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.
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 available2-4 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 andcarbamazepine2,3,13-17 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 respond32,33 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.
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.
1. Baldassano CF. Illness course, comorbidity, gender, and suicidality in patients withbipolar disorder. J Clin Psychiatry. 2006;67(suppl 11):8-11.
2. Suppes T, Dennehy EB, Hirschfeld RM, et al. The Texas implementation of medicationalgorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870-886.
3. American Psychiatric Association. Practice guideline for the treatment of patients withbipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
4. Yatham LN, Kennedy SH, O'Donovan C, et al. Canadian Network for Mood and Anxiety Treatments(CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies.Bipolar Disord. 2005;7(suppl 3):5-69.
5. Weisler RH, Cutler AJ, Ballenger JC, Post RM, Ketter TA. The use of antiepilepticdrugs in bipolar disorders: a review based on evidence from controlled trials. CNS Spectr.2006;11:788-799.
6. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium andplacebo in the treatment of mania. JAMA. 1994;271:918-924.
7. Freeman TW, Clothier JL, Pazzaglia P, Lesem MD, Swann AC. A double-blindcomparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry.1992;149:108-111.
8. Pope HG Jr, McElroy SL, Keck PE Jr, Hudson JI. Valproate in the treatment of acutemania: a placebo-controlled study. Arch Gen Psychiatry. 1991;48:62-68.
9. Pae CU, Nassir Ghaemi S, Patkar A, et al. Adjunctive risperidone, olanzapine andquetiapine for the treatment of hospitalized patients with bipolar I disorder: aretrospective study. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1322-1325.
10. Cole P, Rabasseda X. Quetiapine in bipolar disorder: increasing evidence of efficacyand tolerability. Drugs Today (Barc). 2004;40:837-852.
11. Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A. Mood stabilisers plusrisperidone or placebo in the treatment of acute mania: international, double-blind,randomised controlled trial. Br J Psychiatry. 2003;182:141-147.
12. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM. Lamotrigine: a review of its usein bipolar disorder. Drugs. 2003;63:2029-2050.
13. Post RM, Uhde TW, Roy-Byrne PP, Joffe RT. Correlates of antimanic response tocarbamazepine. Psychiatry Res. 1987;21:71-83.
14. Lerer B, Moore N, Meyendorff E, Cho SR, Gershon S. Carbamazepine versus lithiumin mania: a double-blind study. J Clin Psychiatry. 1987;48:89-93.
15. Small JG, Klapper MH, Milstein V, et al. Carbamazepine compared with lithium inthe treatment of mania. Arch Gen Psychiatry. 1991;48:915-921.
16. Weisler RH, Kalali AH, Ketter TA. A multicenter, randomized, double-blind,placebo-controlled trial of extended-release carbamazepine capsules as monotherapy forbipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004;65:478-484.
17. Weisler RH, Keck PE Jr, Swann AC, Cutler AJ, Ketter TA, Kalali AH. Extended-releasecarbamazepine capsules as monotherapy for acute mania in bipolar disorder: amulticenter, 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 combinationwith valproate or lithium in the treatment of mania in patients partially nonresponsive tovalproate 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 inpatients with bipolar disorder treated with olanzapine added to lithium or valproic acid. JAffect Disord. 2004;81:223-229.
20. Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of amood 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 plusrisperidone 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 moodstabilizers: 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 foradolescent mania. J Am Acad Child Adolesc Psychiatry. 2002;41:1216-1223.
24. Yatham LN, Paulsson B, Mullen J, Vagero AM. Quetiapine versus placebo incombination with lithium or divalproex for the treatment of bipolar mania. J ClinPsychopharmacol. 2004;24:599-606.
25. Sachs G, Chengappa KN, Suppes T, et al. Quetiapine with lithium or divalproex forthe 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, carbamazepineand 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-controlledtrial of oxcarbazepine in the treatment of bipolar disorder in children andadolescents. Am J Psychiatry. 2006;163:1179-1186.
28. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentintreatment of panic disorder. J Clin Psychopharmacol. 2000;20:467-471.
29. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia withgabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19:341-348.
30. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin forthe 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 withrisperidone for acute mania: a randomized open-label study. ProgNeuropsychopharmacol Biol Psychiatry. 2005;29:115-121.
32. Ciapparelli A, Dell'Osso L, Tundo A, et al. Electroconvulsive therapy in medication-non-responsivepatients 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 withlithium in the management of manic states. Arch Gen Psychiatry. 1988;45:727-732.
34. Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp CommunityPsychiatry. 1994;45:444-450.
35. Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA. Nicotine dependence andpsychiatric disorders in the United States: results from the national epidemiologic surveyon 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 ClinPsychiatry. 1996;57(suppl 13):4-9.
37. Oluboka OJ, Bird DC, Kutcher S, Kusumakar V. A pilot study of loading versustitration 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 divalproexsodium 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 andearly 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 ofacute mania. Bipolar Disord. 2000;2:42-46.
41. Goldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L. Rapid titration of moodstabilizers predicts remission from mixed or pure mania in bipolar patients. J ClinPsychiatry. 1998;59(4):151-158.
42. Kupfer DJ, Frank E, Grochocinski VJ, Cluss PA, Houck PR, Stapf DA. Demographicand clinical characteristics of individuals in a bipolar disorder case registry. J ClinPsychiatry. 2002;63:120-125.
43. National Association of State Mental Health Program Directors. Technical Report onPsychiatric Polypharmacy, 2001. Available at:www.nasmhpd.org/general_files/publications/med_directors_pubs/Polypharmacy.pdf.Accessed October 18, 2005.