Dr. Christopher Pittenger is a Professor of Psychiatry at the Yale School of Medicine and Director of the Yale OCD Research Clinic. In this episode, he discusses the neurobiology, symptomology, and treatment of Obsessive-Compulsive Disorder (OCD), including potential new treatments such as psychedelics, neurofeedback, glutamate modulators, and transcranial magnetic stimulation (TMS).
00:00 Introduction
00:41 Why is OCD Underdiagnosed?
02:19 Impact of OCD on Individuals
03:40 Taboo Nature of OCD Thoughts
06:10 Biomarkers
08:06 Neurobiology
14:20 Serotonin
16:48 Heterogeneity of OCD
24:00 Glutamate Modulators
29:33 Ketamine
33:13 Psilocybin
38:23 Neurofeedback
44:01 Transcranial Magnetic Stimulation (TMS)
47:22 Relationship Between Depression and OCD
50:24 Future of OCD Treatment
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
Dr. Christopher Pittenger is a Professor of Psychiatry at the Yale School of Medicine and Director of the Yale OCD Research Clinic. In this episode, he discusses the neurobiology, symptomology, and treatment of Obsessive-Compulsive Disorder (OCD), including potential new treatments such as psychedelics, neurofeedback, glutamate modulators, and transcranial magnetic stimulation (TMS).
00:00 Introduction
00:41 Why is OCD Underdiagnosed?
02:19 Impact of OCD on Individuals
03:40 Taboo Nature of OCD Thoughts
06:10 Biomarkers
08:06 Neurobiology
14:20 Serotonin
16:48 Heterogeneity of OCD
24:00 Glutamate Modulators
29:33 Ketamine
33:13 Psilocybin
38:23 Neurofeedback
44:01 Transcranial Magnetic Stimulation (TMS)
47:22 Relationship Between Depression and OCD
50:24 Future of OCD Treatment
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
NOTE: Transcripts of our episodes are made available as soon as possible and may contain errors. Please check the corresponding audio before quoting in print.
DR. THEA GALLAGHER:
Welcome to NYU Langone Insights on Psychiatry, a clinician's guide to the latest psychiatric research. I'm Dr. Thea Gallagher. Each episode, I interview a leading psychiatric researcher about how their work is shaping clinical practice. Today I'm excited to welcome Dr. Christopher Pittenger. Dr. Pittenger is a Professor of Psychiatry at the Yale School of Medicine and Director of the Yale OCD Research Clinic. In our conversation, we talk about the biology and treatment of obsessive-compulsive disorder, including novel potential treatments like psychedelics, glutamate modulators, and transcranial magnetic stimulation. We also talk about why OCD is so underdiagnosed and what clinicians can do to spot it. So I'm excited to have this conversation about OCD, and we know that it's fairly common affecting about one in 40 people, and yet it remains underdiagnosed. Can you talk a little bit about why that is?
DR. CHRISTOPHER PITTENGER:
Sure. I think there's sort of two broad reasons. One is that unfortunately, we are not training our practitioners particularly well for OCD. I can speak primarily for psychiatric training, but I think that this is true in psychology training and other disciplines as well. I mean, a lot of early training happens in the hospital. Patients with OCD are rarely hospitalized, and if they are, it's in a specialty unit. And it doesn't pop up as much as it should in outpatient training either. And this leads to a sort of self-perpetuating cycle. It's underappreciated, therefore the trainer's underappreciated. Therefore, no one works to change that except at places where there's a strong presence. I'm certainly working at Yale where I teach to make sure everyone is thinking about OCD, but I don't think that's universal.
So I think that when mental health professionals are evaluating a patient, it's very common for us to see a patient who's evaluated for depression or anxiety in very generic terms, not even real diagnoses. And it takes years before someone asks the right questions to get the OCD diagnosis. So I think there's a lot of work to do in professional training to just get it on people's radar as something that they need to be asking about in every evaluation. So that's half of it. The other half isn't within professional circles, but rather in society at large and has to do with the nature of the symptoms of OCD. So folks with OCD have these intrusive thoughts that make them very uncomfortable and feel unwanted, feel foreign in some way, but they almost always have really pretty good insight. They know that these thoughts make no sense. They might feel that they're contaminated and that they are in danger of starting a plague or whatever. They know that that is irrational. They know that it's an excessive fear.
That knowledge doesn't do them any good. That knowledge doesn't make the thoughts go away. In fact, it can be an additional source of suffering because it leads to this sense of being out of control of their own thoughts and mind. But because they know that these thoughts are irrational, because they know that the behaviors, the hand washing, whatever the attendant behavior might be, will be perceived by others as excessive, they often hide those thoughts. And this leads to an underappreciation of what OCD actually is in society at large, and for people to tend to not tell their families, not tell their providers what's actually going on, what's driving their distress. And there the answer is public education and advocacy. And I'll say over the course of my career over the last 20 years, this has gotten better. I think there is better advocacy out there. There is a better understanding of what OCD really is.
DR. THEA GALLAGHER:
There's the piece of not wanting to admit to the excessive nature of the thoughts, but also the taboo nature of some of the OCD thoughts as well, like harming other people, harming children, things that, again, the average person doesn't really know about with OCD, right?
DR. CHRISTOPHER PITTENGER:
Yeah, I'm glad you brought that up because you're right, sometimes the self-consciousness, if you will, is because the thoughts are excessive or seem bizarre, but sometimes it's because they're taboo, as you said. An intrusive thought of harming someone else, an intrusive thought of suicide, an intrusive thought of hurting children or intrusive sexual thoughts. These are quite common. So then, yeah, the fear isn't so much that the thoughts will be seen as bizarre or excessive, but that they'll be seen as repulsive because of their taboo nature. So that also causes people to keep their symptoms to themselves and gets in the way of a proper diagnosis and treatment.
DR. THEA GALLAGHER:
Repulsive or even criminal. I have a colleague who went to a psychiatrist with intrusive thoughts, and he actually called her boyfriend and said she was a danger to him after talking about these intrusive thoughts. And that's obviously an extreme example. But thought it was kind of a duty to warn, even though she had intrusive thoughts about harm, had no intention of ever doing it. But I think, like you're talking about, clinical training is really important. And you were saying for a psychiatrist to ask about it at initial evaluations. Any other kind of things that you hope will happen in, is it just asking the questions or is it, again, having it more part of the training? What other thoughts do you have to make psychiatrists more competent with both assessing and diagnosing OCD?
DR. CHRISTOPHER PITTENGER:
Yeah, I mean, I just think it should be part of every evaluation. We always ask about hallucinations. We always ask about suicidality. We always ask about paranoia or other evidence of psychosis. I think we should always ask about uncomfortable thoughts that come into your mind that are difficult to control and you wish would go away. It's easy. It takes five seconds. And I think that that should be part of every evaluation. And then of course, in someone with anxiety and depression in someone, it's much easier when someone's checking all the time or washing their hands all the time, then people will think of OCD. But that only happens about, I don't know, 60% of the time that they're these obvious compulsions that trigger our pattern recognition and makes everyone say OCD. Just about asking the questions.
DR. THEA GALLAGHER:
Yeah. And one other layer that comes up in a lot of the different diagnoses we're talking about on this podcast is with psychiatry, we feel pretty far behind with regard to precision medicine or having any other ways to diagnose people other than self-report. Is there any promising research with regard to biomarkers or blood tests or other ways to assess OCD in a more objective way?
DR. CHRISTOPHER PITTENGER:
Unfortunately, as I'm sure you're expecting, the short answer is no, that we're a very long way from having biomarkers. There have been some interesting studies that have looked at brain imaging or blood tests or other things and looked to see if they give any useful information. And the answer is almost always that no, they don't. That by far the most useful predictive thing that one can do is a good clinical interview and asking the right questions. I mean, the work is ongoing. The genetics is starting to accelerate with OCD. Now, we don't have clinically actionable genetic tests for anything in psychiatry with the exception of some causes of autism. But that will come over time. And I don't think that the genetics will ever diagnose OCD, but they may give a risk factor for OCD. And if the genetic test tells you that someone is at a 20% risk of OCD rather than the population background risk of 2.5%, well, then your ears are going to perk up and you're going to ask those questions a little more carefully.
I don't think we'll ever get to the point that something like a genetic test replaces asking about symptomatology, but we may get to the point that it helpfully informs the diagnostic process. I think that's probably a little farther away with brain imaging. They're pretty robust brain imaging findings with OCD, but they're not nearly precise enough to be diagnostic. We can make statements about people with OCD as a group compared to people without OCD as a group, but we're pretty far from being able to make those statements at an individual subject level. So I think we have farther to go there.
DR. THEA GALLAGHER:
Speaking of kind of the origins of OCD, we don't know a ton about the causes, but we do know something about the neural circuitry. Can you summarize the current understanding of what's happening neurologically in OCD patients?
DR. CHRISTOPHER PITTENGER:
Sure. There's sort of a canonical circuit that's been implicated in OCD by studies going actually all the way back to the 1980s to the birth of functional neuroimaging. And that's the sort of organizing principle that most people thinking about the neurobiology of OCD apply. In recent years, it's become clear that that's a little more complicated than that, surprise, surprise. But the basic idea, the early functional neuroimaging found that a network of structures in the cortico-basal ganglia circuitry are hyperactive. They're too active in folks with OCD. And those are the orbitofrontal cortex, that's sort of the most robust finding, the anterior cingulate cortex and then the caudate and putamen within the basal ganglia and the thalamus. And if you remember the basic medical school neuroanatomy, the cortex projects to the caudate and putamen, which projects to the thalamus, which projects back to the cortex.
So that led to this idea that there's a hyperactive circuit running through the basal ganglia, and it turns out that the basal ganglia modulates emotion. They also modulate habits, so patterns of behavior that we get stuck in through repetition. And that can be good if the habit lets you do things automatically and skillfully without having to think about them too much. It can be bad if the habit's maladaptive and you can't break out of the loop. And so this idea came up starting about 20 years ago, 25, that one thing that's going on in OCD may be that it's habits gone bad, if you will. Now, that basic idea of the frontal cortex leading to the caudate and putamen leading to the thalamus and back again and hyperactivity in that loop has some more recent data that supports it.
We know, for example, that if you interrupt that circuit surgically, surgical treatment is used in the very worst, most refractory cases of OCD. And if you interrupt that circuit surgically at a couple of different places, you can get therapeutic benefit about 50% of the time in those terribly refractory cases. And then we also know from some recent functional neuroimaging and using a measure not of activity or of size and shape, but of functional connectivity, of how much different parts of the brain are talking to one another, that has validated that there's abnormalities in the connectivity in how synchronized these regions are in OCD. All of this tends to get better with treatment, the hyperactivity gets.
So there's further evidence that's accumulated over the years and decades that there's something fundamentally right about that idea. But there's also new evidence for implication of the hippocampus and amygdala, which are in the temporal lobe, aren't part of that canonical circuit, there's evidence for implication of circuits in the insular cortex and in the parietal cortex not part of that canonical circuit. So unsurprisingly, it's turning out to be a bit more complicated than we originally thought. But I think that core idea that you have this corticostriatal feedback loop that has become a little bit too active, too connected, too rigid, is an important contributor to what's going on.
DR. THEA GALLAGHER:
And you said with surgery you can see changes here. Do you also see changes in maybe the speed of the loop with exposure and response prevention treatment or SRIs?
DR. CHRISTOPHER PITTENGER:
Yeah. The best literature there isn't looking at the connections, but just the activity. So yes, when you treat people with either cognitive behavioral therapy or SRIs and their symptoms get better, the hyperactivity in this circuit also gets better. And that's one of the reasons that we think that this is a difference that makes a difference. And there's a few studies that have shown that over the years. There was a nice meta-analysis in 2017 that put all that work together. It ended up being about 15 studies over the years. So yes, the hyperactivity, the neural abnormalities appear to calm down. I do want to just recapitulating something I said earlier, all of this is at the level of groups. You do a group, you run some stats, you can find a difference. It's not at the level of individual subjects [inaudible 00:12:31], which is what we would need for it to be diagnostic or prognostically useful. We're working on it, but we're not there yet.
DR. THEA GALLAGHER:
And with understanding this about the neural circuitry, what does it really tell us about the nature of the disease and how does that inform treatment and ongoing research?
DR. CHRISTOPHER PITTENGER:
I mean, again, I think that at this moment in time, I have to say the short answer is it doesn't. I mean, the fact is that the SSRIs and the medication treatments have been found through trial and error. And the cognitive behavioral therapies that are very effective came from a theory about extinction learning and inhibitory learning that isn't connected to the neuroanatomy. So as in most of psychiatry, we have these treatments that we stumble upon or develop because of a theoretical framework. We discover that some of them work some of the time, and then we kind of try to reverse engineer and try to figure out how that makes sense. So there is a lot of thinking about what is serotonin doing in this circuitry? What is dopamine doing in this circuitry? There is new research suggesting that glutamate modulating drugs may be beneficial in OCD. We've done some work in that area. So what is glutamate doing in the circuitry? But I can't claim that our understanding of the circuitry has led to the treatment ideas. It's more the reverse.
DR. THEA GALLAGHER:
Kind of going backward through, okay, we're seeing changes happen from the treatment, but not knowing how to go the other direction.
DR. CHRISTOPHER PITTENGER:
Right. And obviously the hope is that over the coming years and decades, that situation will change, that as our understanding of the circuitry, of the genetics, of the role of learning in the development of symptoms, of all these other aspects that my group and others are actively researching, the hope is that we'll get to a point where we can generate new ideas, new theories, and then test them. And we will get to new ways to help people. But we're not at that point yet.
DR. THEA GALLAGHER:
And I know with SRIs for OCD, a higher dose is typically recommended more than for depression or anxiety. What do we understand about serotonin's involvement with OCD?
DR. CHRISTOPHER PITTENGER:
Yeah, the best evidence for a role for serotonin is what you just said, is that the SRI antidepressants are the best in first-line treatment, whereas other kinds of antidepressants don't seem to work or at least haven't been shown to work. The evidence is excellent with SSRIs and with the older SRI clomipramine, but it's quite mixed with the SNRIs, like venlafaxine. And it's negative with some of the other tricyclics, with lithium, with Clozaril, with lots of other things that people have tried. It's weak with mirtazapine. It's something specific about the SRIs. So that's the best evidence that there's a role for serotonin.
Now, I do have to say that from a logical perspective, that's not very good evidence because we in medicine, target treatments at things that aren't the core of the pathophysiology all the time. The best treatments for heart failure target the kidneys. The treatments for infection are antibiotics. That doesn't mean the infection was caused by an antibiotic deficiency. And so the fact that serotonin-targeting antidepressants are the primary pharmacological treatment we have is interesting, but it doesn't prove that OCD derives originally from some abnormality in serotonin. There've been some genetic studies that have looked at serotonin-related genes, and there was some early signal that maybe those contributed to OCD, but it doesn't seem to be panning out in the latest genetic studies, although our understanding of the genetics is immature and time will tell. And then there's a little bit of evidence that serotonin levels in urine or in CSS are altered in people with OCD, but it's not consistent or compelling.
Finally, there's some PET imaging studies that have looked at serotonin receptors and there've been some positive findings, but then some non-replications. So it's hard to put together a story about serotonin abnormalities, deficiency, dysregulation being the cause of OCD. Maybe as our understanding advances, maybe that will turn out to be true, but right now it's hard to put together that story.
DR. THEA GALLAGHER:
Yeah, it's so interesting that putting together the story in a reverse fashion, it sounds like that's what a lot of the research is hoping to do is make meaning of the, "Okay, we're seeing that SRIs work at this dose, but we don't exactly maybe know what the causal factors are there." And we do have great treatments for OCD. We have SRIs and ERP, but we still know that about 25% of cases are refractory to these best evidence-based treatments. What is your theory as to why that is?
DR. CHRISTOPHER PITTENGER:
Well, I think OCD, like most of our disorders, is just very heterogeneous. I mean, the way I think of OCD... Let me take a step back. So OCD is characterized by obsessions, by irrational or excessive thoughts that come into the mind unbidden and are perceived as distressing or troubling. And then those cause anxiety. If they didn't cause anxiety, then we wouldn't call them obsessions, they wouldn't be a cause of distress. Then people engage in some kind of behavior to manage that anxiety. Well, that's the most natural thing in the world. If you have anxiety, you know how to make it go away, you're going to do that. And then unfortunately, that behavior actually makes the thoughts stronger.
And the way that works is, so these irrational or intrusive thoughts, the dirty little secret is everyone has those. In survey studies, surveying usually undergraduate psychology students, saying, "Do you ever have intrusive thoughts that aren't really under your control, that cause you some distress, they seem foreign and you wish they'd go away? Do you ever have those?" And 90% of people will say yes, and I'm pretty sure the other 10% are lying. So what's different in OCD isn't the existence of the thoughts. It's the degree to which they're treated as powerful and important. And so when you engage in compulsions, when you take the thoughts seriously and allow them to control your behavior, you're basically confirming that they're powerful and important. And then you check, you wash your hands, you confess, you ask for reassurance, whatever the compulsive behavior may be. You feel better. That reaffirms that those thoughts were powerful. You let them control your behavior, and that reaffirms that they're powerful, which means next time the thoughts come along, which they will, they're just that much stronger.
So I think of OCD as being stuck in that loop, being stuck in that loop of intrusive thoughts that feel powerful and important, cause distress, control your behavior, you feel a little better, but that reinforces that the thoughts were powerful and important, round and around and around and around. Now, if you think of OCD that way, there are lots of ways you could get stuck in that loop. You could get stuck in that loop because your intrusive thoughts happen to be stronger than most people's for whatever psychological or genetic or developmental reason.
You could be stuck in that loop because you have characterological predispositions that incline you to be more likely to treat the thoughts as powerful and important. For example, perfectionism or intolerance of uncertainty. You got to have things to be clear. Or a feeling of excessive responsibility for what goes on in the world around you. These are traits that all of us have to some extent or another. They vary in the population. And if you're out on the end of one of those distributions, if you have a lot of perfectionism, if you have a lot of intolerance of uncertainty, you're likely to be less able to just discount your intrusive thoughts and move on with your day. They're going to seem more powerful and important. Or it could be that some people have more dysregulated anxiety. So the thoughts are... Anyway. And on and on. I can go around the whole circle and come up with lots of theoretical reasons why someone might have a predisposition to get stuck in this feedback loop.
When you think about OCD that way, it becomes crystal clear that it's going to be heterogeneous, even if the final common pathway is getting stuck in this feedback loop. And even that I'm sure is an oversimplification, but that's one that I find useful. But even if that's true, there's going to be lots of different ways to get there, which makes it unsurprising that not everyone's going to respond to the same treatments. I suspect when we understand it better, we'll be able to parse patients out, I won't say into different diagnoses or even the word subtypes is a little complicated, but different versions or flavors of OCD that will help us predict who's going to respond to what treatment. The dream that you've brought up a couple of times of personalized or precision medicine. I do think that we'll get there, but I think that the heterogeneity and the high degree of resistance to existing treatments is because patients are just so different.
DR. THEA GALLAGHER:
And it's interesting because having treated OCD for a long time myself, you see that it's in some ways very homogenized, the presentation of the OCD itself, or the same kind of fears or concerns or excessive nature, or the feedback loop that we're talking about. But it seems like there's something about the individual's relationship to the thoughts where it's, like you said, maybe a greater intolerance of uncertainty or what we call overvalued ideation. They're really bought in. Because the diagnosis itself, I feel like, the more I treat it, the more it sticks out pretty clearly when someone has it. But it seems like the individual's relationship to the thoughts is where we see that difference and where I run into difficulty in treatment, compliance, adherence, et cetera, for patients.
DR. CHRISTOPHER PITTENGER:
And so it's interesting, CBT tries to weaken the connections. The cognitive portion is trying to attack the treating the thoughts as powerful and important, and the behavioral part is trying to weaken the connections between the thought, the emotion, and the behavior. A different line of treatment, sort of an ACT or a mindfulness-based approach to treatment, is more about trying to recalibrate one's relationship to the thoughts.
And so I think in terms of what you just said, it's interesting to think about... I do think that these kinds of therapy, which I think can both be very effective, I mean the ERP, the symptom evocation and response prevention has been better studied. But mindfulness is widely used, including in my own practice. I think that these can be parts of a treatment program, but they're fundamentally trying to do something a little different. One is about the connections between thoughts and behaviors and the other's about the nature of the relationship to the thoughts, as you put it. And so maybe when we get a little better at parsing out different subtypes of OCD, maybe that'll be the kind of distinction that we'll be making in a systematic way when we make treatment plans for individual patients.
DR. THEA GALLAGHER:
And the one thing we do know is that it seemed to have this chronic nature. Most people endorse having some continued obsessions even after getting good treatment and are doing really well in treatment. So I think both of these treatments really being kind of a lifestyle change in that relationship to the thoughts, something that needs to be ongoing for the rest of their life. And I know that that can be kind of overwhelming for patients, but I think for other patients they've been like, "Oh, okay, this is something I have to deal with forever, hopefully to a lesser intensity at different times in my life. But realizing that these are skills and tools or medication that I kind of have to commit to for the long haul." And let's talk a little bit more about some of the medicines, especially you've been involved in studying some of these, and you mentioned it earlier, but can you talk a little bit about glutamate modulators and what we think is happening with OCD here?
DR. CHRISTOPHER PITTENGER:
Yeah, so just to recap, the first-line treatments are the serotonergic antidepressants, the SSRIs, and then second-line will sometimes go to the older drug clomipramine, which may be slightly better, certainly is better for some patients, but has more side effects. So that's the first-line. And then second-line, sometimes they use dopaminergic drugs like neuroleptics. But as you pointed out earlier, those together we can get 60% of people better, maybe 70% of people better, and a much smaller fraction, much better to the point of remission. So there's a huge need for additional treatments, and some of that's psychotherapy. But on the pharmacology end, there's been interest in saying, "Okay, maybe we're getting all the bang for the buck we can with the serotonin system with high doses of SSRIs. So maybe we need to look elsewhere to other mechanisms and other systems in order to find other ways to treat folks who aren't responsive to the first-line."
And so we got interested, and a couple other people in the field got interested about 25 years ago in the idea that glutamate modulation, that the neurotransmitter glutamate may be out of balance in OCD. The reasons to believe that might be true are complicated, and it's not a clear cut yet, but there's a couple studies that have looked at cerebrospinal fluid from unmedicated patients with OCD and have found there to be elevated glutamate. There's a literature of neuroimaging studies using this technique called magnetic resonance spectroscopy, which can get a snapshot of glutamate levels in the brain. It's kind of a messy inconsistent literature, but there are some studies there suggesting glutamate's out of whack in the cortico-basal ganglia circuitry in OCD, and there's a little bit of a genetic signal that suggests there might be some glutamate modulating genes that contribute. So it's sort of, I call it weak convergent evidence. So several convergent reasons, none of which is a definitive, but together they build this story that maybe glutamate imbalance contributes to OCD.
And so what we and some others started doing about 20, 25 years ago is taking drugs that are already on the shelf that modulate glutamate and trying and seeing if we get any benefit. Most psychiatrists aren't terribly familiar with these drugs because they're mostly developed for neurological conditions. One of them is memantine, Namenda, used for Alzheimer's and probably familiar to many psychiatrists. The one that we have done the most work on is a drug called Riluzole, which was developed for amyotrophic lateral sclerosis or Lou Gehrig's disease, which is a nasty neurodegenerative disease that has nothing to do with OCD. But it just so happens that neurologists studying and treating that condition had developed this drug called Riluzole. And it works to combat excessive glutamate in a couple ways.
It encourages glial cells to sort of vacuum up the excess glutamate, kind of like enhancing. It would be as if you're enhancing serotonin reuptake rather than inhibiting it. But we're enhancing glutamate reuptake. It also seems to block glutamate release, so it works in a couple ways to sort of tamp down excessive glutamate. And we just started treating patients who were refractory to standard pharmacotherapy with a serotonergic med, some of them on dopaminergic meds, a lot of them in psychotherapy, and weren't getting better. We just started treating with this drug and we saw some benefit up to maybe in our first studies, maybe as much as 40% of people getting some benefit. And so that's led to an ongoing series of studies.
Currently, we're actually working with a biotech company, Biohaven Pharmaceuticals, that is doing a large study, not of Riluzole, but of a riluzole prodrug, a new drug that turns into Riluzole in the body. And that's not widely available. It's not FDA-approved yet. It's still an investigation. But it's sort of 20 years later the extension of this work.
Now glutamate is complicated. Something like 60% of the neurons in the brain use glutamate. It's involved in almost every circuit and system in the brain. It has lots of receptors, it has reuptake. It's a very complicated system. And so there are lots of different ways to manipulate the system. Namenda or memantine works in a fundamentally different way. An over-the-counter supplement called N-acetylcysteine that we've done some work on that may modulate glutamate works in yet another way. And there's a bunch of other glutamate agents out there that haven't been investigated as much in OCD. So it's an example of what I was describing earlier where we're just kind of trying things empirically. We don't have a refined enough understanding of what's going on with the glutamate system to develop a really specific or refined hypothesis of how best to intervene. Rather we are taking the tools we have and trying them, and sometimes with some hopeful sign.
DR. THEA GALLAGHER:
And it sounds like it could be really promising in the future. Also because the glutamate modulators seem pretty accessible, like if you're saying you can get them over-the-counter at your pharmacy?
DR. CHRISTOPHER PITTENGER:
Well, though one N-acetylcysteine, which is an antioxidant amino acid, that's available over-the-counter. And the way I answer the question is I think it has a weak benefit for some people maybe. But on the other hand, it's cheap. It's available over-the-counter. It's really benign. The main side effect is flatulence, which is not fun, but it's something most people can live with. And so I think there's little downside to trying it. I don't think it's a magic bullet. The other drugs that I've mentioned, memantine and Riluzole, are prescription drugs. They're not as widely available.
DR. THEA GALLAGHER:
And we're waiting kind of on the research outcomes there as well.
DR. CHRISTOPHER PITTENGER:
Yeah.
DR. THEA GALLAGHER:
Just to pivot a little bit into ketamine, very popular with a lot of mental health conditions that people are very excited about. So what do we know about with ketamine in OCD?
DR. CHRISTOPHER PITTENGER:
Yeah, so ketamine is a blocker of a particular glutamate receptor, the NMDA receptor. And it was found, about, I think the first studies were more than 25 years ago here at Yale. Completely serendipitously it was found to cause a strong antidepressant effect. And the two amazing things about it were, first of all, the antidepressant effect happened quickly, and second of all, it lasts for at least a week or two in most cases after a single dose of ketamine, long after the ketamine is out of the body. So that was a revolutionary finding at the time. And then over the subsequent couple decades, and especially in the last 10 years, as you say, this has taken off, people are very excited about it and it's being used clinically, and I think it'd be incredibly effective in severe depression. I think it could be life-saving in severe depression. And it's been exciting to see that work move forward.
It is a glutamate-modulating drug. It works differently than the other ones I've listed. And so yeah, the idea came up a while ago, 15 years ago, that we should study ketamine in OCD. And the two groups that have done the most work, there are my own and then that of my colleague Carolyn Rodriguez at Stanford. And we've actually gotten somewhat different results, and I think it's because we're studying different patients. We did an early study where we tried ketamine using exactly the same protocol that folks use in depression in people with really bad OCD, many of them on medications, many of them with depression and other comorbidities. The sick patients who failed the first-line treatments and who desperately need something new. That's the group that we tried. And it was disappointing. Those who had comorbid depression, their depression got better, and that was helpful, but their OCD really didn't to any substantial extent. And we haven't pursued it very much because that first finding was disappointing in those sick and complicated patients.
Dr. Rodriguez has taken a different tack and she has been treating patients who don't have comorbidity and aren't on any medications. Sort of asking a sort of proof of principle, can it help question. And she's published a study and then has some more data she's begun showing at conferences, so it's not published yet, suggesting that it can, in nicely controlled studies. So it seems like it can help, in her hands, some people, but mostly people who aren't on medication and don't have the complications. Whereas our experience suggests that in the really sick people for whom we are most desperate to find additional ways to help, maybe it's not so helpful. So I've referred people to ketamine when they have bad comorbid depression, really to target the depression. I don't generally refer people who are refractory and severe to ketamine specifically for the OCD, but for comorbid depression, yeah. For comorbid depression, it can definitely be helpful.
DR. THEA GALLAGHER:
And it sounds like it could be another option for people with maybe mild to moderate OCD, which I think people with OCD haven't had that many options. So maybe to feel like, "Okay, there's something else out there."
DR. CHRISTOPHER PITTENGER:
Yeah, I mean, I don't refer those people to clinical use of ketamine yet because we have such good treatments already, the SSRIs for meds and appropriate cognitive behavioral therapy. So I think it's better to go to those really robustly proven treatments first rather than going to ketamine, which in my mind remains unproven, though, as you say, promising in that group of patients.
DR. THEA GALLAGHER:
And speaking of something that people are even more excited about, and you are doing work in this area, talk a little bit about psilocybin and what we think is the connection with OCD and what your study is looking at specifically.
DR. CHRISTOPHER PITTENGER:
Everyone wants to hear about psilocybin. Yeah, so psilocybin of course is a serotonergic drug found in certain mushrooms that creates a profound psychedelic effect at high enough doses, dissociation, dilation of space and time, sense of boundary dissolution and oneness with the universe, often a spiritual experience, often an experience that people describe as deeply meaningful. It also appears to have lasting benefit in certain psychiatric disorders. The best data out there is in depression, where there've been two large controlled multisite studies. Data looks pretty good in alcoholism, and then there's small studies in a number of other conditions. So yeah, we got interested in that about 10 years ago, eight years ago. And this is work that's really been driven by my colleague Ben Kelmendi, who's a mentee now, and now a faculty member here at Yale, who I've been working with for over 15 years. And I have to say, just like everything else, the idea came from the fact that it appears to work in depression and the fact that we talked to some individuals who had tried psilocybin illicitly and reported some benefit, and that made it look like it was worth trying.
And the first study of psilocybin in OCD was done by Moreno at the University of Arizona back in 2006, and he's doing some ongoing work. So there were these little pieces of evidence suggesting it might be of benefit and was certainly worth looking at. So we're doing the first placebo controlled study of psilocybin in OCD, and we've shown some of the early results from that, and it looks promising. We're hoping to wrap up that study in the spring and hopefully publish it before the end of next year, and then we're moving on to next study. So I'm quite optimistic. And psilocybin is exciting in some of the same ways that ketamine was, is that you take it once, you have this odd day, but then when there are benefits, those benefits appear to last for a long time, long after the psilocybin's out of the system. There aren't benefits for everyone, but when someone benefits, it appears to be lasting.
And that's really exciting. If there was something that you could do once or once every three months or every six months or something like that, that would be a fundamentally new way of approaching treatment. Now I have to say, our first study isn't published yet. There's a couple other folks at Hopkins and in London and at Arizona who are also studying psilocybin in OCD. So I think within a few years we'll have several small studies, and I'm hopeful we'll be able to move towards a big one to really pin down does it work and for whom, for what percentage of people, and can we predict for whom. It is early days. I can't claim it's proven. I can claim that we're excited about it. We wouldn't be doing the work if we didn't believe that this could be of benefit for some people, but I can't claim it's proven yet, so have to stay tuned on the data. But the potential, the upside, if it really does work, is exciting.
DR. THEA GALLAGHER:
And it does seem like with psilocybin, there's this piece that I've heard about through all the studies that it feels like people get some separation maybe from their thoughts or from maybe their alcohol use or their depression. They kind of get this separation. And to me, that sounds like that could be a really powerful piece of psilocybin for OCD because the thoughts feel so intrusive, so contaminating, can feel so intertwined with who they are and maybe getting some of that separation could be part of the powerful nature of psilocybin. I don't know. What are your thoughts there?
DR. CHRISTOPHER PITTENGER:
I think that may be right, and I think it goes back to something you said earlier about the relationship of the person to their thoughts. It's interesting, when we talk to folks who've come through our study and done well on psilocybin. So someone who does well on ERP will typically say, "Yes, I still get those thoughts. They're not as powerful as they were. I still don't like them, but now I have tools to manage them." That's a success for ERP. And this is just anecdotes at this point, but what we're hearing from people after psilocybin is more along the lines of, "Yeah, I still have those thoughts. I don't really understand why they ever mattered so much."
So it's a recalibration or, this is just a theory based on a handful of patients' reports, but feels like a recalibration of the meaning of the thoughts or of the relationship of the self to the thoughts, of the power and importance of the thoughts. They're still there, but their meaning, their importance has been fundamentally recalibrated. And we're doing some work, like we have long interviews with everyone. We're doing some qualitative research, and narrative analysis to try to tease out these themes and get it a little bit beyond anecdotes so that we can start to develop more robust theories to try to explain what's going on and how it differs from the improvement that is seen with other available treatments.
DR. THEA GALLAGHER:
I know you've done some work also with neurofeedback. Can you tell us a little bit about that work and what it does? What's the involvement with the orbitofrontal cortex?
DR. CHRISTOPHER PITTENGER:
So this is another line of work that unfortunately is I think promising but not yet ready to be a general treatment. But we're hopeful and we're still working on it. And it does go back. We talked earlier about how we have all of this understanding of what parts of the brain are hyperactive in OCD, but that knowledge hasn't led to any new treatments. Well, so the neurofeedback is actually an example of where we're trying to get it to lead to a new treatment. I mentioned how there's hyperactivity in this circuit that connects the cortex, the basal ganglia and the thalamus. And I mentioned that the orbitofrontal cortex, which is the cortex sitting right on top of your eyeballs, is the most hyperactive. It's the area of the brain where hyperactivity has been most repeatedly robustly seen in OCD. And that hyperactivity goes down in conjunction with successful treatment.
So we asked the question, "Okay, we know if we treat with SSRIs or CBT that hyperactivity goes down as symptoms get better. What if we could figure out some way to make that hyperactivity go down, would that be a treatment? Could we do that causal relationship in reverse?" Now, we don't want to go poking needles into people's orbitofrontal cortex, though again, I mean, surgery is, it's not in the orbitofrontal cortex, but surgery is an effective treatment of last resort in OCD. But we tried to think, is there a way to non-invasively sort of less dramatically modulate the function of the orbitofrontal cortex? And that's brought us to neurofeedback.
So broadly, neurofeedback is a form of biofeedback. It's basically where I show you something about the activity of your brain on the video screen. And I say, "I know that you can't volitionally control the activity of your orbitofrontal cortex. You look at me funny if I tell you to turn down your orbitofrontal cortex, but I'm not asking you to do that. I'm asking you to trial and error see if you can figure out how to move that line on the screen, push it up, push it down." And it turns out, and just this fact is remarkable, it turns out people can learn to do that. They can learn to volitionally control the activity of their orbitofrontal cortex, not because they can sense it because they can propriocept the activity of the OFC, but because they're being shown it on a screen. So that's what neurofeedback is.
And so what we've done, and this is work that is spearheaded by my collaborator, Michelle Hampson, also here at Yale. What we've done in a collaboration going back 15 years is we take people with OCD, we put them in the scanner, we show them their orbitofrontal cortex, and we tell them, "Try to move the line. See if you can make it go up, see if you can make it go down." Some people can't. Some people can. And when they do, their symptoms get better in a lasting way that lasts for at least a few weeks. And it also leads to an interesting, if you will, rewiring of the brain. It changes the structure of how different parts of the brain are interacting with one another. So that's pretty exciting.
That controlled study in patients with OCD was just published this year after a lot of work. The problem is the effect is pretty small. It's pretty variable between people and it's pretty small. And since the neurofeedback is hard, it requires lying in an MRI machine for hours, which is uncomfortable, it's hard to do. We feel like before we can start to push that out to be a treatment that might be widely applicable, we got to figure out a way to make the effect larger. And we're thinking hard about how to do that.
DR. THEA GALLAGHER:
Kind of getting the juice to be worth the squeeze, it sounds like.
DR. CHRISTOPHER PITTENGER:
Yeah. I do want to say one other thing about neurofeedback, which is, so neurofeedback is actually a very general term. It's kind of like psychotherapy or medications, but you can do neurofeedback on anything that you can measure in the brain. What you need is a way to measure something in the brain that you think is associated with an illness, and then a way to nudge it or to measure when the thing you're measuring gets back in the direction you want it to. So in our case, we measure the orbitofrontal cortex activity and we try to nudge it back towards lower. Neurofeedback in general has been studied much more using EEG, not brain activity in an MRI machine, but electrical waves, brainwaves, using an EEG machine. And so there is neurofeedback that's out there, and this is why I felt this was an important point to make, there's neurofeedback that's out there that you can pay people to do, but it's almost all based on EEG. And there's some evidence that it can be helpful in attention-deficit disorder, in various other conditions.
There isn't any evidence that EEG neurofeedback can be helpful in OCD. And the problem is we don't have any EEG abnormality in OCD. As I said, you need to have something to measure and you need to know how it's abnormal and where you want it to be in order to give people feedback. And we don't know that in OCD. So I have had people come to me and say, "Yeah, I've tried neurofeedback. It didn't work for me in OCD." But the fact is they were trying a kind of neurofeedback that wasn't designed to be helpful in OCD. So it's important since neurofeedback is sort of up and coming less familiar than pharmacotherapy or psychotherapy, it's important for folks to know that it's a broad generic term. And the details matter a lot in terms of what is the neurofeedback targeting and what's the method being used.
DR. THEA GALLAGHER:
And with my last question about treatments, can we talk a little bit about TMS? So transcranial magnetic stimulation. What do we know about TMS with OCD and is it promising and what do we see for the future?
DR. CHRISTOPHER PITTENGER:
Yeah, so TMS is a way of stimulating the brain in a focused way using not electricity, but fluctuating magnetic fields. And so the fluctuating magnetic fields then influence neural activity, and then that, one hopes, can have some benefit. And like neurofeedback and like pharmacotherapy, TMS is a pretty broad thing because it matters where you stimulate, how long you stimulate, what the nature of the stimulation is. So you can have wildly different effects on the brain and brain circuits depending on how and where and when you stimulate. And that's an important thing to realize. Not all TMS is created equal. It was shown some decades ago that TMS targeting the dorsolateral prefrontal cortex can be helpful in depression, and that's well established that that can be helpful. It turns out that that kind of TMS doesn't appear to work very well for OCD. And so for a long time, there were some positive studies, some negative studies, but not a lot of convincing data.
What's happened more recently is TMS protocols have been developed to target the deeper structures in the brain that are associated with OCD. So targeting the medial cortex, like right along the top of the head, seems to work a little better. And targeting the anterior cingulate, the deep medial cortex, seems to work quite a bit better for OCD. But that requires different hardware. The original TMS machines used for depression can't do that. They can't target the deeper structures. There are two companies out there, one called BrainsWay and one called Magventure, that have developed TMS coils that because of that coil is a different shape and they've worked out the physics can stimulate those deeper structures, and there's good evidence that those can be helpful in OCD. There was a particularly, the company BrainsWay did a sham controlled trial that was published back in 2017 that led to FDA approval of their coil and their protocol for the treatment of OCD.
So I think that when it's done properly, I have not done TMS research myself, but I've seen the data and I'm convinced by it. I think when it's done properly, it can be helpful. What's less clear to me is when to use it. TMS is a little hard to access. It's harder to access someone who's doing it properly for OCD. This is another place where it's important to ask the right questions and make sure the proper coil and protocol are being used. And when you can access it, the standard protocol is it requires daily visits five days a week for often six weeks. So that's a really burdensome and fairly costly treatment.
I do think that it can work. I don't know when to use it. I still use SSRIs and appropriate cognitive behavioral therapy first before I even think about TMS. I don't know that they work better. Nobody's done that study. I do know that they are better proven with many studies and they're a lot easier to access, especially the meds obviously are a lot easier to access for every patient. So I think there's still work to be done to figure out when the proper time to use TMS is. But I do think when used properly, the data suggests that it can help.
DR. THEA GALLAGHER:
We've been talking a lot about this relationship even between, or maybe even, I don't know if it's a relationship or the experience of both depression and OCD with someone with OCD. And it sounds like with some of the treatments, if they target what we think is impacting depression, it can help with the OCD. We also know people who go through exposure and response prevention, their OCD gets better. A lot of times their depression gets better too. What are some of your thoughts about this relationship between depression and OCD? Because even when you were talking about TMS, it sounds like, but there it seems like there's no connection, like with the coils for depression don't help OCD. So what do you see as the relationship there with depression and OCD?
DR. CHRISTOPHER PITTENGER:
I think it's complicated. I think there's several different forms the relationship can take. So first of all, I'll just confirm what you said, that the two do go together very often. About 40% of patients with OCD have depression. In the more severe refractory patients I tend to see, that number's more like 75%. So it is common for the two to go together. And often they get worse together, like under stress, when the OCD gets worse, the depression gets worse. Sometimes I've seen cases where they go opposite, the OCD gets better and the depression kind of expands to fill the space and then vice versa. But more commonly, they go together. You can think of at least two different ways that that could happen. And I think both are probably true some of the time. One is they might have similar causes, whether that cause is about serotonin dysregulation or glutamate dysregulation or stress or developmental experience, whatever. They may have overlapping causes. And so the same cause may lead to both in the same people.
Alternatively, we know that depression is often caused, triggered or worsened by chronic stress and especially chronic uncontrollable stress. Well, chronic persistent, intrusive, distressing thoughts are a pretty great example of a chronic uncontrollable stress. So it's very often the case, or at least it certainly clinically feels like the case that the depression is a result of the OCD. And in those cases, you want to, when the OCD gets better, the depression often will. So that's two different ways the two could be related to one another, and I'm sure there are others that one could come up with. And I'm sure that the truth is a complex mix of all the above and varies from patient to patient.
You get a sense when you're evaluating a patient as to whether the depression is because of the OCD, and sometimes they'll just up and tell you. They'll say, "Of course I'm depressed. This illness, this OCD is destroying my relationships and my life. And so wouldn't you be depressed too?" Sometimes it's that. Sometimes they were depressed for years before the OCD started and it feels different and they don't fluctuate together and it feels like a different comorbidity rather than a result. And those impressions will affect how I plan treatment in individual cases. I don't know how to do that systematically as opposed to just on sort of the hunches that you develop when you're getting to know the complexities of an individual patient's case.
DR. THEA GALLAGHER:
Well, I think we have more questions than answers, but I think it's exciting that all of this work is ongoing. It seems like at this point we don't have a silver bullet, but keeping an eye on the literature and the research that's forthcoming, there's some exciting things that could hopefully impact treatment in the next number of years.
DR. CHRISTOPHER PITTENGER:
That's certainly our hope.
DR. THEA GALLAGHER:
Well, thank you so much for this conversation, Dr. Pittenger, and thank you for being on the podcast.
DR. CHRISTOPHER PITTENGER:
It's been a real pleasure to spend this time with you today.
DR. THEA GALLAGHER:
Thanks so much for that conversation, Dr. Pittenger. If you enjoyed this episode, be sure to rate and subscribe to NYU Langone Insights on Psychiatry on your podcast app. For the Department of Psychiatry at NYU Langone, I'm Dr. Thea Gallagher. See you next time.