HippocampalN-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder
- Buckley, P. MD
Background.
Previous research has suggested the therapeutic potential of glutamate-modulating agents for severe mood and anxiety disorders, potentially resulting from enhancement of neuroplasticity. We used proton magnetic resonance spectroscopic imaging (1H MRSI) to examine the acute and chronic effects of the glutamate-release inhibitor riluzole on hippocampal N-acetylaspartate (NAA), a neuronal marker, in patients with generalized anxiety disorder (GAD) and examined the relationship between changes in NAA and clinical outcome.
Methods.
Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by 1H MRSI before drug administration, and 24 hours and 8 weeks following treatment. Patients were identified as responders (n = 9) or nonresponders (n = 5). Seven untreated, medically healthy volunteers, comparable in age, sex, IQ, and body mass index to the patients, received scans at the same time intervals. Molar NAA concentrations in bilateral hippocampus, and change in anxiety ratings were the primary outcome measures.
Results.
A group-by-time interaction was found, with riluzole responders showing mean increases in hippocampal NAA across the three time points, whereas nonresponders had decreases over time. In GAD patients at Week 8, hippocampal NAA concentration and proportional increase in NAA from baseline both were positively associated with improvements in worry and clinician-rated anxiety.
Conclusions.
These preliminary data support a specific association between hippocampal NAA and symptom alleviation following riluzole treatment in GAD. Placebo-controlled investigations that examine hippocampal NAA as a viable surrogate endpoint for clinical trials of neuroprotective and plasticity-enhancing agents are warranted (Figs 2-4).
FIGURE 2.
—Changes in N-acetylaspartate (NAA) concentration in bilateral hippocampus across Baseline magnetic resonance spectroscopic imaging (MRSI) scan, 24-hour MRSI scan (after two doses of riluzole, 50 mg twice daily [b.i.d.]), and Week 8 MRSI scan (after 8 weeks of riluzole, 50 mg b.i.d.). Bars represent standard error of the mean. GAD, generalized anxiety disorder. (Reprinted from Mathew SJ, Price RB, Mao X, et al. Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder. Biol Psychiatry. 2008;63:891-898, with permission from the Society of Biological Psychiatry.)
FIGURE 3.
—Hippocampal N-acetylaspartate (NAA) of healthy volunteers (untreated) and patients with generalized anxiety disorder (GAD) at Baseline and Week 8 magnetic resonance spectroscopic imaging scans (8 weeks of riluzole, 50 mg twice daily). (Reprinted from Mathew SJ, Price RB, Mao X, et al. Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder. Biol Psychiatry. 2008;63:891-898, with permission from the Society of Biological Psychiatry.)
FIGURE 4.
—Scatter plots for percent change in hippocampal N-acetylaspartate (NAA) versus percent decrease in symptom measures at Week 8 (generalized anxiety disorder patients only). HAM-A, Hamilton Anxiety Rating Scale; PSWQ, Penn State Worry Questionnaire. (Reprinted from Mathew SJ, Price RB, Mao X, et al. Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder. Biol Psychiatry. 2008;63:891-898, with permission from the Society of Biological Psychiatry.)