Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents: relationship to anhedonia.

CONTEXT Anhedonia, a core symptom of major depressive disorder (MDD) and highly variable among adolescents with MDD, may involve alterations in the major inhibitory amino acid neurotransmitter system of γ-aminobutyric acid (GABA). OBJECTIVE To test whether anterior cingulate cortex (ACC) GABA levels, measured by proton magnetic resonance spectroscopy, are decreased in adolescents with MDD. The associations of GABA alterations with the presence and severity of anhedonia were explored. DESIGN Case-control, cross-sectional study using single-voxel proton magnetic resonance spectroscopy at 3 T. SETTING Two clinical research divisions at 2 teaching hospitals. PARTICIPANTS Twenty psychotropic medication-free adolescents with MDD (10 anhedonic, 12 female, aged 12-19 years) with episode duration of 8 weeks or more and 21 control subjects group matched for sex and age. MAIN OUTCOME MEASURES Anterior cingulate cortex GABA levels expressed as ratios relative to unsuppressed voxel tissue water (w) and anhedonia scores expressed as a continuous variable. RESULTS Compared with control subjects, adolescents with MDD had significantly decreased ACC GABA/w (t = 3.2; P < .003). When subjects with MDD were categorized based on the presence of anhedonia, only anhedonic patients had decreased GABA/w levels compared with control subjects (t = 4.08; P < .001; P(Tukey) < .001). Anterior cingulate cortex GABA/w levels were negatively correlated with anhedonia scores for the whole MDD group (r = -0.50; P = .02), as well as for the entire participant sample including the control subjects (r = -0.54; P < .001). Anterior cingulate cortex white matter was also significantly decreased in adolescents with MDD compared with controls (P = .04). CONCLUSIONS These findings suggest that GABA, the major inhibitory neurotransmitter in the brain, may be implicated in adolescent MDD and, more specifically, in those with anhedonia. In addition, use of a continuous rather than categorical scale of anhedonia, as in the present study, may permit greater specificity in evaluating this important clinical feature.

[1]  G F Mason,et al.  Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. , 1999, Archives of general psychiatry.

[2]  L O Hall,et al.  Comprehensive processing, display and analysis for in vivo MR spectroscopic imaging , 2006, NMR in biomedicine.

[3]  N. Uranova,et al.  Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium , 2004, Schizophrenia Research.

[4]  Peter Boesiger,et al.  The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. , 2009, Archives of general psychiatry.

[5]  H. Koplewicz,et al.  Adolescent depression: Controlled desipramine treatment and atypical features , 1998, Depression and anxiety.

[6]  Simon J Graham,et al.  Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. , 2005, Archives of general psychiatry.

[7]  Takashi Ogino,et al.  Characterization of macromolecule resonances in the 1H NMR spectrum of rat brain , 1993, Magnetic resonance in medicine.

[8]  Mark A Brown,et al.  Time‐domain combination of MR spectroscopy data acquired using phased‐array coils , 2004, Magnetic resonance in medicine.

[9]  N. Ryan,et al.  The clinical picture of major depression in children and adolescents. , 1987, Archives of general psychiatry.

[10]  H. Silver,et al.  The effect of chronic co-administration of fluvoxamine and haloperidol compared to clozapine on the GABA system in the rat frontal cortex. , 2006, The international journal of neuropsychopharmacology.

[11]  C. Gullion,et al.  Low plasma gamma-aminobutyric acid levels in male patients with depression. , 1992, Biological psychiatry.

[12]  Anand Kumar,et al.  Neurochemistry of late‐life major depression: A pilot two‐dimensional MR spectroscopic study , 2004, Journal of magnetic resonance imaging : JMRI.

[13]  N. Ryan,et al.  Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[14]  Fahmeed Hyder,et al.  Reduced Cortical γ-Aminobutyric Acid Levels in Depressed Patients Determined by Proton Magnetic Resonance Spectroscopy , 1999 .

[15]  E. Nestler,et al.  The Mesolimbic Dopamine Reward Circuit in Depression , 2006, Biological Psychiatry.

[16]  A. L. Garcia-Garcia,et al.  Chronic stress and impaired glutamate function elicit a depressive-like phenotype and common changes in gene expression in the mouse frontal cortex , 2011, European Neuropsychopharmacology.

[17]  J. Price,et al.  Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders , 1998, Molecular Psychiatry.

[18]  A. Schousboe,et al.  The glutamate/GABA‐glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer , 2006, Journal of neurochemistry.

[19]  R. Mattson,et al.  Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Ozgur Yorbik,et al.  Clinical characteristics of depressive symptoms in children and adolescents with major depressive disorder. , 2004, The Journal of clinical psychiatry.

[21]  Gregor Hasler,et al.  Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. , 2007, Archives of general psychiatry.

[22]  J M Wardlaw,et al.  Choice of spectroscopic lineshape model affects metabolite peak areas and area ratios , 2000, Magnetic resonance in medicine.

[23]  K. Behar,et al.  Analysis of macromolecule resonances in 1H NMR spectra of human brain , 1994, Magnetic resonance in medicine.

[24]  W. Drevets,et al.  Dopamine Type-1 Receptor Binding in Major Depressive Disorder Assessed using Positron Emission Tomography and [11C]NNC-112 , 2008, Neuropsychopharmacology.

[25]  D. Pickar,et al.  CSF GABA in depressed patients and normal controls , 1989, Biological Psychiatry.

[26]  A. Lozano,et al.  Deep Brain Stimulation for Treatment-Resistant Depression , 2005, Neuron.

[27]  J. Pettit,et al.  Measuring hedonic capacity in depression: a psychometric analysis of three anhedonia scales. , 2006, Journal of clinical psychology.

[28]  A. Rush,et al.  Low plasma γ-aminobutyric acid levels in male patients with depression , 1992, Biological Psychiatry.

[29]  Fei Wang,et al.  Whiter matter abnormalities in medication-naive subjects with a single short-duration episode of major depressive disorder , 2011, Psychiatry Research: Neuroimaging.

[30]  K. Hashimoto.  Emerging role of glutamate in the pathophysiology of major depressive disorder , 2009, Brain Research Reviews.

[31]  Marcus E Raichle,et al.  Volumetric reduction in left subgenual prefrontal cortex in early onset depression , 2002, Biological Psychiatry.

[32]  A. Beck,et al.  Screening for major depression disorders in medical inpatients with the Beck Depression Inventory for Primary Care. , 1997, Behaviour research and therapy.

[33]  D. Weinberger,et al.  Reproducibility of prefrontal γ‐aminobutyric acid measurements with J‐edited spectroscopy , 2011, NMR in biomedicine.

[34]  John H Krystal,et al.  Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. , 2004, Archives of general psychiatry.

[35]  B. Bogerts,et al.  Suicide and depression in the quantitative analysis of glutamic acid decarboxylase-Immunoreactive neuropil. , 2009, Journal of affective disorders.

[36]  Craig B. Markwardt,et al.  Non-linear Least Squares Fitting in IDL with MPFIT , 2009, 0902.2850.

[37]  S. Totterdell,et al.  Sustained stress-induced changes in mice as a model for chronic depression , 2010, Psychopharmacology.

[38]  B. Bogerts,et al.  Dysregulation of GABAergic Neurotransmission in Mood Disorders , 2007, Annals of the New York Academy of Sciences.

[39]  Dost Öngür,et al.  Magnetic Resonance Spectroscopy Studies of Glutamate-Related Abnormalities in Mood Disorders , 2010, Biological Psychiatry.

[40]  F. Mora,et al.  Melatonin disrupts circadian rhythms of glutamate and GABA in the neostriatum of the awake rat: a microdialysis study , 2000, Journal of pineal research.

[41]  B Luscher,et al.  The GABAergic deficit hypothesis of major depressive disorder , 2011, Molecular Psychiatry.

[42]  David R Rosenberg,et al.  Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression. , 2004, Journal of the American Academy of Child and Adolescent Psychiatry.

[43]  R. Moratalla,et al.  Metabolic interactions between glutamatergic and dopaminergic neurotransmitter systems are mediated through D1 dopamine receptors , 2007, Journal of neuroscience research.

[44]  Marzena Wylezinska,et al.  Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. , 2008, The international journal of neuropsychopharmacology.

[45]  F. Mora,et al.  Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light , 2004, Journal of pineal research.

[46]  G. Rajkowska,et al.  Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. , 2010, The international journal of neuropsychopharmacology.

[47]  H. Silver,et al.  Multifunctional pharmacotherapy: What can we learn from study of selective serotonin reuptake inhibitor augmentation of antipsychotics in negative-symptom schizophrenia? , 2011, Neurotherapeutics.

[48]  C. Hanstock,et al.  Decreased Prefrontal Myo-Inositol in Major Depressive Disorder , 2005, Biological Psychiatry.

[49]  Helena Chmura Kraemer,et al.  Categorical versus dimensional approaches to diagnosis: methodological challenges. , 2004, Journal of psychiatric research.

[50]  J. Port,et al.  The case of the missing glutamine , 2011, NMR in biomedicine.

[51]  A. Andrews,et al.  γ-Aminobutyric Acid-Type A Receptor Deficits Cause Hypothalamic-Pituitary-Adrenal Axis Hyperactivity and Antidepressant Drug Sensitivity Reminiscent of Melancholic Forms of Depression , 2010, Biological Psychiatry.

[52]  P. Fox,et al.  Cingulate function in depression: a potential predictor of treatment response , 1997, Neuroreport.

[53]  G. Rajkowska,et al.  GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression , 2007, Neuropsychopharmacology.

[54]  J. Gabrieli,et al.  Loss of white matter integrity in major depressive disorder: Evidence using tract‐based spatial statistical analysis of diffusion tensor imaging , 2011, Human brain mapping.

[55]  Jullie W Pan,et al.  Quantitative 1H spectroscopic imaging of human brain at 4.1 T using image segmentation , 1996, Magnetic resonance in medicine.

[56]  T. Widiger,et al.  Diagnostic categories or dimensions? A question for the Diagnostic And Statistical Manual Of Mental Disorders--fifth edition. , 2005, Journal of abnormal psychology.

[57]  Gavin Andrews,et al.  Dimensionality and the category of major depressive episode , 2007, International journal of methods in psychiatric research.

[58]  P. Matthews,et al.  Reduction in Occipital Cortex γ-Aminobutyric Acid Concentrations in Medication-Free Recovered Unipolar Depressed and Bipolar Subjects , 2007, Biological Psychiatry.

[59]  B. Kretschmer,et al.  Glutamate and GABA modulate dopamine in the pedunculopontine tegmental nucleus , 2003, Experimental Brain Research.

[60]  D. Rosenberg,et al.  Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls. , 2004, Journal of the American Academy of Child and Adolescent Psychiatry.

[61]  G. Kemp,et al.  Quantification of Metabolic Differences in the Frontal Brain of Depressive Patients and Controls Obtained by 1H-MRS at 3 Tesla , 2003, Investigative radiology.

[62]  Jessica S. Brown,et al.  A test of the tripartite model's prediction of anhedonia's specificity to depression: patients with major depression versus patients with schizophrenia , 2003, Psychiatry Research.

[63]  Bernadette Lipinski,et al.  Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study , 2000, Biological Psychiatry.

[64]  D. Pizzagalli,et al.  Toward an objective characterization of an anhedonic phenotype: A signal-detection approach , 2005, Biological Psychiatry.

[65]  D. Zald,et al.  Reconsidering anhedonia in depression: Lessons from translational neuroscience , 2011, Neuroscience & Biobehavioral Reviews.

[66]  P. Renshaw,et al.  Smaller frontal lobe white matter volumes in depressed adolescents , 2002, Biological Psychiatry.

[67]  B. Cohen,et al.  Blockade of Astrocytic Glutamate Uptake in Rats Induces Signs of Anhedonia and Impaired Spatial Memory , 2010, Neuropsychopharmacology.

[68]  M. Weissman,et al.  A brain-based endophenotype for major depressive disorder. , 2011, Annual Review of Medicine.