Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.
Disclosure: Dr. Kennedy has received research support or honoraria from AstraZeneca, Eli Lilly, Forest, Janssen, Myriad, and Pfizer.
Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: email@example.com.
Pharmacologic and psychosocial treatment options for mania have improved substantially as evidenced by the volume of expert opinion, guidelines, meta-analyses and reports from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. However, these sources offer little direct evidence from the treatment of older patients. The lack of data is troublesome because bipolar disorder in late life is complicated by both mental and physical comorbid conditions, making both diagnosis and treatment challenging. Given the increase in the aging adult population, the frequency with which primary care physicians (PCPs) encounter late-life mania will increase as well. What follows is a brief review of the character and control of late-life mania as well as expert inferences from the Acute Pharmacotherapy of Late-Life Mania (GERI-BD) and STEP-BD studies.
Late-onset mania is often misdiagnosed and, as a result, is likely to be more common than previously reported. With the increase in the older adult population, PCPs and general psychiatrists will inevitably encounter greater numbers of patients with late-life bipolar disorders and mania. The notion that bipolar disorders “burn out” in old age is more myth than reality. Indeed, few older adults with the disorder experience a full functional recovery despite symptom remission. Although substance abuse disorders are less frequently associated with bipolar disorder than in early life,1 impairments in cognitive speed and executive dysfunction are common.2 Late-onset mania occurs equally among men and women. With the exception of less sexual preoccupation among older patients, age has little impact on the symptom profile.3
Manic episodes in older adults often present with confusion, disorientation, distractibility, and irritability rather than elevated, positive mood. The clinical interview may be characterized by irrelevant content delivered with an argumentative, emotionally-intense yet fluent quality. Grossly unrealistic plans concerning finances or travel, inflated self esteem, and contentious claims of certainty in the face of evidence to the contrary are also seen. The unsuspecting examiner may be puzzled (or irritated) by the difficulty of the interchange until the diagnosis of mania is considered.
The presence of psychosis, sleep disturbance, and aggressiveness may lead to the mistaken diagnosis of dementia or depressive disorder rather than mania. Because mania in late life is genuinely less frequent than depression or dementia and less frequently recognized, these patients are often treated with antipsychotics, antidepressants, or benzodiazepines which provide only partial relief. Late-onset mania is more often secondary to or closely associated with other medical disorders, most commonly stroke, dementia, or hyperthyroidism; it is also associated with medications including antidepressants, steroids, estrogens, and other agents with known central nervous system properties.4 A search for treatable components that contribute acutely to the person’s disability should be pursued. Risk factors for cerebrovascular disease, including excessive use of alcohol, tobacco, suboptimal control of hypertension, and other cardiovascular risk factors should be explored.
The workup should also identify indicators such as structural brain changes or dementia that will assist in prognosis. Careful inquiry of the family may uncover repeated hypomanic episodes which did not seriously impair the individual but in retrospect are clear indications of earlier disease. The difficulties of recognizing the diagnosis, care for contributing conditions, age-related vulnerability to medication side effects, and frequency with which structural brain changes are associated all make treatment more difficult. Structural brain changes most frequently include subcortical hyperintensities seen on magnetic resonance imaging.5 Table 1 provides diagnostic criteria for manic and hypomanic episodes. Table 2 portrays diagnoses that are easily confused with mania.
Treatment of Mania
An adequate review of effective, evidenced-based psychosocial interventions for bipolar disorder is beyond the scope of this column. However, the capacity of psychosocial interventions to prevent hospitalization associated with recurrence makes awareness of these interventions crucial to good care. Readers are referred to the works of Miklowitz and colleagues6,7 for a review of the evidence. There is a growing consensus based on expert opinion,8 published guidelines,9,10 and the STEP-BD reports11,12 that antiepileptics, called mood stabilizers in this context, are preferable both for acute treatment and prevention of recurrence in late-life mania and bipolar disorder depression. The anticonvulsant divalproex is increasingly considered first choice for treatment and prevention of mania. A therapeutic level is available; while hepatic toxicity is a risk, it is infrequent. Divalproex inhibits hepatic enzymes that metabolize medications frequently used by older adults. Patients taking β-blockers, type 1c antiarrhythmics, benzodiazepines, or anticoagulants should be monitored more closely until the divalproex dose is stabilized. Dose, precautions, and therapeutic levels for other mood stabilizers appear in Table 3.
Due to the delay in the anti-manic effects of mood stabilizers, a 3-week period including titration to a therapeutic range is the minimum time required to establish treatment responsiveness. In the interim, people whose manic excitement is extreme, exhausting, or overly aggressive will require an antipsychotic or benzodiazepine. As shown in Table 3, numerous atypical antipsychotics are Food and Drug Administration approved for the treatment of mania. Based on meta-analyses, they appear to be equally superior to placebo13 such that the choice of an individual agent is based on side-effect profiles and patient vulnerabilities. However, the available data on the treatment of mania in the STEP-BD study as well as the meta-analyses14 includes few older adults.
On contrast, the GERI-BD study,15,16 sponsored by the National Institute of Mental Health and chaired by Robert Young, MD, included adults ≥60 years of age. They must have a current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,17 diagnosis of bipolar disorder, Type 1 (manic, mixed, hypomanic), be medically stable, and be free of schizophrenia and dementia. These patients will be randomized to receive monotherapy with lithium or divalproex with dose titration to be completed within 3 weeks (Table 4). Doses are increased or decreased based on side effects as well as therapeutic levels across initial, intermediate, and final target ranges. Lithium 150 mg or divalproex 250 mg is initiated BID and is adjusted by increasing or decreasing on a step by step basis, with one step equaling one of the twice daily doses. An increase or decease of one to two steps is made depending upon where the therapeutic level falls in the initial, intermediate, or final range. Therapeutic levels, side effects, and symptomatic response or lack thereof are obtained on days 4, 9, 15, and 21 following baseline. Blood work to ensure safety is collected at baseline and weeks 3, 6, and 9 and includes complete blood count, transaminases, and amylase. Dose reduction is indicated for tremor interfering with self care, ataxia or unsteady gait, excess sedation, or bradycardia <50 beats per minute. Medications may be held or discontinued when the platelet count is <80,000 or if transaminases or amylase are two-fold or more above normal limits. The onset of diabetes insipidous (polyuria, polydipsia) may also be cause for discontinuation of lithium.
Lorazepam, then risperidone, may be added during the first 3 weeks for as needed use when agitation, aggression, anxiety, hyperactivity, or insomnia are excessive. However, if after 3 weeks of treatment symptoms remain substantial or have not declined by 20%, risperidone is added as adjunctive, combined daily therapy to either lithium or divalproex. Risperidone may be titrated up to 3 mg/day with a maximum dose of 4 mg. A score of ≥16 or a decline of <20% from baseline as measured by the Young Mania Rating Scale18 at 3 weeks is the objective severity indicator for adjunctive risperidone. Although study results are not expected to appear before 2010, the GERI-BD protocol provide an expert opinion for aggressive treatment of late-life mania.15,16
Seniors who have experienced good results with lithium should not be switched to an alternative. Nonetheless, numerous concerns argue for caution when considering lithium for the initiation of treatment. Advanced age, absence of family history of bipolar disorder, mania secondary to another medical condition (particularly stroke), or dementia predict poor response to lithium. The age-related decline in renal function means older adults are at increased risk of toxicity because lithium is cleared solely by the kidneys. Structural brain changes which may not be clinically apparent are associated with higher risk of toxicity. Drug interactions which are less dangerous and less common in younger patients complicate the use of lithium in older adults. Laboratory tests which should be checked at least annually in patients treated with lithium include fasting blood sugar, thyroid function, creatinine clearance, blood urea nitrogen, and electrolytes. Diabetes insipidous (polydipsia, polyuria), hyperglycemia, thyroid abnormalities, congestive heart failure or arrhythmia, and psoriasis are among the more frequent reasons for changing to an alternative treatment.19
Manifestations of lithium toxicity include gastrointestinal complaints, ataxia, slurred speech, delirium, or coma. Toxicity in older adults may occur at plasma levels below the therapeutic range of 1.0 mEq/L. However, mild tremor and nystagmus without functional consequences frequently accompany lithium treatment and should not be considered signs of toxicity. Toxicity may result when dehydration due to vomiting, diarrhea, fever, or sweating contracts the extracellular volume of distribution. Lithium is reabsorbed in preference to sodium leaving little margin for error. Renal failure, diuretics, reduced intake of salt or fluids, and concomitant use of nonsteroidal anti-inflammatory agents (excepting aspirin and sulindac), increase the risk of toxicity.20 Long-lasting cerebellar dysfunction is the most common neurologic sequeallae of lithium toxicity, although dementia, parkinsonism, peripheral neuropathies, and brainstem symptoms have also been reported.21 Cautious re-hydration will counter suspected lithium toxicity, but return of the patient’s mental status to baseline may be prolonged. In acute renal failure, dialysis or forced saline diuresis will be required.22
Electroconvulsive Therapy for Mania
Electroconvulsive therapy (ECT) has a long history in the treatment of mania and may be indicated for the severely disturbed older patient when either agitation or the threat of aggression becomes extreme. It may be particularly useful in cases of medication inefficacy or intolerance, imminent suicidal risk, or morbid nutritional status. Advanced age, concurrent antidepressants, and heart disease increase the risk of adverse reactions, with cardiovascular complications being the most frequent events. The cognitive impairment associated with ECT includes transient postictal confusion, anterograde or retrograde amnesia, and less commonly a permanent amnestic syndrome in which recall of events surrounding the treatment is blank. Treatments may be limited to twice weekly and applied bifrontally or unilaterally to the non-dominant hemisphere to minimize confusion. However, bilateral treatment may be more effective.23
With the increasely aging adult population, PCPs and general psychiatrists will inevitably encounter greater numbers of patients with late-life bipolar disorders and mania. Data specific to the treatment of older adults must await the results of the GERI-BD study.15,16 However, reliable inferences based on published guidelines,9,10 meta-analyses,13 and the STEP-BP study7,11,12,14 provide considerable guidance for both biomedical and psychosocial interventions. Initial treatment should begin with a mood stabilizer. A short-acting benzodiazepine or atypical antipsychotic may be necessary during the titration phase of mood stabilizer therapy to “rescue” the patients from intolerable or dangerous symptoms. For people who remain symptomatic or exhibit depressive symptoms despite reaching a therapeutic level of a mood stabilizer, ongoing adjunctive therapy with an atypical antipsychotic appears superior to the addition of an antidepressant. Comorbidities and polypharmacy rather than age per se are the indicators for caution. Because cognitive impairment and recurrence are frequent, family-focused psychotherapy is likely to be as crucial for mania as it is for bipolar depression.2 The risk–benefit-burden comparison of lithium to divalproex remains in question but should be resolved by results from the GERI-BD study.15,16 Table 5 provides consumer and advocacy information. PP
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2. Gildengers AG, Butters MA, Chisolm D, et al. Cognitive functioning and instrumental activities of daily living in late-life bipolar disorder. Am J Geriatr Psychiatry. 2007;15(2);174-179.
3. Young RC, Kiosses D, Heo M, Schulberg HC, Murphy C, Klimstra S, Deasis JM, Alexopoulos GS. Age and ratings of manic psychopathology. Bipolar Disord. 2007;9(3):301-304.
4. Young RC, Moline M, Kleyman F. Estrogen replacement therapy and late life mania. Am J Geriatr Psychiatry. 1997;5(2):179-181.
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6. Miklowitz DJ, George EL, Richards JA, Simoneau TL, Suddath RL. A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Arch Gen Psychiatry. 2003;60(9):904-912.
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8. Keck PE, McElroy SL, Nemeroff CB. Anticonvulsants in the treatment of bipolar disorder. J Neuropsychiatry Clin Neurosci. 1992;4(4):395-405.
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10. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
11. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch on mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163(9):232-239.
12. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms; findings from the STEP-BD. Am J Psychiatry. 2007;164(9):1348-1355.
13. Perlis RH, Weige JA, Vornik LA, Hirshfeld RM, Keck PE. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry. 2006;67(4):509-516.
14. Kogan JN, Otto MW, Bauer MS, et al. Demographic and diagnostic characteristics of the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Bipolar Disord. 2004;6(6):460-469.
15. Treatment of Bipolar Mania in Older Adults. Available at: www.clinicaltrials.gov/ct2/show/record/NCT00254488. Accessed December 11, 2007.
16. Young RC, Beyer J, Gyulai L, et al. A randomized controlled trial of acute treatments in late-life mania. Abstract presented at: the 6th International Meeting of the International Society Bipolar Disorder; Pittsburgh, PA; June 2005.
17. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
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19. McDonald WM, Nemeroff CB. The diagnosis and treatment of mania in the elderly. Bull Menninger Clin. 1996;60(2):174-196.
20. Ragheb M. The clinical significance of lithium-nonsteroidal anti-inflammatory drug interactions. J Clin Psychopharmacol. 1990;10(5):350-354.
21. Verdoux H, Bourgeois M. A case of lithium neurotoxicity with irreversible cerebellar syndrome. J Nerv Ment Dis. 1990;178(12):761-762.
22. Parfrey PS, Ikeman R, Anglin D, Cole C. Severe lithium intoxication treated by forced diuresis. Can Med Assoc J. 1983;129(9):979-980.
23. Lisanby SH. Electroconvulsive therapy of depression. N Engl J Med. 2007;357(19):1939-1945.