Olanzapine-fluoxetine combination

Zanarini MC, Frankenburg FR, Parachini EA A preliminary, randomized trial of fluoxetine, olanzapine, and the olanzapine-fluoxetine combination in women with borderline personality disorder. J Clin Psychiatry 65 903-907, 2004... 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

Conventional antipsychotic drugs such as chlorpromazine and haloperidol have long been used in the treatment of acute mania. More recently, atypical antipsychotic drugs including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasi-done have been approved for the treatment of bipolar mania or mixed mood episodes as monotherapy or in combination with mood-stabilizing drugs.25 Aripiprazole and olanzapine are also approved for maintenance therapy. The combination of olanzapine and fluoxetine is approved for treatment of bipolar depression. Quetiapine is approved for treatment of... 

Alternatively, the current antidepressant may be augmented (potentiated) by the addition of another agent (e.g., lithium, T3), or an atypical antipsychotic (e.g., risperidone). Risperidone has been shown to be effective in combination with fluvoxamine, paroxetine, or citalopram in treatment-resistant depression. Olanzapine and fluoxetine have been found to be safe and effective in treatment-resistant depression. 

Olanzapine (Zyprexa). Olanzapine has received FDA approval for the treatment of acute mania, long-term maintenance therapy, and bipolar depression in a combination product of olanzapine and fluoxetine. The dose range for olanzapine is 5-30mg/day. It is usually given once daily at bedtime. 

Special populations Use a starting dose of 6 mg/25 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine/fluoxetine (eg, female gender, elderly, nonsmoking status). When indicated, perform dose escalation with caution in these patients. Olanzapine/fluoxetine has not been systemically studied in patients older than 65 years of age or in patients younger than 18 years of age. 

Bipolar depression Lithium, lamotrigine, olanzapine-fluoxetine combination... 

The olanzapine-fluoxetine combination is currently the only medication approved by the FDA specifically for the treatment of depression in patients with bipolar disorder. This indication was based on data from a double-bhnd, randomized study in which the combination was superior to both olanzapine monotherapy and placebo (Tohen et al. 2003). Treatment-emergent mania or hypomania did not occur more frequently in the olanzapine-fluoxetine combination group than in the placebo group during the acute trial. 

Lithium, lamotrigine, and olanzapine-fluoxetine combination therapy are first-line treatments for bipolar depression. The response... 

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

Recent case reports have suggested that atypical antipsychotics may also benefit patients with PTSD. For example, low doses of risperidone in combination with an antidepressant or mood stabilizer were reported effective for nightmares and flashbacks in patients with treatment-refractory PTSD ( 292). Both clozapine and olanzapine have also been reported to reduce PTSD symptoms in patients with a co-morbid psychotic disorder ( 293, 294). Finally, olanzapine added to fluoxetine resulted in significant improvement of hyperarousal symptoms in a patient with treatment-refractory PTSD caused by severe childhood physical and sexual abuse (295). 

The depressive phase of manic-depressive disorder often requires concurrent use of an antidepressant drug (see Chapter 30). Tricyclic antidepressant agents have been linked to precipitation of mania, with more rapid cycling of mood swings, although most patients do not show this effect. Selective serotonin reuptake inhibitors are less likely to induce mania but may have limited efficacy. Bupropion has shown some promise but—like tricyclic antidepressants—may induce mania at higher doses. As shown in recent controlled trials, the anticonvulsant lamotrigine is effective for many patients with bipolar depression. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine and fluoxetine has been approved for use in bipolar depression. 

Improvement in galactorrhea has also been observed in a case of trichotillomania refractory to a selective serotonin reuptake inhibitor (857). The patient only had a positive response with risperidone in combination with fluoxetine, but developed hyperprolactinemia and an intolerable galactorrhea. Olanzapine in combination with fluoxetine was started, with significant clinical improvement and without symptoms of galactorrhea however, the patient had undesired weight gain of 3.6 kg after 22 weeks. 

A combination of olanzapine and fluoxetine was used in two randomized, double-blind simultaneous 8-week trials in 249 patients with major depression with psychotic features (trial 1 n = 124, mean age 41 years, 52% women trial 2 n = 125, mean age, 41 years, 50% women), which have been jointly published (69). This multicenter study was completed by 51 subjects in trial 1 (41%) and 59 subjects in trial 2 (47%). Altogether, there were no significant differences in the rates of discontinuation due to adverse events among the different treatment groups placebo (n = 100), monotherapy with olanzapine 5-20 mg/day (n = 101), and olanzapine 5-20 mg/day plus fluoxetine 20-80 mg/day (n = 48). Dropout percentages were 59% in trial 1 (similarly distributed in the three groups) and 53% in trial 2 (ranging from 40% of dropouts... 

Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, Sanger TM, Tollefson GD. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 2004 19 365-73. 

Fluoxetine has been specifically sfudied in combination wifh olanzapine (olanzapine-fluoxetine combination) wIfh excellenf resulfs for bipolar depression, freafmenf-resisfanf unipolar depression, and psychofic depression... 

Actions at 5FIT2C receptors may explain in part fluoxetine s efficacy in combination with olanzapine for bipolar depression and treatment-resistant depression, since both agents have this property... 

HT2C antagonist actions plus serotonin reuptake blockade of fluoxetine add to the actions of olanzapine when given as Symbyax (olanzapine-fluoxetine combination)... 

Olanzapine-fluoxetine combination capsule (mg equivalent olanzapine/mg equivalent fluoxetine) 6 mg/25 mg, 6 mg/50 mg,... 

Antidepressants Fluvoxamlne, a potent inhibitor of the cytochrome P450 enzymes CYP1A2 and CYP2C19 and a moderate inhibitor of CYP3A4, has been reported to cause a 5-10-fold elevation of plasma clozapine concentration. Fluoxetine and paroxetine may also increase plasma clozapine concentrations, while citalopram and sertraline have been reported to cause minimal or no elevation of plasma levels of clozapine. To date, in vivo studies with a combined olanzapine-imipramine regimen have not revealed any pharmacokinetic interactions. 

---