Am J Psychiatry 159:663-665, April 2002
© 2002 American Psychiatric Association
Increased Occipital Cortex GABA Concentrations in Depressed Patients After Therapy With Selective Serotonin Reuptake Inhibitors
Gerard Sanacora, M.D., Ph.D.,
Graeme F. Mason, Ph.D.,
Douglas L. Rothman, Ph.D., and
John H. Krystal, M.D.
|
Abstract
|
OBJECTIVE: Studies have demonstrated low concentrations of  -aminobutyric acid (GABA) in the plasma and CSF of individuals with major depression, and low GABA concentrations have also been found in the occipital cortex of depressed subjects. The goal of this study was to determine whether these occipital cortex GABA concentrations are altered after administration of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. METHOD: By means of proton magnetic resonance spectroscopy, occipital cortex GABA concentrations were measured in 11 medication-free depressed patients before initiation of treatment with SSRI medications and after an average of 2 months of treatment. RESULTS: A significant increase in occipital cortex GABA concentrations was seen after SSRI treatment. CONCLUSIONS: SSRI treatment of major depression is associated with increased occipital cortex GABA concentrations. This appears to result in a normalization of low pretreatment GABA concentrations, an effect that may contribute to a common mechanism of antidepressant action.
|
Introduction
|
Emerging evidence suggests that the -aminobutyric acid (GABA) neurotransmitter system may contribute to the pathophysiology and treatment of major depression (1). Reports demonstrating increased GABAB receptor binding in rodent brains after chronic administration of various antidepressant drugs (2) initially led to a GABA-ergic hypothesis of antidepressant drug action. Although later studies have yielded inconsistent results regarding antidepressant effects on GABAB receptor binding (3), the recent use of several anticonvulsant agents with GABA-enhancing properties in the treatment of mood disorders has renewed interest in GABA’s potential role in the treatment of mood disorders (4).
Several lines of evidence suggest that major depression is associated with impairment of GABA-ergic function. Multiple studies have shown low GABA concentrations in the plasma and CSF of depressed individuals (1). Consistent with these findings were the results of our study (5) using proton magnetic resonance spectroscopy (1H-MRS) that was technically constrained to the region of the occipital cortex, which demonstrated lower GABA concentrations in depressed patients than in healthy subjects. Preliminary results from a second study (6) suggest that these occipital GABA concentrations are higher after a course of ECT. The aim of this study was to determine whether occipital cortex GABA concentrations are also higher in depressed patients after treatment with selective serotonin reuptake inhibitor (SSRI) agents.
|
Method
|
A total of 18 subjects meeting the DSM-IV criteria for major depressive disorder, confirmed by the Structured Clinical Interview for DSM-IV, participated in the study after providing written informed consent. Subjects with a history of alcohol or substance abuse or dependence within the 6 months before the study were excluded, as were any subjects with a lifetime history of bipolar disorder, psychotic disorder, or axis II disorder. Two of the subjects had a comorbid diagnosis of panic disorder, and one had a comorbid diagnosis of social phobia. No subject received psychotropic medications for at least 2 weeks before the first 1H-MRS session. After completing the initial 1H-MRS session, each subject initiated treatment with an SSRI agent.
Eleven subjects (seven male, four female) with a mean age of 39.2 years (SD=8.5) completed the study protocol. Five subjects were not included in the analysis because it was not possible to obtain acceptable-quality spectra on one of the two MRS studies for each patient, and two subjects were not included because they were lost to follow-up before the posttreatment MRS study. Of the final 11 subjects, eight received fluoxetine (mean dose=23.8 mg/day, SD=7.9), and three received citalopram (mean dose=26.7 mg/day, SD=4.7); five patients also received yohimbine in addition to the SSRI as part of a second study. No additional psychotropic medications were allowed during the study period. After receiving the SSRIs for at least 5 weeks (mean=8.6 weeks, SD=2.7), the patients returned for the posttreatment 1H-MRS session. Scores on the Hamilton Depression Rating Scale were obtained before both 1H-MRS sessions.
Occipital cortex GABA concentrations were determined according to the methods described by us elsewhere (5, 7). Briefly, the studies were performed by using a 2.1-T Oxford magnet with a 1-m bore, equipped with a Bruker Avance spectrometer (Bruker Instruments, Billerica, Mass.). With an 8-cm radiofrequency surface coil tuned to the 1H-MRS frequency of 89.43 MHz, a 1.5x3x3-cm volume of interest was centered on the midline of the occipital cortex, 2 cm deep from the dura. Automated first- and second-order shimming was used to optimize B0 homogeneity. Homonuclear editing of the C4 GABA resonance at 3.0 parts per million (chemical shift scale) was performed by using the J-editing pulse sequence described previously (5, 7). Two subspectra of 128 scans each were subtracted to obtain a difference spectrum that isolates total GABA (combined measure of GABA and the GABA-containing dipeptide homocarnosine). Localization techniques included three-dimensional image-selected in vivo spectroscopy with outer volume suppression, selective excitation, and use of a surface spoiler coil. The spectral acquisition characteristics were as follows: repetition time, 3.39 seconds; echo time, 68 msec; sweep width, 1,500 Hz; and acquisition time, 510 msec. The integral of the GABA peak was adjusted for the macromolecular contribution and compared to the total creatine signal for absolute quantification.
The effects of SSRI treatment on GABA concentrations and Hamilton depression scale scores were evaluated by using paired t tests.
|
Results
|
The occipital cortex GABA concentrations after treatment (mean=1.70 mmol/kg brain tissue, SD=0.37) were significantly higher than the pretreatment concentrations (mean=1.27, SD=0.30) (paired t test: t=2.61, df=10, p<0.03), and nine of the 11 subjects had higher posttreatment concentrations (Figure 1). The posttreatment scores on the Hamilton depression scale (mean=9.73, SD=4.96) were significantly lower than the pretreatment scores (mean=26.00, SD=4.22) (paired t test: t=7.25, df=9, p<0.0001); all of the subjects had lower posttreatment scores, and seven of the 11 had reductions of more than 50%. No significant correlation was observed between the change in occipital cortex GABA concentration and clinical improvement, as determined by change in Hamilton depression score, in this small group (r=0.10, N=11, p>0.40). Nor was there a significant correlation between the pretreatment GABA concentration and clinical improvement (r=0.37, N=11, p>0.20). However, the five subjects with the lowest initial GABA concentrations (below 1.20 mmol/kg brain tissue) exhibited large increases in GABA concentration (mean change=0.88 mmol/kg brain tissue, SD=0.47) after SSRI treatment, whereas the five subjects with the highest pretreatment concentrations (above 1.35 mmol/kg brain tissue) showed no appreciable overall change in occipital GABA concentration after treatment (mean change=–0.02, SD=0.23). We did not observe a significant difference between the five subjects who also received yohimbine (mean=56% increase, SD=59) and the six subjects who received only SSRI treatment (mean=32% increase, SD=54) in this small study group (Mann-Whitney U=11.5, p>0.50).
View larger version (52K):
[in this window]
[in a new window]
|
Figure 1. Change in Occipital Cortex GABA Concentrations After SSRI Treatment of Major Depression in 11 Patientsa
aEach patient was treated for at least 5 weeks. Eight patients received fluoxetine, and three received citalopram.
|
|
Discussion
|
This pilot study showed a 34% increase in occipital cortex GABA concentrations after a course of SSRI treatment in a group of depressed patients. We previously demonstrated a similar increase in occipital GABA concentrations after a course of electroconvulsive therapy (6). Together with earlier reports of low plasma, CSF, and cortical GABA concentrations in depressed subjects (5, 8), these findings suggest that normalization of abnormally low cortical GABA concentrations may provide a common mechanism in the treatment of major depression.
The observed effects of the SSRI medications on occipital cortex GABA concentrations could be explained in part by the direct actions of serotonin (5-HT) on the GABA-ergic neurons in the cortex. The majority of serotonergic axons synapse on cortical GABA-ergic interneurons (9). These GABA-ergic interneurons express either 5-HT3 or 5-HT2A receptors (10) that can modulate activity in the short term and increase GABA release (11). Studies by Mitoma and Konishi (12) also demonstrate the ability of monoamines to elicit both short- and long-term enhancement of GABA-ergic inhibitory transmission through presynaptic mechanisms. However, the mechanism of increased presynaptic GABA-ergic transmission remains unclear since long-term administration of sertraline was found to produce either no change or a decrease in expression of glutamic acid decarboxylase in rats (13).
The observation that subjects with the lowest pretreatment GABA concentrations have the largest increases after SSRI treatment is of additional interest. This may simply reflect a ceiling effect on occipital cortex GABA concentrations. Alternatively, it may suggest the existence of different subgroups of depressed patients, i.e., one group with abnormally low baseline GABA concentrations that exhibit large increases after treatment and a second with relatively normal baseline concentrations that show little change after treatment.
In conclusion, this pilot study suggests that like ECT, SSRI medications for the treatment of major depressive disorder result in increased occipital cortex GABA concentrations. This elevation of GABA concentrations after treatment may reflect either a direct action of the treatment on the GABA-ergic system or a reversal of a state-dependent phenomenon.
|
Footnotes
|
Received April 27, 2001; revision received Oct. 30, 2001; accepted Nov. 15, 2001. From the Departments of Psychiatry, Biomedical Engineering, and Radiology, Yale University School of Medicine, New Haven, Conn. Address reprint requests to Dr. Sanacora, Clinical Neuroscience Research Unit, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, 34 Park St., New Haven, CT; gerard.sanacora{at}yale.edu (e-mail). Supported by a grant from the Donaghue Medical Research Foundation to Dr. Sanacora, a grant from the National Alliance for Research on Schizophrenia and Depression to Dr. Sanacora, NIMH grant MH-01715 to Dr. Sanacora, NIMH grant MH-30929 to the Mental Health Clinical Research Center at Yale University, grant AA-00261 from the National Institute on Alcohol Abuse and Alcoholism to Dr. Krystal, the VA Research Enhancement Awards Program, and the Yale Alcohol Center. The authors thank Michael Appel, Donna Fasula, Lisa Roach, and Matthew Wachen for their assistance.
|
References
|
-
Sanacora G, Mason GF, Krystal JH: Impairment of GABAergic function in depression: new insights from neuroimaging. Crit Rev Neurobiol 2000; 14:23-45[Medline]
-
Lloyd KG, Thuret F, Pilc A: Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock. J Pharmacol Exp Ther 1985; 235:191-199[Abstract/Free Full Text]
-
Cross JA, Horton RW: Effects of chronic oral administration of the antidepressants desmethylimipramine and zimeldine on rat cortical GABAB binding sites: a comparison with 5-HT2 binding site changes. Br J Pharmacol 1988; 93:331-336[Medline]
-
Bowden CL: Introduction: the use of mood stabilizers in the treatment of psychiatric disorders. J Clin Psychiatry 1999; 60(suppl 5):3-4
-
Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OAC, Berman RM, Charney DS, Krystal JH: Reduced cortical -aminobutyric acid levels in depressed patients by proton magnetic spectroscopy. Arch Gen Psychiatry 1999; 56:1043-1047[Abstract/Free Full Text]
-
Sanacora G, Mason GF, Rothman DL, Berman R, Charney D, Ciarcia JJ, Krystal JK: ECT effects on cortical GABA levels as determined by 1H-MRS, in ISMRM Seventh Meeting Proceedings. Berkeley, Calif, International Society for Magnetic Resonance in Medicine, 1999, p 1401
-
Rothman DL, Petroff OA, Behar KL, Mattson RH: Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. Proc Natl Acad Sci USA 1993; 90:5662-5666[Abstract/Free Full Text]
-
Petty F: GABA and mood disorders: a brief review and hypothesis. J Affect Disord 1995; 34:275-281[CrossRef][Medline]
-
Smiley JF, Goldman-Rakic PS: Serotonergic axons in monkey prefrontal cerebral cortex synapse predominantly on interneurons as demonstrated by serial section electron microscopy. J Comp Neurol 1996; 367:431-443[CrossRef][Medline]
-
Jakab RL, Goldman-Rakic PS: Segregation of serotonin 5-HT2A and 5-HT3 receptors in inhibitory circuits of the primate cerebral cortex. J Comp Neurol 2000; 417:337-348[CrossRef][Medline]
-
Abi-Saab WM, Bubser M, Roth RH, Deutch AY: 5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology 1999; 20:92-96[CrossRef][Medline]
-
Mitoma H, Konishi S: Monoaminergic long-term facilitation of GABA-mediated inhibitory transmission at cerebellar synapses. Neuroscience 1999; 88:871-883[CrossRef][Medline]
-
Giardino L, Zanni M, Bettelli C, Savina MA, Calza L: Regulation of glutamic acid decarboxylase mRNA expression in rat brain after sertraline treatment. Eur J Pharmacol 1996; 312:183-187[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
M. Taylor, S. Murphy, S. Selvaraj, M. Wylezinkska, P. Jezzard, P. Cowen, and J. Evans
Differential effects of citalopram and reboxetine on cortical Glx measured with proton MR spectroscopy
J Psychopharmacol,
July 1, 2008;
22(5):
473 - 476.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. J. Taylor, N. Freemantle, J. R. Geddes, and Z. Bhagwagar
Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action: Systematic Review and Meta-analysis.
Arch Gen Psychiatry,
November 1, 2006;
63(11):
1217 - 1223.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. W. Goddard, G. F. Mason, M. Appel, D. L. Rothman, R. Gueorguieva, K. L. Behar, and J. H. Krystal
Impaired GABA Neuronal Response to Acute Benzodiazepine Administration in Panic Disorder
Am J Psychiatry,
December 1, 2004;
161(12):
2186 - 2193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Sanacora, R. Gueorguieva, C. N. Epperson, Y.-T. Wu, M. Appel, D. L. Rothman, J. H. Krystal, and G. F. Mason
Subtype-Specific Alterations of {gamma}-Aminobutyric Acid and Glutamate in Patients With Major Depression
Arch Gen Psychiatry,
July 1, 2004;
61(7):
705 - 713.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Bhagwagar, M. Wylezinska, M. Taylor, P. Jezzard, P. M. Matthews, and P. J. Cowen
Increased Brain GABA Concentrations Following Acute Administration of a Selective Serotonin Reuptake Inhibitor
Am J Psychiatry,
February 1, 2004;
161(2):
368 - 370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Ziabreva, G. Poeggel, R. Schnabel, and K. Braun
Separation-Induced Receptor Changes in the Hippocampus and Amygdala of Octodon degus: Influence of Maternal Vocalizations
J. Neurosci.,
June 15, 2003;
23(12):
5329 - 5336.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Sanacora, G. F. Mason, D. L. Rothman, F. Hyder, J. J. Ciarcia, R. B. Ostroff, R. M. Berman, and J. H. Krystal
Increased Cortical GABA Concentrations in Depressed Patients Receiving ECT
Am J Psychiatry,
March 1, 2003;
160(3):
577 - 579.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. N. Epperson, K. Haga, G. F. Mason, E. Sellers, R. Gueorguieva, W. Zhang, E. Weiss, D. L. Rothman, and J. H. Krystal
Cortical {gamma}-Aminobutyric Acid Levels Across the Menstrual Cycle in Healthy Women and Those With Premenstrual Dysphoric Disorder: A Proton Magnetic Resonance Spectroscopy Study
Arch Gen Psychiatry,
September 1, 2002;
59(9):
851 - 858.
[Abstract]
[Full Text]
[PDF]
|
|
|
Get information about faster international access.
Privacy Policy
Copyright © 2002
American Psychiatric Association.
All rights reserved.
Home
| Search
| Current Issue
| Past Issues
| Subscribe
| All APPI Journals
| Help
| Contact Us
|
TOP
Abstract
Introduction
