To the Editor: Although serotonergic agents have been the mainstay in the pharmacotherapy of obsessive-compulsive disorder (OCD), the presumed pathogenesis of OCD implicates glutamatergic dysfunction of cortico-striato-pallido-thalamo-cortical networks (CSPTC).^1,2 Anecdotal reports suggest that agents likely to down-regulate glutamatergic neurotransmission have promising results in OCD^1–6 and offer a treatment option in refractory cases. We report a case in which the addition of a glutamatergic agent led to improvement in a patient with treatment-resistant OCD who, among other drugs, was receiving two other glutamatergic agents.

Mr. X, a 44-year-old man, had suffered from OCD since adolescence. His obsessions included concerns about gaining weight in his abdomen and concerns about symmetry and exactness. His rituals included looking at his abdomen for a specified number of times, counting several numbers in his head before responding to questions, and repeating the same questions in a particular order. He ate little and compulsively rode his exercise bike in order to maintain the shape of his abdomen. He failed adequate trials of all SSRIs, SNRIs, clomipramine, and augmentation with antipsychotic agents. His isolation made cognitive behavior interventions impracticable. He was on a high daily doses of phenelzine (135 mg/day), clonazepam (8 mg/day), lamotrigine (450 mg/day), and topiramate (400 mg/day). Phenelzine was gradually lowered to 75 mg/day, while the rest of his medication was unchanged. Syndrome severity and failure of conventional pharmacotherapy led to the decision to use riluzole, with the rationale that this agent down-regulates glutamatergic neurotransmission through a mechanism different from those of lamotrigine and topiramate. The initial dose was 25 mg/day, with the plan to increase the dose by 25 mg per week, to the target dose of 100 mg/day. About 1 week after the introduction of riluzole, he began to improve. He spent less time looking at his abdomen. His food intake improved. He was able to articulate his questions in a nonstereotypical manner and participate in group therapy.

This patient had severe, drug-resistant OCD that responded to the addition of a small dose of riluzole to a regimen of an MAOI, clonazepam, and two other glutamatergic agents. Assuming that nonpharmacological factors did not fully account for the patient's improvement, the rapid improvement suggests that riluzole may be effective even when agents with a different action on the glutamatergic system failed. The efficacy of riluzole in this case is consistent with the hypothesis of CSPTC hyperactivity in part contributed by glutamatergic excess.¹ The CSPTC consist of parallel loops forming two pathways The first is a direct pathway with cortical projections to the striatum and from there to the internal globus pallidus-substantia nigra-pars reticulata complex (Gpi/SNr), then to the thalamus and finally to cortical structures. The second is an indirect pathway in which cortical projections arrive at the striatum and from there to the external globus pallidus and then to the subthalamic nucleus.¹ Projections from the subthalamic nucleus join the direct pathway and arrive initially at the Gpi/SNr and from there to the thalamus and finally to the cortex. The net effect of the direct pathway is excitatory, whereas the final effect of the indirect pathways is inhibitory. It has been proposed that OCD symptoms are mediated by overactivity of the direct pathway or underactivity of the indirect CSPTC pathway. The rationale for studying glutamatergic-modulating agents in OCD has been based on findings suggesting that glutamate is the principal excitatory neurotransmitter of CSPTC pathways.¹ In summary, hypotheses about the exact mechanism of action of riluzole are premature. However, reduction of glutamatergic activity by reducing glutamate release at the synapse and by stimulating glutamate uptake by astrocytes¹ is a speculation consistent with the glutamatergic hypothesis of OCD. Agents with specific inhibitory actions on the glutamatergic system deserve controlled trials.