K K Jain MD (

Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.

Originally released June 12, 2009; last updated November 13, 2020; expires November 13, 2023


Selective serotonin reuptake inhibitors (SSRIs) increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake. SSRIs are described as “selective” because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants that affect other monoamine neurotransmitters as well. SSRIs are mainly used as antidepressants but are indicated for several other neuropsychiatric disorders. This article describes the pharmacology, uses, and neuroprotective action of some of SSRIs. Personalized use of SSRIs is also discussed for increasing safety and efficacy. Although safer than tricyclic antidepressants, SSRIs have some adverse effects associated with long-term use.

Key points


• Selective serotonin reuptake inhibitors (SSRIs) increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake.


• SSRIs are mainly used as antidepressants but are indicated for several other neuropsychiatric disorders.


• Several SSRIs are available, and a personalized approach is required to select an appropriate agent for safe and effective use.

Historical note and terminology

Since its discovery in the mid-20th century, serotonin, which is also called 5-hydroxytryptamine or 5-HT, has played an increasing part in understanding human diseases, particularly those involving the nervous system. Its plays a role in management of depression and other psychiatric disorders with the demonstration of pharmacological manipulation to prevent reuptake. Its role in other neurologic disorders has also expanded. Development of SSRIs was a major pharmacological achievement. SSRIs are used for the treatment of depression, anxiety disorders, and some personality disorders. Historical landmarks in serotonin, serotonin disorders, and drugs based on manipulation of this system are shown in Table 1. The best known SSRI, fluoxetine, was introduced into medical practice in 1988.

Table 1. Historical Landmarks in Serotonin, Serotonin Disorders, and Drugs Based On Manipulation of the Serotonergic System




Ramon Y Cajal described the raphe nuclei of the brainstem but did not know that they contain serotonin.


Start of investigation of vasoconstrictors in blood by Irvin H Page


Isolation and characterization of serum vasoconstrictor (serotonin) from blood (Rapport et al 1948).


Synthesis of serotonin (Hamlin and Fisher 1951).


Enteramine, a smooth muscle-contracting substance found in the gut wall in 1952 by Erspamer, was found to be identical to serotonin (Erspamer 1963).


Identification of serotonin in various tissues (Twarog and Page 1953).


Discovery of the carcinoid syndrome (wherein tumors derived from chromaffin cells of the gut produce excess serotonin). This was the first disease in which serotonin was implicated (Sjoerdsma and Palfreyman 1990).


Development of urine chemical assay of 5-hydroxyindolacetic acid, a metabolite of serotonin (Udenfriend 1959).


Identification of serotonin in the brain and proposal of its role as a neurotransmitter (Amin et al 1954).


Hypothesis that serotonin and epinephrine might act as opposing central neurochemical systems (Brodie and Shore 1957).


Evidence for involvement of serotonin in migraine based on alleviation of symptoms of migraine by intravenous serotonin (Kimball et al 1960).


Role of serotonin as a neurotransmitter was well recognized.


Description of the anatomy of the serotonergic system of the brain--the wiring diagram of the neurochemical system (Dahlstrom and Fuxe 1965).


Development of selective serotonin reuptake inhibitors and demonstration of their efficacy as antidepressants (Carlsson et al 1969).


Discovery of fluoxetine by scientists at Eli Lilly (Wong et al 1974).


The possibility that some depressed patients have more of a "noradrenergic" depression and others had more of a "serotonergic depression" was suggested (Maas 1975).


Multiple 5-HT receptors were defined, ushering in the modern era of serotonin (Peroutka and Snyder 1979).


Development of selective 5-HT receptor antagonists.


First description of serotonin syndrome due to excess of serotonin in humans (Insel et al 1982).


First SSRI for depression, fluvoxamine, launched by Solvay.


Alterations reported in serotonergic function in obsessive-compulsive states (Zohar and Insel 1987).


Fluoxetine (Prozac) introduced in the medical practice by Eli Lilly & Co.

Currently approved SSRIs include the following:


• Dapoxetine (approved in several countries including most of Europe; in phase 3 trials in the United States)
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline
• Vilazodone
• Zimelidine

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