Obsessive-compulsive disorders can severely limit those affected in their everyday lives. A study has now got to the bottom of the neurochemical basis of the disease. It shows that there is more to these stressful disorders than a purely psychological problem. Accordingly, the ratio of the messenger substances glutamate and GABA is shifted in the brain of compulsive people. Even in healthy people, elevated glutamate levels are associated with compulsive tendencies. The results could help to develop new therapies for obsessive-compulsive disorder.
Around two to three percent of the population suffer from obsessive-compulsive disorder. Typical symptoms are compulsive checking, for example, whether the stove is switched off or the door is locked, constant hand washing, senseless counting or ritualized touching of objects. Many sufferers are also plagued by obsessive thoughts, which they experience as extremely aversive, but from which they can hardly distance themselves. The causes of the disease have so far been unclear and treatment options are limited. Depending on the extent and severity, those affected can benefit from behavioral therapy and drug treatment with antidepressants.
Imbalance between excitation and inhibition
A team led by Marjan Biria from the University of Cambridge in Great Britain has now investigated the neurochemical causes of the disease. Using high-resolution brain scans, they measured the concentration of the brain neurotransmitters glutamate and GABA in the anterior cingulate cortex and in the supplementary motor cortex in 31 people diagnosed with OCD and 30 healthy controls. Both brain regions are involved in controlling habitual actions and have previously been associated with OCD.
“Subjects with OCD showed a shifted ratio of GABA and glutamate in both brain regions,” reports the research team. Compared to healthy subjects, subjects with OCD had increased levels of the excitatory neurotransmitter glutamate and lower levels of the inhibitory neurotransmitter GABA. “Excess glutamate and reduced GABA disrupt neuronal circuitry in key regions of the brain,” explains Biria’s colleague Trevor Robbins.
Association also in healthy subjects
In addition to the brain scans, the team administered tests and questionnaires to all participants to measure compulsive tendencies and habitual behaviors. In a test, the subjects first learned which reaction in a computer game is most likely to lead to a reward. However, after three rounds of play, the probability of winning changed, making another strategy more promising. “We tested whether people are more likely to repeat the same responses, as in a habit, or whether they adjust their behavior to better pursue their goals,” Robbins said.
The researchers then related the results of the tests and questionnaires to the GABA and glutamate levels. It turned out that even in healthy people, the ratio of these messenger substances in the supplementary motor cortex is linked to compulsive tendencies. The more this ratio was shifted in favor of glutamate, the more the healthy subjects tended to maintain their habitual behavior.
Approaches to therapies
“Compulsions and habits are not the same thing, but dysfunctional regulation of habits can underpin compulsions and discourage people from goal-directed behavior,” explains Robbins. “Our results are an important piece of the puzzle for understanding the mechanisms underlying OCD. The results suggest new strategies for the drug treatment of OCD based on available drugs that regulate glutamate.” Already today, some treatments target glutamate imbalances in the brain. “Now we have evidence of why certain approaches appear to have a positive impact,” Biria said.
Source: Marjan Biria (University of Cambridge, UK) et al., Nature Communications, doi: 10.1038/s41467-023-38695-z