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. 2013 Apr;23(4):276-84.
doi: 10.1016/j.euroneuro.2012.05.009. Epub 2012 Jun 26.

A pilot study of hippocampal volume and N-acetylaspartate (NAA) as response biomarkers in riluzole-treated patients with GAD

Chadi G Abdallah  1 , Jeremy D Coplan, Andrea Jackowski, João R Sato, Xiangling Mao, Dikoma C Shungu, Sanjay J Mathew
Affiliations

A pilot study of hippocampal volume and N-acetylaspartate (NAA) as response biomarkers in riluzole-treated patients with GAD

Chadi G Abdallah et al. Eur Neuropsychopharmacol. 2013 Apr.

Abstract

Anxiolytic benefit following chronic treatment with the glutamate modulating agent riluzole in patients with generalized anxiety disorder (GAD) was previously associated with differential changes in hippocampal NAA concentrations. Here, we investigated the association between hippocampal volume and hippocampal NAA in the context of riluzole response in GAD. Eighteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. Participants underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. GAD patients who completed all interventions were classified as remitters (n=7) or non-remitters (n=6), based on final Hamilton Anxiety Rating Scale (HAM-A) scores ≤7. At baseline, GAD patients had a significant reduction in total hippocampal volume compared to healthy subjects (F(1,21)=6.55, p=0.02). This reduction was most pronounced in the remitters, compared to non-remitters and healthy subjects. Delta (final-baseline) hippocampal volume was positively correlated with delta NAA in GAD. This positive association was highly significant in the right hippocampus in GAD [r=0.81, p=0.002], with no significant association in healthy subjects [Fisher r-to-z p=0.017]. Across all GAD patients, delta hippocampal volume was positively associated with improvement in HAM-A (rspearman=0.62, p=0.03). These preliminary findings support hippocampal NAA and volume as neural biomarkers substantially associated with therapeutic response to a glutamatergic drug.

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Conflict of interest statement

Conflict of interest

JDC receives grant support from NIMH, NYSTEM, GlaxoSmithKline, Pfizer, and Alexza Pharmaceuticals. He is on the Pfizer advisory board and gives talks for BMS, AstraZeneca, GSK, and Pfizer. SJM: Grant or Research Support: NIMH, NARSAD, Dept. of Veterans Affairs. Consultant (last 24 months): Cephalon, Roche, Noven, AstraZeneca. No biomedical financial interests or potential conflicts of interest are reported for CGA, AJ, JRS, XM, and DCS.

Figures

Figure 1
Figure 1. Study Design
Medication-free patients with primary diagnosis of generalized anxiety disorder (GAD) were treated with riluzole 50mg twice a day for 8 weeks. Healthy controls and GAD participants received magnetic resonance imaging and spectroscopy at baseline and at the end of week 8.
Figure 2
Figure 2. Baseline Total Hippocampal Volume Differences Among Response Groups
Post-hoc analyses showed a significantly smaller hippocampus in remitters (HAM-A ≤ 7) as compared to non-remitters and healthy subjects. However there were no significant hippocampal differences between non-remitters and healthy subjects. a. General Linear Model univariate analysis controlling for intracranial volume; b. post-hoc pairwise comparison of estimated marginal means with Bonferroni adjustment for multiple comparisons; * p ≤ .05; *** p ≤ .001; ns: non-significant.
Figure 3
Figure 3. Hippocampal Volume Changes from Baseline to the End of Week 8
Riluzole had no statistically significant effect on hippocampal volume changes over the study period.
Figure 4
Figure 4. Association Between Delta Right Hippocampal Volume and N-Acetylaspartate (NAA)
Delta right hippocampal volume highly correlated with delta right hippocampal NAA in GAD patients receiving 8 weeks of riluzole treatment. This correlation was not evident in a sex- and age-matched healthy control group who did not receive the study drug.
Figure 5
Figure 5. Association Between Delta Right Hippocampal Volume and Penn State Worry Questionnaire (PSWQ)
Delta right hippocampal volume positively correlated with delta PSWQ in GAD patients receiving 8 weeks of riluzole treatment (r = 0.68, n = 12, p = 0.01).
See this image and copyright information in PMC

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