The multifaceted effects of fluoxetine treatment on cognitive functions

Abstract

Fluoxetine, the prototypical selective serotonin reuptake inhibitor (SSRI), is widely used to treat major depressive disorder (MDD) and a variety of other central nervous system conditions, primarily due to its established clinical safety profile. Although its efficacy in treating depression is well-recognized, the impact of fluoxetine on cognitive functions remains inconsistent and elusive. In this review, we first examine the well-substantiated biological mechanisms underlying fluoxetine's antidepressant effects, which include serotonin reuptake inhibition and activation of TrkB receptors-key to brain-derived neurotrophic factor (BDNF) signaling. Subsequently, we delve into the cognitive side effects observed in both preclinical and clinical studies, affecting domains such as memory, attention, and executive functions. While certain studies indicate cognitive improvements in patients with underlying disorders, there is also evidence of negative effects, influenced by variables like gender, duration of treatment, age, disease pathology, and the specifics of cognitive testing. Significantly, the negative cognitive outcomes reported in preclinical research often involve healthy, non-diseased animals. This review underscores the necessity for heightened caution in fluoxetine prescription and further investigation into its potentially detrimental cognitive effects, even when used prophylactically.

Keywords: SSRIs; antidepressants; cognition; memory; side-effects.

FIGURE 1

Multidimensional Model of Fluoxetine’s Therapeutic Response. This graphical abstract synthesizes the integrated preclinical and clinical findings, illustrating how the efficacy of fluoxetine therapy is modulated by allostatic load and dosing. The surface’s color gradient delineates the therapeutic optimum, pinpointing where allostatic load and fluoxetine dosage intersect to provide the greatest therapeutic advantage. For instance, comparable allostatic stress levels yield divergent therapeutic outcomes when fluoxetine is administered during different life stages; early life exposure (e.g., prenatal or adolescent phases) may be less beneficial than treatment in adulthood. Moreover, the therapeutic impact of a constant fluoxetine dose varies significantly with allostatic intensity, peaking at moderate levels (e.g., Mood disorders) while diminishing when levels are too low (Neurological/psychiatric homeostasis) or excessively high (Neurodegeneration).