Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder
Mathew SJ, Price RB, Mao X, Smith EL, Coplan JD, Charney DS, et al.;
Commented by , 31 Mar 2008
Aim of Study
To assess whether riluzole treatment changes the concentration of N-acetylaspartate (a marker of neuronal integrity) in the hippocampus of generalised anxiety disorder patients and whether any change detected correlates with clinical outcome.
Hypotheses tested:
- Hippocampal N-acetylaspartate (NAA) will increase after both acute and chronic riluzole treatment in riluzole responders;
- NAA concentrations will correlate with a reduction in symptoms of worry and anxiety.
Method
Fourteen medication free generalised anxiety disorder patients who were administered open label riluzole 50mg b.i.d. treatment were included in the analysis. They were assessed at baseline, 24 hours and 8 weeks with proton magnetic resonance spectroscopy (1H MRS).
Seven healthy, matched volunteers also underwent 1H MRS at the same timepoints with no medication. Clinical outcome was assessed using the changes from baseline to eight weeks on the Hamilton Anxiety rating scale (HAM-A) and Penn State Worry Questionnaire (PSWQ).
Results
Nine patients were classified as responders to riluzole (HAM-A <7 or PSWQ <45) at 8 weeks. Hippocampal NAA concentrations increased in responders and healthy controls, but decreased in non-responders, a significant group by time interaction. Hippocampal NAA was inversely correlated with anxiety scores at week 8 (i.e. greater hippocampal NAA was associated with less anxiety).
Dr Christmas', Dr Hood's and Prof Nutt's comments
This paper used a riluzole, a glutamate release inhibitor to treat generalised anxiety disorder. Glutamate overactivity has been implicated for some time in the pathology of anxiety disorders. Much of this evidence comes from animal models, such as glutamate NMDA receptor antagonists being anxiolytic in rats (ref. 1, ref. 2).
Unfortunately, development of direct NMDA receptor antagonists in humans has been limited by serious side effects such as sedation, memory impairment and psychotic symptoms (ref. 3, ref. 4). Therefore, other mechanisms by which the glutamate system can be attenuated are being explored to treat anxiety disorders.
Nevertheless, randomised placebo-controlled trials are necessary to confirm whether riluzole is effective in anxiety disorders, especially when a large placebo response in anxiety trials can be expected.
Hippocampal dendritic atrophy occurs following stress in animal models (ref. 5). In humans the correlate of this may be reduced hippocampal volume reported in mood disorders (ref. 6). Simon and Gorman have hypothesised that dendritic atrophy occurs in response to glutamate overactivity following stress.
This has the function of protecting the neurone against glutamatergic toxicity, but may have the unwanted effect of precipitating anxiety or depression (ref. 7). As NAA is thought to be a marker of neuronal integrity (ref. 8) it is tempting to postulate that hippocampal NAA concentrations could act as a biomarker for anxiety, or depressive, disorders.
This study shows that hippocampal NAA concentrations are significantly different between responders and non-responders at 8 weeks, suggesting this test could be used as a measure of response to treatment.
However, this result must be interpreted with caution for several reasons. First, MRSI studies have shown divergent results, such as a positive correlation between anxiety severity and NAA concentrations (albeit in a different disorder and different brain area) (ref. 9).
Second, in the case of this paper, baseline NAA concentrations were not correlated with anxiety measures; this suggests that NAA levels may not be directly related to the underlying process driving anxiety.
Third, this 8 week study is not long enough to determine if NAA levels are correlated with long term outcome. Fourth, it is not clear if hippocampal NAA concentrations increase with established treatments of anxiety.
Fifth, it is possible that other confounding factors are having an effect. One such possibility is the brain-derived neurotrophic factor (BDNF) gene polymorphism Val66Met, in which the Met allele is associated with smaller hippocampal volumes (ref. 10) (and therefore possibly lower NAA concentrations).
Therefore although this is clearly a very promising area of research, there remain many questions to be answered before hippocampal NAA concentrations can be considered as biomarkers. In this regard it may be helpful to first characterise NAA concentrations comprehensively in healthy subjects, before studying it in different medication free patients groups and finally treated patients.
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