Results of a new clinical trial shed light on mechanisms that may give rise to some of the repetitive behaviors experienced in obsessive-compulsive disorder (OCD) and Tourette’s disorder. The results also add to past evidence suggesting that an FDA-approved medicine called ondansetron, when added to treatment with an SRI drug (serotonin reuptake inhibitor), may help reduce symptom severity in OCD.

A team of investigators led by 2008 BBRF Young Investigator Emily R. Stern, Ph.D., of the Nathan Kline Institute for Psychiatric Research and New York University Grossman School of Medicine, and including three other recipients of BBRF grants and prizes, reported on the trial in a paper appearing in the American Journal of Psychiatry.

At the focus of the team’s research are so-called “sensory phenomena” (SP), aversive and often uncomfortable sensations that drive repetitive behaviors in OCD and Tourette’s. The researchers point out that some models of OCD propose compulsions are driven by thoughts of preventing harm and avoiding feared outcomes. Yet, they add, “many individuals with OCD experience SP that include both physical urges and other experiences that do not involve a concrete fear.” In Tourette’s, they note, SP often manifest as a feeling that something—often, unpleasant—is about to happen and takes the form of “sensory tics” that involve the build-up of sensory discomfort in the body that persists until a tic is performed.

Although “highly distressing and associated with reduced quality of life,” SP are not well addressed by standard treatments in either OCD or Tourette’s, the team notes.

Research on the neural underpinnings of SP is limited, they say, but points to a brain network (the insula-sensorimotor network) involved in processing sensation and motor responses. Past studies have found that in the sensorimotor cortex, the volume of grey matter (composed mostly of neurons) may be higher in OCD patients with SP vs. those who don’t experience SP. Dr. Stern and colleagues have found in their research that in a small OCD cohort, greater severity of SP was associated with increased activity in the mid-insula and sensorimotor regions of the brain.

In the trial they have just reported, the team set out to explore the potential therapeutic impact upon SP of an agent which they say might have the effect of modulating circuitry involved in SP. The agent, ondansetron, specifically blocks one of the several types of receptors for serotonin found in brain cells, the serotonin type 3 receptor. The drug is approved for use in nausea and vomiting. It is of interest in OCD and tic disorders because there is a high density of serotonin type 3 receptors in neurons that populate the spinal cord and brainstem. These neurons relay sensory signals from the body “upward” to parts of the cortex that process them. Experiments have been performed in which ondansetron has been used to treat pruritis (itching), neuropathic pain, and visceral hypersensitivity (oversensitivity of internal organs).

The largest past trial in which ondansetron was tested in patients with OCD did not yield encouraging results, but the drug was used at a very low dose (1-1.5mg/day). The drug has been tested only once in patients with Tourette’s, and results were encouraging, with the drug given at the highest approved clinical dose of 24mg. Following up on this preliminary study and others conducted to date, the team sought to test ondansetron at 24mg/day, comparing it with placebo over 4 weeks in patients with OCD and/or Tourette’s. Their paper describes the impact on SP severity and brain connectivity in the “resting state” (when one is not focused on any particular task) as measured by MRI scanning.

Patients were recruited for the trial at three study sites, of whom 51 completed all phases and whose results were used for analysis. They were randomized to receive 24mg/day ondansetron or placebo and assigned to these groups randomly, with 27 in the final group receiving the active drug. Prior to randomization, each participant was given an MRI scan and assessed for clinical symptoms; the same procedure was followed at the end of 4 weeks. A “moderate or higher” score on a standard rating scale measuring sensory phenomena was required so that those with significant SP symptoms would be well represented in the cohort.

Among the 51 “completers,” 45 were diagnosed with OCD, five of whom had comorbid Tourette’s disorder. Six were diagnosed with Tourette’s but not OCD. The cohort was about evenly divided among men and women, and the average age was about 30. Importantly, 51% of completers were not taking any other psychotropic medicine, but the remainder were.

Analysis showed that 4 weeks of high-dose ondansetron alone did not reduce the severity of sensory phenomena in this cohort, nor did it lessen the overall symptoms of OCD in those with that diagnosis, when compared with placebo treatment. There were too few Tourette’s patients in the cohort to analyze findings in that subgroup. But important results were noted in a subset of the 45 participants with OCD—specifically, those who were assigned to the ondansetron group and during the trial were also taking other psychotropic medicines. These individuals “had a significantly greater reduction in overall OCD severity as well as a decrease in connectivity in the medial portion of the sensorimotor network.” These effects, the team stressed, “were not found in participants with OCD who were not taking concomitant medications.” Among those OCD patients taking another medicine in addition to ondansetron, all were taking at least one SRI medicine.

The team considered the apparent paradox: administration of ondansetron, which blocks certain serotonin receptors, appeared to augment the beneficial effects of SRIs, which are designed to enhance serotonin in the brain. They offered a number of possible explanations. Most of the serotonin 3 receptors in the brain “co-localize” to GABA neurons, i.e., they appear on the same neurons that are sensitive to GABA, the brain’s primary inhibitory neurotransmitter. This suggests the possibility that ondansetron inhibits dopamine release downstream of these neurons, and that its efficacy in OCD is related to synergistic serotonin and dopamine effects.

A similar explanation has been proposed by others to account for the efficacy of augmentation of SRIs with antipsychotic medications, which are taken by some people with OCD. Other possibilities mentioned in the paper are that blocking the serotonin 3 receptor may actually lead to greater serotonin release through “a multisystem feedback loop,” or that biological mechanisms associated with treatment resistance in OCD are especially sensitive to modulation by ondansetron.

Further study, preferably in larger groups involving more patients, might try to replicate the effect noted in this trial, and explore possible mechanisms of the effects noted, the team said. At this point, they say their results “suggest that ondansetron’s efficacy in reducing sensory phenomena may depend on its ability to alter the function of brainstem targets of the drug.” Why this affects only some patients is one outstanding question, although if trial results are replicated, its impact in OCD patients taking SRIs may be a significant finding with clinical relevance.

The team included Katherine E. Burdick, Ph.D., 2021 BBRF Colvin Prize winner, 2014 BBRF Independent Investigator and 2005 Young Investigator; Dan V. Iosifescu, M.D., 2006 and 2001 BBRF Young Investigator; and James W. Murrough, M.D., 2009 BBRF Young Investigator.