Prozac

Featured on the covers of national newsmagazines and acclaimed on talk shows, Prozac became a household word in the course of the 1990s--and, nearly from the beginning, a source of controversy.

The first of a new class of drugs called selective serotonin reuptake inhibitors (SSRIs) to be approved for use in the U.S., Prozac revolutionized the treatment of depression and several other mental disorders. Since its introduction in 1987, it has been approved and marketed in more than 90 countries and used by more than 54 million people worldwide.

Depressive disorders are fairly common, affecting about 19 million American adults--nearly 10% of the population--each year, according to the National Institute of Mental Health. In addition to depressive disorders, anorexia, obsessive-compulsive disorder, obesity, and panic disorder are treated with SSRIs.

Prozac's success was due not so much to increased effectiveness as compared with other drugs, but rather to its comparative lack of side effects. The first modern drugs used to treat major depression were the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants, both introduced in the 1950s. Although effective, these classes of drugs are not specific and interact with a range of receptors in addition to those most relevant for the treatment of depression. The resulting side effects include hypertension, blurred vision, and severe headache. In addition, tricyclics and MAOIs can easily be toxic in overdose--dangerous when some patients are already suicidal.

Depression is thought to be caused, as least partly, by problems in the regulation of certain neurotransmitters, particularly serotonin (known to chemists as 5-hydroxytryptamine). As part of the neural signaling pathway, serotonin is stored in nerve terminals and then released into the synapses between neurons, where it can be transported back into the sending cell, destroyed by enzymes in the synaptic cleft, or taken up by the receiving cell. In patients with depressive disorders, levels of serotonin in the synapse are unusually low.

SSRIs block the reuptake pump on the sending cell, making more serotonin available in the synapse to be taken in by the receiving cell. They probably have other effects as well, possibly leading to long-term changes in brain structure. "The mechanisms are completely unknown," says Alan Frazer, chairman of psychopharmacology at the University of Texas, San Antonio, in Andrew Solomon's book "The Noonday Demon." "There's the immediate action of the medication, which leads to some black box we don't know anything about, which leads to a cure."

THE DISCOVERY of Prozac was an early example of rational drug design. In the late 1960s, Bryan B. Molloy and Klaus K. Schmiegel, organic chemists at Eli Lilly & Co., began synthesizing compounds based on the antihistamine Benadryl. A colleague at Lilly, David T. Wong, tested Molloy's compounds and found that one--with a CF₃ in the para position--blocked the uptake of serotonin and very little else. In 1974, the team publicly announced their discovery, and later clinical trials proved fluoxetine--soon branded as Prozac--to be effective in the treatment of depression and to lack the significant side effects of its predecessors.

But even as SSRIs transformed psychiatry, persistent critics warned that significant risks were being ignored. Prozac's relative lack of side effects allowed it to be prescribed more freely to less severely ill patients, and some critics expressed fears that people who are not clinically ill could be using the drug as an "emotional cosmetic" to change their personalities.

In addition, a number of lawsuits against Eli Lilly claimed that the drugs were responsible for violent and suicidal behavior, particularly in children and teens. As a result of such concerns, the Food & Drug Administration recently ruled that SSRIs and other antidepressants must have "black box warnings" about suicide risk in children and teens on their package information.

Studies on the suicidal risks of antidepressants have had some conflicting results but generally support the drugs' safety, particularly in adults. In one review of studies published between 1960 and 2004, it was found that suicide rates have dropped steadily since Prozac and similar antidepressants hit the market (Nat. Rev. Drug Discovery 2005, 4, 165).

The FDA action came after health officials last September examined 24 trials involving more than 4,000 children and nine antidepressant drugs. Although there were no suicides in either group, the analysis showed a 4% risk of suicidal thoughts in those receiving antidepressants--twice the placebo group's risk of 2%.

Meanwhile, Eli Lilly maintains that no credible evidence establishes a causal connection between Prozac and suicidal behavior, and many researchers and professional groups, including the American Psychiatric Association, argue that undertreated depression carries a greater suicide risk.

With the ongoing debate about suicidal side effects, the use of SSRIs to alleviate milder symptoms might be scaled back, but they still remain doctors' primary tools against major depression and related disorders. In 2004, they were the third most commonly prescribed class of drugs in the U.S.

Fluoxetine Hydrochloride

Name: N-Methyl- γ-[4-(trifluoro-methyl)phenoxy]benzenepropanamine

CAS Registry: 56296-78-7

Other names: Prozac

Introduced: 1987, Eli Lilly & Co

Sales: $631 million in 2003