Over 17 percent of Americans suffer from major depressive disorder (MDD). MDD is one of the oldest and most researched psychiatric disorders, around 30% of patients fail to respond to treatment. However, a cutting-edge therapy is providing hope to many suffering from MDD. The treatment: an anesthetic and party drug known as Ketamine.
Ketamine was synthesized in 1956 and was introduced into clinical settings in the 1960s as an anesthetic. Although highly effective, it often produces side effects, including increases in blood pressure, salivation, hallucination, and excitation. Nevertheless, ketamine was used as a field anesthetic during the Vietnam War and has become a popular form of anesthesia in veterinary medicine.
Image source: Yale News
In the 1980s and '90s, Ketamine gained popularity as a recreational drug for its euphoric and hallucinogenic effects. Commonly known as “special K,” Ketamine was categorized as a class III illicit substance in the 1999 US Controlled Substances Act. Despite its illicit status, over the past 50 years, investigators have taken advantage of ketamine’s neurophysiological effects to gain insights into its therapeutic properties.
Research into the anti-depressive properties of ketamine was pioneered by John Krystal, MD (pictured left), chief psychiatrist at Yale Medicine. Krystal, along with colleagues Dennis Charney, MD, and Ronald Duman, PhD, began testing ketamine as a pharmacological intervention for depression in the 1990s.
Selective Serotonin Reuptake Inhibitors (SSRIs) currently are the most common pharmacological treatment for depression. These medications work by inhibiting serotonin reuptake after it is released into the synaptic cleft, allowing more serotonin to remain in the synapse. However, these medications can take months to become effective, and around a third of patients do not respond to SSRI treatment.
Ketamine works differently...
Krystal and colleagues administered 0.5 mg/kg ketamine to patients intravenously over 40 minutes. Low doses of ketamine were associated with robust decreases in depressive symptoms. Moreover, such decreases were not associated with the drug's initial euphoric “high.”
The antidepressant effects of ketamine begin almost immediately after administration and can last for weeks. One-third of patients with treatment-resistant symptoms achieve remission using ketamine therapy, and treatment has been found to reduce nearly all symptoms of depression, including suicidal ideation in over 50% of patients.
Image Source: WIRED
How does ketamine change the brain?
Watch this short video from Yale Medicine to learn more ketamine therapy.
Ketamine acts on receptors for the neurotransmitter glutamate, known as NMDA receptors. Glutamate is the primary excitatory neurotransmitter in the brain. At high doses, Ketamine binds to NMDA receptors, acting as an antagonist and blocking glutamate activity. This results in the drugs' anesthetic effects. At lower doses, ketamine has been shown to disrupt the balance of excitatory and inhibitory signals in the brain. Ketamine may block the action of GABAergic neurons, preventing their inhibitory signal and allowing for a spike in glutamate. This mechanism is known as the disinhibition hypothesis.
The influx of glutamate may have several downstream effects, including the stimulation of AMPA receptors. AMPA receptors are heavily involved in learning in memory. Activation of these receptors may trigger the formation of new synaptic connections and the growth of dendritic spines in the prefrontal cortex and hippocampus. The formation of new connections may boost neural circuits regulating stress and mood and increase neuroplasticity. These mechanisms may help ease the symptoms of depression.
Image source: University of Vienna
"This is a game-changer," Krystal says. "When you take ketamine, it triggers reactions in your cortex that enable brain connections to regrow. It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects."
The discoveries of Ketamine’s mechanisms by researchers at Yale Medicine have led to the development of esketamine- an FDA-approved nasal spray designed to treat depression. Currently, the drug is only recommended for individuals with severe depression who have failed to respond to at least two other medications.
Esketamine (brand name Spravato) was approved for medical use in 2019. Image source: NPR.
Like any new drug, there is still a lot that we do not know about the effects of ketamine, especially long-term use. Side effects of esketamine include dizziness, a rise in blood pressure, and feelings of detachment. To date, the medication has only been shown to be effective when taken in combination with an oral antidepressant (SSRI).
Image source Scientific American
What is the future of depression treatment?
We still do not fully understand how depression affects the brain. Because no two individuals respond to treatment the same way, depression treatment continues to be a dynamic and ongoing process. However, researchers like Dr. Krystal believe that ketamine therapy could be the future of depression treatment. For the 30 percent of MDD patients who fail to respond to traditional treatments, ketamine could provide more than just a good trip. It could be the light at the end of the tunnel and the last hope of relief.
Most importantly, research into ketamine therapy and the underlying neurological mechanisms of depression must continue, and treatments should be made accessible and safe for those who need them.
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