The NMDA glutamate receptor modulator rapastinel may reduce symptoms of obsessive-compulsive disorder without the dissociative side effects reported by patients treated with ketamine.

Carolyn Rodriguez, M.D., Ph.D.

“I can’t stop these thoughts,” said Samantha, on the verge of tears, during a recent appointment with me. Looking down, she tugged at the surgical gloves she always wears to protect her hands from potential exposure to germs. “Every day is a struggle. I can’t work and I can’t have a normal life.”

Samantha was diagnosed with obsessive-compulsive disorder (OCD) when she was 14 years old and has had waxing and waning symptoms for the past 20 years. She asked to meet with me for a consultation and second opinion.

She has already tried serotonin reuptake inhibitors (SRIs) and cognitive-behavioral therapy with exposure and response prevention (EX/RP)—both first-line treatments for OCD—as well as recommended augmentation strategies (1) without clinically meaningful improvement in her OCD symptoms.

Before trying neurosurgical options such as deep brain stimulation, Samantha wanted to know more information about the latest pharmacological strategies for treating OCD that have supportive emerging data.

Increasing evidence indicates that glutamate plays a role in OCD symptoms. Ketamine, which at high doses is used primarily as an anesthetic, acts on brain glutamate receptors, and has shown remarkable therapeutic effects in depression and other disorders (2). I led the first randomized proof-of-concept clinical trial comparing low-dose ketamine (0.5mg/kg I.V.) with placebo in OCD patients (n=15) suffering from constant obsessions (3).

After a single I.V. ketamine dose, 50 percent of the patients met response criteria (35 percent reduction in the Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score) score one week post-injection after a single administration. The effect was rapid (within hours), with patients reporting remarkable benefit. In some but not all individuals, the therapeutic effects persisted for a total of two to four weeks (4).

Could we extend ketamine’s effects by combining it with a brief course of EX/RP cognitive-behavioral therapy? Our rationale drew from two lines of research: previous studies suggest ketamine may enhance plasticity and extinction learning in animal models (5-7); and trials that combined therapy with medications thought to facilitate extinction learning reported increased cognitive-behavioral therapy gains (8, 9).

Our design comprised a single dose of open-label I.V. ketamine given to adult subjects (n=10) with OCD followed by an abbreviated course of EX/RP (10 one-hour exposure sessions) delivered during the time interval when ketamine putatively facilitates extinction learning (two weeks) (6). We found that somewhat more than half of adults with OCD (60 percent) met response criteria (35 percent reduction in Y-BOCS score) at two weeks post-injection after a single administration (10).

Although these results are promising, patients reported side effects including transient dissociation in both studies (3, 10). Additionally, enthusiasm must be tempered by what we don’t know. No large-scale studies of risks for ketamine abuse or of its safety with long-term administration have been conducted (11-13).

To find rapidly acting treatments lacking the dissociative and other side effects reported with I.V. ketamine, my lab is working to identify new compounds that act on the glutamate pathway. Rapastinel, an NMDA glutamate receptor modulator, has rapid antidepressant activity with a minimal risk of ketamine-like side effects (14, 15), and is currently in a large phase 3 program that may identify it as a first-in-class FDA-approved treatment for depression.

Does raspastinel have similar effects in OCD patients? In an open-label, proof-of-concept study (n=7), I found raspastinel (10 mg/kg I.V.) decreased symptoms of OCD, anxiety, and depression within hours, and was well tolerated (16). Rapastinel did not produce the dissociative or other side effects seen with ketamine in OCD (3, 10, 17, 18). The effects of a single administration of rapastinel on OCD symptoms did not persist to one week post-injection. Next steps for developing rapastinel in OCD are to try repeated dosing and test follow-on compounds (new formulations within a therapeutic class).

I tell Samantha that more research is needed to replicate my group’s findings in clinical trials enrolling larger samples and using active control conditions. Such trials will require OCD patients like her to partner with us by participating.

Samantha stopped tugging at her glove and looked up at me: “I am not sure I will get better.” She is right; we don’t know which individuals with OCD will be most helped by this approach. But, I saw a shift in her behavior as she started asking more about the science behind our work and became more energized about getting better.

Although medications that act on glutamate are unlikely to be a “one-size-fits-all” approach, I am hopeful that this new work will open a line of investigation that will help link changes in brain to changes in behavior and will produce rapid-acting, personalized treatments for patients suffering from OCD. ■

References 1. Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. 2007;164:5-53. 2. Mathew SJ, Zarate CA: Ketamine for Treatment-Resistant Depression: The First Decade of Progress. Switzerland, Springer; 2016. 3. Rodriguez CI, Kegeles LS, Levinson A, Feng T, Marcus SM, Vermes D, Flood P, Simpson HB. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013;38:2475-2483. 4. Rodriguez CI, Levinson A, Zwerling J, Vermes D, Simpson HB. Open-Label Trial on the Effects of Memantine in Adults With Obsessive-Compulsive Disorder After a Single Ketamine Infusion. J Clin Psych. 2016; 77(5): 688-689. 5. Duman RS. Neurobiology of stress, depression, and rapid acting antidepressants: remodeling synaptic connections. Depress Anxiety. 2014;31:291-296. 6. Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71:996-1005. 7. Gideons ES, Kavalali ET, Monteggia LM. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci U S A. 2014. 8. Craske MG, Treanor M, Conway CC, Zbozinek T, Vervliet B. Maximizing exposure therapy: An inhibitory learning approach. Behav Res Ther. 2014;58C:10-23. 9. Hofmann SG. D-cycloserine for treating anxiety disorders: making good exposures better and bad exposures worse. Depress Anxiety. 2014;31:175-177. 10. Rodriguez CI, Wheaton M, Zwerling J, Steinman SA, Sonnenfeld D, Galfalvy H, Simpson HB. Can exposure-based CBT extend the effects of intravenous ketamine in obsessive-compulsive disorder? an open-label trial. J Clin Psychiatry. 2016;77:408-409. 11. Sanacora G, Schatzberg AF. Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders? Neuropsychopharmacology. 2014. 12. Schatzberg AF. A word to the wise about ketamine. Am J Psychiatry. 2014;171:262-264. 13. Sanacora G, Heimer H, Hartman D, Mathew SJ, Frye M, Nemeroff C, Robinson Beale R. Balancing the Promise and Risks of Ketamine Treatment for Mood Disorders. Neuropsychopharmacology. 2016. 14. Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskal JR. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013;38:729-742. 15. Moskal JR, Burch R, Burgdorf JS, Kroes RA, Stanton PK, Disterhoft JF, David Leander J. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin Investig Drugs. 2014;23:243-254. 16. Rodriguez CI, Zwerling J, Kalanthroff E, Shen H, Filippou M, Jo B, Simpson HB, Burch R, Moskal JR. Effect of a Novel NMDA Receptor Modulator, Rapastinel (formerly GLYX-13) in OCD: A Pilot Study. American Journal of Psychiatry. 2016;173:1239-1240. 17. Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, Pittenger C. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012;72:964-970. 18. Niciu MJ, Grunschel BD, Corlett PR, Pittenger C, Bloch MH. Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after ketamine infusion in patients with obsessive-compulsive disorder and a history of major depressive disorder. J Psychopharmacol. 2013;27:651-654.