Unlocking the Mysteries of the Glutamate System
Q: Can you explain how ketamine works in the body and how it is different from other antidepressants?
A: It's different, most fundamentally, in that it does not impact the monoamine systems directly. So it doesn't impact serotonin, norepinephrine, and dopamine directly. I mean certainly there are indirect effects on multiple systems. How ketamine is actually working as an antidepressant is part of the talk I'll be giving at Psych Congress, and it's a complex story and it's an evolving story. We know its initial target is on the glutamate N-methyl-D-aspartate (NMDA) receptor and it's a channel blocker, so it works within the ion channel and binds to the phencyclidine (PCP) site within the channel pore. So it's a channel blocker but at the same time it may potentiate the activity of other glutamate receptors, namely the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. We know the AMPA receptor is critical for a whole host of processes involving learning, memory, and mood. And AMPA receptor potentiation is critical to neuroplasticity and the growth of synaptic connections, or so-called synaptic connectivity. So the pathways involve enhancement of brain-derived neurotrophic factor (BDNF) and other neurotrophic factors and proteins that are involved in this process that makes synapses or spaces between neurons connect better with each other. So that's sort of a long-winded explanation of a very exciting area in basic science.
There's been recent work by Conor Liston at Weill Cornell Medicine in New York, and then building on work from Ron Duman and others from Yale, showing that the enhancement of spines, so-called dendritic spines, is required for sustaining the antidepressant activity of ketamine. And it explains why, when ketamine's out of your system in several hours, there are effects longer term, well beyond the time the drug has left your body. And it may be because, what's been shown in animals, is the formation of these newly formed dendritic spines. Very exciting work.
Now it should be mentioned that there's controversy regarding the role of glutamate and NMDA in ketamine's activity. Work by Alan Schatzberg most recently, and his colleagues at Stanford, including Carolyn Rodriguez and Nolan Williams, they've shown that if you give naltrexone, which is a mu-opioid receptor blocker, you can attenuate the antidepressant activity of ketamine. So they've argued that ketamine acts by an opioid mechanism, either directly as a mu receptor agonist, or through an endogenous opiate mechanism, which remains to be determined. And so that's very intriguing data in a small group of patients, and there have been arguments back and forth, both clinically and preclinically, suggesting that ketamine's opiate activity is not a critical aspect. So I think that argument remains in progress and it's an interesting one, particularly as this is a Schedule III agent, a potential agent of abuse. We know it's misused in regions in the country and internationally, and so the last thing we want to do as clinicians is start another opiate abuse epidemic, and so we need to be very careful and mindful about this product and its mechanism of action. I think we just need to learn a lot more about it.
Also at Psych Congress: When Antidepressant Treatment Leads to Sexual Dysfunction
Q: Has ketamine shown promise in treating any conditions other than depression and suicidal ideation?
A: Post-traumatic stress disorder (PTSD) is probably been the other main indication that's under study. There's initial pilot reports with a single infusion showing rapid reductions in broad PTSD symptoms across multiple dimensions of the illness, including the hyperarousal that we experience in the mood and cognitive symptoms associated with PTSD. There's now an ongoing trial funded by United States Department of Veterans Affairs (VA) and Department of Defense, run by John Krystal at Yale and John Roache in San Antonio, studying two doses of ketamine vs placebo in almost 200 patients with PTSD. So I think that'll be the definitive largest trial of ketamine.
There's also been some other smaller studies of obsessive-compulsive disorder (OCD) based on some initial work that there could be reductions in obsessions and compulsions associated with this illness. There's also been some interesting work from Elias Dakwar, at Columbia University and the New York State Psychiatric Institute, where he's combining ketamine with a mindfulness-based group psychotherapy. And he's using that as a means to enhance the effectiveness of this mindfulness therapy to decrease relapse for cocaine use disorder patients. And so this is a study that I think soon will be published in the American Journal of Psychiatry, showing remarkable persistence of the benefit of coadministration of ketamine with this group psychotherapy. So there's a number of potential applications beyond major depression, but I think the most promising, certainly have been the suicide and the PTSD indication. I should also mention there's been work in bipolar depression, which would be a natural sort of extension of the work in treatment-resistant depression.
Q: What risks or possible side effects do patients face when taking ketamine?
A: The most commonly observed side effects would be dissociation, and dissociation can entail feelings of unreality, feeling outside of yourself, feeling outside of your body, like you're looking outside yourself from above, and feelings of floating, levitation, feelings that your body parts are unusually big or unusually small, an altered sense of time.So these are strange experiences, some have called it a K-hole type experience. Users of ketamine get into this sort of altered state and for some it can be a scary experience, but for many, it's not unpleasant. And these are transient effects that generally normalize within an hour and one of the reasons that there is a 2-hour recommended monitoring period is to make sure patients, after their treatments, are no longer having dissociation or sedation. Sedation is another commonly observed side effect. Dizziness you see as a transient effect. You see nausea, some patients may have vomiting. For some patients we may premedicate with ondansetron to help mitigate that. There could be elevations in blood pressure, and in small proportions of patients, you may see more dramatic elevations of systolic or diastolic blood pressure, so blood pressure is something we regularly check at several time points during the treatment. For patients with uncontrolled hypertension, this is not something we would recommend. And ketamine is also contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or history of intracerebral hemorrhage. So there are some absolute contraindications, but what I've mentioned are the most common side effects: the sedation, dissociation, the increase in blood pressure. And we recommend patients don't drive or operate heavy machinery on the day that they're receiving the ketamine.