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Unveiling the Brain's Secrets: The History of Antidepressants
Jules Washington
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.
The Arrival of SSRIs: Progress but Room for Improvement
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.
Current Status of Antidepressants: Complicating the Chemical Imbalance
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: An Anesthetic Repurposed
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.
Beyond Medications: Transcranial Magnetic Stimulation
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).
Your Future: Finding the Treatment That Works for You
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.
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A recent study compared the effects of TMS therapy and Antidepressants. TMS therapy provided more relief from patients depressive symptoms compared to Antidepressants.
You may feel isolated and alone when you have clinical depression, and depression also affects your relationships with family and friends. While the primary focus of your treatment is to improve your mental health, it’s also essential to understand your loved ones may experience their own issues as they try to support you. An understanding of how depression affects relationships can help everyone maintain healthy connections and navigate problems. Here are some of the ways depression may affect the people in your support network.
We’ve all heard the common health-related misconceptions or myths-- chocolate causes acne, carrots will improve your night vision, and cracking your knuckles gives you arthritis. Subscribing to these particular myths is relatively harmless, but other health-related misconceptions can have far more serious consequences. This is the case for depression—the myths surrounding it can prevent people from getting the help they need. This is the case for depression—the myths surrounding it can prevent people from getting the help they need. Because untreated depression can have a serious physical and psychological impact, it’s imperative to have the right information in order to make the best decisions for yourself and for your health. Here are 5 common misconceptions about depression, and the facts behind them:
Starting any medical treatment for the first time can leave you with questions, especially if you’re looking forward to the benefits it may bring. It’s no different when you’re preparing for your nasal esketamine treatment. Your previous mental health treatments may have consisted solely of taking antidepressants at home or visiting a therapist’s office for cognitive behavioral therapy (CBT), so nasal esketamine is probably a new treatment experience for you. If you're wondering what it's like to start nasal esketamine and get ready for your first session, keep reading. Getting Started with the Nasal Esketamine Treatment As with any new treatment, you’ll first talk to your primary care provider or psychiatrist about whether nasal esketamine is a good fit for you. Alternatively, you can schedule your esketamine nasal spray consultation with a treatment center (such as Greenbrook) that has certification by the FDA’s Risk Evaluation and Mitigation Strategy (REMS). At Greenbrook's REMS-certified nasal esketamine treatment centers, our Greenbrook-affiliated psychiatrists and psychiatric nurse practitioners will review your medical history and also conduct our own assessment to help determine whether nasal esketamine treatment is right for you. Certain conditions, including blood vessel disease and a history of psychosis, may make treatment a risk for you. Make sure you discuss all previous and present conditions with your doctor or nasal esketamine provider before beginning treatment. If the medication is deemed a good fit, you’ll receive your prescription from the Greenbrook-affiliated provider. Your Greenbrook Care Team will put together a personalized care plan for the weeks and months to follow. Keep in mind that you will need to take a standard (oral) antidepressant along with your nasal esketamine treatment. There are two important regulations to note when it comes to preparing for treatment: Each treatment is followed by a mandatory two-hour observation period. This means you will need to plan to stay at the center for at least two hours following your self-administration of the esketamine nasal spray. You cannot drive during the rest of the day after treatment and must arrange for transportation. These regulations are mandatory. It may be helpful to sit down and plan out several weeks’ worth of transportation once you know your treatment schedule. In addition, if you’re wondering what to bring for the treatment, we recommend entertainment such as an audiobook or playlist of favorite songs and a pair of headphones. You may want them during the two-hour observation period. What to Expect During Nasal Esketamine Treatment On the day of treatment, you’ll need to stop eating any food two hours before your appointment and stop drinking all fluids 30 minutes before you come in. Your Greenbrook Care Team will confirm that you are prepared for the two-hour observation period and that you have a ride home. You’ll get the opportunity to practice using a “trainer sprayer” that mimics the real nasal esketamine sprayer but does not release any medication. The Care Team will encourage you to use the restroom and set up your preferred environment in your private treatment bay or room. Some patients like reduced lighting, for example, while others don’t request light adjustments. You’ll complete a depression scale before each treatment session. Your Greenbrook provider will confirm that the dose kit is yours, show you how to administer it, and then hand it to you. Each sprayer contained 28mg of Spravato esketamine nasal spray. Patients usually start with two sprayers (56mg) and soon increase to 84mg (three sprayers) per treatment. But, your dosage maybe vary. Should you be left with a metallic taste by the spray, the Care Team will offer suckers to help make the flavor dissipate. After your dose, you’ll be encouraged to lie back in your comfortable recliner. While most patients enjoy a quiet setting, Greenbrook is prepared to accommodate patients with a more animated reaction to the medication. You may feel sleepy, dizzy, mildly dissociated, and/or nauseated during treatment. Greenbrook's Care Team is readily available if you need assistance. How to Prepare for after your Nasal Esketamine Treatment Most side effects begin to wane in the second hour of observation, but if you’re wondering, “Is it safe to drive immediately after nasal esketamine treatment?” the answer is a resounding no. In addition to the mandatory ride home, you will need to block off time to rest and let side effects fully dissipate. This extended rest period is especially important in the first weeks of treatment when you’ll have treatment twice a week. Do not drive or operate machinery of any kind until the day after treatment. Just take it easy, relax, and take care of yourself. If you’re unsure what activities you can do or should avoid during this time, talk to your Care Team for more information. While side effects tend to dissipate completely after a good night’s sleep, many nasal esketamine patients begin feeling relief from depression symptoms within hours of their treatment. Other Tips in Preparing for Your Nasal Esketamine Treatment At Greenbrook, we make every effort to schedule your treatment in the afternoons or whenever it is most convenient for you. We encourage you to see each treatment session as an opportunity to relax and take care of your mental health. If you have any questions or concerns, talk to your doctor or the Greenbrook Care Team. At Greenbrook, we’ll help you feel at ease when preparing for each treatment session. Schedule A Free Consultation To get started with nasal esketamine, schedule your free consultation today.
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