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Evidence-Based Reviews


Corticosteroid-induced mania: Prepare for the unpredictable

Head off this common psychiatric side effect.

Vol. 5, No. 6 / June 2006
This week's quiz:
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Can corticosteroids “unlock” hidden potential for mania, or are steroid-induced mood symptoms a temporary reaction? And when these mood symptoms occur, what is the best way to treat them?

Psychiatric symptoms develop in 5% to 18% of patients treated with corticosteroids. These effects—most often mania or depression—emerge within days to weeks of starting steroids. To help you head off manic and mixed mood symptoms, this paper examines how to:

  • treat steroid-induced mania or mixed bipolar symptoms
  • reduce the risk of a mood episode in patients who require sustained corticosteroid therapy.

‘Steroid psychosis’

Jane Pauley, NBC’s Today Show broadcaster, described in her autobiography how hypomania developed within weeks after she started corticosteroids for idiopathic urticaria edema: “I was so energized that I didn’t just walk down the hall, I felt like I was motoring down the hall. I was suddenly the equal of my high-energy friends who move fast and talk fast and loud. I told everyone that I could understand why men felt like they could run the world, because I felt like that. This was a new me, and I liked her!”1

Pauley’s hypomania led to a manic episode and eventually to depression. She was started on antidepressants, which triggered another manic episode. Pauley—who had no history of bipolar disorder—spent 3 weeks in a New York psychiatric hospital.1

Diagnostic symptoms. Corticosteroids’ psychiatric effects—cognitive, mood, anxiety, and psychotic symptoms—were first described as “steroid psychosis.” Psychosis can occur, but mood symptoms are more common:

  • Among 122 patients, 40% experienced depression, followed by mania (28%), psychosis (14%), delirium (10%), and mixed mood episodes (8%).2
  • Among 130 patients, mania was most prevalent (35%), followed by depression (28%), mixed mood episodes (12%), delirium (13%), and psychosis (11%).3
  • Corticosteroids caused 54% of organic mania cases on a hospital psychiatric consult service.4
  • In a prospective study of 50 patients treated with corticosteroids, 13 developed hypomania and 5 developed depression.5

Steroid-induced symptoms emerge from 3 to 4 days to a median of 11 days after a patient starts corticosteroid therapy. After steroids are discontinued, depressive symptoms persist approximately 4 weeks, mania 3 weeks, and delirium a few days. Approximately one-half of patients with steroid psychosis improve in 4 days and one-half within 2 weeks.2,6

Who is at risk?

Corticosteroids include the steroids produced in the adrenal gland (such as corticosterone) and their synthetic—and often more potent—analogues (such as prednisone).7 Because of their glucocorticoid, immunosuppressant, mineralocorticoid, and anti-inflammatory properties, steroids are used as replacement therapy and to treat a wide variety of illnesses (Table 1).

Table 1

Medical conditions for which corticosteroids are commonly used

Disorder

Indications for corticosteroids

Acute adrenal insufficiency

Acute; replacement therapy

Addison’s disease

Chronic; replacement therapy

Asthma

Acute and chronic; anti-inflammatory

Inflammatory bowel disease

Acute; anti-inflammatory

Multiple sclerosis

Acute; exacerbations, immunosuppressant

Organ transplant

Chronic; immunosuppressant

Rheumatoid arthritis

Chronic; anti-inflammatory

Systemic lupus erythematosus

Acute; severe exacerbation, immunosuppressant (high doses are used)

Age and gender. Patient age appears unrelated to development of psychiatric symptoms after corticosteroid use.2 One study suggested women are twice as likely as men to develop psychiatric symptoms (77 versus 38 cases in 115 patients),3 but many illnesses that require corticosteroid treatment occur more frequently in women. Other researchers found a slight female predominance (58% versus 42% of cases) when they excluded patients with systemic lupus erythematosus and rheumatoid arthritis, which are more common in women than in men.2

Dosage. Higher corticosteroid dosages increase the risk of psychiatric symptoms. In patients taking prednisone, the Boston Collaborative Drug Surveillance Project8 found the incidence of psychiatric side effects to be:

  • 1.3% in patients taking <40 mg
  • 4.6% in those taking 41 to 80 mg
  • 18.4% in those taking >80 mg.

Psychiatric history. Past psychiatric illness does not seem to be a risk factor for psychiatric side effects of corticosteroids,9 although patients with a history of posttraumatic stress disorder are more likely to suffer depression while taking corticosteroids.10

Corticosteroid exposure. Patients who did not experience psychiatric side effects with corticosteroids in the past appear not to be protected if corticosteroids are used again. One report examined 17 cases of steroid-induced psychiatric illness in patients with previous exposure to corticosteroid therapy. Six patients had previous psychiatric side effects while taking corticosteroids, and 11 did not.2

Bipolar trigger?

Do corticosteroids’ acute psychiatric side effects have long-term sequelae? Longitudinal evidence is scarce, but a few reports suggest corticosteroids could play a role in the onset of primary bipolar I disorder:

  • A 28-year-old woman with no known mood symptoms before a short course of prednisone experienced six episodes of mania and depression when not taking corticosteroids during the subsequent 18 months.11
  • Among 16 patients with first-onset mood symptoms after corticosteroid use, a retrospective chart review found 7 had recurrent manic and depressive symptoms unrelated to additional corticosteroid use.12

Although intriguing, these case reports are inconclusive. Because bipolar type I incidence in the general population is 1.5%,13 many persons with bipolar disorder undergo corticosteroid treatment. Nevertheless, these results—especially from the retrospective review12—suggest that corticosteroid use may contribute to the onset of bipolar I illness.

Symptomatic treatment

Corticosteroid-induced side effects are usually managed by tapering off the steroids and treating the psychiatric symptoms.2,3 Simply tapering off the steroids—without additional treatments—led to recovery in 33 of 36 patients.2 Stopping corticosteroids is not always possible or desirable, however, especially in many medically complicated cases seen by psychiatric consult services.

In a recent case, I was asked to see a man, age 69, on the oncology service who was receiving corticosteroids every 2 weeks as part of his chemotherapy. The patient was admitted to the hospital for acute mental status changes 2 days after his last corticosteroid dose. He had pressured speech, grandiosity, and had not slept in 2 days. We started risperidone, 1 mg bid, and most of his manic symptoms resolved within 2 days. His chemotherapy was continued without corticosteroids. If this had not been not possible, I would have recommended continuing risperidone prophylactically.

No double-blind, placebo-controlled studies have examined prevention or treatment of steroid-induced mania or other psychiatric symptoms. Uncontrolled trials and case reports suggest benefit from some symptomatic and preventive treatments (Table 2).

Table 2

Mood stabilizers with evidence of benefit in treating corticosteroid-induced mania

Indication

Medication

Dosage/blood level

Evidence

Preventing psychiatric effects in patients requiring long-term corticosteroids

Lithium

0.8 to 1.2 mEq/L

Prospective trial (27 with multiple sclerosis)24

Preventing recurrence of manic symptoms in patients requiring additional steroid pulses

Carbamazepine

600 mg qd (to therapeutic range of 8 to 12 μg/mL)*

Case report16

Gabapentin

300 mg tid

Case report26

Treating steroid-induced manic symptoms

Olanzapine

Initially 2.5 mg/d, titrated to 20 mg/d

Open-label trial (12 patients)14

Lithium

0.7 mEq/L

Case report15

Quetiapine

25 mg qhs and 12.5 mg bid prn

Case report17

Carbamazepine

600 mg qd (to therapeutic range of 8 to 12 μg/mL)*

Case reports12,16

Haloperidol

2 to 20 mg/d*

Case reports12,16

Treating steroid-induced depressive symptoms

Fluoxetine

20 mg/d

Case report18

Amitriptyline

30 mg/d (usual effective range is 50 to 300 mg/d)*

Case report12

Lamotrigine

Up to 400 mg/d

Case report19

Lithium

0.1 to 0.8 mEq/L

Case reports20,21

Treating steroid-induced psychotic symptoms

Haloperidol

5 mg IV on day 1, then 2 mg po bid

Case report22

Risperidone

1.5 mg/d

Case report23

*Dosage not included in published report; recommendation based on experience or anecdotal information

Treating manic and mixed mood symptoms. Twelve outpatients with manic or mixed symptoms from corticosteroid use received olanzapine in a 5-week, open-label trial. Flexible dosing started at 2.5 mg/d and was increased as needed (maximum 20 mg/d). One patient dropped out for lack of efficacy. For the others, manic and mixed symptoms improved significantly, as indicated by scores on the Young Mania Rating Scale, Hamilton Rating Scale for Depression, and Brief Psychotic Rating Scale.14 Patient weight, blood glucose, and involuntary movements did not change significantly.

Evidence from case reports indicates that lithium,15 carbamazepine,12,16 haloperidol,12,16 or quetiapine17 also can successfully treat steroid-induced manic symptoms.

Treating other psychiatric symptoms. Case reports support electroconvulsive therapy,2,15 fluoxetine,18 amitriptyline,12 lamotrigine,19 or lithium20,21 for steroid-induced depression, and haloperidol22 or risperidone23 for steroid-induced psychosis.

In four cases,6 tricyclic antidepressants appeared to worsen corticosteroids’ psychiatric side effects. These case patients might have had steroid-induced delirium instead of mood disorders or psychosis, however, and the tricyclics’ anticholinergic effects could have worsened the delirium.9

Preventing steroid-induced symptoms

Although clear guidelines on when to start preventive treatments do not exist, potential candidates for pretreatment with lithium or other agents include patients who:

  • have developed psychiatric symptoms multiple times after repeated corticosteroid use
  • are at high risk if psychiatric side effects occur.

Lithium. Prophylactic lithium was given to 27 patients with multiple sclerosis and taking corticosteroids for acute exacerbations. None developed psychiatric symptoms.24 At the same clinic, 6 of 44 patients with multiple sclerosis or retrobulbar neuritis developed psychiatric side effects after using corticosteroids without lithium.

Be cautious when using prophylactic lithium because some conditions treated with corticosteroids—such as systemic lupus erythematosus—can impair renal function.20 Corticosteroids also can affect sodium balance and increase the risk of lithium intoxication.25

Check renal function before and during lithium titration, and initiate corticosteroid therapy when lithium is at effective blood levels (0.8 to 1.2 mEq/L). Monitor lithium levels and renal function frequently during steroid treatment.

Other mood stabilizers. Two case reports describe patients who repeatedly developed manic symptoms after multiple corticosteroid doses. Carbamazepine, 600 mg qd,16 and gabapentin, 300 mg tid,26 prevented manic symptoms after additional corticosteroid pulses.

Related resources

  • Brown ES, Chandler PA. Mood and cognitive changes during systemic corticosteroid therapy. Prim Care Companion J Clin Psychiatry 2001;3(1):17-21. www.psychiatrist.com/pcc/abstracts/pcc030103.htm.
  • Merrill W. Case 35-1998: use of lithium to prevent corticosteroid-induced mania. N Engl J Med 1999;340:1123.

Drug brand names

  • Amitriptyline • Elavil
  • Carbamazepine • Tegretol
  • Fluoxetine • Prozac
  • Gabapentin • Neurontin
  • Haloperidol • Haldol
  • Lamotrigine • Lamictal
  • Lithium • Eskalith, others
  • Olanzapine • Zyprexa
  • Quetiapine • Seroquel
  • Risperidone • Risperdal

Disclosures

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

References

1. Pauley J. Skywriting: a life out of the blue. New York: Random House; 2004.

2. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes. A report of 14 cases and a review of the literature. J Affect Disord 1983;5:319-32.

3. Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry 2003;25:27-33.

4. Rundell JR, Wise MG. Causes of organic mood disorder. J Neuropsychiatry Clin Neurosci 1989;1:398-400.

5. Naber D, Sand P, Heigl B. Psychopathological and neuropsychological effects of 8-days’ corticosteroid treatment. A prospective study. Psychoneuroendocrinology 1996;21:25-31.

6. Hall R, Popkin M, Stickney S, Gardner E. Presentation of the steroid psychoses. J Nerv Ment Dis 1979;167:229-36.

7. Schimmer B, Parker K. Adenohypophyseal hormones and their hypothalamic releasing factors. In: Hardman J, Limbird L, Gilman A (eds). Goodman and Gilman’s the pharmacological basis of therapeutics, 9th ed. New York: McGraw-Hill;1996:1459-86.

8. The Boston Collaborative Drug Surveillance Program. Acute adverse reactions to prednisone in relation to dosage. Clin Pharmacol Ther 1972;13:694-8.

9. Patten SB, Neutel CI. Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis and management. Drug Saf 2000;22:111-22.

10. Brown ES, Suppes T, Khan DA, Carmody TJ, 3rd. Mood changes during prednisone bursts in outpatients with asthma. J Clin Psychopharmacol 2002;22:55-61.

11. Pies R. Persistent bipolar illness after steroid administration. Arch Intern Med 1981;141:1087.-

12. Wada K, Yamada N, Suzuki K, et al. Recurrent cases of corticosteroid-induced mood disorder: a clinical characteristics and treatment. J Clin Psychiatry 2000;61:261-7.

13. Narrow WE, Rae DS, Robins LN, Regier DA. Revised prevalence estimates of mental disorders in the United States: using a clinical significance criterion to reconcile 2 surveys’ estimates. Arch Gen Psychiatry 2002;59:115-23.

14. Brown ES, Chamberlain W, Dhanani N, et al. An open-label trial of olanzapine for corticosteroid-induced mood symptoms. J Affect Disord 2004;83:277-81.

15. Blazer DG, 2nd, Petrie WM, Wilson WP. Affective psychosis following renal transplant. Dis Nerv Syst 1976;37:663-7.

16. Wada K, Yamada N, Yamauchi Y, Kuroda S. Carbamazepine treatment of corticosteroid-induced mood disorder. J Affect Disord 2001;65:315-7.

17. Siddiqui Z, Ramaswamy S, Petty F. Quetiapine therapy for corticosteroid-induced mania. Can J Psychiatry 2005;50:77-8.

18. Wyszynski AA, Wyszynski B. Treatment of depression with fluoxetine in corticosteroid-dependent central nervous system Sjogren’s syndrome. Psychosomatics 1993;34:173-7.

19. Brown ES, Frol A, Bobadilla L, et al. Effect of lamotrigine on mood and cognition in patients receiving chronic exogenous corticosteroids. Psychosomatics 2003;44:204-8.

20. Terao T, Mizuki T, Ohji T, Abe K. Antidepressant effect of lithium in patients with systemic lupus erythematosus and cerebral infarction, treated with corticosteroid. Br J Psychiatry 1994;164:109-11.

21. Terao T, Yoshimura R, Shiratuchi T, Abe K. Effects of lithium on steroid-induced depression. Biol Psychiatry 1997;41:1225-6.

22. Ahmad M, Rasul FM. Steroid-induced psychosis treated with haloperidol in a patient with active chronic obstructive pulmonary disease [letter]. Am J Emerg Med 1999;17:735.-

23. DeSilva CC, Nurse MC, Vokey K. Steroid-induced psychosis treated with risperidone. Can J Psychiatry 2002;47:388-9.

24. Falk WE, Mahnke MW, Poskanzer DC. Lithium prophylaxis of corticotropin-induced psychosis. JAMA 1979;241:1011-2.

25. Saklad SR. Management of corticosteroid-induced psychosis with lithium. Clin Pharm 1987;6:186.-

26. Ginsberg DL, Sussman N. Gabapentin as prophylaxis against steroid-induced mania. Can J Psychiatry 2001;46:455-6.

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