Fluoxetine administration potentiates the effect of olanzapine on locus coeruleus neuronal activity

Background: As many as 30% of individuals diagnosed with depression are nonresponsive to traditional antidepressant medication. Augmentation and combination strategies have emerged in an attempt to address this issue. A typical antipsychotics (e.g., olanzapine), when added to a selective serotonin reuptake inhibitor (e.g., fluoxetine) have shown great promise in the treatment of these treatment-resistant patients. As of yet, the precise neural mechanisms reponsible for the beneficial clinical effects of these combinations are not completely understood. Methods: Separate groups of rats received either saline or fluoxetine (10 mg/kg/day) for 24 hours or 3 weeks via subcutaneously implanted osmotic pumps. The effects of either intravenous saline or olanzapine (.3, 1.0, or 3.0 mg/kg) on locus coeruleus (LC) neuronal activity were then assessed via extracellular single-unit recordings. Results: Acute administration of olanzapine produced a significant elevation of the firing rate and burst firing of LC cells, and chronic, but not acute, administration of fluoxetine decreased baseline and burst firing of LC cells; however, when given in combination, an interaction of fluoxetine and olanzapine was observed, with olanzapine causing a significantly greater increase in LC firing rate and burst firing after acute and chronic administration of fluoxetine. Conclusions: These results provide a potential neural mechanism for the beneficial clinical effects of the olanzapin/fluoxetine combination. The increase in baseline and burst firing of LC neurons in the groups receiving both fluoxetine and olanzapine would result in enhanced norepinephrine release in projection areas (e.g., prefrontal cortex), which could lead to a reduction in depressive symptoms.