Science, serotonin, and sadness: the biology of antidepressants

In 1988, the first member of a new drug family arrived on the United States pharmaceutical market with rock star pizzazz and excitement. Fluoxetine, trademarked as Prozac, was featured on the cover of Newsweek as a breakthrough drug and discussed with passion on radio and television, often by grateful users and sometimes by those concerned over its widespread use for a growing number of conditions. Today, Prozac remains the most widely prescribed antidepressant medicine in history, having been used by more than 54 million people in 90 countries. Prozac also helped change the definition of depression. In the not so distant past, depression was regarded as an affliction of the human heart, mind and soul. When patients complained of persistent depression, so severe that they were unable to work, sleep, or enjoy once pleasurable activities, psychiatrists often suggested they were repressing anger toward others and turning it toward themselves or asked if they had felt unloved by their mothers. Friends and associates were more likely to tell the troubled person to “snap out of it. ” Individuals suffering from depression often felt ashamed, stigmatized. With the availability of drugs that relieved symptoms of severe depression by acting upon a specific biochemical mechanism in the brain, depression became more commonly viewed as a medical problem like hypertension and diabetes, amenable to pharmaceutical interventions. Prozac and the other Selective Serotonin Reuptake Inhibitor (SSRI) drugs that followed were not the first medicines to demonstrate success in treating depression, as this story describes, but they were the first class of antidepressants to be rationally designed based on new understanding of how the brain works to affect mood, especially the role and behavior of naturally-occurring chemicals called neurotransmitters that deliver messages from nerve to nerve. The SSRIs may also have been one of the first categories of drugs whose mechanism was widely discussed by the general public. If most people did not remember what SSRI stood for, much less know the discoveries that underlay every word in the long, cumbersome name, there was a widespread, shorthand understanding of how the drugs worked. It went like this: Individuals with depressive disorders have lower levels of the neurotransmitter serotonin in their brains. Selective Serotonin Reuptake Inhibitor drugs selectively focus on serotonin and inhibit its recapture or reuptake by the nerve cells, alleviating the serotonin shortage and leaving more of the mood-enhancing chemical outside the neuron and thus available for the brain’s use. Thanks to the new SSRI drugs, the phrase “chemical imbalance” entered the national consciousness and vocabulary as at least a partial and biological explanation of severe depression, thus lifting much of the stigma and blame that had added to depressed patients’ woes. Like all scientific breakthroughs, the development of the SSRI drugs was built on a scaffolding of earlier discoveries, some of them chance clinical observations, some of them excruciatingly detailed basic science results whose clinical significance would not be realized for decades. And like all such breakthroughs, the new drugs continue to raise more questions and opportunities as yet newer information and technology becomes available.