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Subtype-Specific Alterations of ␥-Aminobutyric Acid and Glutamate in Patients with Major Depression

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Subtype-Specific Alterations of ␥-Aminobutyric Acid and Glutamate in Patients with Major Depression ORIGINAL ARTICLE Subtype-Specific Alterations of ␥-Aminobutyric Acid and Glutamate in Patients With Major Depression Gerard Sanacora, MD, PhD; Ralitza Gueorguieva, PhD; C. Neill Epperson, MD; Yu-Te Wu, MPH; Michael Appel, MS; Douglas L. Rothman, PhD; John H. Krystal, MD; Graeme F. Mason, PhD Background: Measurement of cortical ␥-aminobu- atine, and choline-containing compounds, along with sev- tyric acid (GABA) and glutamate concentrations is pos- eral measures of tissue composition, were compared sible using proton magnetic resonance spectroscopy. An between the 2 groups. initial report, using this technique, suggested that oc- cipital cortex GABA concentrations are reduced in pa- Results: Depressed subjects had significantly lower oc- tients with major depressive disorder (MDD) relative to cipital cortex GABA concentrations compared with healthy healthy comparison subjects. controls (P=.01). In addition, mean glutamate levels were significantly increased in depressed subjects compared with Objectives: To replicate the GABA findings in a larger healthy controls (PϽ.001). Significant reductions in the sample of MDD patients, to examine the clinical corre- percentage of solid tissue (P=.009) and the percentage of lates of the GABA reductions in these subjects, and to white matter (P=.04) in the voxel were also observed. An examine other critical metabolite levels. examination of a combined database including subjects from the original study suggests that GABA and gluta- Design: Study for association. mate concentrations differ among MDD subtypes. Setting: Academic clinical research program. Conclusions: The study replicates the findings of de- creased GABA concentrations in the occipital cortex of Participants: The GABA measurements were made on subjects with MDD. It also demonstrates that there is a 38 healthy control subjects and 33 depressed subjects. change in the ratio of excitatory-inhibitory neurotrans- mitter levels in the cortex of depressed subjects that may Interventions: Occipital cortex metabolite levels be related to altered brain function. Last, the combined were measured using proton magnetic resonance spec- data set suggests that magnetic resonance spectroscopy troscopy. GABA measures may serve as a biological marker for a subtype of MDD. Main Outcome Measures: The levels of occipital cor- tex GABA, glutamate, N-acetylaspartate, aspartate, cre- Arch Gen Psychiatry. 2004;61:705-713 EVERAL LINES OF EVIDENCE cently been used to demonstrate reduced from animal and human stud- occipital cortex GABA concentrations in ies suggest that the ␥-amino- a sample of severely depressed subjects.13 butyric acid (GABA) system Other recent studies14,15 demonstrating that contributes to the neurobio- treatment of depression with electrocon- Slogical features underlying major depres- vulsive therapy or selective serotonin re- sive disorder (MDD). This subject has been uptake inhibitor agents increases occipi- examined by several researchers.1-5 Collec- tal cortex GABA concentrations in MDD tively, the studies suggest MDD is associ- patients suggest that GABA abnormali- From the Departments of ated with deficits in GABAergic function. ties may be normalized following treat- Psychiatry (Drs Sanacora, This hypothesis has been clearly sup- ment. If reproducible, these findings sig- Gueorguieva, Epperson, ported by consistent findings of reduced nificantly strengthen the association Krystal, and Mason), GABA content in the plasma and cerebro- between impaired GABAergic function and Epidemiology and Public spinal fluid of depressed individuals rela- MDD, and may provide a novel perspec- Health (Dr Gueorguieva and 6-12 Ms Wu), and Diagnostic tive to comparison subjects. tive into the pathophysiological pro- Radiology (Mr Appel and Consistent with reports of wide- cesses related to MDD. The primary ob- Drs Rothman and Mason), Yale spread reductions in GABA content, in vivo jectives of this study were as follows: (1) University School of Medicine, proton magnetic resonance spectroscopy to replicate the original findings of re- New Haven, Conn. (hydrogen 1 [1H]–MRS) has more re- duced GABA levels in the occipital cor- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 61, JULY 2004 WWW.ARCHGENPSYCHIATRY.COM 705 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 tex of MDD subjects in a larger sample, with a broader range the much larger and sharper creatine and choline resonances of depression severity, controlling for cortical volume and caused well-defined subtraction errors that prevented the mea- tissue composition; (2) to expand the analysis to include surement of GABA, and any pairs of subspectra with such pa- glutamate and other metabolites detectable by 1H-MRS; and tient movement were not processed further. The level of GABA (3) to explore potential clinical correlates to the differ- was determined by adding together the scans that showed no signs of patient motion. The concentration of GABA was de- ences in GABA and metabolite concentrations. termined from the ratio of GABA–total creatine resonances ac- cording to the following18: METHODS [GABA-]=(AreaGABA/AreaCreatine−0.07) ϫ(0.93ϫ1.01)ϫ(3/2)ϫ[Creatine] SUBJECTS where 0.07 was subtracted to account for the contribution of co- All subjects provided written informed consent using forms and edited macromolecules20-23 to the GABA resonance, 0.93 is the procedures approved by the Yale Human Investigations Com- integral correction factor for the difference in integration limits mittee. Forty-four depressed subjects meeting DSM-IV criteria due to the 0.03–part per million difference in the chemical shift for MDD based on the Structured Clinical Interview for DSM-IV of creatine and GABA, 1.01 corrects for the editing efficiency, Axis I Disorders: Patient Edition16 were recruited through news- and 3/2 adjusts for the difference of 2 protons detected in GABA paper advertisement and referrals from community physi- vs 3 in creatine. The concentration of creatine was 9 mmol/kg.24 cians. An active substance abuse disorder within the 6 months In 55 subjects, spectroscopic measurements of N- preceding study enrollment was considered an exclusion cri- acetylaspartate (NAA) and other metabolites were obtained in terion. Subjects who were taking medication for the treatment the same voxel. Some subjects were not able to tolerate the ad- of their depression completed a minimum 2-week medication ditional time in the scanner. The sequence was applied in pairs washout before spectroscopy, with only diphenhydramine hy- to yield subspectra that contain either macromolecules alone drochloride, 25 to 50 mg, being administered for insomnia. or macromolecules combined with the metabolites of inter- The 38 healthy control subjects had no personal, or first- est.25 Briefly, one subspectrum was acquired with a hyperbolic degree family, history of MDD or other DSM-IV diagnoses, per secant inversion pulse applied across the spectral bandwidth, interview. followed by an inversion-recovery delay to null the metabo- lites, and one subspectrum was acquired without the inver- MAGNETIC RESONANCE SPECTROSCOPY sion pulse. The macromolecule subspectrum was subtracted from the other subspectrum to obtain a spectrum of metabo- Studies were performed with a 2.1-T magnet (Oxford Magnet lites alone. The data were acquired in interleaved fashion, tog- Technology, Oxford, England) with a 1-m bore and a spec- gling between individual 48-second sets of inverted and unin- trometer (Avance; Bruker Instruments, Billerica, Mass). Sub- verted acquisitions. Each block was stored, and the sequence jects lay supine with the occipital surface of the head against a run for 20 minutes to yield 16 pairs of subspectra. The subspec- 7-cm distributed capacitance surface coil. Gradient-echo scout tra were acquired with 8000 data points in a 510-millisecond ac- images were acquired from 5-mm-thick slices, with a 1-cm cen- quisition, with a 5-second repetition time and an echo time of ter-to-center slice separation and a field of view of 240 mm di- 12 milliseconds. A scan of unsuppressed tissue water was also vided into 128ϫ128 pixels. Noniterative shimming was per- acquired to evaluate the absolute level of creatine and for eddy formed using an in vivo automatic method (FASTERMAP)17 current correction of the short-echo sequence. By using techni- in a 3.4-cm-diameter spherical volume. A 3.0ϫ3.0ϫ1.5-cm cal computing software (MATLAB), each sub-free induction de- volume was selected across the midline of the brain, centered cay was processed using a lorentzian-to-gaussian conversion of 2 cm from the dura. Localization was achieved with selective −1 and 6 Hz, Fourier transformation, spectral phasing, and sub- excitation; 3-dimensional, image-selected, in vivo spectros- traction. The peak amplitudes at 3.23, 3.03, 2.75, 2.60, 2.45, 2.29, copy; outer volume suppression; and a surface spoiler. After ad- and 2.02 parts per million were measured and deconvolved us- justing the radiofrequency power levels, a J-editing se- ing model spectra obtained in solutions of GABA, creatine, glu- quence18,19 yields pairs of subspectra that are subtracted to obtain tamate, glutamine, aspartate, and NAA to determine the metabo- the edited GABA signal. Briefly, one subspectrum was acquired lite levels relative to the resonance of total creatine, deconvolving with an inversion pulse applied to the GABA C4 proton and one GABA using its concentration from the subject’s J-edited GABA subspectrum was acquired without the
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