Abstract
BackgroundFluoxetine and olanzapine combination therapy is rapidly becoming an effective strategy for managing symptoms of treatment-resistant depression. Determining drug-drug interactions, drug metabolism and pharmacokinetics is of particular interest for revealing potential liabilities associated with drug augmentation in special patient populations. In the current studies, we chronically administered fluoxetine and olanzapine in non-stressed rats to extend our previous findings regarding body weight dynamics.ResultsChronic fluoxetine (10 mg/kg) and olanzapine (5 mg/kg and 0.5 mg/kg) treatment decreased weight gain irrespective of olanzapine dosing. At the 10 mg/kg and 5 mg/kg dose, respectively, fluoxetine and olanzapine also significantly reduced food and water consumption. This pharmacodynamic event-related effect, however, was not observed at the 10 mg/kg and 0.5 mg/kg dosing paradigm suggesting differences in tolerability rates as a function of olanzapine dose. The decrease in weight gain was not associated with apparent changes in glucose metabolism as vehicle- and drug-treated rats showed undistinguishable serum glucose levels. The combination of fluoxetine and olanzapine in rats yielded drug plasma concentrations that fell within an expected therapeutic range for these drugs in psychiatric patients.ConclusionsThese data suggest that fluoxetine and olanzapine treatment decreases weight gain in rats; a pharmacodynamic event-related effect that differs considerably from what is observed in the clinical condition. The possibility of mismatched models regarding body weight changes during drug augmentation therapy should be seriously considered.
Highlights
Fluoxetine and olanzapine combination therapy is rapidly becoming an effective strategy for managing symptoms of treatment-resistant depression
Whereas fluoxetine and olanzapine alone activate several signaling pathways involved in cell survival and plasticity [8,9,10], drug augmentation therapy reduces the levels of certain transcription factors implicated in the chemical circuitry underlying emotional behaviors [5]
Anorectic phenomena are observed in rats chronically treated with valproic acid and lithium [31]; both valproic acid and lithium are widely touted as effective prophylactic agents for manic-depressive illness [32]
Summary
Fluoxetine and olanzapine combination therapy is rapidly becoming an effective strategy for managing symptoms of treatment-resistant depression. The limited literature on this issue suggests that drug augmentation therapy, at least in the rat brain, is likely to be more complicated and perhaps more indirect than a simplistic version of fluoxetine or olanzapine would imply [4,5,6,7]. Whereas fluoxetine and olanzapine alone activate several signaling pathways involved in cell survival and plasticity [8,9,10], drug augmentation therapy reduces the levels of certain transcription factors (e.g., cAMP response element binding protein and FOS-like proteins) implicated in the chemical circuitry (e.g., prefrontal cortex and hippocampus) underlying emotional behaviors [5]. It is conceivable that fluoxeine plus olanzapine treatment is effective against treatment-resistant depression due to their combined actions on numerous brain regions and various interconnected intracellular signaling pathways that promote some type of prophylactic effect
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