Selective Serotonin Reuptake Inhibitors

   (SSRIs)

   SSRIs represent a class of drugs based on the concept that inhibiting the "reuptake" of the neurotransmitter serotonin in the brain, at the synaptic junction between neurons, could bring relief in depression and other illnesses. (See Neurotransmitter; Synapse.) Reuptake means reabsorbing into the upstream (presynaptic) neuron the quantity of neurotransmitter that has just been discharged into the synaptic cleft in order to make the downstream (postsynaptic) neuron fire. Inhibiting reuptake would, in theory, increase the quantity of serotonin available at the synapse and thus relieve psychiatric symptoms. Inhibiting reuptake does relieve symptoms. What has never been con-firmed scientifically, however, is that there was anything wrong with the serotonin system.

   Zimeldine. The story: The study of serotonin uptake and its modification by drugs was initiated by Julius Axelrod (1912–) and a co-worker at the National Institute of Mental Health in 1963; the researchers used a radiolabeled form, reporting their first results in the Journal of Pharmacology and Experimental Therapeutics. Then in 1968, Swedish pharmacologist Arvid Carlsson (1923–) of Gothenborg University discovered that the tricyclic antidepressant imipramine blocked the reuptake of serotonin in serotonin-type neurons (work co-authored by Kjell Fuxe [1938–] and Urban Ungerstedt [1942–], published in the Journal of Pharmacy and Pharmacology). "This action may be of importance for its antidepressant properties," the authors said.* (In 2000, Carlsson won a Nobel Prize for Physiology or Medicine for his research on dopamine.) This work excited interest at a number of pharmaceutical houses in the development of SSRIs (although that acronym did not come into use until the early 1990s).

   * This hypothesis was spelled out in greater detail in an article co-authored by Carlsson, Corrodi, Fuxe, and Tomas Hökfelt in the European Journal of Pharmacology in 1969.

   Yet, it turned out that another tricyclic antidepressant drug, clomipramine, had an even more powerful effect on serotonin than did imipramine. Around 1970, therefore, Carlsson and an organic chemist named Hans Corrodi (1929–1974) at the Hässle Company in Mölndal, Sweden (which shortly thereafter became part of the Astra company), set out to design a molecule that would have an elective effect on serotonin reuptake (and that could be patented). Using an antihistamine called chlorpheniramine as a base, they came up with a strong selective serotonin reuptake inhibitor that Astra called zimeldine (after the drug was patented in 1972) and that was marketed in Europe in 1982 under the brand name Zelmid. This was the first SSRI in psychiatry. (The antihistamines had always been SSRIs.) Unfortunately, Zelmid was withdrawn in 1983 because it caused isolated cases of Guillain–Barré syndrome, a polyneuritis that affects neuromuscular function. This was one of the first occasions in which rational principles of drug design had actually been used to sculpt a pharmaceutical.

   Six further SSRIs followed and are listed below in the order in which they were patented.

   Paroxetine (1974). Patented by the Ferrosan company, which in 1980 sold the license to the company then known as SmithKline Beecham (folded into Glaxo SmithKline after 2000), the drug was launched as "Paxil" in the United States in 1993 and was advertised under the catchy acronym "SSRI," which the company coined. (Ferrosan had also made in 1974 the SSRI femoxetine, which died in development.)

   Fluvoxamine (1975). The Philips-Duphar Company patented the molecule in 1975; it was launched by Duphar as "Floxyfral" in Switzerland in 1983 for depression (in the United Kingdom as "Faverin") and in the United States by the Solvay Company as "Luvox" in 1995 for obsessive-compulsive disorder.

   Fluoxetine (1975). Patented by Lilly in 1975, the company apparently considered bringing it out initially as a weight-loss drug, then launched it as Prozac in the United States in 1988 for depression. (It was approved by the Food and Drug Administration in December 1987.) Prozac was one of the most successful products in the history of pharmaceuticals and virtually gave its name to an era.

   Indalpine (1977). Patented by the French firm Mar-Pha Société, Fournier Frères acquired the license and marketed it in 1983 as an antidepressant, "Upstène," "the first specific inhibitor of the reuptake of serotonin," the company claimed. The drug was later withdrawn because of liver toxicity.

   Citalopram (1977). Patented by Kefalas A/S, a subsidiary of the Lundbeck Company of Denmark, Lundbeck brought out citalopram in Denmark in 1989 as "Cipramil"; Lundbeck sold U.S. rights to Forest Pharmaceuticals, which marketed it in the United States in 1998 as "Celexa," an antidepressant.

   Sertraline (1981). Patented by Pfizer, the company launched sertraline in 1992 as "Zoloft": "Gets depressed patients back into the mainsteam." As with the other "American" SSRIs, Pfizer subsequently extracted a number of other indications for the compound in the anxiety area from the Food and Drug Administration, in this case, for panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and social anxiety disorder, as well as for "major depression." Sertraline was the last "SSRI."* The Achilles’ heel of this particular drug class, as Anita H. Clayton (1956–) of the University of Virginia and collaborators pointed out in an article in the Journal of Clinical Psychiatry in 2002, was the 30% to 40% rate of sexual dysfunction the various SSRIs produce.

   It is an ironical consequence of the long delays required for licensing a drug, and of the interplay between science and marketing, that a drug class conceived in the 1960s, with numerous "me-toos" in the 1970s, became the latest new thing in psychopharmaceuticals in the 1990s.