What is ketamine?
Ketamine is a medication that was developed in the 1960s. It was approved as an anesthetic agent for use during medical and surgical procedures by the Food and Drug Administration (FDA) in 1970. Since that time, it has been used primarily as a medication to induce anesthesia (loss of consciousness), and has been used in the management of chronic pain conditions. It is generally given to patients through an IV, but can also be given in inhaled and oral forms. Ketamine is also a drug of abuse that is used illicitly in the United States, and can lead to addiction.
What does ketamine have to do with treating depression?
In the year 2000, a small scientific study by Berman et al. demonstrated that ketamine can act rapidly as an antidepressant (1). A group of patients with major depressive disorder was given a single intravenous infusion of ketamine. For a significant number of patients, the infusion of ketamine appeared to cause a 50% or greater decrease in their burden of depressive symptoms. Much of this improvement occurred within the first 24 hours after the infusion. This speed of response was remarkable – standard antidepressant medications typically take at least four weeks to alleviate symptoms.
In the years since Berman et al.’s publication, a number of studies have replicated these findings (2). A single ketamine infusion can lead to a rapid, clinically-significant antidepressant response. A promising aspect of these studies is that several of them demonstrated the ability of ketamine to improve depression even in patients with “treatment-resistant” depression (that is, depression that has not responded to previous trials of antidepressant medication). Unfortunately, the other consistent finding is that the improvement associated with ketamine treatment is short-lived, usually disappearing within less than a week (2). Several of these studies are well-designed, double-blinded and placebo-controlled trials; the sound design of these small studies makes their results more encouraging. However, the total number of patients who have been treated with ketamine in a controlled study still remains quite low (N = 277, in total), which limits our ability to draw firm conclusions about the use of ketamine (3).
How does ketamine treat depression?
The short answer is, we’re not sure yet. Research on this question is ongoing. We do know that ketamine affects a chemical in our brain called glutamate. Glutamate is one of several brain chemicals that is responsible for transmitting signals between neurons, the cells that make up our brain and the rest of our nervous system. As a group, we call these compounds “neurotransmitters.” It can be argued that glutamate is perhaps the most important neurotransmitter in the brain, as the majority of the signaling occurring in our brains is in fact mediated by glutamate (4). Ketamine is unique among antidepressant treatments in its ability to directly influence the activity of the glutamate system.
There are a few theories as to how ketamine, through its influence on glutamate signaling, may be able to improve depression. Glutamate has a particularly important role in a brain process called “long-term potentiation.” Long-term potentiation refers to our brain’s ability to strengthen the connection between certain neurons, leading them to send signals to each other more easily. This is part of how our brains make connections between pieces of information, and is thought to be the basis of memory formation. In recent years, studies have found that when we are depressed, our brains are impaired with regards to making and strengthening connections, and that improvement in depression occurs in concert with an increase in the ability to make new brain connections (4). Ketamine treatment has been shown to improve long-term potentiation in just such a manner, though the mechanism of this effect is not fully elucidated (3).
Another theory about how ketamine works has to do with its ability to influence the health of brain neurons. As noted above, glutamate plays an important role in normal brain functioning. However, it also plays a significant role in many brain diseases, including stroke, multiple sclerosis, and various forms of dementia. You might think of glutamate as a “Goldilocks” chemical. The brain needs to have the right amount, in just the right places. When there is too much glutamate in one place at one time, a phenomenon called “excitotoxicity” occurs. In essence, an excess of glutamate overwhelms the neuron with stimulation, so much so that the neuron may shut down and die. This process is known to occur in the brain diseases noted above, but increasingly it is being recognized as potentially contributing to depression and other mental health conditions (5). Ketamine may be helpful in preventing excitotoxicity in depression due to its ability to act as a glutamate-blocker, preventing neurons from being overwhelmed by high levels of glutamate (3).
Traditional antidepressant medications don’t have the same effect on glutamate as does ketamine. Instead, traditional antidepressants cause changes in other neurotransmitters including serotonin, norepinephrine, and dopamine. These neurotransmitter systems contain far fewer neurons than does the glutamate system, but they project diffusely throughout the brain, influencing activity in many regions. They are also known to influence the activity of the glutamate system, so it is possible that traditional antidepressants also exert some of their efficacy also via indirect effects on glutamatergic signaling.
What don’t we know about ketamine for depression?
There is a lot that we don’t know. First, we don’t know if ketamine can cause lasting improvements in symptoms of depression. Ketamine can cause a rapid improvement in symptoms of depression, but in most people, that improvement disappears quickly as well, usually in less than a week (3). Right now, it’s not clear how to make the effects of ketamine last longer. This is a problem. Some studies have tried to address this issue by giving patients repeated ketamine treatments, usually about two to three times a week, and this appears to sustain the antidepressant effect for at least 2-4 weeks (6, 7). However, these studies have not followed patients for longer than this 2-4 week period. Beyond 2-4 weeks, it isn’t really clear what to do in order to sustain the response. The only known way to prolong the effects of ketamine is to indefinitely give patients ketamine infusions at least twice weekly.
If we’re going to give patients ketamine on a regular basis, this leads to another area of uncertainty: we don’t really know how safe it is to repeatedly give people ketamine for depression. The safety studies that looked at ketamine when it was approved by the FDA examined the safety of infrequent or one-time use of ketamine for anesthesia. It isn’t clear yet whether using ketamine in the same person multiple times (or indefinitely) would cause new or different problems. In studies of repeat ketamine administration so far, there don’t seem to be major problems, but there simply haven’t been enough studies looking at this question. Some of the known risks of repeated ketamine use are discussed below.
Third, we don’t yet know what sort of depression is most likely to be helped by ketamine treatment. Most of the studies looking at this topic have treated patients with major depressive disorder (also called “unipolar” depression). Whether it will be helpful in bipolar depression and other forms of depression remains to be seen. Bipolar depression responds differentially to medication, when compared to unipolar depression, though the two may appear similar. There are two small studies that have examined whether patients with bipolar depression improve with ketamine treatment (8, 9). These studies suggest that ketamine may be helpful to these patients, but the total number of patients in which this question has been tested remains exceedingly small (N = 33). One area of concern regarding the treatment of bipolar patients with ketamine is whether there is a potential to induce mania or hypomania, since almost all of our current antidepressant treatments have some potential to induce mania in bipolar patients. Again, little research has been done, so it is difficult to quantify the size of the risk of mania in a bipolar patient receiving ketamine.
What are some of the risks of using ketamine?
One of the major risks of using ketamine is the risk of addiction or drug abuse. Even when it is given as a medicine, many people report a feeling of being “high,” and this may lead to some persons becoming addicted. Ketamine is already widely used as a street drug, and in some countries, it is one of the most commonly abused drugs (10). This is problematic in itself – addiction can cause major difficulties including dysfunction at work and in relationships, financial strain, physical illness and injury, and psychological distress. But addiction is also a highly comorbid problem in people who suffer from depression. The negative effects of addiction can interact with the negative effects of depression, rendering both problems much more difficult to treat and resolve. Therefore, we need to be concerned that the use of ketamine in depression may lead to addiction, especially in a population of people who are already vulnerable to this possibility.
Ketamine is also an anesthetic agent, meaning at higher doses it leads to loss of consciousness. At the doses given in trials for depression, there appears to be relatively low likelihood of a problematic decrease in alertness. Due to the possibility of loss of consciousness, IV ketamine administration is usually performed with equipment that allows for monitoring of cardiovascular and respiratory status, and equipment and staff for resuscitation if that need should arise.
Transient dissociative or hallucinatory reactions are another potential side effect of ketamine. Dissociative effects are essentially feelings of unreality or the experience of being disconnected from one’s body. The hallucinatory effects can include hearing voices and seeing visions. Some patients dislike the “high” feeling that can occur with ketamine use, experiencing it as a frightening and unpleasant sensation. In studies thus far, when ketamine is given under appropriate conditions, it seems that these effects last only a few short hours and are not severe (11).
Last, severe kidney and bladder problems, and long-term brain changes that mimic schizophrenia have been reported in those who abuse ketamine. Because abuse is generally associated with much higher doses than those used in the treatment of depression, we don’t know whether these side effects will be a risk in routine clinical use of ketamine (11). Because of the potential for ketamine to cause hallucinatory experiences, or to induce a schizophrenia-like state, there is reason to be concerned about whether ketamine is safe for patients with a previous history of psychotic symptoms, or a family history of a psychotic illness.
Are doctors currently using ketamine for the treatment of depression?
Ketamine is currently being used by a relatively small number of psychiatrists as an off-label treatment for depression, but most psychiatrists find that there are still too many unanswered questions about ketamine for them to feel confident recommending it to their patients at this time. Given the uncertain risks of repeated long-term use described above, the relatively small number of patients who have received it in clinical trials, and the availability of a variety of other, more robustly studied treatment options for treatment resistant depression, most psychiatrists do not consider ketamine to be ready for clinical practice.
For those patients considering off-label clinical treatment with ketamine outside of a clinical trial, it is important to be aware that there is no established guideline or treatment protocol endorsed by any regulatory or professional entities. A task force of the American Psychiatric Association (APA) recently published a consensus statement on the use of ketamine for depression which attempts to highlight concerns regarding the clinical use of ketamine. While not a formal guideline, this document may be a useful tool for patients who want to assess the quality and safety of a treatment plan involving the use of ketamine. For this statement, see Sanacora et al. 2017 (12).
For patients who are interested in treatment with ketamine, it is also possible that there is a clinical trial that may be appropriate for them. The advantage to receiving a relatively new treatment in a clinical trial is that there are many safeguards and procedures in place to monitor for and prevent any unexpected problems or side effects. The best resource for finding such clinical trials is the national database maintained by the National Institutes of Health (NIH), available at: https://clinicaltrials.gov/.
Though it is not widely considered to be ready for clinical use, the promise of ketamine’s rapid antidepressant effect cannot be ignored. Scientists are hard at work at exploring the viability of other compounds that affect the glutamatergic system, in the hopes that these other agents might be effective for depression but not pose the same concerns as ketamine. For those interested in further review of novel glutamatergic antidepressant treatments, see Murrough et al. 2017 and Machado-Vieira et al. 2017 (3, 13).
In summary, ketamine has been shown in several studies to be able to rapidly improve depression, but only for a short period of time. The total number of patients in which this has been demonstrated remains small. Most of the existing evidence concerns the use of ketamine in uncomplicated unipolar depression. There are concerns as to whether the effect of ketamine can be prolonged, and whether it is safe to repeatedly give ketamine to patients. There is a significant risk that patients may become addicted to ketamine, even in a therapeutic setting. Other risks include dissociative and psychotic symptoms, mania or hypomania, and bladder and kidney disease. Due to these uncertainties and risks, the decision to use ketamine for the treatment of depression at this time must be carefully considered. For treatment of depression, there are several interventions that have demonstrated efficacy with fewer concerns and a more robust evidence base including conventional antidepressants, ECT and rTMS, augmentation, psychotherapy, and chronotherapy (14, 15, 16, 17, 18, 19). Thus, any decision to use ketamine in the treatment of depression should include an assessment and discussion of whether these other treatment options have been explored or would be more appropriate.
Kurt Kastenholz, M.D.