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.

Download full-text


Available from: Dikoma C Shungu, Oct 09, 2015
31 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Prior imaging studies have shown structural, functional and biochemical impairments in patients with generalized anxiety disorder (GAD), particularly in the right hemisphere. In this study we investigated, for the first time to the best of our knowledge, the white-matter microstructure organization in GAD.MethodA total of 12 patients with DSM-IV GAD and 15 matched healthy controls underwent a magnetic resonance imaging session of diffusion weighted imaging, exploring white-matter water molecules by the means of apparent diffusion coefficients (ADCs). Regions of interests were placed in the frontal, parietal, temporal and occipital lobes and in the splenium and genu of the corpus callosum, bilaterally. RESULTS: ADC measures were significantly greater in patients with GAD in the right splenium and right parietal cortex compared with healthy controls (p⩽0.002). No significant correlations between ADCs and age or clinical variables were found. CONCLUSIONS: We provide evidence that GAD is associated with disrupted white-matter coherence of posterior right hemisphere regions, which may partly sustain the impaired cognitive regulation of anxiety. Future diffusion imaging investigations are expected to better elucidate the communication between the parietal cortex and other right hemisphere regions in sustaining the cognitive processing of social and emotional stimuli in patients with GAD.
    Psychological Medicine 07/2011; 42(2):1-8. DOI:10.1017/S0033291711001255 · 5.94 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We have demonstrated in a previous study that a high degree of worry in patients with generalized anxiety disorder (GAD) correlates positively with intelligence and that a low degree of worry in healthy subjects correlates positively with intelligence. We have also shown that both worry and intelligence exhibit an inverse correlation with certain metabolites in the subcortical white matter. Here we re-examine the relationships among generalized anxiety, worry, intelligence, and subcortical white matter metabolism in an extended sample. Results from the original study were combined with results from a second study to create a sample comprised of 26 patients with GAD and 18 healthy volunteers. Subjects were evaluated using the Penn State Worry Questionnaire, the Wechsler Brief intelligence quotient (IQ) assessment, and proton magnetic resonance spectroscopic imaging ((1)H-MRSI) to measure subcortical white matter metabolism of choline and related compounds (CHO). Patients with GAD exhibited higher IQ's and lower metabolite concentrations of CHO in the subcortical white matter in comparison to healthy volunteers. When data from GAD patients and healthy controls were combined, relatively low CHO predicted both relatively higher IQ and worry scores. Relatively high anxiety in patients with GAD predicted high IQ whereas relatively low anxiety in controls also predicted high IQ. That is, the relationship between anxiety and intelligence was positive in GAD patients but inverse in healthy volunteers. The collective data suggest that both worry and intelligence are characterized by depletion of metabolic substrate in the subcortical white matter and that intelligence may have co-evolved with worry in humans.
    Frontiers in Evolutionary Neuroscience 01/2011; 3:8. DOI:10.3389/fnevo.2011.00008
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Early life stress is a potential precursor of eventual neuropsychiatric diseases and may result in altered neurodevelopment and function of the hippocampus, which thus provides a site at which potential interventions to modify the effects of early life stress may act. In this study, Sprague-Dawley rat pups comprising male and female animals underwent maternal separation (MS) for 180 min from postnatal days (PND) 2 to 14, or were left with their dams. They subsequently received daily administration of saline (0.9%), escitalopram (10 mg/kg), or no treatment during adolescence (PND 43-60). All adult animals underwent brain magnetic resonance imaging (MRI) and bilateral hippocampal proton magnetic resonance spectroscopy ((1)H-MRS). Neither MS nor escitalopram treatment had a significant effect on hippocampal volume. Adult rats that experienced MS displayed significantly increased choline-containing compounds (Cho) and decreased N-acetylaspartate (NAA), glutamate (Glu) and Myo-inositol (MI) relative to the stable neurometabolite creatine (Cr) in hippocampus. Administration of escitalopram during adolescence could modify the alterations of NAA/Cr, Glu/Cr and MI/Cr. The effects of MS on hippocampal neurochemistry were most significant in the right hippocampus. These results indicate that MS in rats has long-term consequences on hippocampal neurochemistry reflective of neural density/functional integrity, especially on the right hippocampus, and adolescent administration with escitalopram can at least partially ameliorate these neurochemical alterations. Furthermore, these metabolite changes seem to be more sensitive indicators of the results from early life stress than volume changes.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2010; 20(12):875-83. DOI:10.1016/j.euroneuro.2010.08.010 · 4.37 Impact Factor
Show more