Abstract

Depression is a chronic medical condition afflicting about 245 million individuals worldwide, with 3
trillion of healthcare expenditure despite the availability of multiple antidepressant drug classes. SSRI
being the first-line therapy holds the majority of market share with Fluoxetine and Fluoxetine/Olanzapine
as most prescribed drugs, but patient profile, poor efficacy, and tachyphylaxis, apart from tolerability,
many times warrant switching and augmentation therapies. However, there are no head-to-head preclinical
clinical studies within and across drug classes for this to facilitate a smooth therapeutic switch. This study
in immobilized and dark cycle-induced acute and chronic SD rat models of depression was conducted to
assess if fluoxetine and olanzapine effects are class effects. The forced swimming test (FST) conducted in
acute and chronic models treated with typical antidepressants (SSRI-fluoxetine, SNRI-duloxetine,
TCA- (amitriptyline) or atypical antidepressants (Bupropion) alone and in combination with Olanzapine, a
mood stabilizer indicated that all drugs showed statistically significant antidepressant effect and that
synergistic efficacy seen in fluoxetine and olanzapine is not a class effect and other drugs, except Bupropion,
can also yield a similar effect. Additionally, among all the tested drugs, Amitriptyline showed the highest
Anhedonia reversal effects, as assessed by the sucrose preference test (SPT), while others all showed
statistically significant effects as monotherapy and synergistic effects as combination therapy. This data
provides direction to the physicians to personalize the antidepressant based on the patient subtype as well
as their comorbidity and adverse effects risk profile and focus on augmenting the primary drugs with
Olanzapine, rather than switching between antidepressants to attain Olanzapine effects through the only
FDA-approved combination. Additionally, this data suggests the potential to switch patients from
Fluoxetine and Olanzapine during Tachyphylaxis across other drug classes rather than choosing an
inferior SNRI. Thirdly, the data positions Amitriptyline as an additional anhedonia reversal drug for
patients without cardiovascular risk factors.