Does olanzapine-fluoxetine combination increase the risk of mania in poorly compliant bipolar depressed patients?To the Editor: Fluoxetine fluoxetine /flu·ox·e·tine/ (floo-ok´se-ten) a selective serotonin reuptake inhibitor used as the hydrochloride salt in the treatment of depression, obsessive-compulsive disorder, bulimia nervosa, and premenstrual dysphoric disorder. is useful for the treatment of depression and olanzapine for the treatment of schizophrenia The concept of a cure as such in the treatment of schizophrenia remains controversial, as there is no consensus on the definition of "treatment" in the case of schizophrenia, although some criteria for the remission of symptoms have recently been suggested. 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 bipolar disorder, formerly manic-depressive disorder or manic-depression, severe mental disorder involving manic episodes that are usually accompanied by episodes of depression. 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 valproate /val·pro·ate/ (val-pro´at) a salt of valproic acid; the sodium salt has the same uses as the acid. val·pro·ate n. and a number of antidepressants Antidepressants Medications prescribed to relieve major depression. Classes of antidepressants include selective serotonin reuptake inhibitors (fluoxetine/Prozac, sertraline/Zoloft), tricyclics (amitriptyline/ Elavil), MAOIs (phenelzine/Nardil), and heterocyclics 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 sertraline /ser·tra·line/ (ser´trah-len) a selective serotonin reuptake inhibitor used as the hydrochloride salt in the treatment of depression, obsessive-compulsive disorder, and panic disorder. 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 flight of ideas (flit of i-de´ahz) a nearly continuous flow of rapid speech that jumps from topic to topic, usually based on discernible associations, distractions, or plays on words, but sometimes disorganized and incoherent. , 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 paroxetine /par·ox·e·tine/ (pah-rok´se-ten) a selective serotonin uptake inhibitor used as the hydrochloride salt to treat depression and obsessive-compulsive, panic, and social anxiety disorders. (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 unipolar /uni·po·lar/ (u?ni-po´ler) 1. having a single pole or process, as a nerve cell. 2. pertaining to mood disorders in which only depressive episodes occur. 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 package insert Pharmacology A synopsis of key physicochemical, pharmacologic, clinical efficacy, and clinical safety properties of a prescription drug, bundled therewith, intended to be highly readable and helpful to clinicians looking for specific (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 antidepressant, any of a wide range of drugs used to treat psychic depression. They are given to elevate mood, counter suicidal thoughts, and increase the effectiveness of psychotherapy. 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 manic episode Psychiatry A period characterized by a persistently elevated, expansive, or irritable mood, with ↑ energy, ↓ sleep, distractibility, impaired judgement, grandiosity, flights of ideas, and so on, most often affecting Pts < age 25; MEs 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 Metabolites Substances produced by metabolism or by a metabolic process. Mentioned in: Interactions 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 The University of Mississippi School of Medicine (UMSOM) is one of the graduate schools of the University of Mississippi. It is an American medical school and was created in 1903 on the Oxford, Mississippi campus. 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 Eli Lilly and Company (NYSE: LLY) is a global pharmaceutical company and one of the world's largest corporations. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States. . 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 hypomania /hy·po·ma·nia/ (-ma´ne-ah) an abnormality of mood resembling mania but of lesser intensity.hypoman´ic hy·po·ma·ni·a n. by atypical antipsychotics: an updated review of reported cases. J Clin Psychiatry 2004;65:1537-1545. Letters to the Editor are welcomed. They may report new clinical or laboratory observations and new developments in medical care or may contain comments on recent contents of the Journal. They will be published, if found suitable, as space permits. Like other material submitted for publication, letters must be typewritten type·write intr. & tr.v. type·wrote , type·writ·ten , type·writ·ing, type·writes To engage in writing or to write (matter) with a typewriter. , double-spaced, and submitted in duplicate. They must not exceed two typewritten pages in length. No more than five references and one figure or table may be used. See "Information for Authors" for format of references, tables, and figures. Editing, possible abridgment, and acceptance remain the prerogative of the Editors. |
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