Bowden CL. Dosing strategies and time course of response to antimanic drugs. J Clin Psychiatry. 1996;57(suppl 13):4-9.
37. Oluboka OJ, Bird DC, Kutcher S, Kusumakar V. A pilot study of loading versus titration of valproate in the treatment of acute mania. Bipolar Disord. 2002;4:341-345.
38. Martinez JM, Russell JM, Hirschfeld RM. Tolerability of oral loading of divalproex sodium in the treatment of acute mania. Depress Anxiety. 1998;7:83-86.
39. Hirschfeld RM, Baker JD, Wozniak P, Tracy K, Sommerville KW. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry. 2003;64:841-846.
40. Keck PE Jr, McElroy SL, Bennett JA. Pharmacologic loading in the treatment of acute mania. Bipolar Disord. 2000;2:42-46.
41. Goldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L. Rapid titration of mood stabilizers predicts remission from mixed or pure mania in bipolar patients. J Clin Psychiatry. 1998;59(4):151-158.
42. Kupfer DJ, Frank E, Grochocinski VJ, Cluss PA, Houck PR, Stapf DA. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin Psychiatry. 2002;63:120-125.
43. National Association of State Mental Health Program Directors. Technical Report on Psychiatric Polypharmacy, 2001. Available at: www.nasmhpd.org/general_files/publications/med_directors_pubs/Polypharmacy.pdf. Accessed October 18, 2005.
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