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Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have contributed to the major advances as antidepressants where they have revolutionised the treatment of depression and other psychiatric disorders. The SSRIs are e.g. therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder (also known as social phobia), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD) and anorexia. There is also clinical evidence of SSRIs efficiency in the treatment of the negative symptoms of schizophrenia and their ability to prevent cardiovascular diseases.〔 SSRIs primarily inhibit serotonin transporter (SERT) in the brain and have negligible effects on dopamine transporter (DAT) and norepinephrine transporter (NET). Inhibiting the binding of the neurotransmitter, serotonin (5-HT), to SERT results in increased 5-HT concentration in the synaptic cleft leading to increased binding of 5-HT to postsynaptic receptors which results in improvement of depression symptoms. Today, SSRIs have dominated the market of antidepressants〔 and are recommended by the National Institute for Health and Clinical Excellence (NICE) as a first-line treatment of depression, because they typically have fewer adverse effects than other type of antidepressants with the same effectiveness. == Development history == Before the discovery of SSRI drugs the treatment for mood disorders were relatively limited and crude. Since then we have come a long way and there are now dozens of antipsychotics on the market for the treatment of depression. Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were the first drugs to be developed for the treatment of depression, dating back to the early 1950s. Because of their undesirable adverse-effect profile and high potential for toxicity, due to their non-selective pharmacological effects, strict regiments were for taking the drugs which limited their use.〔 Because of this, researchers looked for other alternative with similar effectiveness but fewer adverse effects e.g. drugs that did not cause cardiac conduction abnormalities in overdoses or had the tendency to cause seizures, which led to the discovery of the SSRI drugs. The SSRIs are the most significant class of antidepressants marketed in recent years and make one of the major medicinal discoveries of the last few decades. SSRIs were the first drugs to establish beyond doubt a pathophysiological role for 5-HT in affective illnesses and in the broad spectrum of anxiety disorders. Likewise, they were the first to confirm the inhibition of neurotransmitter re-uptake as an important therapeutic principle. The SSRIs are the first rationally designed class of psychotropic medications. The strategy behind rational drug design is to develop a new drug that is capable of affecting a specific biological target, or in this case a special neural site of action (uptake pumps, receptors), while trying to avoid effects on other site of actions. The goal in such development is to produce pharmacological agents that are more efficacious, safer and better tolerated than older medications.〔 An initial success was achieved when medicinal chemists set out in search of the ideal SSRI with the chemical synthesis of zimelidine (figure 1) from the antihistamine drug brompheniramine,〔 which exhibited selective inhibition of 5-HT re-uptake with minimal inhibition of norepinephrine (NE) re-uptake. Most importantly zimelidine did not come with the adverse effect profile as the TCAs and therefore it became the template for the second generation SSRIs.〔 Zimelidine was the first SSRI to be marketed but several cases of Guillain-Barré syndrome were associated with the use of the drug which led to withdrawal from the market in 1983. Subsequently, several non-tricyclic SSRIs were discovered and marketed. Fluoxetine, which was FDA approved in 1987 and is usually thought to be the first SSRI to be marketed, paved the way for the next generation of SSRIs and was thought to be some kind of prototype.〔 Introduction of fluoxetine to the market is hailed as a miracle drug for the treatment of depression because it had fewer adverse effects, simpler dosing strategies and greater margin of safety when overdoses were consumed and thus it had better adherence, compared to the older antidepressants (TCAs and MAOIs).〔〔 Since then the number of drugs in the SSRI class has become bigger and they are now six (fluoxetine, paroxetine, citalopram, escitalopram, sertraline and fluvoxamine),〔〔 as demonstrated in table 1. Table 1 SSRI drugs used to treat depression. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Development and discovery of SSRI drugs」の詳細全文を読む スポンサード リンク
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