Olanzapine/Fluoxetine

Olanzapine/fluoxetine (Symbyax®) is an oral once-daily fixed-dose combination of the atypical antipsychotic olanzapine and the selective serotonin reuptake inhibitor (SSRI) fluoxetine that is approved in the US for the treatment of depressive episodes associated with bipolar disorder in adults. Combination therapy with olanzapine plus fluoxetine is effective in the treatment of patients with acute bipolar depression. The combination improves depressive symptoms and symptom severity in this patient population, with an efficacy greater than that of olanzapine alone or lamotrigine. Furthermore, olanzapine plus fluoxetine is generally well tolerated. Although associated with weight gain and potential elevations in glucose, lipid and prolactin levels, the combination does not increase the risk of treatment-emergent mania. Additional placebo- and active comparator-controlled studies are required in order to confirm the efficacy of olanzapine/ fluoxetine in the treatment of bipolar depression and to definitively position olanzapine/fluoxetine with respect to other agents. In the meantime, fixed-dose olanzapine/fluoxetine offers an effective and generally well tolerated first-line option for the treatment of acute bipolar depression.

Olanzapine is an atypical antipsychotic agent that binds to a variety of neurotransmitter receptors, including serotonin and dopamine receptors. It has been suggested that the antidepressant activity of the drug may be linked to antagonism and down-regulation of serotonin 5-HT_2A receptors. Fluoxetine is a potent SSRI that inhibits dopamine and noradrenaline (norepinephrine) transporters only weakly. The drug enhances serotonergic neurotransmission, which may, in part, mediate its antidepressant effects. However, the exact mechanism(s) of action responsible for the clinical benefits of olanzapine plus fluoxetine combination therapy in patients with bipolar depression is unclear at present, although it has been proposed to involve the activation of serotonin, dopamine and noradrenaline neural systems. In addition, preclinical data suggest the agents in combination may be more effective than the individual agents in upregulating dopamine and noradrenaline levels and fibroblast growth factor-2 expression in the brain.

Coadministration of olanzapine and fluoxetine has no clinically relevant effects on the pharmacokinetic profile of olanzapine. Both olanzapine and fluoxetine are well absorbed following oral administration, reaching maximum plasma concentrations approximately 4 and 6 hours after a fixed oral dose of olanzapine/ fluoxetine 12 mg/50 mg. The agents are extensively metabolized in the liver; olanzapine predominantly via cytochrome P450 (CYP) 1A2 and the flavincontaining mono-oxygenase system, and fluoxetine via CYP2D6 and CYP2C. Olanzapine/fluoxetine dosage adjustments are recommended in patients with hepatic impairment and in those who have a combination of factors that may affect olanzapine or fluoxetine metabolism; caution is advised in elderly patients. Several pharmacokinetic drug interactions have been shown to occur between both olanzapine and fluoxetine and some drugs that are either substrates and/or inducers/inhibitors of CYP isoenzymes; dosage adjustments may be required in some cases. Furthermore, the concomitant use of olanzapine/fluoxetine with certain drugs is contraindicated (e.g. monoamine oxidase inhibitors or pimozide), not recommended (e.g. some other serotonergic drugs, such as SSRIs) or requires caution owing to several potential pharmacodynamic interactions.

The efficacy of olanzapine plus fluoxetine combination therapy in adult patients with bipolar I depression has been demonstrated in two randomized, double-blind, multicentre, flexible-dose trials of 7 or 8 weeks’ duration.

In the 8-week study, olanzapine used in combination with fluoxetine improved symptoms of depression (Montgomery-Åsberg Depression Rating Scale [MADRS] total score) and symptom severity (Clinical Global Impressions [CGI] Bipolar Version-Severity of Depression [CGI-BP-S] scale score) to a significantly greater extent than placebo, with rates of response and remission also being significantly higher with the combination therapy. Moreover, olanzapine plus fluoxetine produced significantly greater improvements than placebo in measures of both mania (Young Mania Rating Scale [YMRS]) and anxiety (Hamilton Anxiety Rating scale [HAM-A]).

Furthermore, data from the 7- and 8-week studies demonstrated that olanzapine plus fluoxetine was more effective than olanzapine alone or lamotrigine in improving depressive symptoms (MADRS total score) or symptom severity (CGI-Severity of Illness scale score or CGI-BP-S score) in patients with bipolar depression. Recipients of olanzapine plus fluoxetine also had rates of response and remission that were significantly higher than olanzapine monotherapy recipients and similar to those seen in lamotrigine recipients. There was no significant difference between olanzapine plus fluoxetine and olanzapine alone with regard to improvements on the YMRS or HAM-A scale, although improvements on the YMRS were significantly greater with the combination therapy than with lamotrigine. Olanzapine plus fluoxetine also appeared to be more effective than lamotrigine in reducing suicidal thoughts (MADRS item 10) in the 7-week trial.

In addition, olanzapine in combination with fluoxetine improved certain aspects of health-related quality of life (Medical Outcomes Study 36-Item Short-Form Health Survey and Quality of Life in Depression Scale) to a significantly greater extent than olanzapine alone and was superior to lamotrigine in improving functioning (Global Assessment of Functioning score) in patients with bipolar depression in these short-term trials.

Olanzapine plus fluoxetine was generally well tolerated in adult patients with bipolar I depression in clinical trials of up to 8 weeks’ duration. Compared with placebo, olanzapine plus fluoxetine was associated with a significantly higher incidence of weight gain, increased appetite, dry mouth, asthenia and diarrhoea. The tolerability profile of the combination was broadly similar to that of olanzapine monotherapy, although was less favourable than lamotrigine in terms of adverse events such as somnolence, increased appetite, dry mouth, weight gain, sedation and tremor. However, limited data suggest olanzapine plus fluoxetine may be associated with a lower incidence of suicidal and self-injurious behaviour than lamotrigine.

Olanzapine used in combination with fluoxetine was not associated with an increase in treatment-emergent mania compared with placebo, olanzapine alone or lamotrigine in these trials, and had a low incidence of extrapyramidal symptoms generally similar to that with placebo or olanzapine monotherapy.