0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Reductions in Occipital Cortex GABA Levels in Panic Disorder Detected With 1H-Magnetic Resonance Spectroscopy FREE

Andrew W. Goddard, MD; Graeme F. Mason, PhD; Ahmad Almai, MD; Douglas L. Rothman, PhD; Kevin L. Behar, PhD; Ognen A. C. Petroff, MD; Dennis S. Charney, MD; John H. Krystal, MD
[+] Author Affiliations

From the Departments of Psychiatry (Drs Goddard, Mason, Almai, and Krystal), Biomedical Engineering (Dr Mason), Internal Medicine (Dr Rothman), Radiology (Dr Rothman), and Neurology (Drs Behar and Petroff), Yale University School of Medicine, New Haven, Conn; and the National Institute of Mental Health, Rockville, Md (Dr Charney).


Arch Gen Psychiatry. 2001;58(6):556-561. doi:10.1001/archpsyc.58.6.556.
Text Size: A A A
Published online

Background  There is preclinical evidence and indirect clinical evidence implicating γ-aminobutyric acid (GABA) in the pathophysiology and treatment of human panic disorder. Specifically, deficits in GABA neuronal function have been associated with anxiogenesis, whereas enhancement of GABA function tends to be anxiolytic. Although reported peripheral GABA levels (eg, in cerebrospinal fluid and plasma) have been within reference limits in panic disorder, thus far there has been no direct assessment of brain GABA levels in this disorder. The purpose of the present work was to determine whether cortical GABA levels are abnormally low in patients with panic disorder.

Methods  Total occipital cortical GABA levels (GABA plus homocarnosine) were assessed in 14 unmedicated patients with panic disorder who did not have major depression and 14 retrospectively age- and sex-matched control subjects using spatially localized 1H-magnetic resonance spectroscopy. All patients met DSM-IV criteria for a principal current diagnosis of panic disorder with or without agoraphobia.

Results  Patients with panic disorder had a 22% reduction in total occipital cortex GABA concentration (GABA plus homocarnosine) compared with controls. This finding was present in 12 of 14 patient-control pairs and was not solely accounted for by medication history. There were no significant correlations between occipital cortex GABA levels and measures of illness or state anxiety.

Conclusions  Panic disorder is associated with reductions in total occipital cortex GABA levels. This abnormality might contribute to the pathophysiology of panic disorder.

Figures in this Article

DYSREGULATION in brain γ-aminobutyric acid (GABA) neuronal function might contribute to the pathophysiology of human panic disorder. For example, lowered brain GABA levels are associated with anxietylike behaviors in animals,%1,2 and elevated brain GABA levels tend to be associated with anxiolysis.%2,3 Although clinical studies of GABA levels in patients with panic disorder have shown normal plasma%4,5 and cerebrospinal fluid GABA levels,%6 to date there have been no in vivo studies, to our knowledge, evaluating brain GABA levels in this patient population. Other components of the GABA system, such as the benzodiazepine (BZD) receptor, have been implicated in the pathophysiology of panic. For instance, impaired brain GABAA/BZD receptor functioning has been directly linked to neophobic behaviors in mice,%7,8 behaviors that resemble human agoraphobia. Furthermore, a generalized cortical reduction in BZD receptor binding in patients with panic disorder was recently observed using a positron emission tomographic technique, with effects being most pronounced in the right orbitofrontal and insular cortices,%9 although, subsequently, other groups%10,11 also using positron emission tomography did not detect these abnormalities. In addition, regional cortical reductions in BZD receptor binding have been identified with single-photon emission computed tomographic techniques in frontal,%1214 temporal,%12,13 left hippocampal, precuneus,%15 and occipital%12 areas of patients with panic disorder.

We hypothesized, based on the previously mentioned observations, that there are deficits in GABA neuronal functioning in panic disorder. We therefore executed a study using a novel 1H-magnetic resonance spectroscopic (MRS) technique%16 to test whether total occipital cortex GABA levels (GABA plus homocarnosine) are abnormally reduced in panic disorder. In this study, we chose to evaluate GABA levels in an occipital cortex region of interest (ROI) because researchers%1719 have developed a reliable method to measure GABA in this location and have used it successfully to detect GABA abnormalities in other neuropsychiatric illnesses.%1719 Also, when we began the study, our ability to reliably examine other ROIs more traditionally related to anxiety (eg, the frontal cortex) was limited because of technical issues (patient immobilization, shimming adjacent to the sinuses, and variable head shape in the frontal regions). Finally, the imaging literature, although consistently implicating frontal areas in panic, also suggests that more generalized cortical GABA abnormalities could be present.

PARTICIPANTS

This study was conducted at the Yale Anxiety Clinic and the Yale Magnetic Resonance Center, New Haven, Conn. Most patients (12 of 14) responded to paid advertisements in local newspapers and on television; patient 3 was self-referred and patient 9 was a clinic referral (Table 1). After a psychiatric evaluation performed by a research psychiatrist (A.W.G. or A.A.), patients were informed of the study rationale and procedures. All patients gave their written informed consent to participate and received their own copy of the Yale institutional review board–approved informed consent document.

Table Graphic Jump LocationOccipital Cortex γ-Aminobutyric Acid (GABA) Levels in Patients With Panic Disorder and Control Subjects

We studied 14 outpatients with panic disorder (8 women and 6 men; mean ± SD age, 37 ± 10 years) who were moderately ill judging by their mean ± SD total prescan Panic Disorder Severity Scale (PDSS)%20 score (13 ± 4; n = 13). The PDSS samples 7 symptom domains (each scored on a scale from 0-4) relevant to panic disorder, including frequency of panic symptoms, distress during panics, phobic symptoms, anticipatory anxiety, and functioning (see Shear et al%20 for a review of psychometric properties). All patients had a weekly panic attack frequency of 1 or more in the month before study entry. Baseline mean ± SD scores were as follows: Hamilton Anxiety Rating Scale (HAM-A),%21 17 ± 8 (n = 14); 25-item Hamilton Depression Rating Scale (HAM-D),%22 20 ± 10 (n = 14); 17-item HAM-D,%23 14 ± 6; and Clinician-Rated Anxiety Scale (CRAS) (contains 37 items, each rated on a scale from 0-4, covering panic attacks, phobias, and many symptoms of generalized anxiety),%24,25 31 ± 16 (n = 14). All patients had normal physical examination findings and normal results on follow-up tests, including urine toxicology, urinalysis, electrocardiogram, serum electrolytes and glucose, liver and thyroid function tests, blood cell count and serum gonadotrophin levels (for women), and human immunodeficiency virus testing. Of the women, 1 was menopausal, 1 was perimenopausal, 3 were at the end of their menstrual cycle just before the scan, 1 was midcycle, 1 was in the first half of the cycle, and 1 was in the second half of the cycle. Patients met DSM-IV criteria%26 for a current principal diagnosis of panic disorder with or without agoraphobia. The panic diagnosis was confirmed using a semistructured interview (either the Anxiety Disorders Interview Schedule DSM-IV version%27 or the Structured Clinical Interview for DSM-IV%28) administered by experienced research personnel under the supervision of the principal investigator (A.W.G.).

Patients with a lifetime history of a psychotic disorder, a bipolar disorder, major depressive disorder, obsessive-compulsive disorder, an eating disorder, posttraumatic stress disorder, alcohol dependence, or a major personality disorder were excluded. In addition, patients were excluded if they had had a substance abuse disorder within 6 months of the diagnostic interview. Patients 2, 9, and 14 (Table 1) were smokers (>10 cigarettes per day). Patient 11 had a probable comorbid somatoform disorder (conversion disorder), and patient 8 carried an additional diagnosis of social phobia–specific subtype. Of 14 patients studied, 9 were medication naive (patients 1, 4, 5, 7, 10, 11, 12, 13, and 14). Of the remaining 5 patients, 2 had discontinued medication use 3 months before study entry (patient 9 was taking desipramine hydrochloride and clonazepam and patient 6 was taking sertraline hydrochloride and clonazepam) and 3 were taking occasional as-needed doses of short-acting BZD medications (patients 3 and 10 were taking 0.25- and 0.5-mg tablets of alprazolam, respectively, and patient 2 was taking one half of a 0.5-mg tablet of clonazepam). The 3 patients who had taken medications as needed were completely medication free for at least 1 week before the first MRS scan.

Control subjects (in good physical health and medication free) were part of the Yale Magnetic Resonance Center's control database of 30 subjects. They had no lifetime history of psychiatric illness by clinical assessment. Structured Clinical Interview evaluations were not conducted on controls. Controls were paired with patients retrospectively based on sex and age. Complete sex matching was accomplished, and we attempted to ensure that patient-control pairs were close in age (mean ± SD age difference in the 14 patient-control pairs, 4 ± 4 years). The mean ± SD time between matched control and patient scans was 6 ± 4 months, with control scans generally occurring before patient scans. Recruitment and assessment procedures for controls and patients remained constant during MR data acquisition (27 months). Controls were recruited from flyers placed in the Yale Medical Center.

SPECTROSCOPIC AND IMAGING PROCEDURES

We used a parallel-group design to test whether unmedicated patients with panic disorder had lower occipital cortical total GABA levels (cortical GABA plus homocarnosine, a GABA-containing dipeptide) than retropsectively age- and sex-matched controls. Each patient and control subject underwent an MRS scan (lasting approximately 1.5 hours). The concentration of GABA was measured by comparing the integrated GABA resonance from the MRS edited spectrum with the integrated creatine resonance obtained during the same scan.

A trained research assistant or registered nurse under supervision of the principal investigator accompanied the patient throughout the MRS test (approximately 1.5 hours). The imaging and spectroscopy work was conducted at Yale Magnetic Resonance Center using a 2.1-T, 1-m bore magnet (Oxford Magnet Technologies, Oxford, England) with a spectrometer (Bruker Avance Biospec; Bruker Instruments, Billericay, Mass) and actively shielded magnetic field gradients (Oxford Magnetic Technologies). A workstation (Silicon Graphics Inc, Chippewa Falls, Wis) was used for image and spectroscopic analysis.

Before spectroscopy, T1-weighted, gradient echo magnetic resonance images were taken to select a 13.5-cm3 (1.5 × 3.0 × 3.0-cm) volume in the occipital cortex for MRS. The 1.5-cm dimension was along the axis that was perpendicular to the surface coil plane, and the volume was centered 1.5-cm deep to the dura mater. For each ROI, approximately 95% of the nuclear magnetic resonance signal was derived from the voxel selected. The occipital ROI was centered on the midline, included the visual cortex (on the left and right sides), and was identical to the ROI used in previous works.%16,19 Participants lay supine on a pallet with their occiput resting next to an 8-cm radiofrequency surface coil tuned to the 1H-nuclear magnetic resonance frequency of 89.43 MHz. An automated shimming protocol was used to maximize B0 field uniformity in the ROI.%29 Three-dimensional localization of the sensitive volume was accomplished by means of an image-selected in vivo spectroscopy sequence (comprising 8-millisecond phase-swept, hyperbolic secant inversion pulses, µ = 5; bandwidth, 2000 Hz). Water suppression was achieved by an 80-millisecond hyperbolic secant-selective inversion pulse and a semiselective refocusing pulse (90° pulse; duration, 120 microseconds).%16 Other spectral acquisition parameters for collection of GABA data included a sweep width of 2500 Hz, an acquisition time of 510 milliseconds, a repetition time of 3.39 seconds, and an echo time of 68 milliseconds.

GABA Editing Procedure

A homonuclear J-editing procedure was used to separate the GABA C4 triplet resonance at 3.0 ppm from overlapping resonances. This was done by applying a 26.5-millisecond DANTE (Delays-Alternating with Nutations-for Tailored Excitation) inversion pulse to the 1.9-ppm C3 GABA multiplet resonance.%16 Subtraction of a spectrum acquired with the DANTE pulse from one in which the DANTE pulse was not applied provided the edited spectrum that reflected total cortical GABA levels.

Cortical GABA Measurement

The C4 GABA resonance from the edited spectrum was integrated and compared with an integrated creatine resonance (3.03 ppm) obtained during the same acquisition. In vivo time domain data were zero filled to 32K and multiplied by a 3-Hz exponential function before Fourier transformation. In the edited spectrum, the C4 GABA resonance was integrated over a 0.30-ppm bandwidth centered over 3.0 ppm. The creatine signal was integrated over a 0.2-ppm bandwidth centered at 3.0 ppm of the GABA-inverted spectrum. Cortical GABA concentrations were calculated from the following formula, which compares the integrated GABA resonance from the MRS edited spectrum with the integrated creatine resonance%16:

where G* is the GABA integral in the edited spectrum, Cr* is the creatine integral, M is the contribution of macromolecule resonances at 3.0 ppm, ICF is a correction factor for the limited integral bandwidths determined from localized edited spectra of solutions of GABA and creatine line broaded to match the in vivo processed line widths, EE is a correction factor for loss of signal intensity during the editing procedure, 3/2 is the creatine-GABA proton ratio, and [Cr] is the concentration of creatine in the human occipital cortex (average cortical concentration, 9 mmol/kg).

The correction factors ICF and EE were obtained by subjecting a GABA solution in an 11.5-cm bottle to the same localization and editing procedure used in vivo. The GABA signal from the cortex was also calibrated by comparison with phantoms containing known solutions of GABA and creatine (the phantom studies were designed to simulate in vivo coil loading).%16 Integration of GABA over a 0.3-ppm bandwidth was based on the assumption that the GABA line shape was constant. The assumption was validated based on the creatine line width, which was measured to vary by less than 1 Hz between studies. Measurements of pure GABA and creatine levels in solution show that small changes in line width have a minimal effect on the relative integrals.

STATISTICAL ANALYSIS

Nonparametric statistical procedures were used for all analyses. Paired tests were performed for all between-group analyses because the control sample had been carefully age and sex matched to the patient sample. The primary analysis, testing for a patient-control difference in cortical GABA levels, used the Wilcoxon signed rank test. Other subgroup analyses comparing groups on some clinical and demographic characteristics also used this test. Within-group Spearman correlational analyses were performed to determine whether cortical GABA levels were associated with measures of clinical illness severity, such as the HAM-A, PDSS, HAM-D, and CRAS, as well as to examine whether age correlated with cortical GABA levels in either group. The α level for all statistical analyses was set at .05, and all tests were 2-tailed. Values are expressed as mean ± SD.

EFFECT OF PANIC DIAGNOSIS ON TOTAL CORTICAL GABA LEVELS

Inspection of the cortical GABA raw scores revealed that 12 of 14 patients with panic disorder had lower occipital cortex GABA levels compared with their matched controls (Table 1). Sex matching was perfect and age matching was good. The effect of diagnosis on cortical GABA level was statistically significant, with a 22% reduction in mean GABA levels in patients with panic disorder vs controls (1.38 ± 0.38 vs 1.77 ± 0.35 mmol/kg; Wilcoxon W = −75.0, n = 14 pairs; P<.02) (see Figure 1 for examples of representative spectra from a patient and a nonpaired control). There was no significant effect of sex on cortical GABA levels (women, 1.64 ± 0.47 mmol/kg; men, 1.49 ± 0.31 mmol/kg; Mann-Whitney U26 = 76.5; P = .37). However, women panickers vs controls (GABA level, 1.39 ± 0.43 vs 1.89 ± 0.38 mmol/kg; W = −30, n = 8 pairs; P = .04) had a statistically significant reduction in occipital cortex GABA concentration compared with men vs controls (GABA level, 1.35 ± 0.32 vs 1.61 ± 0.26 mmol/kg; W = −11, n = 6 pairs; P = .31). Age did not correlate with cortical GABA levels in either patients (n = 14; r = −0.09; P = .8) or controls (n = 14; r = −0.28; P = .34). A statistically significant reduction in patient GABA levels relative to controls remained (W = −60, n = 12 pairs; P<.02) despite removal of 2 patient-control pairs (pairs 4 and 5) from the Wilcoxon analysis who were not closely age matched. Inspection of a subgroup of medication-naive patients with panic disorder (patients 1, 4, 5, 7, and 10-14) indicated that 7 of 9 had lower GABA levels compared with controls (1.39 ± 0.47 vs 1.85 ± 0.4 mmol/kg; W = −33, n = 9 pairs; P = .055).

Place holder to copy figure label and caption

Representative γ-aminobutyric acid (GABA) spectra from a control subject and a patient with panic disorder (not paired). Top 2 traces, Subtraction spectra (control and patient) highlighting the GABA peaks. Bottom 2 traces, Control spectra with and without application of the DANTE (Delays-Alternating with Nutations-for Tailored Excitation) pulse. Cho indicates choline; Cr, creatine; NAA, N-acetylaspartate; and diff, difference.

Graphic Jump Location
OTHER CLINICAL VARIABLES AND TOTAL CORTICAL GABA LEVELS

To examine possible associations between cortical GABA levels and some illness severity measures (HAM-A, HAM-D, PDSS, and CRAS), we performed Spearman correlations on the patient data. The following correlation coefficients were observed: for GABA levels and the HAM-A, r = 0.35, n = 14, P = .23; the HAM-D, r = 0.29, n = 14, P = .32; the PDSS, r = 0.28, n = 13, P = .36; and the CRAS, r = 0.27, n = 14, P = .34. A modest positive correlation was observed between cortical GABA concentration and degree of agoraphobia, as measured on PDSS item 4 (r = 0.56; n = 13; P = .048). However, this finding did not remain statistically significant after Bonferroni correction. Finally, we found no significant association between prescan state anxiety (as measured on a visual analogue scale of anxious mood from 0-100 mm) and cortical GABA levels (r = −0.03; n = 13; P = .9).

MEASUREMENTS OF THE REFERENCE METABOLITE, CREATINE

We did not systematically collect additional short echo spectra for analysis of creatine, water, and other metabolites in our study sample. However, we have these data for patients 8 and 12 and controls 4, 13, and 14. Creatine values of 9.0 mmol/kg were observed in each case. Thus, these limited data suggested that creatine levels were similar between groups and similar to those reported in the literature.%30

We observed abnormally reduced total occipital cortex GABA levels in a sample of unmedicated patients with panic disorder who did not have major depression, adding support to preclinical and clinical evidence suggesting that deficits in GABA function contribute to the pathophysiologic process of panic. The finding was relatively consistent, with 12 of 14 patients having lower GABA levels than their respective matched controls. The result was not fully explained by previous medication exposure. Women with panic disorder seemed to have more pronounced reductions in cortical GABA levels than men in our sample, although the significance of this finding is uncertain because it might be more related to sample size.

There are several limitations of the present study that merit additional comment. First, we used a retrospective control group, which limited our ability to match for variables such as age and, in females, phase of the menstrual cycle, both of which might affect central nervous system GABA levels.%31,32 Follow-up studies should more carefully control for these variables by assessing control groups prospectively.

Second, we obtained data from a single occipital cortex ROI and therefore cannot say at this point whether our observation is limited to certain cortical regions or present throughout the cortex.

Third, in most of our sample, we did not apply a segmentation procedure to adjust our GABA measurements based on the percentage of gray matter per voxel of interest. However, we obtained this information systematically for the last 3 patient-control pairs using a method devised by our group.%33 The mean percentage of gray matter per voxel in these patient scans was 61% compared with 63% in controls (as determined from quantitative images of the T1 relaxation constant of tissue water). Thus, these pilot data suggest that the reduction in GABA is not due to reduced cortical gray matter content. However, subsequent studies are benefiting from the systematic application of segmentation protocols.

Fourth, the related compound, homocarnosine (GABA plus a histidine residue),%34 is coresonant with GABA and was not assessed in this study. Thus, the observed changes could be related to changes in the central nervous system level of homocarnosine in panic. Homocarnosine is of particular interest because of its potential neuromodulatory role in the central nervous system.%35

Fifth, we determined the concentration of cortical GABA by reference to total creatine level (creatine plus phosphocreatine). Although this is a common method of quantification in MRS, changes in creatine levels would alter the GABA measurements. However, total cortical GABA levels determined by our MRS technique%16 compare favorably to GABA levels determined using standard chemical assays of postmortem brain tissue and brain biopsy tissue in animals and humans.%36,37 The GABA transaminase inhibitor vigabatrin produces marked amplification of the GABA MRS signal in animals and humans, as expected.%38,39 Magnetic resonance spectroscopic measurements of occipital cortex GABA levels in healthy humans performed by the University of Alabama group,%40 with a highly sensitive 4-T magnet, compared favorably with the data our group has already generated. Further validity and reliability%41 studies are ongoing.

If replicated, the low occipital cortex GABA finding is likely to have implications for our understanding of the relationship between panic and other neuropsychiatric disorders. Recently, abnormally low occipital cortex GABA levels were observed in depressed patients.%19 Therefore, the low cortical GABA concentration observed in this study might be a nonspecific finding reflecting a history of neuropsychiatric disease. However, it is notable, in this regard, that our group has not observed low occipital cortex GABA levels in schizophrenia (W. Abi-Saab, MD, unpublished data, 2000) or in patients with bipolar depression.%42 Alternatively, low cortical GABA concentration could be a traitlike abnormality that predisposes to a variety of behavioral disturbances (depression, panic disorder, and alcoholism). Another possibility is that low cortical GABA levels are associated with distinct pathophysiologic processes (eg, panic disorder, depression, epilepsy, and alcoholism). Follow-up investigations are indicated to discriminate among these possibilities. Attention to the prescan medication-free period (>4 weeks; including no as-needed medications), to protect against the potentially confounding effects of medication withdrawal syndromes, and the within-scan acquisition of other informative metabolite measurements (eg, creatine, choline, N-acetylaspartate, glutamate, and homocarnosine) will add to the quality of future studies.

Accepted for publication January 22, 2001.

This work was supported by grants NIMH K-08 MH-01322 and R01 MH-58657 (Dr Goddard); grant NIMH MH-30929 (Mental Health Clinical Research Center at Yale, New Haven, Conn) (Drs Goddard, Krystal, and Mason); the Department of Veterans Affairs VA–Yale Alcohol Research Center and National Center for PTSD, West Haven, Conn (Dr Krystal); grants NIAAA K02 1 AA00261-01 (Dr Krystal), NINDS R01-N53218 (Dr Petroff), R29-N5032126 (Dr Rothman), and R01-NS34813 (Dr Behar); and by the Connecticut Department of Mental Health and Addiction Services, Hartford.

Presented in part at the 8th International Society for Magnetic Resonance in Medicine Meeting, Philadelphia, Pa, May 25, 1999.

We thank the staff of the Yale Anxiety Clinic and Program for their contributions to this work.

Corresponding author and reprints: Andrew W. Goddard, MD, Yale Anxiety Clinic, Yale Department of Psychiatry, 100 York St, Room 2J, New Haven, CT 06511 (e-mail: andrew.goddard@yale.edu).

Shekhar  AKeim  SRSimon  JRMcBride  WJ Dorsomedial hypothalamic GABA dysfunction produces physiological arousal following sodium lactate infusions. Pharmacol Biochem Behav. 1996;55249- 256
Link to Article
Dalvi  ARodgers  RJ GABAergic influences on plus-maze behaviour in mice. Psychopharmacology (Berl). 1996;128380- 397
Link to Article
Sherif  FOreland  L Effect of the GABA-transaminase inhibitor vigabatrin on exploratory behaviour in socially isolated rats. Behav Brain Res. 1995;72135- 140
Link to Article
Roy-Byrne  PPCowley  DSHommer  DGreenblatt  DJKramer  GLPetty  F Effect of acute and chronic benzodiazepines on plasma GABA in anxious patients and controls. Psychopharmacology. 1992;109153- 156
Link to Article
Goddard  AWNarayan  MWoods  SWGermine  MKramer  GLDavis  LLPetty  F Plasma levels of γ-aminobutyric acid and panic disorder. Psychiatry Res. 1996;63223- 225
Link to Article
Rimon  RLepola  UJolkkonen  JHalonen  TReikkinen  P Cerebrospinal fluid γ-aminobutyric acid in patients with panic disorder. Biol Psychiatry. 1995;38737- 741
Link to Article
Gunther  UBenson  JBenke  DFritschy  JMReyes  GKnoflach  FCrestani  FAguzzi  AArigoni  MLang  Y Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of γ-aminobutyric acid type A receptors. Proc Natl Acad Sci U S A. 1995;927749- 7753
Link to Article
Crestani  FLorez  MBaer  KEssrich  CBenke  DLaurent  JPBelzung  CFritschy  JMLuscher  BMohler  H Decreased GABAA receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci. 1999;2833- 839
Link to Article
Malizia  ALCunningham  VJBell  CJLiddle  PFJones  TNutt  DJ Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry. 1998;55715- 720
Link to Article
Abadie  PBoulenger  JPBenali  KBarre  LZarifian  EBaron  JC Relationships between trait and state anxiety and the central benzodiazepine receptor: a PET study. Eur J Neurosci. 1999;111470- 1478
Link to Article
Cameron  OHuang  GFrey  KMinoshima  SRose  D Brain benzodiazepine binding sites in panic disorder. Neuroimage. 2000;11 ((5, pt 2)) S185
Link to Article
Schlegel  SSteinert  HBockisch  AHahn  KSchloesser  RBenkert  O Decreased benzodiazepine receptor binding in panic disorder measured by IOMAZENIL-SPECT: a preliminary report. Eur Arch Psychiatry Clin Neurosci. 1994;24449- 51
Link to Article
Kaschka  WFeistel  HEbert  D Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. J Psychiatr Res. 1995;29427- 434
Link to Article
Kuikka  JTPitkanen  ALepola  UPartanen  KVainio  PBergstrom  KAWieler  HJKaiser  KPMittelbach  LKoponen  H Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nucl Med Commun. 1995;16273- 280
Link to Article
Bremner  JDInnis  RBWhite  TFujita  MSilbersweig  DGoddard  AWStaib  LStern  ECappiello  AWoods  SBaldwin  RCharney  DS SPECT-[I-123] iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry. 2000;4796- 106
Link to Article
Rothman  DLPetroff  OACNovotny  EJPrichard  JWShulman  RG Localized 1H NMR measurements of γ amino butyric acid in human brain in vivo. Proc Natl Acad Sci U S A. 1993;90562- 566
Link to Article
Petroff  OARothman  DLBehar  KLMattson  RH Low brain GABA level is associated with poor seizure control. Ann Neurol. 1996;40908- 911
Link to Article
Behar  KLRothman  DLPetersen  KFHooten  MDelaney  RPetroff  OAShulman  GINavarro  VPetrakis  ILCharney  DSKrystal  JH Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients. Am J Psychiatry. 1999;156952- 954
Sanacora  GMason  GFRothman  DLBehar  KLHyder  FPetroff  OABerman  RMCharney  DSKrystal  JH Reduced cortical γ-aminobutyric acid levels in depressed patients determined by 1H-magnetic resonance spectroscopy. Arch Gen Psychiatry. 1999;561043- 1047
Link to Article
Shear  MKBrown  TABarlow  DHMoney  RSholomskas  DEWoods  SWGorman  JMPapp  LA Multicenter collaborative Panic Disorder Severity Scale. Am J Psychiatry. 1997;1541571- 1575
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol. 1959;3250- 55
Link to Article
Mazure  CNelson  JCPrice  LH Reliability and validity of the symptoms of major depressive illness. Arch Gen Psychiatry. 1986;43451- 456
Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Sheehan  DV The Anxiety Disease.  New York, NY Bantam Books1986;
Albus  MMaier  WShera  DBech  P Consistencies and discrepancies in self- and observer-rated anxiety scales. Eur Arch Psychiatry Clin Neurosci. 1990;24096- 102
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
DiNardo  PABrown  TABarlow  DH Anxiety Disorders Interview Schedule: Lifetime Version (ADIS-IV-L).  Albany, NY Phobia and Anxiety Disorders Clinic1994;
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders–Patient Edition (SCID-I/P, Version 2.0).  New York Biometrics Research Dept, New York State Psychiatric Institute1995;
Shen  JRycyna  RERothman  DL Improvements on an in vivo automatic shimming method [FASTERMAP]. Magn Reson Med. 1997;38834- 839
Link to Article
Kreis  RErnst  TRoss  BD Absolute quantitation of water and metabolites in the human brain, II: metabolite concentrations. J Magn Reson. 1993;B1029- 19
Link to Article
Brot  MDAkwa  YPurdy  RHKoob  GFBritton  KT The anxiolytic-like effects of the neurosteroid allopregnanolone: interactions with GABA(A) receptors. Eur J Pharmacol. 1997;3251- 7
Link to Article
Epperson  CNMason  GRothman  DRSanacora  GKrystal  JH GABA dysregulation in premenstrual dysphoric disorder.  Abstract presented at: 29th Annual Meeting of the Society for Neuroscience October 23-28, 1999 Miami Beach, Fla.Abstract 887.1.
Mason  GF T1-based segmentation of brain tissue with a surface coil.  Proceedings of the Seventh Annual Meeting of the International Society for Magnetic Resonance in Medicine May 22-28, 1999 Philadelphia, Pa1999a;123
Rothman  DLBehar  KLPrichard  JWPetroff  OA Homocarnosine and the measurement of neuronal pH in patients with epilepsy. Magn Reson Med. 1997;38924- 929
Link to Article
Petroff  OAHyder  FCollins  TMattson  RHRothman  DL Acute effects of vigabatrin on brain GABA and homocarnosine in patients with complex partial seizures. Epilepsia. 1999;40958- 964
Link to Article
Perry  THansen  SGandham  SS Postmortem changes of amino acid compounds in human and rat brain. J Neurochem. 1981;36406- 410
Link to Article
Petroff  OASpencer  DDAlger  JRPritchard  JW High-field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy. Neurology. 1989;391197- 1202
Link to Article
Manor  DRothman  DLMason  GFHyder  FPetroff  OABehar  KL The rate of turnover of cortical GABA from [1-13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA). Neurochem Res. 1996;211031- 1041
Link to Article
Petroff  OARothman  DLBehar  KLCollins  TLMattson  RH Human brain GABA levels rise rapidly after initiation of vigabatrin therapy. Neurology. 1996;471567- 1571
Link to Article
Kuzniecky  RHetherington  HHo  SPan  JMartin  RGilliam  FHugg  JFaught  E Topiramate increases cerebral GABA in healthy humans. Neurology. 1998;51627- 629
Link to Article
Petroff  OACHyder  FMattson  RHRothman  DL Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy. Neurology. 1999;52473- 478
Link to Article
Mason  GFSanacora  GAnand  AEpperson  CNGoddard  AWRothman  DLCharney  DSKrystal  JH Cortical GABA differs in unipolar and bipolar depression.  Proceedings of the 38th Annual Meeting of the American College of Neuropsychopharmacology December 12-16, 1999 Acapulco, Mexico.1999b;101

Figures

Place holder to copy figure label and caption

Representative γ-aminobutyric acid (GABA) spectra from a control subject and a patient with panic disorder (not paired). Top 2 traces, Subtraction spectra (control and patient) highlighting the GABA peaks. Bottom 2 traces, Control spectra with and without application of the DANTE (Delays-Alternating with Nutations-for Tailored Excitation) pulse. Cho indicates choline; Cr, creatine; NAA, N-acetylaspartate; and diff, difference.

Graphic Jump Location

Tables

Table Graphic Jump LocationOccipital Cortex γ-Aminobutyric Acid (GABA) Levels in Patients With Panic Disorder and Control Subjects

References

Shekhar  AKeim  SRSimon  JRMcBride  WJ Dorsomedial hypothalamic GABA dysfunction produces physiological arousal following sodium lactate infusions. Pharmacol Biochem Behav. 1996;55249- 256
Link to Article
Dalvi  ARodgers  RJ GABAergic influences on plus-maze behaviour in mice. Psychopharmacology (Berl). 1996;128380- 397
Link to Article
Sherif  FOreland  L Effect of the GABA-transaminase inhibitor vigabatrin on exploratory behaviour in socially isolated rats. Behav Brain Res. 1995;72135- 140
Link to Article
Roy-Byrne  PPCowley  DSHommer  DGreenblatt  DJKramer  GLPetty  F Effect of acute and chronic benzodiazepines on plasma GABA in anxious patients and controls. Psychopharmacology. 1992;109153- 156
Link to Article
Goddard  AWNarayan  MWoods  SWGermine  MKramer  GLDavis  LLPetty  F Plasma levels of γ-aminobutyric acid and panic disorder. Psychiatry Res. 1996;63223- 225
Link to Article
Rimon  RLepola  UJolkkonen  JHalonen  TReikkinen  P Cerebrospinal fluid γ-aminobutyric acid in patients with panic disorder. Biol Psychiatry. 1995;38737- 741
Link to Article
Gunther  UBenson  JBenke  DFritschy  JMReyes  GKnoflach  FCrestani  FAguzzi  AArigoni  MLang  Y Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of γ-aminobutyric acid type A receptors. Proc Natl Acad Sci U S A. 1995;927749- 7753
Link to Article
Crestani  FLorez  MBaer  KEssrich  CBenke  DLaurent  JPBelzung  CFritschy  JMLuscher  BMohler  H Decreased GABAA receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci. 1999;2833- 839
Link to Article
Malizia  ALCunningham  VJBell  CJLiddle  PFJones  TNutt  DJ Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry. 1998;55715- 720
Link to Article
Abadie  PBoulenger  JPBenali  KBarre  LZarifian  EBaron  JC Relationships between trait and state anxiety and the central benzodiazepine receptor: a PET study. Eur J Neurosci. 1999;111470- 1478
Link to Article
Cameron  OHuang  GFrey  KMinoshima  SRose  D Brain benzodiazepine binding sites in panic disorder. Neuroimage. 2000;11 ((5, pt 2)) S185
Link to Article
Schlegel  SSteinert  HBockisch  AHahn  KSchloesser  RBenkert  O Decreased benzodiazepine receptor binding in panic disorder measured by IOMAZENIL-SPECT: a preliminary report. Eur Arch Psychiatry Clin Neurosci. 1994;24449- 51
Link to Article
Kaschka  WFeistel  HEbert  D Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. J Psychiatr Res. 1995;29427- 434
Link to Article
Kuikka  JTPitkanen  ALepola  UPartanen  KVainio  PBergstrom  KAWieler  HJKaiser  KPMittelbach  LKoponen  H Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nucl Med Commun. 1995;16273- 280
Link to Article
Bremner  JDInnis  RBWhite  TFujita  MSilbersweig  DGoddard  AWStaib  LStern  ECappiello  AWoods  SBaldwin  RCharney  DS SPECT-[I-123] iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry. 2000;4796- 106
Link to Article
Rothman  DLPetroff  OACNovotny  EJPrichard  JWShulman  RG Localized 1H NMR measurements of γ amino butyric acid in human brain in vivo. Proc Natl Acad Sci U S A. 1993;90562- 566
Link to Article
Petroff  OARothman  DLBehar  KLMattson  RH Low brain GABA level is associated with poor seizure control. Ann Neurol. 1996;40908- 911
Link to Article
Behar  KLRothman  DLPetersen  KFHooten  MDelaney  RPetroff  OAShulman  GINavarro  VPetrakis  ILCharney  DSKrystal  JH Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients. Am J Psychiatry. 1999;156952- 954
Sanacora  GMason  GFRothman  DLBehar  KLHyder  FPetroff  OABerman  RMCharney  DSKrystal  JH Reduced cortical γ-aminobutyric acid levels in depressed patients determined by 1H-magnetic resonance spectroscopy. Arch Gen Psychiatry. 1999;561043- 1047
Link to Article
Shear  MKBrown  TABarlow  DHMoney  RSholomskas  DEWoods  SWGorman  JMPapp  LA Multicenter collaborative Panic Disorder Severity Scale. Am J Psychiatry. 1997;1541571- 1575
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol. 1959;3250- 55
Link to Article
Mazure  CNelson  JCPrice  LH Reliability and validity of the symptoms of major depressive illness. Arch Gen Psychiatry. 1986;43451- 456
Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Sheehan  DV The Anxiety Disease.  New York, NY Bantam Books1986;
Albus  MMaier  WShera  DBech  P Consistencies and discrepancies in self- and observer-rated anxiety scales. Eur Arch Psychiatry Clin Neurosci. 1990;24096- 102
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
DiNardo  PABrown  TABarlow  DH Anxiety Disorders Interview Schedule: Lifetime Version (ADIS-IV-L).  Albany, NY Phobia and Anxiety Disorders Clinic1994;
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders–Patient Edition (SCID-I/P, Version 2.0).  New York Biometrics Research Dept, New York State Psychiatric Institute1995;
Shen  JRycyna  RERothman  DL Improvements on an in vivo automatic shimming method [FASTERMAP]. Magn Reson Med. 1997;38834- 839
Link to Article
Kreis  RErnst  TRoss  BD Absolute quantitation of water and metabolites in the human brain, II: metabolite concentrations. J Magn Reson. 1993;B1029- 19
Link to Article
Brot  MDAkwa  YPurdy  RHKoob  GFBritton  KT The anxiolytic-like effects of the neurosteroid allopregnanolone: interactions with GABA(A) receptors. Eur J Pharmacol. 1997;3251- 7
Link to Article
Epperson  CNMason  GRothman  DRSanacora  GKrystal  JH GABA dysregulation in premenstrual dysphoric disorder.  Abstract presented at: 29th Annual Meeting of the Society for Neuroscience October 23-28, 1999 Miami Beach, Fla.Abstract 887.1.
Mason  GF T1-based segmentation of brain tissue with a surface coil.  Proceedings of the Seventh Annual Meeting of the International Society for Magnetic Resonance in Medicine May 22-28, 1999 Philadelphia, Pa1999a;123
Rothman  DLBehar  KLPrichard  JWPetroff  OA Homocarnosine and the measurement of neuronal pH in patients with epilepsy. Magn Reson Med. 1997;38924- 929
Link to Article
Petroff  OAHyder  FCollins  TMattson  RHRothman  DL Acute effects of vigabatrin on brain GABA and homocarnosine in patients with complex partial seizures. Epilepsia. 1999;40958- 964
Link to Article
Perry  THansen  SGandham  SS Postmortem changes of amino acid compounds in human and rat brain. J Neurochem. 1981;36406- 410
Link to Article
Petroff  OASpencer  DDAlger  JRPritchard  JW High-field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy. Neurology. 1989;391197- 1202
Link to Article
Manor  DRothman  DLMason  GFHyder  FPetroff  OABehar  KL The rate of turnover of cortical GABA from [1-13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA). Neurochem Res. 1996;211031- 1041
Link to Article
Petroff  OARothman  DLBehar  KLCollins  TLMattson  RH Human brain GABA levels rise rapidly after initiation of vigabatrin therapy. Neurology. 1996;471567- 1571
Link to Article
Kuzniecky  RHetherington  HHo  SPan  JMartin  RGilliam  FHugg  JFaught  E Topiramate increases cerebral GABA in healthy humans. Neurology. 1998;51627- 629
Link to Article
Petroff  OACHyder  FMattson  RHRothman  DL Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy. Neurology. 1999;52473- 478
Link to Article
Mason  GFSanacora  GAnand  AEpperson  CNGoddard  AWRothman  DLCharney  DSKrystal  JH Cortical GABA differs in unipolar and bipolar depression.  Proceedings of the 38th Annual Meeting of the American College of Neuropsychopharmacology December 12-16, 1999 Acapulco, Mexico.1999b;101

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 130

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections