The development of antidepressant drugs was largely based on the notion that a deficiency of monoaminergic function, specifically noradrenaline, was thought to contribute to depression. The first-generation antidepressant drugs, tricyclic antidepressants and monoamine oxidase inhibitors, were therefore developed to inhibit either monoamine reuptake or its degradation, respectively. Although both drug classes were somewhat effective, they were fraught with adverse effects (such as dizziness, constipation and high toxicity of monoamine oxidase inhibitors), which were largely attributable to their lack of target specificity.
In addition to noradrenaline, serotonin (also known as 5-HT) was another monoamine yet to be discovered as a crucial regulator of mood. In 1974, a seminal study described the first selective serotonin reuptake inhibitor (SSRI), fluoxetine hydrochloride, to exclusively inhibit 5-HT uptake. Using an ex vivo rat brain, Wong et al. showed selective inhibition of 5-HT uptake into synaptosomes of fluoxetine-treated brains (cerebral cortex and brainstem), without affecting the uptake of other monoamines. When compared with another tricyclic antidepressant, chlorimipramine (also known as clomipramine), fluoxetine was notably more effective (56% versus 24%) at inhibiting 5-HT uptake with a sustained inhibitory effect, lasting 24 hours. After identifying that inhibiting 5-HT reuptake could treat depression, the same research group later successfully treated patients with major depression with fluoxetine, while observing minimal adverse effects commonly observed with other antidepressants.
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