Does olanzapine-fluoxetine combination increase the risk of mania in poorly compliant bipolar depressed patients?

To the Editor: Fluoxetine is useful for the treatment of depression and olanzapine for the treatment of schizophrenia and acute bipolar mania. In 2001, olanzapine-fluoxetine combination was found to be effective in a small sample of patients with nonbipolar depression. (1) Subsequently, a controlled study demonstrated olanzapine to be more effective than placebo and olanzapine plus fluoxetine more effective than olanzapine plus placebo for treatment of bipolar depression, without significant risk of development of mania. (2) We describe a patient with bipolar depression with development of mania related to treatment with olanzapine-fluoxetine combination.

A 34-year-old female was diagnosed with bipolar disorder in her early twenties. She had no history of medical problems or substance abuse. She had two episodes of mania (at ages 23 and 27 years) and recurrent episodes of depression. She attempted suicide at age 32. She was treated with valproate and a number of antidepressants with no recurrence of mania but continued to have intermittent depression. By 2004, she was taking 750 mg of valproate b.i.d and 100 mg of sertraline daily.

In March 2004, she was hospitalized with depression. Previous medications were discontinued, and she was started on 6 mg olanzapine/25 mg fluoxetine combination daily. Over a period of 2 weeks, her mood improved and she was discharged on 6 mg olanzapine/50 mg fluoxetine daily. During clinic visits in April and May, she was euthymic and without complaints. Then, in June, concerned that her weight had increased from 110 to 118 pounds, she abruptly discontinued her medication. About 5 days later, her husband noted that she was grandiose with rapid speech. Over the next 3 days she worsened, sleeping only a few hours per night, and was readmitted. Examination revealed markedly elevated mood, pressured speech, flight of ideas, and grandiose delusions.

She was given 10 mg of olanzapine b.i.d. After 1 week, the mania resolved and the dosage was decreased to 15 mg at bedtime. Paroxetine (20 mg daily) was added because her depression was returning. She was discharged several days later and over the following 2 months had no significant problems with depression or mania. Because her weight gain persisted, olanzapine was changed to 4 mg of risperidone daily, and she continued to do well.

Induction of mania has not been significant in studies of olanzapine-fluoxetine combination. Mania did not occur in the initial study of 28 unipolar depressed patients. (1) In the larger study of patients with bipolar depression, (2) rates of treatment-emergent mania were 6.7% for patients randomly assigned to placebo, 5.7% for those randomly assigned to olanzapine treatment, and 6.4% for those randomly assigned to olanzapine-fluoxetine treatment (differences insignificant, P = 0.86). Young Mania Rating Scale scores were significantly lower for treatment groups than for placebo. The findings indicated no additional risk of treatment-emergent mania when fluoxetine was added to olanzapine. The Symbyax package insert (3) also describes two controlled studies of bipolar depression with rates of mania not significantly higher for Symbyax than for placebo.

A conceivable explanation for this patient's mania is that it was induced by the presence of fluoxetine or its active metabolites remaining in her body after discontinuation of the olanzapine-fluoxetine combination. Olanzapine has a half-life of 30 hours, whereas fluoxetine has a long half-life of 1 to 4 days, and its active metabolite, nor-fluoxetine, up to 15 days. Thus, for practical purposes, a few days after stopping the olanzapine-fluoxetine combination, the patient had the pharmacological effects of an antidepressant alone. That antidepressants can induce mania in susceptible patients is well established. (4)

Other explanations are possible. There are reports of induction of mania by antidepressants, including fluoxetine, (4) and by atypical antipsychotics, including olanzapine, (5) so either of these could theoretically have precipitated her mania. However, were this the case, mania would have been more likely while she was taking medications rather than subsequent to discontinuing them. It is also possible that she had spontaneous emergence of mania as part of her bipolar disorder, but she had not had a manic episode in 7 years, and the timing of the episode was directly concomitant with discontinuation of the olanzapine-fluoxetine combination. Thus, the most likely cause of this patient's mania was persistence of fluoxetine metabolites after discontinuation of the olanzapine-fluoxetine combination.

Caution should probably be exercised when prescribing this preparation for bipolar depressed patients who might not be compliant. Patients should be advised not to stop the olanzapine-fluoxetine combination suddenly. Otherwise, mania may be precipitated by persisting fluoxetine metabolites. When the olanzapine-fluoxetine combination must be discontinued, consideration should be given to administering olanzapine or another mood stabilizer for a period of time to protect the patient from fluoxetine-induced mania.

Roy R. Reeves, DO, PHD

Mark E. Ladner, MD

G.V. (Sonny) Montgomery VA

Medical Center and the University of Mississippi School of Medicine Jackson, MS

References

1. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001; 158:131-134.

2. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60:1079-1088.

3. Eli Lilly and Company. Symbyax (olanzapine and fluoxetine) package insert. Indianapolis, IN; 2003.

4. Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry 1994;164:835-836.

5. Rachid F, Bertschy G, Bondolfi G, et al. Possible induction of mania or hypomania by atypical antipsychotics: an updated review of reported cases. J Clin Psychiatry 2004;65:1537-1545.

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