Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder

Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Biological psychiatry (Impact Factor: 10.26). 06/2008; 63(9):891-8. DOI: 10.1016/j.biopsych.2007.09.012
Source: PubMed


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 ((1)H 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.
Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by (1)H 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.
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.
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.

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    • "It is associated with somatic and psychological symptoms, which may progressively lead to impairments in interpersonal and occupational functioning (Nutt et al. 2002 ; Whalen et al. 2008). Although GAD is one of the most prevalent anxiety disorder affecting the general population with a lifetime prevalence of about 2–3 % across different countries (Lieb et al. 2005 ; Lim et al. 2005 ; Comer et al. 2011), its neurobiology is still not completely elucidated (Gorman et al. 2002 ; Mathew et al. 2008, 2010). Nonetheless , recent magnetic resonance imaging (MRI) studies have tried to explore the neural correlates of GAD (Cannistraro & Rauch, 2003). "
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    • "Eighteen healthy volunteers (eight males and 10 females) and 26 patients with GAD (12 males and 14 females) served as subjects . The sample comprised patients from the original, abovementioned study (Study #1; Coplan et al., 2006) with the addition of patients from a second study (Study #2; Mathew et al., 2008). From the original study, this represents an increase in sample size of 20% for the control group and 73% for the GAD group (and an increase of 100% for the GAD group when excluding subjects with early trauma). "
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    • "Magnetic resonance spectroscopy (MRS) is a noninvasive technique which can determine in vivo, in localized brain regions, several cerebral metabolites considered relevant to neural density/functional integrity (N-acetylaspartate, NAA; choline-containing compounds, Cho; glutamate, Glu; Myoinositol , MI) (Lyoo and Renshaw, 2002). Previous clinical studies have reported changes of hippocampal MRS measures in stress-related neuropsychiatric disorders, such as depression (Yildiz-yesiloglu and Ankerst, 2006; Capizzano et al., 2007), anxiety (Mathew et al., 2008), bipolar disorder (Capizzano et al., 2007), posttraumatic stress disorder (PTSD) (Freeman et al., 1998; Schuff et al., 2001, 2008; Villarreal et al., 2002; Mohanakrishnan et al., 2003; Mahmutyazicioglu et al., 2005) and schizophrenia (Deicken et al., 1998). To our knowledge, there has been only one published clinical MRS study addressing the brain neurochemical changes mainly associated with early life stress, suggesting reduced NAA of anterior cingulate cortex (ACC) in abused children and adolescences with PTSD, although this did not report measures in the hippocampus (De et al., 2000). "
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