Ketamine is the newest drug in the treatment of major depressive disorder (MDD). But how does it work? In this post, we’ll look at how ketamine is an antagonist of the neurotransmitter glutamate and why this can help fight depression.
For years serotonin has been the main focus of causes and cures for depression. As low levels of serotonin and serotonergic dysfunction are commonly linked with depression, logically the focus for treatment has been on boosting serotonin levels. This is why the SSRI drugs (that increase serotonin) have been the first choice drug for psychiatrists. However, ketamine is an up and coming superstar in the world of drug therapy. This is because the neurotransmitter glutamate could be the key to understanding the origins of depression. Ketamine works because it’s an antagonist, so let’s look at exactly how and why it could be used in the fight against depression.
What is an antagonist?
Agonists and antagonists are chemicals that bind to the receptor sites of specific neurotransmitters. An antagonist binds to the receptor and then stops that neurotransmitter from binding and sending a signal.
Remember that the process of neurotransmission is a bit like a lock-and-key: the right neurotransmitters can only bind with the right receptor sites on the post-synaptic neuron (see image).
Neurotransmitters bind to specific receptors and send signals to the next neuron.
Glutamate is one neurotransmitter that has specific receptor sites that it binds to. Glutamate is an excitatory neurotransmitter, so when it binds to its receptor sites it sends a signal for the post-synaptic neuron to “fire.” But ketamine is an antagonist of the receptor sites for glutamate. So when ketamine binds to the receptor sites, it blocks the glutamate and prevents that neuron from firing.
Ketamine binds to glutamate receptor sites and blocks it from having an effect. Because glutamate is high in people with depression, this inhibitory effect of the antagonist ketamine could help treat depression.
How does this affect our behaviour? Blocking the glutamate could help to reduce depression symptoms by reducing the transmission of glutamate in key areas of the brain.
Not surprisingly, multiple studies have found that people with depression have high levels of glutamate (source). Ketamine reduces symptoms because it binds to the receptor to reduce the excitatory effect of glutamate. It’s like the opposite of SSRIs and serotonin – low serotonin is restored by having SSRIs that boost it, whereas high glutamate is treated by having antagonists that block it.
Read more: Synaptic pruning and neural networks (link)
Glutamate, Ketamine and Depression
According to some experts, ketamine is the most significant breakthrough for the treatment of depression in over 50 years (source). Grady et al. (2017) reviewed 7 clinical drug trials that tested the safety and effectiveness of ketamine for treating depression. They found that ketamine had a significant effect on the reduction of depression symptoms and was more effective than placebos. They conclude that ketamine “…has shown promise in quickly reducing symptoms in patients with treatment resistant depression and bipolar depression.” (source). One of these experiments is explained in more detail below.
Key Study: (Lapidus et al. 2014) (Link)
Aim: to test the safety and effectiveness of using ketamine to treat depression.
Methods: 20 people with major depressive disorder were randomly allocated into one of two conditions. One group were given ketamine while the other was given a placebo (saline solution). The treatments were administered intranasally (up the nose). The effect this had on depression was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) one day after the treatment.
An intranasal injection – it’s not as bad as it sounds. (image credit: U.S. Air Force photo/Staff Sgt. Tia Wilson – https://www.eielson.af.mil)
Results: After 24 hours, the results showed that the ketamine group had a significant decrease in their depression symptoms. There were also no reported side-effects of the ketamine.
The researchers’ conclusions are similar to many others – ketamine could be a safe and effective way to treat depression. One of its major benefits is that it’s fast acting (much faster than SSRI’s).
Test Yourself!
How well did you read this article?
- What is an antagonist?
- How does ketamine affect the neurotransmission of glutamate?
- Why is ketamine a promising new drug for depression?
- What were the results of Lapidus et al.’s study?
IB Psychology Exam Tips:
- Remember that “agonists and antagonists” could be asked in SAQs only (not essays).
- The effects of ketamine on glutamate neurotransmission can be used to explain how neurotransmission (glutamate) and antagonists (ketamine) affect behaviour, biological treatments of depression, and research methods.
References
Grady, S. E., Marsh, T. A., Tenhouse, A., & Klein, K. (2018). Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature. The mental health clinician, 7(1), 16–23. doi:10.9740/mhc.2017.01.016 (Link)
Lapidus, K. A., Levitch, C. F., Perez, A. M., Brallier, J. W., Parides, M. K., Soleimani, L., … Murrough, J. W. (2014). A randomized controlled trial of intranasal ketamine in major depressive disorder. Biological psychiatry, 76(12), 970–976. doi:10.1016/j.biopsych.2014.03.026 (Link)
Liu, W., Ge, T., Leng, Y., Pan, Z., Fan, J., Yang, W., & Cui, R. (2017). The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex. Neural plasticity, 2017, 6871089. doi:10.1155/2017/6871089 (Link)
Sanacora, G., Treccani, G., & Popoli, M. (2012). Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology, 62(1), 63–77. doi:10.1016/j.neuropharm.2011.07.036 (Link)
Travis Dixon is an IB Psychology teacher, author, workshop leader, examiner and IA moderator.