Glutamate in Pediatric Obsessive-Compulsive Disorder and Response to Cognitive-Behavioral Therapy: Randomized Clinical Trial

Abstract

Cognitive-behavioral therapy (CBT) is effective for pediatric obsessive-compulsive disorder (OCD), but non-response is common. Brain glutamate (Glu) signaling may contribute to OCD pathophysiology and moderate CBT outcomes. We assessed whether Glu measured with magnetic resonance spectroscopy (MRS) was associated with OCD and/or CBT response. Youths aged 7-17 years with DSM-IV OCD and typically developing controls underwent 3 T proton echo-planar spectroscopic imaging (PEPSI) MRS scans of pregenual anterior cingulate cortex (pACC) and ventral posterior cingulate cortex (vPCC)-regions possibly affected by OCD-at baseline. Controls returned for re-scan after 8 weeks. OCD youth-in a randomized rater-blinded trial-were re-scanned after 12-14 weeks of CBT or after 8 weeks of minimal-contact waitlist; waitlist participants underwent a third scan after crossover to 12-14 weeks of CBT. Forty-nine children with OCD (mean age 12.2±2.9 years) and 29 controls (13.2±2.2 years) provided at least one MRS scan. At baseline, Glu did not differ significantly between OCD and controls in pACC or vPCC. Within controls, Glu was stable from scan-to-scan. Within OCD subjects, a treatment-by-scan interaction (p=0.034) was observed, driven by pACC Glu dropping 19.5% from scan-to-scan for patients randomized to CBT, with minor increases (3.8%) for waitlist participants. The combined OCD participants (CBT-only plus waitlist-CBT) also showed a 16.2% (p=0.004) post-CBT decrease in pACC Glu. In the combined OCD group, within vPCC, lower pre-CBT Glu predicted greater post-CBT improvement in symptoms (CY-BOCS; r=0.81, p=0.00025). Glu may be involved in the pathophysiology of OCD and may moderate response to CBT.

Figure 1

The left upper and lower panels feature sagittal and the right upper and lower panels axial-oblique whole-brain T1-weighted MRI showing prescription of 9-mm thick proton echo-planar spectroscopic imaging (PEPSI) MRS slabs (fine white lines). Upper panels show sampling of bilateral pregenual anterior cingulate cortex (pACC) and the lower panels ventral posterior cingulate cortex (vPCC). The 32 × 32 grids of 7.6 × 7.6 mm² voxels are not shown, nor the 7 saturation bands arrayed on all sides to suppress extracranial lipids during acquisition. Thick white lines mark the ‘shim boxes’, target regions where the B₀ field is homogenized prior to excitation. The pACC shim box is laterally symmetric at the dorsal–ventral midpoint of the genu corpus callosum and runs thence anterior to frontal pole. Caudomesial portions of the box sample pACC. The vPCC is sampled caudal to splenium corpus callosum within a larger shim box that also interrogates basal ganglia, thalamus, and posterior white matter. The center panel shows a sample PEPSI MR spectrum from pACC with the prominent glutamate–glutamine complex (‘Glu+Gln’) labeled.

Figure 2

Within the pediatric obsessive-compulsive disorder sample, the left panel shows that participants randomized to active cognitive-behavioral therapy (CBT; filled circles) experience a notable posttreatment (Scan 2 vs Scan 1) drop in glutamate (Glu) levels in pregenual anterior cingulate cortex (pACC), while participants randomized to waitlist (open circles) do not (interaction p=0.034). Waitlist participants subsequently crossed over to undergo the same CBT regimen. When prepost CBT data for these crossover participants are combined with those for active CBT participants (right panel), a significant post-CBT reduction in pACC Glu was again registered (16.2% F_1,24.6=10.0, p=0.004).

Figure 3

Left panel: In pediatric obsessive-compulsive disorder (OCD) participants undergoing cognitive-behavioral therapy (CBT), glutamate (Glu) levels in ventral posterior cingulate cortex (vPCC) at pretreatment baseline correlated positively (Pearson r=0.81, p=0.00025) with post–pre-CBT %change in Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score, reflecting severity of OCD core symptoms. Red circles denote patients defined as ‘Responders’ to CBT based on experiencing a post-CBT drop of ⩾35% in CY-BOCS and a Clinical Global Impression—Improvement (CGI-I) score of 2 (‘much improved’) or 1 (‘very much improved’); yellow circles denote patients who are ‘Non-responders’ based on these criteria; striped circles denote patients who are Responders per CY-BOCS but not CGI-I. Right panel: pre-CBT vPCC Glu was significantly lower for patients who later responded (per CGI-I) to CBT (group-mean 10.2±3.0 IU) than for those who failed to respond (17.4±2.7 IU) to 12–14 weeks of weekly CBT (p<0.0005). Similar results were obtained when using a post-CBT drop of ⩾35% in CY-BOCS score as criterion for response. A full color version of this figure is available at the Neuropsychopharmacology journal online.