The sun is shining. The temperature is warm. No clouds can be seen in the sky. And you have plans to meet with friends at the beach. Sounds like the potential for a great day, right? But if you suffer from depression, despite the sunny blue skies, you tend to always have a cloud over you.
Depression can be experienced in different ways in different people. In general, it is a mood disorder that can cause feelings of sadness, loss of interest in activities that you found once enjoyable, insomnia, excessive sleep, hopelessness, among a multitude of other possible signs. Symptoms can range widely from mild to debilitating. Psychiatrists and psychologists are the key to diagnosis and treatment, and primary care physicians are usually the first to be told about symptoms. Selective serotonin reuptake inhibitors, or SSRI’s, are a commonly prescribed antidepressant. In fact, it is the most commonly prescribed antidepressant in many countries. However, many times, traditional treatments are not as effective or timely as we would want or need. SSRI’s can take weeks or months to have an effect, and there is a chance they may not work. There are many potentially significant side effects as well, not to mention the need for compliance to maintain the control of depression.
Ketamine has been studied fairly extensively, and it has been shown to be effective in treating refractory depression at least in the short-term time frame. There is usually a relatively immediate response within hours of receiving the IV ketamine treatment. A positive response to ketamine can last anywhere from a few days to up to a few weeks, despite ketamine being metabolized in a few hours. At the Mayo Clinic in Rochester, MN, researchers have found a way to extend the antidepressant effects for several weeks by, what they call, continuation-phase administration of intravenous ketamine. This involved weekly IV infusions of ketamine for four weeks following the acute protocol, which is typically six infusions over a two to three week period. They found this continuation-phase protocol to be helpful in prolonging effects of IV ketamine and not increasing adverse effects other than transiently with each infusion which were generally mild.
The scientific community has studied ketamine extensively, but we do not know enough and still need to learn more. Ketamine is an NMDA (N methyl d aspartate) receptor antagonist and an anti-inflammatory agent. This is the main mechanism discussed when it is used as an anesthetic, but interestingly not the mechanism by which it works in depression.
The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, or AMPA receptor, is where the interest lies in ketamine and depression. The AMPA receptor is involved in glutamate neurotransmission, and ketamine’s antidepressant effects may be due at least partially to activation of the AMPA receptor by a ketamine metabolite (2R, 6R)-hydroxynorketamine. In a study in mice, ketamine and its (2R, 6R)-hydroxynorketamine metabolite each generated antidepressant responses that did not occur with other ketamine metabolites. In addition, the investigators found that (2R, 6R)-hydroxynorketamine activates AMPA receptors, but does not bind to or inhibit (antagonize) the NMDA receptor, and that blocking the AMPA receptors blocked the antidepressant effects of the metabolite.
Other studies have examined ketamine’s mechanism of action at the level of brain structures. Functional MRI neuroimaging studies in patients with treatment resistant depression suggest that ketamine may improve depression by activating the anterior cingulate cortex. Ketamine was also shown to possibly increase connectivity between the insula and default mode network, or DMN. The default mode network is a network of interacting regions of the brain that are known to have activity highly correlated with each other and unique in comparison to other networks in the brain.
Another study suggested that neuronal vascular endothelial growth factor (VEGF) signaling in the prefrontal cortex may mediate the rapid antidepressant actions of ketamine. Another preclinical study that administered ketamine to rodents with depression-like behaviors found that neuronal activity in the habenula (this, and the pineal gland, which makes melatonin, form the epithalamus) decreased to the level observed in the control group, and that the depressed-like rodents behaved like the non-depressed control rodents.
Another promising ketamine treatment is for those who have thoughts of suicide. While anyone who is actively suicidal should immediately go to the emergency department or get help, those who have had suicidal thoughts due to severe depression have been shown to benefit rather rapidly from just one ketamine infusion. Ketamine, however, may or may not prevent future suicide attempts or death.
But, a lot more research is currently being performed on ketamine. It is opening up a new avenue for possible treatment for refractory depression where there is such limited success as of now unfortunately. For example, researchers at the Mayo Clinic are also looking for biomarkers in the peripheral blood that could potentially predict responsiveness to ketamine and/or other antidepressants. Other researchers are also evaluating why pretreatment with ACTH (adrenocorticotropic hormone) contributes to a poorer response to antidepressant medications and the biological mechanisms behind this poorer response.
As more is learned about ketamine and people are having more experience with the intravenous infusion of ketamine, there is more and more evidence of the infusion helping people with mood disorders, including refractory depression, PTSD, and OCD. When traditional treatments for mood disorders do not work as well as we would want or take a long time to create some beneficial effect, intravenous ketamine has a potentially important role in helping treat these people. It is essential that IV ketamine should be used in conjunction with psychiatrists and not as a replacement. However, the evidence is mounting for IV ketamine as a great alternative treatment or additional treatment for mood disorders, as well as a treatment that should be utilized more frequently.