July 3, 2018
Written by: Greer Prettyman
In addition to discovering new chemical compounds to use as therapeutic drugs, researchers and doctors look for novel ways to use existing drugs as treatments for a variety of diseases. Ketamine, also called Special K or Vitamin K, is taken as a recreational drug and can have mild psychedelic effects. Recently, though, ketamine has been making headlines not as a recreational drug but as a potential treatment for one of the most common and hard-to-treat illnesses: depression.
It’s likely that you or someone you know has experienced depression. Currently, to be diagnosed with Major Depressive Disorder (MDD) a person must report feelings of depressed mood and loss of interest or pleasure that lasts at least two weeks. They also have symptoms that affect their daily lives, such as trouble sleeping, eating, or concentrating. Some patients experience thoughts of suicide. MDD affects 6.7% of all U.S. adults and more than half of people with MDD have severe impairment and are unable to function normally in their lives.
Decreased levels of particular neurotransmitters, particularly serotonin, are thought to be associated with depression, although the causes of MDD are complex and not well understood. Currently, the main methods for treating MDD are a combination of therapy and medications. The most common class of medications used to treat depression are known as Selective Serotonin Reuptake Inhibitors (SSRIs), which include recognizable brand names like Prozac, Zoloft, and Celexa. First given to patients in the late 1980s, these drugs work by acting at the junction, or synapse, between neurons in the brain. Serotonin normally crosses the synapse and binds to receptors on nearby neurons, where it works to regulate mood and emotion. Extra serotonin in the synapse is then usually reabsorbed back into the neuron. SSRIs are thought to block this reuptake of serotonin, leaving more of the serotonin to cross the synapse. In some patients, these elevated levels of serotonin in the synapse help to reduce symptoms of MDD.
While SSRIs are among the most popular and effective treatments for depression, they do not work for everyone. SSRIs can have unpleasant side effects such as nausea, weight gain, and sexual problems that lead some people to stop taking the medication. Typically, patients must take the drug for several weeks before they see a noticeable improvement on mood and behavior. There can also be a lengthy period of trial and error while doctors try to find a drug and dose that relieve symptoms without creating side effects. Some patients never experience relief of symptoms from taking SSRIs.
Despite their drawbacks, they remain the first-line treatment for depression 30 years later. However, about 45% of people with depression have “treatment resistant” cases of depression that are not alleviated by SSRIs. Researchers and doctors have been trying to find other drugs that might be more effective and reliable treatments for these severe cases of depression. Treating depression with medication is challenging and potential new treatments tend to generate a lot of hype. Ketamine has recently been making headlines as a possible “miracle drug” for hard-to-treat depression. But what is ketamine and will it be the next big depression treatment breakthrough?
Ketamine was developed in the 1960s and was first given to humans during the Vietnam War in the 1970s. It is currently used clinically during general anesthesia, pain relief, and veterinary medicine, and is marketed under the brand name Ketalar. Ketamine is also similar to PCP and used as a recreational drug. People who take ketamine recreationally report mild psychedelic effects at low doses and at high doses enter a “k-hole” marked by dissociation from the physical environment and inability to move.
So how might ketamine help to reduce depression? Ketamine is classified as an NMDA antagonist. This means that it blocks NMDA receptors, special types of channel in neurons that affect signaling of glutamate, an excitatory neurotransmitter. The mechanism of action by which ketamine alleviates depression is not yet well understood, but it is believed to reduce abnormal glutamate signaling associated with MDD1.
Recent research has begun to investigate the specific cases in which ketamine can reduce symptoms of depression. A study published in the American Journal of Psychiatry in April 2018 found that intranasal ketamine could be used as a fast-acting treatment for acute suicidal feelings2. In this double-blind study, sixty-eight patients with depression and imminent risk of suicide were randomly assigned to receive either standard care plus esketamine (a type of ketamine) or standard care plus placebo (treatment that looks like the ketamine treatment but contains no active ingredients). Those patients who received esketamine showed a significant decrease in ratings of depression and suicidality 4 hours after receiving the drug. However, those taking esketamine had no differences from the placebo group at a 24 hour and 25 day follow-up assessment.
This study showed that esketamine may be very effective for treating immediate suicide risk, in conjunction with currently available treatments. While SSRIs take weeks or months to provide relief, and in some cases are ineffective as treatments, ketamine has been shown to reduce suicidal feelings in just a few hours. The fast-acting relief makes ketamine a promising option for severe acute depression episodes. However, the fact that ketamine was no better than placebo at 24 hours and 25 days suggests that it likely won’t be as effective for long term treatment of depression.
Additionally, many questions about the safety and efficacy of ketamine use still need to be determined, like whether people form a dependence on ketamine after long-term use or whether frequently taking ketamine has negative effects on the brain or body. Overall, ketamine appears to be mostly safe for long-term use in people with treatment resistant depression3. However, some studies have also indicated that frequent ketamine use over a long period of time may lead to decreased cognitive performance, which may limit its usefulness as a long-term treatment4,5. Future studies will be needed to examine this potential risk.
Developing new treatments for psychiatric disorders is challenging, which is why doctors are still using the same medications to treat depression now as they were in the 1980s. A potential new treatment like ketamine is exciting, especially for cases of depression that aren’t improved by current treatment options. After additional research, ketamine may soon be part of the standard course of treatment for those with severe depression.
- Mathews DC, Henter ID, Zarate CA. Targeting the Glutamatergic System to Treat Major Depressive Disorder: Rationale and Progress to Date. Drugs. 2012;72(10):1313-1333.
- Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, Pinter C, Hough D, Sanacora G, Manji H, Drevets WC. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018 Jul 1;175(7):620-630.
- Wan LB, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, Foulkes A, Mathew SJ, Charney DS, Murrough JW. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry. 2015 Mar;76(3):247-52.
- Kim M, Cho S, Lee JH. The Effects of Long-Term Ketamine Treatment on Cognitive Function in Complex Regional Pain Syndrome: A Preliminary Study. Pain Med. 2016 Aug;17(8):1447-51.
- Zhang MWB, Ho RCM. Controversies of the Effect of Ketamine on Cognition. Frontiers in Psychiatry. 2016;7:47.
Cover image from Dominic Milton Trott and The Honest Drug Book via flickr, CC BY-NC-SA 2.0. https://www.flickr.com/photos/157786281@N07/40780397295