Prozac Fluoxetine development

A major challenge to the development of new drugs is the discovery of new therapeutic targets. For example, the phenomenal success of fluoxetine (Prozac ) has been due to the fact that it was the first selective serotonin re-uptake inhibitor approved for world market release, combined with its improved adverse drug reaction profile. However, no new classes of antidepressants have emerged in recent years. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

Other Antidepressants. Antidepressant refinements for the next 30 years primarily consisted of the development of new TCAs. However, in 1988, a novel antidepressant class, the selective serotonin reuptake inhibitors (SSRIs), was introduced in the United States. The chief innovation of the SSRIs was that they afforded the comparable effectiveness of the TCAs with fewer side effects and minimal toxicity. The debut of the SSRIs coincided with the reworking of the nosology of the anxiety disorders in DSM-III and DSM-IV. As a result, the SSRIs have been studied extensively in each of the respective anxiety disorders and in many cases have obtained FDA approval for the treatment of one or more of these anxiety syndromes. The SSRIs currently available in the United States include citalopram (Celexa), escitalo-pram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). 

It should be possible to treat the disease by increasing the concentration of the neurotransmitter in the synaptic cleft. There are, in principle, three ways in which this could be achieved, (i) Neurotransmitter synthesis could be increased, (ii) The rate of exocytosis could be increased, (iii) Removal of neurotransmitter from the synapse could be inhibited. Drugs that affect process (iii) have been developed. The tricyclic antidepressants and the specific serotonin (5-hydroxytryptamine) reuptake inhibitors (abbreviated to SSRIs) inhibit uptake of the neurotransmitter into the presynaptic on postsynaptic neurone. The most prescribed SSRI is fluoxetine (Prozac). 

Besides sertraline (no. 10, see Section 3.10) other recently developed antidepressants have become very popular, including two fluorinated compounds, fluoxetine (Prozac , no. 13) and paroxetine (Paxil , no. 14). 

Atomoxetine (Straterra , originally tomoxetine or tomoxetin, 3) was first described and synthesized by chemists at Eli Lilly in the late 1970s and was one of the few compounds that was known to display meaningful selectivity for the norepinephrine reuptake transporter (NET) versus the serotonin reuptake transporter (SERT) and the dopamine reuptake transporter (DAT) (Barnett, 1986 Molloy and Schmiegel, 1997). Atomoxetine was one of several structurally related and commercially successful monoamine reuptake inhibitors that were developed by Lilly for the treatment of various psychiatric disorders (Eig. 17.4). Fluoxetine (43) and duloxetine (44) have both gained approval in the United States as Prozac and Cymbalta , respectively, and nisoxetine (45) is widely used as a tool in biology. 

Over the next 20 years, the benzodiazepines, TCAs, MAOIs, and beta-blockers were used to treat anxiety disorders. By the mid-1980s, up to 10% of all Americans were taking a benzodiazepine. In 1988, fluoxetine (Prozac) was introduced by Eli Lilly as the first selective serotonin reuptake inhibitor (SSRI) for the treatment of mood and anxiety disorders. Its success led to the development of several other SSRI drugs. Today, these drugs are the first line of drug treatment for most anxiety disorders. 

Jafri and Greenberg (1991) described the case of a 15-year-old boy who became psychotic directly related to his receiving fluoxetine. After his medication was stopped, he improved over about 1 week s time. Hersh et al. (1991), physicians from Cornell University Medical College, described an 11-year-old girl who developed a delusional system on Prozac. 

In the 1980s an entirely new class of antidepressant arrived with the SSRIs, firstly fluvoxamine immediately followed by fluoxetine (Prozac). Within 10 years, the SSRI class accounted for half of antidepressant prescriptions in the United Kingdom. Further developments in the evolution of the antidepressants have been novel compounds such as venlafaxine, reboxetine, nefazodone and mirtazapine, and a reversible monoamine oxidase inhibitor, moclobemide. 

Wong. D.T. etal. (1995) Development of antidepressant drugs. Fluoxetine (Prozac) and other selective serotonin uptake inhibitors. Adv Exp. Med. Biol., 363.77-95. 

Drugs that block binding sites include selective serotonin reuptake inhibitors (SSRIs). In 1970, the Eli Lilly Company developed fluoxetine (Prozac). Their research began with nizoxetine, a selective norepinephrine reuptake inhibitor. Of the compounds that inhibited reuptake of serotonin, norepinephrine, and dopamine, fluoxetine was the most potent and selective inhibitor of serotonin reuptake. It was approved for use by the FDA in December, 1987, and used to reduce excessive serotonin secretion from carcinoid tumors. 

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