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.