Unveiling the Brain's Secrets: The History of Antidepressants

The history of antidepressants began, by chance, in the 1950s. Chemists developing a new treatment for tuberculosis tested the drug iproniazid on patients at Seaview Hospital on Staten Island. It was a crucial step in the history of depression treatment, as these patients experienced a dramatic change in well-being. Formerly lethargic and sad, they now reported better mood, increased appetite, and improved sleep. Life magazine even sent a photographer to document this remarkable story.

Iproniazid blocks an enzyme called MAO, which in turn breaks down chemical messengers such as serotonin, norepinephrine, and dopamine. Blocking MAO seems to restore these chemical messengers. Iproniazid helped to confirm the importance of the MAO system in depression, heralding a new class of depression medications called MAO inhibitors . However, their widespread use was limited by side effects such as elevated blood pressure and liver damage.

In the 1950s, the tricyclic antidepressants emerged. While imipramine was first tested in people with schizophrenia and proved ineffective, it showed better results in people with depression and was approved as a depression drug in 1959.

In the early 1970s, evidence for the role of serotonin in depression was gathering just as concerns were growing about the side effects of MAO inhibitors and tricyclic antidepressants.

Scientists thus turned their attention to SSRIs , or selective serotonin reuptake inhibitors. These drugs enhanced serotonin activity and seemed to carry fewer side effects than other antidepressants. A famous development in the history of antidepressants, fluoxetine was approved by the FDA in 1987 and reached the market the following year as Prozac ^® . A year later, almost 2.5 million prescriptions had been dispensed. Other SSRIs since released include paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine.

In the 1980s and 1990s, new antidepressants that targeted the monoamine neurotransmitter system emerged, including bupropion (a dopamine-norepinephrine reuptake inhibitor) and venlafaxine (a serotonin-norepinephrine reuptake inhibitor).

Despite these advances, any history of depression treatment must admit to several drawbacks related to these medications. All antidepressants can carry side effects, including nausea, dizziness, insomnia, and sexual dysfunction. They usually take several weeks to take effect. Up to a third of people with depression don't respond to these drugs . These shortcomings meant a new era of depression treatment was needed.

Depression was traditionally viewed as a chemical imbalance: a deficiency in a single chemical messenger in the gaps (or synapses) between nerve cells was believed to disrupt communication between these cells.

However, studies in the 1980s and beyond found some patients with depression had increased rather than decreased levels of these chemical messengers (or neurotransmitters). In addition, some effective depression medications decreased the level of a chemical messenger rather than increasing it. Finally, many treated with medications that enhanced serotonin didn't show an improvement in mood.

It was clear that depression wasn't related to a simple, single chemical deficiency. Instead, scientists designing new treatments began to understand that people with depression had widespread alterations in the function of neurotransmitters, structural changes in brain regions that regulated their mood and emotions, and changes in the brain's wiring or connectivity.

The next step was to find a drug that worked on the wider circuits and connections of the brain. That drug turned out to be one that had been used in operating theaters and on battlefields for decades.

Ketamine has been used as an anesthetic since the 1960s. It targets the glutamate system, which is disrupted in depression (the glutamate pathway is an excitatory pathway that dials up brain processes).

In an influential study in 2000, a single injection of ketamine exerted a rapid antidepressant effect within 72 hours. This benefit lasted for several weeks. A nasal spray version called Spravato (esketamine) received FDA approval in 2019 as an add-on therapy for treatment-resistant depression.

The exciting story of ketamine has highlighted the need to think beyond a single chemical messenger when developing modern antidepressants. Esketamine triggers positive changes in the function of brain circuits and stimulates the regrowth of synapses, restoring connections between brain cells.

That said, there are drawbacks. Esketamine side effects include dissociative symptoms (out-of-body experiences and hallucinations), and it carries the potential for abuse. Response rates may be lower in older patients . It must be administered in a doctors' office or clinic.

Despite their long and storied history, medications are only one option, and important advances have been made in the non-medication treatment of depression.

Transcranial Magnetic Stimulation (TMS) is a non-drug, non-invasive option with a well-established position in the history of depression treatment. The technology dates to experiments on nerves and muscles in the 1790s. In his 1859 lecture at the Royal Institution of Great Britain, scientist Michael Faraday outlined some of the principles of electromagnetism that would influence the development of TMS. A fully functioning magnetic stimulator was introduced into clinical practice in the 1980s in Sheffield, England.

TMS applies highly focused magnetic pulses to brain regions that are crucial in the regulation of mood. TMS goes beyond correcting a simple chemical imbalance. Instead, it addresses the complex brain changes of depression, helping to form new connections between nerve cells in affected brain regions . It can help to relieve some, or even all, depression symptoms in many patients.

TMS is FDA-cleared for Major Depressive Disorder when one medication hasn't been effective (though most insurance policies will only cover it after two medications).

Treatment has come a long way since those early TB drugs in the 1950s when the history of depression treatment first began.

At this new frontier, your choice of depression treatment goes beyond replacing a single chemical or modifying a single brain pathway. Depression researchers are beginning to see the bigger picture, and you should benefit from these scientific breakthroughs. By reaching out for your treatment of choice, you can take your next step toward living life the way you want to.