Carolyn Rodriguez, MD, PhD | Taming the Unquiet Mind: Next Frontiers in OCD Treatment and Research

Main Ideas

What OCD Is—and Why It Is Often Missed

• OCD has two core components:
  • Obsessions: Intrusive thoughts, images, or urges that cause anxiety.
  • Compulsions: Repeated behaviors or mental rituals intended to reduce or neutralize that anxiety.
• OCD is broader than visible behaviors such as handwashing or arranging objects. Some obsessions and compulsions happen entirely in a person’s mind. Themes can include contamination, fears of having harmed someone, and distressing thoughts that conflict with a person’s values or beliefs.
• Symptoms can be profoundly disruptive. Dr. Rodriguez described a college student whose need for things to “feel right” led to repeated changes of clothes and rewriting, ultimately affecting school and relationships.
• Rodriguez cited a long delay between symptom onset and treatment: people may wait 14–17 years to receive evidence-based care. She also noted that symptoms often begin young, with about a quarter starting by age 14.
• Author John Green’s description of OCD as thought spirals that hijack attention illustrated how symptoms can feel like a loss of control or agency.

Existing Treatments and the Challenge of Access

• Common first-line treatments are serotonin reuptake inhibitor medications (SSRIs) and cognitive behavioral therapy with exposure and response prevention (ERP).
• In ERP, a therapist helps a person gradually face feared situations while refraining from compulsions. Exposures are scaled to the person’s current ability and advanced through a hierarchy. For example, someone afraid of contamination might begin with manageable contact with a feared object, then progress to more challenging exposures without washing.
• ERP is effective, but its demands can make it difficult to start or sustain. Rodriguez’s lab is exploring ways to help people engage with it.
• Other options include noninvasive neuromodulation and, for some patients, deep brain stimulation.

Research Directions and Methods

Earlier Detection and Objective Measurement

• Rodriguez’s group is exploring whether digital information—such as patient messages—can reveal patterns like reassurance-seeking or repetition and help identify OCD sooner.
• Researchers in Stanford’s Human Neural Circuitry Program study brain activity in people undergoing intracranial monitoring for epilepsy. The aim is to investigate how thoughts and emotions are represented in the brain.
• OCD severity is commonly assessed through interviews about obsessions, compulsions, time spent on symptoms, distress, impairment, and ability to resist symptoms. The Yale-Brown scale produces a total score of up to 40.
• The lab is also interested in more objective measures, including sensors, behavioral tasks, and brain imaging.

Ketamine: Rapid Symptom Relief and Ongoing Questions

Rodriguez became interested in glutamate-related treatments after research on SAPAP3 knockout mice, which show excessive grooming. Restoring SAPAP3 in the striatum reduced grooming in the animal model.

Her group tested ketamine as a possible rapid-acting OCD treatment:

• An initial case report compared saline with ketamine and found an immediate reduction in symptoms after ketamine that lasted about a week.
• A randomized pilot study of 15 people found that symptoms decreased within an hour after ketamine, compared with saline. Participants were not taking medication. Symptoms later returned toward baseline, while the reported relief continued.
• A subsequent double-blind study of 45 people, randomized 2:1 to ketamine or midazolam, reportedly replicated the effect. Rodriguez said the advantage of a single infusion over midazolam was statistically significant for up to three weeks, and about 55% of participants responded. These results were described as unpublished at the time of the talk.

The studies also raised cautions:

• Ketamine can cause dissociation, wooziness, nausea, and temporary changes in blood pressure or heart rate.
• It has abuse potential and is not FDA-approved for OCD. The studies excluded people with a history of substance misuse.
• Midazolam provided a stronger comparison than saline, but blinding was imperfect because participants might recognize ketamine’s effects.

Unanswered questions include why ketamine works quickly, how long benefits persist, and why only some people respond.

Studying Brain Circuits and Drug Mechanisms

• One OCD hypothesis involves an overactive circuit connecting the orbitofrontal cortex, striatum, and thalamus.
• In a magnetic resonance spectroscopy study, the team expected to see changes in glutamate-related measures after ketamine. They did not find a change in GLX (glutamate and glutamine); instead, they observed increased GABA, an inhibitory messenger. This finding prompted further questions about ketamine’s mechanism.
• In animal studies, researchers used optogenetics to turn brain-circuit activity on and off. Results linked activity in a frontal-striatal circuit to compulsive grooming and suggested that ketamine’s effects involved this circuit.
• The group is also using fMRI, EEG, and remote cognitive-control tasks to examine brain changes and investigate whether baseline measures can predict who will benefit.

Other Treatments Under Investigation

• Naltrexone and ketamine: In depression research, naltrexone—a mu-opioid blocker—reduced ketamine’s antidepressant effect but did not block dissociation. This suggests the opioid system may contribute to ketamine’s antidepressant effects. Rodriguez said a related OCD study was underway: 120 participants would receive ketamine and be randomized to naltrexone or placebo.
• RR-HNK: The team had obtained a ketamine metabolite thought not to produce the same dissociation or rewarding effects. A study was beginning, but whether it would help OCD was unknown.
• MDMA plus ERP: A pilot study was planned for 40 adults with OCD. The idea is that MDMA’s prosocial and bonding effects might help people who have struggled to undertake ERP. Desoxyn (d-methamphetamine) was selected as an active stimulant comparison. Rodriguez emphasized that the study could show MDMA does not help; the results were not yet known.
• Memantine: In response to a question, Rodriguez noted that memantine, a glutamate modulator approved for Alzheimer’s disease, has some study evidence in OCD and may be considered after first-line treatments have not worked.

Advice for Families

• Learn to recognize family accommodation—for example, washing items for a loved one or repeatedly reassuring them that something is not contaminated.
• Work with a professional to reduce accommodation, since it can reinforce OCD symptoms.
• Rodriguez pointed families to the International OCD Foundation for information and resources.

Points Raised in the Q&A

• Autism: Rodriguez said repetitive behaviors in autism can overlap with OCD-related behaviors but are not the same. Her group was piloting ketamine research in adults with autism; she described the question as exploratory.
• Eating disorders: The audience noted similarities between OCD and some eating-disorder behaviors. Rodriguez agreed that diagnostic categories may not neatly reflect shared traits or circuits and said the overlap could be worth studying.
• OCPD: Rodriguez distinguished obsessive-compulsive personality disorder from OCD. She noted that medication options are limited and referred to Anthony Pinto’s work.
• Trauma: Rodriguez said a traumatic event can precede symptoms in some cases, but many people describe symptoms beginning suddenly or having been present for as long as they can remember. She noted research into the overlap between PTSD and OCD.
• PANS/PANDAS: She discussed the possibility that infection-related inflammation may affect brain circuits and mentioned Stanford specialist Jennifer Frankovich’s work and clinical trials. An audience member described a child whose symptoms appeared after an infection and later resolved.
• Measuring improvement: In addition to symptom interviews and rating scales, the lab hopes to develop objective ways to track symptoms, including time spent at a sink, behavioral tasks, and imaging.
• Neuroimaging: Rodriguez said an ongoing opioid-related study includes fMRI before and after treatment, examining reward circuitry and performance on cognitive-control tasks. The relationship between those measures and OCD ratings remained under study.

Speakers and Sources Mentioned

Event Speakers

• Johnny Powell — Third-year Stanford medical student; introduced the event.
• Sophia Baskett — Stanford biology PhD student; introduced the event.
• Carolyn Rodriguez, MD, PhD — Lecturer and principal speaker.
• Jaime Garcia — Psychiatrist and audience questioner.
• Other audience members — Asked questions; most were not named in the subtitles, including a psychiatrist who discussed a patient’s symptoms following a traumatic incident.

People and Works Cited During the Lecture

• John Green — Author of Turtles All the Way Down; Rodriguez referred to his descriptions of OCD in a book, film adaptation, and YouTube video.
• Karl Deisseroth, Vivek Buch, and Pol Nuyujukian — Collaborators in the Human Neural Circuitry Program.
• JiYoung Kim and Eleni Linos — Digital mental-health research collaborators.
• Leanne Williams, Shua Zhang, Peter Venn Russell, and Daniel Spielman — Collaborators on imaging, prediction, cognitive-control, and spectroscopy work.
• Lisa Genaidan and Gwen Davis — Collaborators on SAPAP3 animal research.
• Carlos Zarate — Cited for ketamine research and the RR-HNK depression study.
• Alan Schatzberg, Nolan Williams, and Boris Heifetz — Collaborators on research into ketamine and opioid mechanisms.
• Antonio Harden — Mentioned in connection with autism research.
• Evelyn Stuart — Mentioned in connection with memantine studies in children.
• Anthony Pinto — Mentioned for work on OCPD.
• Jennifer Frankovich — Mentioned for research and clinical trials related to PANS/PANDAS.

Organizations and Research Resources Mentioned

• Stanford OCD Research Lab
• Human Neural Circuitry Program
• Center for Digital Mental Health
• National Institutes of Health (NIH) and National Institute of Mental Health (NIMH)
• International OCD Foundation
• Palo Alto VA
• Brain & Behavior Research Foundation
• American Foundation for Suicide Prevention
• American College of Neuropsychopharmacology
• American Psychiatric Association
• American Journal of Psychiatry
• Neuropsychopharmacology