Dorsolateral Prefrontal Cortical Pathology in Generalized Anxiety Disorder: A Proton Magnetic Resonance Spectroscopic Imaging Study

Fifteen adult patients with DSM-IV generalized anxiety disorder (seven men and eight women; mean age=39.3 years, SD=13.3) and 15 healthy volunteers (mean age=39.1, SD=13.5) recruited through advertisements and clinic/physician referrals were prospectively pair-matched with respect to age and sex. As determined with the Structured Clinical Interview for DSM-IV Axis I Disorders (5), comorbid disorders in the generalized anxiety disorder group were dysthymia (N=5), social anxiety disorder (N=2), and concurrent social anxiety disorder and dysthymia (N=1). Inclusion criteria required that generalized anxiety disorder precede onset of comorbid axis I disorders. Exclusion criteria were a major depressive episode or substance abuse within 6 months of study entry; a lifetime history of psychotic, bipolar, obsessive-compulsive, posttraumatic stress, or eating disorder; substance dependence (other than nicotine); mental retardation or learning disability; autism; or significant medical or neurological conditions. Of the generalized anxiety disorder patients, six were medication-naive, and no subject had psychotropic exposure at least 4 weeks before scanning. Healthy participants had no history of axis I disorder, either personally or in first-degree relatives. All participants had unremarkable urine toxicology, urinalysis, CBC, blood chemistry, and ECG results. Timing of scans in female participants was matched relative to their menstrual phase. Groups did not differ in ethnic composition, educational level, IQ, height, weight, or use of hormonal contraception. Patients had screening and day-of-scan scores of at least 18 on the Hamilton Anxiety Rating Scale (mean=22.6, SD=3.5) and at least 45 on the Penn State Worry Questionnaire (mean=63.3, SD=8.1). Scores of healthy participants were substantially lower, and did not overlap those of patients (Hamilton anxiety scale mean=0.2 [SD=0.4]; Penn State Worry Questionnaire mean=29.1 [SD=8.6]). Participants were classified as having experienced early trauma (six generalized anxiety disorder patients, no comparison subjects) if they reported recurrent and severe prepubertal physical or sexual abuse, as determined with a modified Early Trauma Inventory (6, 7). The current study was approved by the Columbia University Institutional Review Board; all subjects provided written informed consent before participation.

Generalized anxiety disorder patients had a 16.5% higher N-acetylaspartate/creatine ratio in the right dorsolateral prefrontal cortex than did their matched comparison subjects (mean=3.46 [SD=0.69] versus mean=2.97 [SD=0.36], respectively; t=2.58, df=14, p<0.03). Furthermore, the N-acetylaspartate/creatine ratio in the right dorsolateral prefrontal cortex was higher in 13 of 15 generalized anxiety disorder patients than in their matched comparison subjects (Figure 1). However, the six generalized anxiety disorder patients reporting childhood abuse had a lower mean N-acetylaspartate/creatine ratio (mean=2.95, SD=0.67) in the right dorsolateral prefrontal cortex than did the nine nonabused generalized anxiety disorder patients (mean=3.80, SD=0.67) (t=2.89, df=13, p<0.006); the ratio of the abused generalized anxiety disorder patients did not differ significantly from the mean N-acetylaspartate/creatine ratio of comparison subjects. The N-acetylaspartate/creatine ratio in the right dorsolateral prefrontal cortex was not significantly associated with clinical ratings. Patients and healthy subjects did not differ in right dorsolateral prefrontal cortex choline/creatine ratio (t=0.67, df=14, p=0.52). Among generalized anxiety disorder patients, N-acetylaspartate/choline in the right dorsolateral prefrontal cortex correlated with N-acetylaspartate/creatine (r=0.65 in the right dorsolateral prefrontal cortex, p=0.009), although elevations in N-acetylaspartate/choline did not reach significance (t=1.53, df=14, p=0.15). Between-group metabolite ratio differences were not found in the left dorsolateral prefrontal cortex or in either the right or left hippocampus. Within the healthy subjects, N-acetylaspartate/creatine ratios did not differ between the right and left dorsolateral prefrontal cortex.

Contrary to our initial hypotheses, the N-acetylaspartate/creatine ratio, a measure of neuronal viability, was increased in the right dorsolateral prefrontal cortex in generalized anxiety disorder patients versus healthy comparison subjects. However, generalized anxiety disorder patients with self-reported childhood abuse had significantly lower N-acetylaspartate/creatine in this region than nonabused patients. These data suggest a potential biological subtype in generalized anxiety disorder, which is consonant with reports in major depressive disorder identifying biological subgroups based on history of early trauma (7). The direction of N-acetylaspartate/creatine abnormality in generalized anxiety disorder contrasts with that reported in posttraumatic stress disorder and mood disorders but is potentially consistent with findings suggesting prefrontal cortical hypermetabolism in generalized anxiety disorder (1) and increased cerebral blood flow in the right dorsolateral prefrontal cortex in persons with social phobia anticipating public speaking (9).

Methodological limitations of the study constrain interpretation. Ratio analyses of the N-acetylaspartate/creatine ratio may reflect changes in creatine, which is typically higher in gray matter than in white matter. Confounding effects of partial volume averaging cannot be ruled out, since tissue segmentation was not performed. Research using tissue segmentation techniques and absolute metabolite quantitation in larger samples will clarify these findings.

Presented in part at the 58th annual meeting of the Society of Biological Psychiatry, San Francisco, May 15–17, 2003. Received July 22, 2003; revision received Dec. 2, 2003; accepted Dec. 4, 2003. From the Department of Biological Psychiatry, New York State Psychiatric Institute; the Departments of Psychiatry and Radiology, Columbia University College of Physicians and Surgeons, New York; the Department of Psychiatry, Mount Sinai School of Medicine, New York; and the Department of Psychiatry, Downstate Medical Center, Brooklyn, N.Y. Address reprint requests to Dr. Mathew, Department of Biological Psychiatry, New York State Psychiatric Institute/Columbia University, 1051 Riverside Dr., Unit 126, New York, NY 10032; [email protected] (e-mail). Supported in part by a grant from GlaxoSmithKline and NIMH grant R24 MH-61274. The authors thank Manuel de la Nuez, B.A.; Justine Kent, M.D.; Jose Martinez, M.S.; Mary Beth Reynoso, M.A.; Curtis Whittman, B.A.; and Ezekiel Young, M.A., for their assistance. Drs. Coplan and Gorman have received compensation and honoraria from GlaxoSmithKline for speaking and consulting.