History of Antidepressants

The use of pharmaceutical agents to treat common psychiatric disorders such as anxiety and depression is a phenomenon that has arisen only over the past fifty years. Prior to the 1950s, patients were treated for depression and anxiety using psychotherapy. All mental disorder, psychiatrists believed, was caused by anxiety resulting from internal conflicts. This picture began to change in 1949 with the accidental discovery of the psychotherapeutic value of lithium by John Cade, a previously unknown Australian psychiatrist who observed the sedating effects of lithium in guinea pigs. Cade, who determined lithium to be safe for human consumption by trying it himself, administered this element to manic patients, who were subsequently relieved of their manic symptoms. Although widespread use of lithium did not develop until the 1960s, the drug remains to this day the primary treatment for bipolar, or manic-depressive, disorder. Pharmaceutical treatment of unipolar depression began in 1953 with the observation that a drug designed to treat tuberculosis, iproniazid, also had the unusual side-effect of giving tuberculosis patients boundless energy. Iproniazid was termed a "psychic energizer" by Nathan Kline, who first investigated its psychological effects and proposed that this property might prove useful in treating depression. In 1957, following initial clinical success in depression trials, over four hundred thousand prescriptions were issued within a year.

Unfortunately, a number of people treated with iproniazid developed jaundice, and bad publicity caused the manufacturer to withdraw the drug from the market. Meanwhile, the 1952 introduction of chlorpromazine, the first modern psychotherapeutic medication, which was effective in treating schizophrenia, inspired the search for antidepressant agents among similar compounds, a familiar class of drugs found in many cough syrups known as the antihistamines. After testing several antihistamines, Robert Kuhn discovered one such compound, imipramine, effective at treating depression without producing the stimulation experienced by those taking iproniazid. This he took as evidence that this antihistamine worked on the root of depression rather than by simply masking it with an energy burst. The drug in fact produced sedation, not elevation of mood, in undepressed subjects. Imipramine proved to be effective in over 60% of classical depression cases.

imipramine

The antidepressant story may have ended here, had it not been for imipramine's major flaw--unpleasant side-effects such as heart palpitations, dry mouth, constipation, and drowsiness. Antidepressant drug therapy made little progress beyond imipramine in the thirty years that followed. Several analogues to iproniazid and imipramine were synthesized in hopes of producing an effective compound free of the undesirable side-effects that accompanied these drugs. However, the side-effects stemmed from the action of these two classes of compounds, known as the monoamine oxidase inhibitors and tricyclic antidepressants, respectively, on multiple neurotransmitters, resulting in diverse physiological response. The new objective became the synthesis of a compound that would specifically affect a single neurotransmitter, thereby reducing the potential side effects. This goal proved elusive however due to the similar structures of the various neurotransmitters.

All this changed however in 1971 when David Wong, a disaffected antibiotics researcher at Eli Lilly began toying with neurochemistry. Having learned a new laboratory technique that allowed direct observation of neurotransmitter reuptake by rat neurons, Wong began, like other researchers at the time, testing anithistamines for blockage of norepinephrine reuptake. Around this time, however, Dr. Wong read a book summarizing early research that pointed to a role for serotonin in depression. After realizing through his antihistamine studies that similar compounds can have dramatically differing effects on neurotransmitter systems, Wong began testing compound that had failed to block norepinephrine reuptake. One of these nearly forgotton compounds, fluoxetine hydrochloride, he discovered, blocked reuptake of serotonin but not of other neurotransmitters. The seemingly unattainable neuroscientific goal was realized. Over a decade later, after countless animal and clinical studies, fluoxetine hyrdrochloride was released to the world as Prozac. No one knew it at the time, but Prozac was to change the landscape of psychiatry forever, expanding the pharmaceutical treatment of depression to epidemic proportions.

Chris Liverman [liverman@grinnell.edu]