In October 2019, the U.S. Food and Drug Administration (FDA) approved esketamine, a substance chemicallyrelated to the party drug ketamine, as a nasal spray to treat depression (Bahr, 2019). The effectiveness of ketamine for depression was first shown in studies in 2000 when it was found to be a rapid-acting antidepressant. It’s also been successful in decreasing suicidal ideation.
A single low, sub-anesthetic dose of ketamine given via intravenous infusion can produce antidepressant effects within four hours in people with depression. These antidepressant effects can persist for up to several weeks following a single infusion. This is in contrast to conventional antidepressants like selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), which generally require at least several weeks for their benefits to occur and become maximal. What’s more, based on the available preliminary evidence, the magnitude of the antidepressant effects of ketamine appears to be more than double that of conventional antidepressants. On the basis of these findings, ketamine has been described as the single most important advance in the treatment of depression in over 50 years.
Ketamine and Depression Research
Ketamine has not been approved for use as an antidepressant, but its enantiomer, esketamine, was developed as a nasal spray for treatmentresistant depression and was approved for this indication. It’s the first new medication for major depression that has been allowed in the U.S. in decades. Because treatment with esketamine might be so helpful for patients with treatment-resistant depression, the FDA expedited the approval process to make it more quickly available.
In 2016, Johnson & Johnson submitted five phase 3 studies on the drug to the FDA: three-short term studies, one maintenance study and a longterm safety study. One was a randomized trial in adults under age 65 with treatment-resistant depression who were started on an oral antidepressant and intranasal esketamine. After a month, roughly 70% of patients who received the treatment were significantly better compared to the placebo group. The researchers considered an improvement of 50% or more on a common depression rating scale as a successful response.
According to researchers, esketamine works differently than other drugs. With most medications, like valium, the anti-anxiety effect you get lasts as long as it is in your system. When the valium wears off, you can get rebound anxiety. With ketamine, it triggers reactions in the cortex of the brain, enabling connections to regrow. It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects. This is exactly what makes ketamine unique as an antidepressant.
GABA and glutamate are neurotransmitters that are used by more than 80% of the neurons in the brain. Researchers believe they’re responsible for regulating the majority of brain activity, including mood. Intense stress can alter glutamate signaling in the brain and make the neurons less adaptable and less able to communicate with other neurons. When this occurs, stress and depression make it harder to deal with negative events, a cycle that can make matters even worse for people struggling with difficult life events.
Studies from Yale University research labs found that ketamine triggers glutamate production, which—in a complex, cascading series of events—prompts the brain to form new neural connections. This makes the brain more adaptable and able to create new pathways, giving patients the opportunity to develop more positive thoughts and behaviors. This effect had not been seen before, even with traditional antidepressants.
For the last two decades, researchers at Yale have conducted ketamine research, using ketamine delivered intravenously in controlled clinic settings for patients with severe depression who hadn’t improved with standard antidepressant treatments. The results have been dramatic: In several studies, more than half of participants had a significant decrease in depression symptoms after just 24 hours. These were patients who had no improvement on other antidepressant medications.
In the end, though, the FDA approval of esketamine gives therapists and patients another valuable tool in their arsenal against depression and offers new hope for patients who couldn’t be helped before. Other novel applications for ketamine are sure to follow.
Randi Fredricks, Ph.D.
References
Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, Sos P, Wang G, Zarate CA, Sanacora G (2018). The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am J Psychiatry, 175(2), 150–158.
Zhang K, Hashimoto K (2018). An update on ketamine and its two enantiomers as rapid-acting antidepressants. Expert Review of Neurotherapeutics, 19(1), 83–92.
Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sánchez E, Gutiérrez-Rojas L, Meana JJ (2018). Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS Drugs, 32(5), 411–420.
Ionescu I et al. (2019). Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients at imminent risk for suicide: ASPIRE-2 study. Presented at European College of Neuropsychopharmacology (ECNP) Congress, September 2019, Copenhagen, Denmark.
Johnson & Johnson Press Release. (2016). Esketamine Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for Major Depressive Disorder with Imminent Risk for Suicide. August 16, 2016. https://www.jnj.com/media-center/press-releases/esketamine-recieves-breakthrough-therapy-designation-from-us-food-and-drug-administration-for-major-depressive-disorder-with-imminent-risk-of-suicide
Stone JM et al. (2012). Ketamine effects on brain GABA and glutamate levels with 1H-MRS: Relationship to ketamine-induced psychopathology. Molecular Psychiatry, 17(7), 664-665.
Abdallah CG, Sanacora G, Duman RS, Krystal JH. (2015). Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutic. Annual Review of Medicine, 509-523.
Krystal J, Abdallah C, Sanacora G, Charney D, Duman R. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101, 774-778.
