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Out of the Pipeline


Olanzapine/fluoxetine combination: Evidence for using the first treatment indicated for bipolar depression

Vol. 3, No. 4 / April 2004
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Patients with bipolar disorder spend half their lives significantly symptomatic, mainly in the depressive phase.1 Treating bipolar depression poses a clinical challenge, although new research is starting to uncover some answers. Antidepressant drugs are commonly used, but recent data question the effectiveness of this practice.2

An olanzapine-fluoxetine combination (OFC), FDA-approved for treating bipolar type I depression, has demonstrated efficacy in clinical trials.

How it works

Most atypical antipsychotics—including olanzapine—are potent 5-HT2A (serotonin) receptor antagonists. This effect is similar to that of some antidepressants and may mediate some antidepressant and antianxiety effects of these drugs.3

Like most atypicals, olanzapine is also a potent 5-HT2C blocker. While binding to this receptor, serotonin inhibits dopamine release in the nucleus accumbens and frontal cortex.4 Thus, serotonin blockade would increase dopamine release in these areas. One study showed that olanzapine and fluoxetine together increased dopamine and norepinephrine in the frontal cortex of rats, compared with either drug given individually.5 Dopamine is critical to regulating motivation, defined as the ability to exert energy to obtain rewards.6 Olanzapine also interacts with dopaminergic (D1-5), muscarinic (M1-5), alpha1 adrenergic, histamine1, serotonin (5-HT2B,2C,3,6), and glutamate and other receptors.

Pharmacokinetics

Combining olanzapine and fluoxetine in one capsule raises potential kinetic problems. Olanzapine’s mean half-life is 30 hours,7 but fluoxetine’s is 24 to 72 hours and its principal active metabolite, norfluoxetine, has a half-life of 4 to 16 hours.7 Because fluoxetine and norfluoxetine inhibit the cytochrome P (CYP)-450 2D6 enzyme—which is involved in their metabolism—autoinhibition of degradation occurs with chronic dosing, thereby increasing the relative half-life of fluoxetine and norfluoxetine. Therefore, maximum steady-state plasma levels will be achieved with olanzapine and fluoxetine at very different rates, although this has not posed a problem in clinical trials. Still, consider this disparity when evaluating potential side effects or drug-drug interactions.

Table 1

Drugs that may interact with OFC

Drugs metabolized by CYP 2D6 isoenzymes

Drugs metabolized by CYP 2C isoenzymes

Citalopram

Citalopram

Codeine

Clomipramine

Dextromethorphan

Diazepam

Haloperidol

Imipramine

Metoprolol

Nonsteroidal

Other SSRIs

anti-inflammatory drugs

Perphenazine

Omeprazole

Propafenone

Phenytoin

Propranolol

Proguanil

Risperidone

Tolbutamide

Thioridazine

Tricyclic antidepressants

Trazodone

Warfarin

Tricyclic antidepressants (most)

 

Venlafaxine

 

Source: reference 8

Both compounds reach maximum concentration in 4 to 6 hours. 7 Although food’s effect on OFC’s absorption has not been tested, a clinically important effect is unlikely. Food does not significantly alter absorption kinetics of olanzapine or fluoxetine. 7

Avoid giving OFC concomitantly with drugs metabolized by CYP 2D6 and 2C (Table 1), because fluoxetine is a potent inhibitor of these isoenzymes. The resulting altered plasma concentrations could lead to drug-drug interactions.8

Efficacy

In an 8-week, double-blind, multinational trial,9 833 patients with bipolar I disorder in the depressive phase randomly received placebo, olanzapine alone (5 to 20 mg/d), or OFC in several fixed combinations (all shown as olanzapine/fluoxetine): 6/25 mg/d, 6/50 mg/d, or 12/50 mg/d. Dosage titration was allowed.

The researchers found that:

  • OFC was significantly more effective than placebo. A mean 18.5-point improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores was reported in the OFC group, compared with a mean 11.9-point improvement in the placebo group.
  • Olanzapine alone produced a mean 15-point MADRS score reduction. Remission criteria were achieved in 24.5%, 32.8%, and 48.8% of patients treated with placebo, olanzapine, and OFC, respectively.
  • Both OFC and olanzapine alone produced greater MADRS score reductions than did placebo at every follow-up week. Mania induction rates were low in the olanzapine and OFC treatment groups (5.7% and 6.4%, respectively) as measured with the Young Mania Rating Scale.

Shelton et al3 also compared OFC to olanzapine and fluoxetine alone in treatment-resistant unipolar depression. Thirty-two patients with major depression who responded inadequately to two types of antidepressants were treated with fluoxetine, up to 60 mg/d. After 7 weeks, 28 patients who did not respond to fluoxetine then received fluoxetine alone (mean modal dose: 52 mg/d), olanzapine alone (12.5 mg/d), or OFC (13.5 mg/52 mg/d) for another 8 weeks.

Olanzapine alone produced a transient effect at week 3 with relapse thereafter, possibly because of interactions between olanzapine and falling fluoxetine plasma concentrations over the first 3 weeks. Fluoxetine monotherapy produced minimal results across the 8-week random phase.

The OFC group, however, achieved significant improvement in MADRS scores compared with the placebo group after week one. The effect continued throughout the trial and during a subsequent 8-week open-label phase.3

Recent data suggest continued benefit in treatment- and nontreatment-resistant depressed patients for up to 1 year.10 Two follow-up trials—one using a lead-in with venlafaxine, the second with nortriptyline—produced negative results. In both studies, however, patients achieved a robust effect while continuing the same drug during the double-blind phase, suggesting that initial trials were inadequate.11,12 OFC showed early onset of effect in both studies. Other large-scale attempts at replication are anticipated.

Tolerability

Common side effects of OFC include increased appetite, weight gain, somnolence, fatigue, nausea, diarrhea, and dry mouth—the same effects associated with olanzapine or fluoxetine.

Combining the agents does not lessen the side effects, particularly olanzapine-induced weight gain. Simple, assertive dietary and exercise counseling can counteract olanzapine-induced weight gain.13 Sexual dysfunction was reported infrequently in clinical trials but is possible with exposure to fluoxetine.

Extrapyramidal side effects, including akathisia, appear to be relatively infrequent. Tardive dyskinesia (TD) is unlikely, although cases putatively associated with olanzapine have been reported.5 Many patients with TD have taken conventional antipsychotics, however, so the causal link with olanzapine is obscure. Still, alert patients and families to the possibility of TD and its emerging features.

Table 2

Olanzapine-fluoxetine: Fast facts

Drug brand name: Symbyax

Class: Combined atypical antipsychotic/selective serotonin reuptake inhibitor

FDA-approved indication: Bipolar type I depression

Approval date: Dec. 24, 2003

Manufacturer: Eli Lilly and Co.

Dosing forms: 6/25 mg/d, 12/50 mg/d, 12/25 mg/d, 12/50 mg/d

Dosing recommendations: Start at 6/25 mg at bedtime. Titrate according to tolerability and therapeutic benefit. Once the antidepressant effect is achieved, continue dosage indefinitely if no adverse effects occur. Dosages up to 18/75 mg/d have been used in clinical trials.

Although considered rare, isolated cases of neuroleptic malignant syndrome have been attributed to olanzapine.14 Cycle induction has not been reported in clinical trials, but be mindful of this possibility with long-term treatment.

Clinical implications

Taking olanzapine and fluoxetine as a single capsule could save the patient substantial cost. OFC comes in four dosing forms (Table 2), allowing for some flexibility.

It is unclear whether clinicians will prefer the single combination capsule or prescribe each drug separately to increase flexibility. Starting treatment with olanzapine and fluoxetine individually allows the psychiatrist to change the dosages independently and in smaller increments. Taken as separate agents, however, the two products are more expensive than the combined formula. OFC costs about the same as olanzapine alone. On the other hand, if the clinician begins the compounds individually, converting to the dosages in the combined product probably will not be exactly 1:1.

Tolerability is another major advantage of OFC; the combined agent exhibited a 10% dropout rate because of adverse effects compared with 4.6% for placebo.7 Moreover, some patients will prefer the convenience of using a single capsule instead of two medications.

Related resources

  • Tollefson GD, Sanger TM. Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy? Schizophr Res 1999;35(suppl):S13-S21.
  • Symbyax Web site. www.symbyax.com

Drug brand names

  • Citalopram • Celexa
  • Clomipramine • Anafranil
  • Diazepam • Valium
  • Fluoxetine • Prozac
  • Haloperidol • Haldol
  • Imipramine • Tofranil
  • Metoprolol succinate • Toprol
  • Nortriptyline • Aventyl
  • Olanzapine • Zyprexa
  • Omeprazole • Prilosec
  • Phenytoin • Dilantin
  • Proguanil • Malarone
  • Propafenone • Rythmol
  • Propranolol • Inderal
  • Risperidone • Risperdal
  • Tolbutamide • Orinase
  • Venlafaxine • Effexor
  • Warfarin • Coumadin

Disclosure

Dr. Shelton receives research grants from Abbott Laboratories, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals; is a consultant to Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals; and is a speaker for Abbott Laboratories, Eli Lilly and Co., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth Pharmaceuticals

References

1. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59:530-7.

2. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001;158:906-12.

3. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158:131-4.

4. Shelton RC. The combination of olanzapine and fluoxetine in mood disorders. Expert Opin Pharmacother 2003;4:1175-83.

5. Zhang W, Perry KW, Wong DT, et al. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 2000;23:250-62.

6. Salamone JD, Cousins MS, Snyder BJ. Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci Biobehav Rev 1997;21:341-59.

7. Symbyax package insert. Eli Lilly and Co., 2003.

8. Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996;153:311-20.

9. 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;60:1079-88.

10. Corya SA, Andersen SW, Detke HC, et al. Long-term antidepressant efficacy and safety of olanzapine/fluoxetine combination: a 76-week open-label study. J Clin Psychiatry 2003;64:1349-56.

11. Dube S. Olanzapine-fluoxetine combination in treatment-resistant depression. Eur Psychiatry 2002;17(suppl 1):98.-

12. Dube S, Corya SA, Andersen SW, et al. Efficacy of olanzapine/fluoxetine combination in treatment resistant depression (presentation). San Juan, PR: American College of Neuropsychopharmacology annual meeting, 2002.

13. Ball MP, Coons VB, Buchanan RW. A program for treating olanzapine-related weight gain. Psychiatr Serv 2001;52:967-9.

14. Kogoj A, Velikonja I. Olanzapine-induced neuroleptic malignant syndrome—a case review. Hum Psychopharmacol 2003;18:301-9.

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