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?