OCD & Ketamine | Carolyn Rodriguez

In this episode of "From Our Neurons to Yours," we're taking a deep dive into the neuroscience of obsessive-compulsive disorder (OCD) and the recent discovery that the anesthetic ketamine can give patients a week-long "vacation" from the disorder after just one dose.

Join us as we chat with Dr. Carolyn Rodriguez, a leading expert in the field, who led the first clinical trial of Ketamine for patients with OCD. She sheds light on what OCD truly is, breaking down the misconceptions and revealing the reality of this serious condition.

Dr. Rodriguez, a professor of psychiatry at Stanford Medicine, discusses her research on ketamine for OCD, current hypotheses about how it works in the brain, and her approach to developing safer treatments. Listeners are encouraged to seek help if they or a loved one are struggling with OCD.

Learn more:

Rodriguez's OCD Research Lab (website)
Rodriguez at the World Economic Forum (video - WEF)
International OCD Foundation (IOCDF) (website)
Rodriguez pioneers VR therapy for patients with hoarding disorder (video - Stanford Medicine)
The rebirth of psychedelic medicine (article - Wu Tsai Neuro)
Researcher investigates hallucinogen as potential OCD treatment (article - Stanford Medicine)

Episode credits:

This episode was produced by Michael Osborne at 14th Street Studios, with production assistance by Morgan Honaker. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute. 

Thanks for listening! If you're enjoying our show, please take a moment to give us a review on your podcast app of choice and share this episode with your friends. That's how we grow as a show and bring the stories of the frontiers of neuroscience to a wider audience.

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Chapters

• 0:00 Episode Intro
• 1:33 What is OCD?
• 5:31 How has our understanding changed?
• 7:38 What drew Rodriguez to the field?
• 9:20 Ketamine and OCD
• 13:52 First-line treatments
• 16:27 How does ketamine work?
• 20:58 Conclusion

Transcript

Nicholas Weiler:

This is From Our Neurons to Yours, a show from the Wu Tsai Neurosciences Institute at Stanford University. On this show, we bring you to the Frontiers of Neuroscience to meet the scientists building the tools that will let us communicate better with our brains. 

This week we're talking about obsessive-compulsive disorder — OCD — and Ketamine. 

OCD is something that we almost joke about. It's synonymous with being uptight and particular, but make no mistake, this is a serious condition and it's something that it causes a great deal of anxiety and distress to patients who have it. There are a variety of treatments available for OCD but they don't work for everyone.

Recently, there's been a lot of excitement around a new treatment, Ketamine. Ketamine is an anesthetic drug and it's been in the news a lot. Ketamine has proved useful in a number of psychiatric disorders, not just OCD, but depression and post-traumatic stress disorder or PTSD, but it's complicated. Ketamine has serious side effects and it is a scheduled drug. 

This week we're going to be talking about OCD and Ketamine with a leader in this field, Carolyn Rodriguez, who led the first clinical trial of Ketamine for patients with OCD. I began our conversation by asking Dr. Rodriguez, what exactly is OCD?

Carolyn Rodriguez:

Thank you so much for the opportunity. So simply put, OCD is comprised of obsessions, which are intrusive thoughts, images and urges that are experienced by the person as increase in anxiety. Then there's the aspect that is compulsions, which are repetitive behaviors or thoughts or ritualized patterns of thinking that serve to then decrease anxiety for that individual. In order to meet criteria for obsessive-compulsive disorder, it not only has to have those elements and components, but also needs to get to the point where it's impairing and impacting the person's life. Either there's relationships, their social functioning, their ability to work and cause a lot of distress. So they need to have those thoughts and behaviors for at least one hour a day, for at least a year.

Nicholas Weiler:

It's so interesting because as you say, there are a lot of misconceptions about this disorder. I think people use the term OCD very casually, but I'd be interested to learn more about the role of anxiety in this disorder. You said that the obsessions increase anxiety and the compulsions serve to reduce that anxiety. Could you talk a little bit more about that and maybe give us some examples?

Carolyn Rodriguez:

Absolutely. So there are different themes that people can have this template of obsessions and compulsions, for example, in terms of intrusive thoughts of contamination, so people thinking that things are contaminated or they may get contaminated or infected. Then the compulsive behavior is ritualized behavior such as hand washing or cleaning. So that's one that's been highlighted in a lot of different movies, but one that has not been highlighted so much is intrusive thoughts of harm.

To give you an example, somebody with OCD may be driving along the road and all of a sudden have an intrusive unwanted thought that they've run somebody over, which if you can imagine, if you had that thought, it would be incredibly distressing and you spoke to the anxiety component of it. And then the accompanying behavior would be something like circling back to where they had that thought, stopping the car looking in the bushes to see if anybody has been run over, going home, looking at the news, checking on the internet to see if there's been any accidents.

So you can see quickly how that can be very time-consuming and really impact somebody's ability just to get to something simple from point A to point B. Another is intrusive thoughts of needing to have everything symmetric or exact. If it's not, then the behavior is to make everything organized. But some people have a thought that if they don't have these things organized, then a loved one will die. This is very classic OCD, but somebody maybe misdiagnosed with something like psychosis. And then still yet, another theme would be something like taboo thoughts.

So these can be a nature of sexuality, religion. These are individuals that have intrusive thoughts of things that are contrary to their moral compass, to their beliefs, and that discrepancy is very anxiety producing. The accompanying behavior can be things like ritualistic prayers, repeating certain things, repeating numbers. So sometimes people don't think that that's OCD because they see the vision of somebody washing their hands repeatedly, and so having a thought and then doing these ritualistic thoughts and counting and prayers, they don't connect it to OCD. So hopefully just to illustrate the intrusive thoughts and the repetitive behaviors, but it can have all different flavors and patterns to it.

Nicholas Weiler:

Right. Looking at your research and some of the new treatments that you're involved in, it seems like our understanding of this disorder is changing quite rapidly. Is that right? How are people thinking about the disorder when you were trained in psychiatry and how's that changing now?

Carolyn Rodriguez:

This really is a renaissance time for OCD, and there's been so much advances in discovery and we're just at the tip of the iceberg in terms of translating that into knowledge. As I was being trained, one of the converging lines of evidence is that there is a OCD circuit that is hyperactive, including the orbitofrontal cortex, which is responsible for thoughts and the striatum, which is responsible for behaviors. Then the thalamus and then the thalamus is a relay back to the orbitofrontal cortex. That hyperactivity has been shown in a lot of different neuroimaging studies. The thinking now is looking at brain regions that are even outside of that hyperactive circuit.

As I was being trained, glutamate, the main excitatory neurochemical messenger in the brain was one that was being tested, and drugs that modulated that system seemed to relieve OCD symptoms. And so our lab is going beyond that in terms of being able to combine and pair drugs that act through that system. How do those drugs that change OCD symptoms then impact the neurobiology? Is it at the circuit level? Is it at the network synchrony or EEG level? So how the neurons are acting together at a more fundamental or molecular level of changing levels of glutamate. So those are all questions on the horizon and exciting avenues to try and get us to understand more about the pathology of OCD.

Nicholas Weiler:

That's fascinating. Yeah, I'd love to dive into some more of those, and I think we will when we start talking about some of the treatments that your lab and others have been investigating, particularly interested to talk about what we think that overactive cognitive emotional circuit is and how tweaking those things can lead to very specific improvements in this disorder. But first, I just wanted to quickly ask, out of curiosity, what drew you to this field? What made you interested in working with patients with OCD and working towards new treatments?

Carolyn Rodriguez:

For me, I think when I was in training in residency, it was just so heartbreaking to see how long it took for people to get recognition and treatment and just seeing the physical manifestations. People that had to wear gloves because their fingers were cracked and raw and bloody at times because of the hand washing and how it's very hidden. People can be going about their lives and it feels to them that their mind is a prison that they don't have control over their thoughts and feelings. At the same time, it was very appealing to me that individuals with obsessive compulsive disorder really have a lot of insight into these thoughts are unwanted and you can actually have a conversation with them about their illness and they can be true partners in every sense of the term. In terms of the clinical trials that I was interested in pursuing, we need that really strong partnership with somebody who's able to talk about their thoughts and feelings and how the interventions are working for their pathology.

Nicholas Weiler:

That's fantastic. Yeah, I mean it's so important to have people expressing what they need, what real treatment looks like, and what is working and what's not working. I thought it was very interesting that you mentioned that often very self-aware. It's not a delusion. It's not that they believe necessarily that these things are happening, but they can't get rid of the thought.

Carolyn Rodriguez:

Exactly.

Nicholas Weiler:

Well, I'd love to switch gears a little bit now and talk about your lab's pioneering use of ketamine as a potential treatment for OCD. Ketamine's been in the news a lot. People may have read about excitement about ketamine for a variety of mood and anxiety disorders, depression, bipolar, PTSD, but also of course it's a drug with potential for abuse. There have been recent reports about Elon Musk's reported ketamine use and the potential implication of ketamine in Matthew Perry's death, I believe.

And so as with many drugs, there's always a risk of either over hyping or demonizing, that conversation could go a million places. So I'd love to focus here on what ketamine is teaching us specifically about OCD. So my understanding is that ketamine has been used for a long time and an anesthetic, and it's a type of anesthetic called a dissociative, which means it creates a sense of separation between the mind and the body. Is that dissociative property, that separation related to how it helps people with anxiety and mood disorders and potentially OCD, or is it something different?

Carolyn Rodriguez:

I think that is an area of active investigation. What we have come to know about ketamine and OCD, our initial studies really knocked my socks off when we gave the first low-dose IV infusion of ketamine to OCD to see if it could be helpful based on a couple different hypotheses. But when we saw somebody just have complete relief of their OCD symptoms, it was an incredible epiphany, both with the potential being mindful of the abuse and other risks, but to really have it be a probe to say like, "Okay, here is a brain, an individual. Their brain currently is having these intrusive OCD thoughts." Then with ketamine, there's a moment of time where they don't have that. So now we can start to use this as a tool to really compare what are the differences with and without. So ketamine is not FDA approved for OCD currently, and I have real reservation in terms of individuals using it at home or in other ways.

I think the FDA is increasing regulatory capacity. This is a drug that has you highlighted out. It's called special K. It has addictive potential and should be administered either within the context of research studies, which we are doing or with a clinician because it can do things like change blood pressure, it can change heart rate. People can't drive for twenty-four hours after getting a single dose of ketamine. This is a drug that is a scheduled drug and should be used with great respect. We also exclude individuals who have history of substance use or active substance use because of the abuse potential. That said, we are finding that a single dose of low-dose ketamine and about half of individuals that take it have dramatic rapid decrease in OCD. And as the results of our latest RO-one study, which is an NIH-funded study that took place over the course of five years, we found that on average individuals that got ketamine versus midazolam, which is an act of control that makes people feel woozy and hides the effects of ketamine, it isn't perfect, but it is an act of control.

Nicholas Weiler:

So that's to make it hard for people to know whether they're getting ketamine or not?

Carolyn Rodriguez:

Exactly. So after single infusion on average, there's statistical significance in ketamine three weeks out, but not four weeks out. So it's exciting to see that. It's a replication of our previous findings. And now with that study, we have also done neuroimaging using magnetic resonance spectroscopy to get to your point earlier, within the anterior cingulate, this front part of the brain, we can measure changes and glutamate, glutamine and gaba, which is an inhibitory molecule to actually get at mechanism within the neural circuit, within the brain, at a very molecular level. We're looking at circuit function, so cognitive control, ability to stop and start thoughts with functional magnetic imaging and also EEG. So we could have people whether they're getting ketamine, have a cap that records electrical activity and ensembles of neurons. We're at early days in analyzing this data. We've shown that we can replicate the rapid effects, but now what does that give us a handle in terms of the mechanism of action?

Nicholas Weiler:

Fascinating, and I was realizing as you were saying this, I think one thing that we may not have touched on earlier is that, am I right in thinking that the first line of treatment for people with OCD is SSRI antidepressants and cognitive behavioral therapy to help people break that link between the obsessive thoughts and the compulsive behavior? Is that right?

Carolyn Rodriguez:

Absolutely.

Nicholas Weiler:

And then with the people who you're treating it with the ketamine therapy, those are the 20% of people for whom those front line therapies are not effective?

Carolyn Rodriguez:

So with OCD, and we think about first line treatments, there is a half glass full scenario that we have first line treatments, SSRIs and cognitive behavioral therapy with exposure and response prevention. Both of these are first line, and I like to say that not one size fits all. Some people like to start with medication. Some people like to start with therapy. One of the advantages of the therapy is that it doesn't have the side effects of medication. So oftentimes that is the entry point for a lot of people. The good news is that half of people will be helped by one of these two first-line treatments. So about eight out of 10 individuals will be helped with just the evidence base that we currently have. So my research really takes off for those individuals who aren't helped by those treatments. What else can we use?

Also, FDA approved are things like transcranial magnetic stimulation, so non-invasive neuromodulation and FDA has compassionate use approval for deep brain stimulation. That is a surgical intervention that stimulates directly these circuits. So there is right now a whole host of things that are available, but despite that, there are still people who aren't helped. And so these exploratory novel treatments are needed for those individuals, and you're absolutely right. How can we use those to help potentially even augment cognitive behavioral therapy? Cognitive behavioral therapy is having people in a hierarchy, exposing them to those things that they're so afraid of in a systematic way and encouraging them to not do the compulsions. So anxiety naturally goes down on its own. So you need to actually train the brain to unlink those two things. So you're absolutely right.

Nicholas Weiler:

Okay. Yeah, so that's very helpful context to understand. For many people that you can train your brain out of some of these patterns of thought. Not everyone is able to do that. And even in these extreme cases, I think it's so remarkable that people who've been experiencing these intrusive thoughts for their whole lives, you get one dose of ketamine, it seems to take it away for weeks. I remember reading one person said it was like a vacation from OCD, but as you say, ketamine's not necessarily the best solution on its own, and it gives you this ability to say, "Okay, what has happened to the brain now? Why are they on a vacation from OCD? How has this circuit changed?"

Can you give us any insights into some of the hypotheses about what may be happening? We've talked about a brain circuit between cognitive control and emotional centers of the brain that may be overactive. We've talked about discrepancies in the way the brain is processing glutamate, which is the main excitatory chemical neurotransmitter the brain uses, and there's also been research on using transcranial magnetic stimulation. I know you're working with Nolan Williams, who we've had on the show before as well as deep brain stimulation to target particular brain circuits. So what is this all adding up to? What are you thinking about why ketamine works and what that tells us about the disorder?

Carolyn Rodriguez:

Yeah, absolutely. So you have summarized it very nicely, which those are the different avenues that we are exploring, and I think not one size fits all. There are different subtypes of people, so not a hundred percent of people are responsive to ketamine. So I see it in two lines of investigation. For the patients who are coming into the clinic, how do we help those people now with treatments and what can we learn about those individuals that aren't helped or as we're doing the research trying to understand who is more likely to respond to which type of treatment. Those are two parallel avenues of investigation. Specifically for ketamine, the work that we've done so far points to a fork in the road currently, which is it more glutamate dependent? Is that the act of component? Could it also be the opioid mechanism?

So when you get ketamine, you have this euphoric elated feeling. And so Alan Chathberg and I are funded by the NIH to do another RO-one study, but this time using naltrexone as a pharmacological manipulation to block the new opioid receptors when individuals are getting ketamine to see if the anti-obsessional effects are also blocked. And the reason why this is important is because should we as a field invest more in drugs that work through the glutamate pathway? So things like ketamine metabolite called RRHNK that has less addictive properties, that has less side effects, is that the road to go for those individuals, or is it more investing in opioid drugs that don't have addictive potential?

Nicholas Weiler:

Yeah. Oh, it's fascinating. Well, it's an exciting time that we have these leads and there's a lot of work to be done. I know you did some work with Boris Heifetz here as well recently showing that the antidepressant effects may be related to the opioid side of things, but not ketamines dissociative effects, the mind body separation. So maybe that also helps try to understand, is it the opioid reward pathway? Is it the dissociative, cognitive hallucinogenic effects? Which of those is going to be more productive as an avenue to find more therapies?

Carolyn Rodriguez:

Yeah, thank you so much. And that work was in depression led by Nolan Williams, Boris Heifetz and Alan Schatzberg and yeah, exactly. So if those are the clues in depression, then what does it mean for OCD? So we're poised and excited to find out. And just to give a shout-out also to Boris Heifetz, which we're partnering on a study to look at MDMA. He's done some really exciting work in animal models, looking at the mechanisms of the pro-social effects of MDMA, and we're partnering to do a study in obsessive compulsive disorder to see if we can use MDMA as a way to boost more the cognitive behavioral therapy for patients with OCD. Why? Because as you can imagine, it's really hard to do something that you're really fearful of, and not everybody can do the therapy and so could MDMA, and its pro-social rewarding aspects, boost the engagement with the therapist and takes an evidence-based treatment, but really boosts the ability for people to actually do the therapy.

Nicholas Weiler:

Exactly. Well, thank you for correcting that. Yes, that study I was referencing was in depression, not in OCD. We're definitely out of time here. This has been such a fascinating conversation and I think really speaks to how far we've come in psychiatry, where for many years there was very little biological that we could do for people, but your work and the work of other neuroscientists at Stanford and around the world is taking us to a place where we're starting to understand mechanisms finally. So thank you for that.

Carolyn Rodriguez:

Well, thank you so much and thank you for this wonderful platform. Again, there are people who are going to be listening to this that may be thinking, "Do I have OCD and what can I do?" And what I would say is, you're not alone. You have so many resources. There's the Nonprofit International OCD Foundation, iocdf.org that has educational information videos, things that you can look at to try and determine like, should I reach out for help? And if you're listening and that's the case for you or a loved one, please reach out. Also, feel free to reach out to me. I really am passionate about getting people connected to care in their communities.

Nicholas Weiler:

That's great. And we'll have links for all those things in the show notes. All right, well, Carolyn Rodriguez, thank you so much for joining us on the show.

Carolyn Rodriguez:

Wonderful. Thank you for having me.

Nicholas Weiler:

Thanks again so much to our guest, Dr. Carolyn Rodriguez. You can read more about her work and the field in the show notes. This show is produced by Michael Osborne at 14th Street Studios, with production assistance by Morgan Honecker. Our logo is by Amy Garza. I'm Nicholas Weiler at the Wu Tsai Neurosciences Institute at Stanford University. See you next time.