## 1 Introduction  
### Background  
Fluoxetine hydrochloride (3-(p-trifluoromethylophenoxyoxy)-N-methyl-3-phenylpropylamine HCl) (**1**, Figure 1) was presented to the community of physicians and medicinal chemists in the early 1970s, when it was described in a scientific journal as a selective serotonin-reuptake inhibitor [1]. Nevertheless, several years were required to fully develop this compound, which was later approved for the treatment of depression by the Food and Drug Administration (FDA, 1987) and marketed as Prozac (Eli Lilly) [2]. Fluoxetine is the prototype of selective serotonin-reuptake inhibitors (SSRIs), the first member of a new class of antidepressants initially introduced in the United States (U.S.) [2]. Moreover, it was also the first SSRI made available for clinical use in most countries besides the U.S. [3]. Despite early skepticism, Prozac became a true symbol of successful \"blockbuster\" drugs through the years. In fact, a fluoxetine capsule was depicted in the cover of _Newsweek_, celebrated as \"a breakthrough drug for depression\" by the same magazine (1990), as one of the \"Pharmaceutical Products of the Century\" by Fortune (1999) and, more in general, as the \"happiness pill\" in the pop culture [2]. By blocking the reuptake of serotonin (**2**, Figure 1) binding the neuronal presynaptic serotonin transporter SLC6A4 (Solute Carrier Family 6 Member 4), fluoxetine promotes an increase of the concentration of the neurotransmitter in the synaptic cleft. This leads to enhanced postsynaptic neuronal activity of the serotoninergic neurotransmission with limited effects on catecholaminergic neurons, differently from tricyclic antidepressantsants (TCAs) [4; 5; 6]. The observed therapeutic results are mainly due to the effect on the 5-HT\({}_{\text{2C}}\) receptors [7]. Fluoxetine is structurally related to diphenylhydamine, which is an antihistaminic that had been developed 30 years before [5]. It is a racemic mixture of two enantiomers, R(-)-fluoxetine and S(+)-fluoxetine, the latter being 1.5 times more potent in inhibiting serotonin reuptake [3; 8]. Figure 1: Fluoxetine (**1**) and its metabolites (**M1** and **M2**); serotonin (**2**). The molecular basis and the binding mode justifying this difference were studied from a structural point of view [9]. After the patent on racemic fluoxetine expired, attempts to develop S(+)-fluoxetine formulations were pursued [10]. Fluoxetine has been marketed in capsules (the typical dose is 20 mg for the treatment of depression), but formulations for prolonged drug release were also studied [5; 11]. It has been approved worldwide for the treatment of major depression, but it is also effective against several other syndromes [1; 5], with a clinical efficacy similar to that of TCAs and fewer cardiovascular and anticholinergic side effects [5]. Fluoxetine effectively acts on a wide spectrum of mood disorders and protects against the adverse effects of different types of stressors by decreasing some effects of stress on the immune system and by protecting against oxidative damage. Different molecular mechanisms have been proposed to explain its neuroprotective effects, including BDNF (Brain-derived Neurotropic Factor) release, antagonism on NMDA (N-methyl-D-aspartate) receptors, the inhibition of NF-kB (Nuclear Factor Kappa B Subunit 1) activity, and inhibition of the release of pro-inflammatory factors (TNF-\(\alpha\), Tumor Necrosis Factor-Alpha, IL-1\(\beta\), Interleukin 1 Beta) from microglial cells [12]. However, the underlying mechanisms of its therapeutic efficacy remain unclear, particularly those related to its antioxidant activity. The brain is very susceptible to oxidative stress, since it has a high energy requirement, and oxidative stress has been implicated in the pathogenesis of many psychiatric and degenerative disorders.