Olanzapine combination studies

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. 

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. 

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. 

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. 

The combined regimen is safe and effective, although severe cardiovascular or respiratory adverse effects may occur with high doses of clozapine when combined with diazepam and lorazepam. There are no reports of pharmacokinetic interactions between olanzapine and benzodiazepines (studied mainly with diazepam). 

Augmentation is called for when there is partial or non-response to the above approaches. Combinations of SSRIs with buspirone, clonazepam, clonidine, inositol, lithium, pindolol, olanzapine, risperidone, trazodone, tryptophan, and venlafaxine have been reported, with limited benefit. To date, only two augmenting agents have been found to be effective in double-blind studies risperidone and pindolol. Augmentation of SSRIs with clomipramine (or vice versa) is a common practice in non-responders however, this combination may lead to a substantial increase in the level of tricyclics in the blood and/or increase the risk of serotonin syndrome. Phenelzine may be helpful in symmetry-related or other atypical obsessions. Electroconvulsive therapy (ECT) should be reserved for severely depressed and suicidal OCD patients. Neurosurgery is the last resort current operations include anterior cingulotomy, anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy. The outcome of such operations is questionable. 

Another study in 24 schizophrenic patients investigated the effect of adding mirtazapine 30 mg at bedtime, for 6 weeks, to treatment with clozapine (9 patients), risperidone (8), or olanzapine (7). Mirtazapine had a negligible effect on the metabolism of all three drugs and the combination was well tolerated. ... 

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