The
selective serotonin reuptake inhibitors (
SSRIs) have emerged as a major therapeutic advance in psychiatry. They have emphasized the pathophysiological role of
serotonin (5-HT) in
affective disorders. Indeed,
SSRIs were developed for inhibition of the neuronal uptake for
serotonin (5-HT), a property shared with the TCAs (tricyclic anti-depressants), but without affecting the other various central neuroreceptors (ie,
histamine,
acetylcholine and
adrenergic receptors) that are responsible for many of the safety and tolerability problems with TCAs. In this way,
fluoxetine and other
SSRIs represent a major advance over tricyclics, because of their lower toxicity. While the position of
fluoxetine relative to other selective serotoninergic
antidepressants requires further investigation,
fluoxetine has a more favorable tolerability profile for a similar efficacy in comparison to
tricyclic antidepressants. The pharmacokinetic and pharmacodynamic properties of
fluoxetine are well described. After
oral administration,
fluoxetine is almost completely absorbed. Due to hepatic first-pass metabolism, the oral bioavailability is < 90%.
Fluoxetine has a half-life of 2-7 days, whereas the half-life of
norfluoxetine ranges between 4 and 15 days. This long half-life of
fluoxetine may be advantageous when the patient omits a dose since
drug concentrations decrease slightly. On the other hand, in the case of
fluoxetine non-response, long washout periods are necessary before switching the patient to a TCA or a
MAO inhibitor to avoid drug interactions or the development of a
5-HT syndrome. As a class,
SSRIs are considerably more selective in comparison to TCAs in terms of their central nervous system mechanisms, but differ in other clinically relevant aspects. This action affects several specific
5-HT receptors, which, in turn, effects a multitude of neural systems and signalization pathways. However, despite the facilitating serotoninergic neurotransmission, the direct mechanism by which a SSRI exerts its anti-depressant activity remains uncertain. The therapeutic response in major depression for
SSRIs (ie 15-20 days) maybe due to a progressive desensitization of somatodendritic
5-HT autoreceptors in the midbrain raphe nucleus. On the other hand, it has also been postulated that
5-HT is a modulator of several neurophysiological pathways, including
dopamine,
noradrenaline, but also
neurotrophic factors, intra-cytoplasmic phosphorylations and nuclear genes expression. Therapeutic activity of
SSRIs may finally results in a complex modulation and homeostasis between monoaminergic neurotransmisson and neuronal plasticity. In term of health-care, the introduction of
fluoxetine and other
SSRIs in the 1980s has radically changed the treatment of
depressive disorder worldwide and they have emerged as the first line of treatment for
depressive disorders. The efficacy of
fluoxetine is now well established in the treatment of
major depressive disorder. Indeed, this efficacy has been assessed in numerous clinical controlled trials involving patients with
major depressive disorders. Meta-analysis were carried out and confirmed that
fluoxetine was as effective as the
tricyclic antidepressants, and appeared more effective than placebo in improving the symptoms of depression. However, there is no scientific evidence to suggest that any one SSRI is more effective than another, but not all patients respond to the same agent. Looking to the future, we need further comparative studies of the
SSRIs with the next generation of
antidepressants such as
5-HT noradrenaline reuptake inhibitors (
SNRIs,
Venlafaxine). Actually, it is interesting to note that, whereas the emphasis with the
SSRIs has been on their selectivity, recent developments have tended to move towards less selective agents, and now to other neurobiological pathways (ie
neurotrophic factors). Finally,
fluoxetine, in common with other
SSRIs, remains today a first-line treatment option for
major depressive disorder.