Ketamine & depression: Changing your state of mind

Published On: Aug 14 2013 12:29:53 PM CDT   Updated On: Aug 14 2013 05:49:14 PM CDT

One in ten adults in the US suffers from depression. For many, the symptoms are debilitating and the current treatments just don’t work. Researchers say a drug that’s used in hospitals and abused on the streets, may dramatically change your state of mind.

In hospitals, it’s a commonly used anesthetic. In the clubs, ketamine is ‘aka, Special K,’ a popular hallucinogenic drug, but what can make ketamine truly “special” for millions of people, is its potential to, quickly and effectively, treat chronic depression.

“It has been one of the major new findings in the field for at least a few decades,” Doctor Gerard Sanacora, MD., Ph.D., Professor of Psychiatry at Yale University and Director of the Yale Depression Research Program, told Ivanhoe.

Unlike standard antidepressants, which can take weeks or months to work, Yale researchers say ketamine can improve your mood in hours, “by reconnecting brain regions and allowing proper control of mood and emotion," Doctor Ron S. Duman, Ph.D., at Yale University School of Medicine, told Ivanhoe.

Even for treatment-resistant patients. However, researchers are still figuring out how to safely administer ketamine as a routine treatment. “It’s not strongly addictive, but it does have high abuse potential,” Doctor Duman said.

While ketamine is currently not FDA approved for depression, a growing number of private clinics across the country are offering it “off label.” Doctor Gerard Sanacora is concerned. “There are several very important questions that we still don’t know about ketamine and probably the most important is what is the long term benefit? Is repeating dosing of this actually a good idea,” said Doctor Sanacora.

Doctors say the fast-acting quality of ketamine can help save lives of those in danger of committing suicide. Infusions at the private ketamine clinics can run you thousands of dollars, with no guarantee of any results; they’re also not covered by insurance.   


DEPRESSION: Depression can come in many forms, but when the symptoms begin to interfere with people’s daily lives these feelings become an illness. Signs of depression include feelings of hopelessness or guilt, loss of interest in activities that used to be enjoyable, thoughts of suicide, and many more. Some people have minor bouts of depression, but major depressive disorder can be disabling. Other forms of depression are postpartum depression, which occurs after giving birth, and seasonal affective disorder, which comes on during the winter months due to lack of natural sunlight. Medications and psychotherapy may help to alleviate depression symptoms, but are ineffective in helping some individuals. (Source:


KETAMINE: The drug ketamine was first developed in 1963 to be used as an anesthetic in humans as well as animals. When used for medical purposes, ketamine comes as a liquid that is injected into patients and is chemically similar to PCP. Although doctors and veterinarians continue to administer the drug as an anesthetic, ketamine is also used recreationally as a “street drug.” Typically snorted or ingested in powder form, ketamine has been known to cause dream-like states and hallucinations. When taken in large amounts ketamine can cause an effect called the “K-hole” in which people experience an inescapable, often terrifying out-of-body experience. (Source:


MEDICAL BREAKTHROUGH:  A new study, conducted by researchers at the Baylor College of Medicine in Houston and Mount Sinai School of Medicine in New York, shows that the experimental party drug, ketamine, can alleviate depression symptoms in just hours. The drug was shown to quickly reduce depression in participants after just one 40-minute IV dose. Most medications available today can take days, if not weeks, to reduce symptoms. The drug also has long-lasting results. After one week, 46 percent of the ketamine-assigned patients still reported reduced depression symptoms after taking the ketamine, compared to 18 percent in the placebo group. Although the ketamine has obvious benefits, it is still a hallucinogenic drug that is very dangerous. (SOURCE:



Ron S. Duman, PhD, Professor of Psychiatry and Neurobiology at Yale University School of Medicine, talks about a new treatment option for depression.

What causes depression? 

Dr. Duman: Depression is a complex illness that has a complicated neurobiology.  One of the things that has been the focus of research is that there is a decrease in the size of brain regions that are implicated in depression and evidence that there is atrophy of these brain regions. In other words, there is evidence that the brain may undergo atrophy in response to stress and exposure to depression.  And evidence from animal studies has shown that stress actually causes atrophy of neurons in brain regions implicated in depression.  

Now how big of a deal is ketamine in depression research? 

Dr. Duman: Ketamine is major finding in the field of depression.  It is the first compound, first drug with a new mechanism of action different from the typical antidepressants like the serotonin reuptake inhibitors. The significance of ketamine is based on the fact that it produces a very rapid response within a matter of hours, compared to the very slow onset of action of drugs like the serotonin selective reuptake inhibitors, which take weeks to months. Ketamine also works in patients who are considered treatment resistant, in that they have not responded to the typical antidepressants.  By virtue of the fact that it is a new mechanism of action, that it acts very rapidly in a difficult to treat group of patients, indicates that ketamine is one of the biggest findings in almost 50 years in the field of depression. 

How does the drug work in a simplified form?

Dr. Duman: Ketamine acts on the glutamate neurotransmitter system, which is the major excitatory system in the brain. The evidence indicates that it is actually causing a burst of glutamate activity, very rapid, but transient burst of glutamate activity that then sets up a cascade of events leading to an increase in synaptic connections that we believe is responsible for the antidepressant effect of ketamine, by reconnecting brain regions and allowing proper control of mood and emotion.

You said that this is good for people who are resistant. Can you just explain a little bit more as to why they make better candidates than for this drug regime?

Dr. Duman: Up until now, ketamine has been used primarily in research protocols and research studies. Usually patients who are nonresponsive or are very ill are those that qualify for these types of studies. So we do not know yet. We certainly think that ketamine would be very effective for the general depressed population, but the fact that ketamine works in these treatment-resistant patients is a really important aspect of what ketamine is able to do.

Can you tell us a little bit more about what your studies showed?

Dr. Duman: Our studies in rodents have shown that ketamine is able to very rapidly activate glutamate signaling and increase signaling pathways that lead to an increase in synaptic connections within a very short period of time.  That increase, in the synaptic connections, correlates with antidepressant behavioral responses in our rodent models. 

How do you take the drug?  

Dr. Duman: Ketamine is an anesthetic.  It is used in pediatric medicine and chronic pain management and it is typically given IV. When these clinical trials were first studied, it was the simplest way to get approval for the studies. It is administered in a very similar way, but a much lower dose that causes some mild psychotomimetic effects, some mild dissociative effects that are very transient.

I was going to move onto that, about the possible side effects and dangers.  I mean obviously, all drugs can carry some form of side effect and possible danger if misused, so what is the situation here?

Dr. Duman: Ketamine has potential for general use as an antidepressant, but it does have side effects.  It is a dissociative anesthetic and an anesthetic at high doses. At low doses, it does produce some psychotomimetic effects, it produces some dissociative effects, so this is not the perfect drug by any means and that is why we want to continue to our studies, to try to identify the mechanism, so we can develop even better types of agents that have the ketamine like antidepressant effects but without the side effects.

Could people become addicted to this drug?  

Dr. Duman: The side effects and abuse potential of ketamine are certainly a consideration as well. There is evidence in rodent models that ketamine has some addictive properties, it is not strongly addictive, but it does have high abuse potential.  It is a street drug.  It is used commonly as a drug of abuse, so that is another concern with use of ketamine.

Do you believe that the risks or the potential outweigh the risks when it comes to ketamine? 

Dr. Duman: The question for many people is would they prefer to take a drug like ketamine that has some risk and with the promise of treating a difficult illness like depression. I think in many cases, they would opt to take ketamine and take that risk.  A lot of people are extremely ill, even suicidal and you have to remember that if someone is suicidal and not responding to any typical antidepressant, they are also unable to function normally and that many of these people would gladly take a drug like ketamine with some risk. There is evidence in some cases that psychiatrists have continued to use ketamine for people that do not respond to any other type of antidepressant.

Where do you go from here with the research?

Dr. Duman: We have some basic ideas of how ketamine is acting, but we need to learn a lot more about the exact mechanisms that underlie the effect of ketamine. Looking at the neurotransmitter systems that are involved, the circuits and neurocircuits that are involved, the types of neurons that are being influenced; we hope in doing that we will be able to develop an even better drug like ketamine, but without the side effects.

Ultimately for patients, I mean, depression is a very debilitating condition, what is the outlook, how quickly can people possibly hope to be using this new generation of faster acting antidepressants? 

Dr. Duman: Drug development goes slowly. However, because there are compounds that have been developed by pharmaceutical companies for a variety of other indications that are now being repurposed and may potentially be used to produce a ketamine like response.  I think the best case scenario is that maybe in 3 to 5 years, we might see a new generation of compounds that act with a mechanism similar to ketamine.


Gerard Sanacora, MD, PhD, Professor of Psychiatry at Yale University and Director of the Yale Depression Research Program, talks about a new treatment option for depression.

Can you tell us a little bit about ketamine the drug and what makes it so special? 

Dr. Sanacora: Most of the antidepressant drugs that are currently being used were developed out of the monoaminergic hypothesis, which really focuses on serotonin or norepinephrine and dopamine to some extent.  Ketamine is a very novel drug that actually targets glutamate, which is a completely different neurotransmitter system that up to this point has not really been targeted for the treatment of depression or other mood disorders. 

The other thing about ketamine is it has been around for a while.

Dr. Sanacora: Correct, ketamine is one of what is called a dissociative anesthetic class of drugs which has been around for quite a while and it is actually a very commonly used anesthetic in pediatric anesthesia or in the emergency room setting.

Who does it work best for?

Dr. Sanacora: There have not been hundreds of studies for us to really look at which patient population would benefit most from this.  There are some hints that it might work better in people with more severe depression; there are some hints that it might work better with people with certain subtypes or certain symptoms of depression, but there has also been some very preliminary studies suggesting that it might be beneficial even in cases of PTSD, and in patients that have comorbid alcohol abuse, so I think the short answer is we really do not know at this point.  It is too early to say.

What about your own clinical studies? What sort of things are you finding out?

Dr. Sanacora: We remain very interested in the mechanism by which ketamine is producing this antidepressant effect. A lot of our work is actually trying to understand the changes that occur after a dosing of ketamine that are associated with the clinical benefit. We are currently doing a lot of neuroimaging studies trying to understand exactly what ketamine is doing in the brain to generate this rapid onset of antidepressant effect. We also have several other studies looking at drugs very similar to ketamine, but maybe having fewer side effects and a little bit better safety profile that might also have the antidepressant effect.

Tell us a little bit more about the clinical studies and the research you are continuing to undertake 

Dr. Sanacora: My laboratory and our clinic are very interested in several aspects of ketamine.  We are very interested in pursuing studies that will help us learn more about the mechanism of action. What is the drug doing to the brain that is leading to these antidepressant like effects? We are also very interested in some of the very simple questions about the drug that have not been answered like what is the exact, or what is the optimal dose to be giving; how frequently can it be dosed to maintain a response, and whether other drugs that are very similar to ketamine, but potentially with a better side effect profile or safety profile, could also be used to generate the antidepressant effect without having to worry about the same side effects as you would with ketamine?

There are private clinics popping up across the US, which are offering ketamine to patients. What sort of advice would you give to people and is it a wise choice or should they be guarded about this?  

Dr. Sanacora: It is a very difficult question to answer. As we know depression is in some cases an incredibly disabling and very severe for many people. When the classic treatments have not been effective, there is a real desire to go out and get whatever treatment may be beneficial. In that sense, I think ketamine does offer some hope, but what I really caution people about is, there are several very important questions that we still do not know about ketamine and probably the most important is what is the long term benefit? Is repeated dosing of this actually a good idea? Both in terms of efficacy, does it actually work when it is used repeatedly, but also in terms of safety? We really do not have all that much information on repeated dosing in patients with depression.

How important is this research overall in the field of depression? We hear about medical breakthroughs in other areas of medicine all the time, so is this really major stuff for this area of medicine?

Dr. Sanacora: At this point, I would say it has been one of the major new findings in the field for at least a few decades. For two reasons, one is it might actually offer a more direct immediate benefit to the patients, clinical benefit for the patients, but also in terms of the scientific knowledge that it is giving us.  It has really opened up a new vista or a whole new landscape of new targets and treatments that can be developed for the treatment of depression that is not specifically ketamine by itself.

I was going to say, because ketamine is really just the tip of the iceberg. 

Dr. Sanacora: I really think ketamine is the tip of the iceberg here.  It has opened our eyes to new avenues to pursue for the treatment of not only depression, but many other neuropsychiatric disorders. 




Madonna Fasula, A.P.R.N

Yale University School of Medicine