| Abstract|| |
Magnetic Resonance Spectroscopy (MRS) is a unique technique that can directly assess the concentration of various biochemical metabolites in the brain. Thus, it is used in the study of molecular pathophysiology of different neuropsychiatric disorders, such as, the major depressive disorder and has been an area of active research. We conducted a computer-based literature search using the Pubmed database with 'magnetic resonance spectroscopy', 'MRS', 'depression', and 'major depressive disorder' as the key words, supplemented by a manual search of bibliographic cross-referencing. Studies in depression report abnormalities in the frontal cortex, basal ganglia, hippocampus, anterior cingulate cortex, and the occipital cortex. These abnormalities improve after treatment with selective serotonin reuptake inhibitor, electroconvulsive therapy, and yoga, and thus, are possibly state-dependent. The findings are consistent with other morphometric and clinical studies and support the proposed pathophysiological theory of dysfunction in the neuronal circuits involving the frontal cortex, limbic cortex, and basal ganglia. Spectroscopy also has potential implications in predicting the response to treatment and formulating individualized pharmacotherapy.
Keywords: Depression, gamma-aminobutyric acid, magnetic resonance spectrosocpy, N-Acetyl Aspartate, neuroimaging, proton MRS
|How to cite this article:|
Rao NP, Venkatasubramanian G, Gangadhar BN. Proton magnetic resonance spectroscopy in depression. Indian J Psychiatry 2011;53:307-11
| Introduction|| |
Advances in neuroimaging techniques have helped to identify brain regions involved in psychiatric disorders. Among neuroimaging modalities, Magnetic Resonance Spectroscopy (MRS) is a unique technique that can directly assess the concentration of various biochemical metabolites in the brain. MRS in addition to being noninvasive has a high spatial resolution and requires neither radioactive tracers nor ionizing radiation - a distinct advantage over other imaging modalities. Thus, in the last two decades MRS has been used to study molecular pathophysiology of different neuropsychiatric disorders, including major depressive disorder (MDD). Among the several nuclei assessed in MRS, proton ( 1 H) MRS is the most commonly used. The goal of this article is to review literature on MRS in depression and the potential applications of this technique.
Magnetic resonance spectroscopy - principle and procedure
Magnetic resonance spectroscopy, similar to magnetic resonance imaging, is based on the principles of nuclear magnetic resonance. MRS requires a magnetic field and a radio frequency transmit pulse at a particular resonant frequency, to observe the signal of specific nuclei, like protons, in the sample of interest. Protons resonate at a particular frequency depending on the surrounding magnetic field. As different molecules surround protons in different compounds, they experience differing magnetic fields, and thus, resonate at different frequencies. These small differences in frequency are processed using Fourier transformation and plotted on a graph as the output. This output is called as the 'MRS spectrum,' with a frequency in parts per million along the X-axis and signal amplitude along the Y-axis. Specific nuclei contained in a metabolite give rise to either a single peak or multiple peaks that are uniquely positioned along the frequency axis, and the peak position is known as the chemical shift. The area under the curve gives the tissue concentration of each metabolite. Thus, the MRS spectrum reflects the biochemical composition of the brain and each metabolite is identified accurately by its unique position.
A variety of factors determine the type of MRS used in a study. Important among them are the region of interest, nuclei of interest, and field strength of the magnet. MRS provides the selection of a particular region of the brain for analysis, known as the 'region of interest'. The region of interest is determined by selecting the appropriate voxel - a volume element representing a value in three-dimensional space, analogous to a pixel in two-dimensional space. Depending on what biochemical information is to be assessed, the metabolite is chosen and is known as the 'nuclei of interest'. Two kinds of spectroscopy are commonly used: 1 H (proton) spectroscopy and 31 P (Phosphorus) spectroscopy. 1 H spectroscopy can assess the metabolite levels of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln), glutamatergic componds (Glx), g-aminobutyric acid (GABA), and myoinositol (MI). This gives information on the viability of neurons, the neuronal system, neurotransmission cycling, and the second messenger metabolism, respectively. Phosphorus spectroscopy can measure metabolite levels of adenosine tri phosphate, Phosphocreatine, and inorganic orthophosphate, which are associated with high-energy phosphate metabolism. The field strength of magnets used is important as higher field strength magnets offer better sensitivity, signal-to-noise ratio, and spatial resolution.
| Materials and Methods|| |
We used a computer literature search of the National Library of Medicine, the Medline-Pubmed search, with 'magnetic resonance spectroscopy', 'MRS', 'depression', and 'major depressive disorder' as key words, supplemented by a manual search of bibliographic cross-referencing. In vivo MRS studies were included.
Magnetic resonance spectroscopy correlates of depression - metabolites of interest
Studies have examined NAA or NAA/Cr in the prefrontal cortex (PFC), anterior cingulate cortex (ACC), basal ganglia, hippocampus, and amygdala. Studies have given discrepant findings. Most of the studies have reported no significant difference in basal ganglia. ,, However, decreased NAA/Cr ratio in the thalamus  and decreased concentration of NAA in the caudate,  in comparison with healthy controls are also reported in a few studies. No differnce in the NAA/Cr ratio in the PFC has been noted in most of the studies, ,,, with a few exceptions.  Similarly, no difference is present in the ACC. ,,, Studies in amygdala-hippocampus, have consistently reported the absence of a difference between patients and controls at baseline. , In one study, there was an increase in NAA after electroconvulsive therapy (ECT).  NAA studies in children and adolescents have consistently reported negative results: no difference between patient and controls in PFC, ACC, amygdala or basal ganglia. ,,,,,
Studies in ACC were consistent: Depressed patients had decreased Glu/Gln in ACC ,, and these abnormalities improved after ECT.  Similarly, decreased Glu/Gln was noted in PFC at the baseline, which improved after treatment with ECT.  However, there were negative reports.  Decreased concentration was also noted in amygdala-hippocampus.  In children and adolescents, increased Glx was seen in the basal ganglia,  while there was no difference in PFC. 
g-Amino Butyric Acid
A number of MRS studies have reported reduced GABA concentration in the occipital cortex of depressed patients than healthy controls. ,, Reduction in GABA concentration was more (around 50%) in patients with melancholic depression than in those without melancholic depression (around 20%). However, these abnormalities in GABA concentration were found in the occipital cortex and not in the anterior brain regions, which were directly involved in the pathophysiology of mood disorder. Studies in the prefrontal cortex have not consistently replicated these findings. In earlier studies, there was no difference in the prefrontal GABA between the remitted patients and controls.  However, a recent study reported decreased GABA in the ACC. 
Studies in basal ganglia have given conflicting findings. Some studies have reported increased choline/Cr ratio, , while others show a decreased ratio. , In a few, there was no significant difference. , On further analysis of subdivisions of the basal ganglia, increase in choline was seen in the putamen, but not in the caudate or thalamus.  Interestingly, an elevated choline concentration reversed after treatment with an antidepressant, similar to GABA abnormality reversal.  Studies have consistently reported no significant differnce in PFC ,,,, and ACC. ,, Similar negative results were present in amygdala-hippocampus.  Similar to NAA, there was an increase in choline after treatment with ECT.  Inconsistent results were seen in children and adolescents, with few studies reporting no significant difference,  while others reported either increased or decreased choline levels. ,,,, In a recent study, adolescents with major depression had significantly elevated concentration of choline and creatine in left caudate. 
Most of the studies have reported negative findings in ACC , and basal ganglia.  In PFC, discrepancy has been noted, with some reporting a decreased MI/Cr ratio, ,, and other reporting an increased ratio.  In one study, there was no difference.  Similarly, an earlier study in children reported no significant difference.  However, in a recent study there was an increased ratio in PFC. 
A recent meta-analysis concluded the absence of difference in NAA/Cr and NAA in the basal ganglia, frontal lobes, and myoinositol in the frontal lobes, between patients and healthy controls. It also indicated significantly higher Cho/Cr levels in the basal ganglia and lower Glx values in the frontal lobes and occipital cortex of patients. 
Overall, MRS studies in depression report abnormalities in the frontal cortex, basal ganglia, hippocampus, anterior cingulate cortex, and occipital cortex. In PFC, significantly decreased Glu/Gln, but not choline is noted. Most of the studies in the basal ganglia have reported no difference in NAA and results are inconsistent with choline and glutamate. Consistent findings across studies are, decreased Glx and absence of difference in NAA in amygdala-hippocampus, decreased Glu/Gln and GABA in the ACC, and decreased GABA in the occipital cortex. These findings suggest an involvement of the cortical, subcortical, and limbic brain regions, in depression, in accordance with evidence from the clinical and morphometric studies.
Correlation with pathophysiology
N-Acetyl Aspartate functions in the brain as an acetyl donor for acetyl coenzyme A and takes part in lipid biosynthesis, including myelin.  NAA is commonly considered to be a putative neuronal marker,  as it is localized only in neurons, but not in glial cells or blood. Thus, NAA resonance measured by MRS is a marker of neuronal viability and function.  Thus, reduction in NAA concentration possibly reflects an underlying neurodegenerative process in major depression.
Choline is an essential precursor of the neurotransmitter acetylcholine and membrane lipids, phosphatidylcholine and sphingomyelin.  The Cho peak is considered as a potential biomarker for the status of membrane phospholipid metabolism, , and an elevated Cho signal most likely reflects an increase in the membrane turnover.  Alterations in the Cho signal may have an impact on signal transduction in MDD.  Based on theories of cholinergic overactivity  in phosphatidylcholine / membrane phospholipids metabolism and signal transduction systems in depression, the Cho peak in proton MRS has received considerable attention in MDD.
Inositol has a function in osmoregulation in brain glial cells.  Glial cells store myoinositol and then gradually pass it on to the neurons, where it becomes a precursor of phosphoinositide.  In the cerebrospinal fluid, markedly reduced levels of myoinositol have been reported in depressed patients with unipolar and bipolar affective disorder,  and double blind trials have shown improvement in depression following inositol treatment. 
Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in central nervous system and is integral in managing brain excitability.  GABA has an important function in cortical inhibition and in the pathophysiology of mood disorders, as evidenced by the decreased GABA levels in the plasma and cerebrospinal fluid, in acutely depressed patients. 
Glutamate and N-methyl-d-aspartate (NMDA) receptors are implicated in the pathophysiology of depression. , Although most studies in unipolar depression report decreased glutamate levels in the frontal lobe, a majority of studies on bipolar patients suggest higher glutamate / glutamine levels. Thus, the direction of change seems to be opposite in bipolar and unipolar affective disorders: a hyperglutamatergic state in the bipolar disorder and a hypoglutamatergic state in the unipolar disorder.
It is not clear whether these abnormalities in depression are trait markers or state markers. A useful way to delineate trait/state markers is by assessing the brain metabolites before and after treatment. Although there are discrepant results in these longitudinal studies, most of them show that the abnormalities are reversible with treatment and possibly state-dependent.
Effect of electroconvulsive therapy and selective serotonin reuptake inhibitor
Decreased Glu/Gln in ACC and PFC were reported to improve after ECT. , Similarly, there was an increase in occipital GABA  and hippocampal choline after ECT.  In addition, an increase in occipital GABA was noted after treatment with selective serotonin reuptake inhibitor (SSRI). , These suggest that MRS abnormalities are more likely to be 'state markers'.
However, this view is not universally accepted, as discrepant results are present in other studies. In one study, depressed patients had decreased occipital GABA levels even in the recovered phase, raising the possibility of trait vulnerability to mood disorder.  In addition, an increase in occipital GABA is noted in healthy volunteers after SSRI (Citalopram) treatment.  Thus, with the current reports, it is difficult to conclude whether the improvement noted after treatment is a reflection of change in the pathophysiology or a confounding effect of the medication.
Effect of Yoga
Streeter and colleagues  assessed the effect of yoga on the brain GABA levels. They assessed GABA/creatine ratio in yoga practitioners and non-practitioners before and after a 60-minute session of yoga. A reading task for 60 minutes was given to non-practitioners. There was a 27% increase in the brain global GABA levels in yoga practitioners. The authors concluded that the practice of yoga should be explored for disordres with low GABA levels, such as depression.
Renshaw and colleagues measured brain purine levels by proton spectroscopy and found approximately 30% decrease in female depressed patients who subsequently responded to fluoxetine, than in those who did not respond.  These preliminary findings suggest that MRS could possibly predict response to treatment.
Magnetic resonance spectroscopy is also useful in determining the pharmacokinetics of therapeutic compounds in brain. This is an important use to explore the dose-dependent therapeutic effect as well as the side effects following abrupt discontinuation. In a study comparing fluoxetine and paroxetine discontinuation, there was a significant decrease in the brain fluorine signal following paroxetine discontinuation, but not fluoxetine, reflecting the difference in their half-lives.  There was also a correlation between the clinical effects and the brain drug levels, suggesting a dose-dependent response.
| Conclusions and Future Directions|| |
Proton MRS studies in depression have shown abnormalities in different metabolites like NAA/Cr, GABA, choline, and glutamate/glutamine in different regions of the brain. These findings are consistent with other morphometric and clinical studies and support the proposed pathophysiological theory of dysfunction in neuronal circuits involving the frontal cortex, limbic cortex, and basal ganglia.
As reviewed, studies in MRS have contrasting findings, possibly due to methodological issues, importantly, the confounding effect of psychotropic drugs and heterogeneous samples. Antidepressants have a significant effect on MRS findings, and thus, inclusion of psychotropic naive subjects is preferred in future studies. In addition, it is preferrable to include a specific clinical subgroup such as familial depression or a subgroup based on age at onset, to decrease the heterogeneity in the sample. Use of higher strength magnets will help in a better delineation of individual metabolites.
Further studies are required to examine whether these changes seen in the symptomatic state are present in unaffected relatives, for elucidating the endophenotypes. Identifying the biochemical markers of treatment response will help to develop individualized pharmacological treatment.
Dr. Ganesan Venkatasubramanian's work was partially supported by Innovative Young Biotechnologist Award by Department of Biotechnology, Government of India.
| References|| |
|1.||Hamakawa H, Kato T, Murashita J, Kato N. Quantitative proton magnetic resonance spectroscopy of the basal ganglia in patients with affective disorders. Eur Arch Psychiatry Clin Neurosci 1998;248:53-8. |
|2.||Renshaw PF, Lafer B, Babb SM, Fava M, Stoll AL, Christensen JD, et al. Basal ganglia choline levels in depression and response to fluoxetine treatment: An in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 1997;41:837-43. |
|3.||Charles HC, Lazeyras F, Krishnan KR, Boyko OB, Payne M, Moore D. Brain choline in depression: In vivo detection of potential pharmacodynamic effects of antidepressant therapy using hydrogen localized spectroscopy. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:1121-7. |
|4.||Mu J, Xie P, Yang ZS, Yang DL, Lv FJ, Luo TY, et al. 1 H magnetic resonance spectroscopy study of thalamus in treatment resistant depressive patients. Neurosci Lett 2007;425:49-52. |
|5.||Vythilingam M, Charles HC, Tupler LA, Blitchington T, Kelly L, Krishnan KR. Focal and lateralized subcortical abnormalities in unipolar major depressive disorder: An automated multivoxel proton magnetic resonance spectroscopy study. Biol Psychiatry 2003;54:744-50. |
|6.||Binesh N, Kumar A, Hwang S, Mintz J, Thomas MA. Neurochemistry of late-life major depression: A pilot two-dimensional MR spectroscopic study. J Magn Reson Imaging 2004;20:1039-45. |
|7.||Coupland NJ, Ogilvie CJ, Hegadoren KM, Seres P, Hanstock CC, Allen PS. Decreased prefrontal Myo-inositol in major depressive disorder. Biol Psychiatry 2005;57:1526-34. |
|8.||Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B. Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression. Psychol Med 2003;33:1277-84. |
|9.||Brambilla P, Stanley JA, Nicoletti MA, Sassi RB, Mallinger AG, Frank E, et al. 1 H Magnetic resonance spectroscopy study of dorsolateral prefrontal cortex in unipolar mood disorder patients. Psychiatry Res 2005;138:131-9. |
|10.||Gruber S, Frey R, Mlynarik V, Stadlbauer A, Heiden A, Kasper S, et al. Quantification of metabolic differences in the frontal brain of depressive patients and controls obtained by 1 H-MRS at 3 Tesla. Invest Radiol 2003;38:403-8. |
|11.||Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F. Reduced glutamate in the anterior cingulate cortex in depression: An in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 2000;47:305-13. |
|12.||Kumar A, Thomas A, Lavretsky H, Yue K, Huda A, Curran J, et al. Frontal white matter biochemical abnormalities in late-life major depression detected with proton magnetic resonance spectroscopy. Am J Psychiatry 2002;159:630-6. |
|13.||Pfleiderer B, Michael N, Erfurth A, Ohrmann P, Hohmann U, Wolgast M, et al. Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients. Psychiatry Res 2003;122:185-92. |
|14.||Ende G, Braus DF, Walter S, Weber-Fahr W, Henn FA. The hippocampus in patients treated with electroconvulsive therapy: A proton magnetic resonance spectroscopic imaging study. Arch Gen Psychiatry 2000;57:937-43. |
|15.||Caetano SC, Fonseca M, Olvera RL, Nicoletti M, Hatch JP, Stanley JA, et al. Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients. Neurosci Lett 2005;384:321-6. |
|16.||Mirza Y, Tang J, Russell A, Banerjee SP, Bhandari R, Ivey J, et al. Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression. J Am Acad Child Adolesc Psychiatry 2004;43:341-8. |
|17.||Kusumakar V, MacMaster FP, Gates L, Sparkes SJ, Khan SC. Left medial temporal cytosolic choline in early onset depression. Can J Psychiatry 2001;46:959-64. |
|18.||Farchione TR, Moore GJ, Rosenberg DR. Proton magnetic resonance spectroscopic imaging in pediatric major depression. Biol Psychiatry 2002;52:86-92. |
|19.||Steingard RJ, Yurgelun-Todd DA, Hennen J, Moore JC, Moore CM, Vakili K, et al. Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy. Biol Psychiatry 2000;48:1053-61. |
|20.||Rosenberg DR, Seraji-Bozorgzad N, Wilds IB, Stewart CM, Moore GJ. Brain chemistry in pediatric depression. Biol Psychiatry 2000;47:95S. |
|21.||Sanacora G, Rothman DL, Mason G, Krystal JH. Clinical studies implementing glutamate neurotransmission in mood disorders. Ann N Y Acad Sci 2003;1003:292-308. |
|22.||Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004;61:705-13. |
|23.||Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA, et al. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999;56:1043-7. |
|24.||Hasler G, Neumeister A, van der Veen JW, Tumonis T, Bain EE, Shen J, et al. Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy. Biol Psychiatry 2005;58:969-73. |
|25.||Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, Matthews MP, et al. Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol 2008;11:255-60. |
|26.||Sonawalla SB, Renshaw PF, Moore CM, Alpert JE, Nierenberg AA, Rosenbaum JF, et al. Compounds containing cytosolic choline in the basal ganglia: A potential biological marker of true drug response to fluoxetine. Am J Psychiatry 1999;156:1638-40. |
|27.||Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B. Neurotrophic effects of electroconvulsive therapy: A proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression. Neuropsychopharmacology 2003;28:720-5. |
|28.||Gabbay V, Hess DA, Liu S, Babb JS, Klein RG, Gonen O. Lateralized caudate metabolic abnormalities in adolescent major depressive disorder: A proton MR spectroscopy study. Am J Psychiatry 2007;164:1881-9. |
|29.||Frey R, Metzler D, Fischer P, Heiden A, Scharfetter J, Moser E, et al. Myo-inositol in depressive and healthy subjects determined by frontal 1 H-magnetic resonance spectroscopy at 1.5 tesla. J Psychiatr Res 1998;32:411-20. |
|30.||Yildiz-Yesiloglu A, Ankerst DP. Review of 1 H magnetic resonance spectroscopy findings in major depressive disorder: A meta-analysis. Psychiatry Res 2006;147:1-25. |
|31.||Moore GJ, Galloway MP. Magnetic resonance spectroscopy: Neurochemistry and treatment effects in affective disorders. Psychopharmacol Bull 2002;36:5-23. |
|32.||Stanley JA. In vivo magnetic resonance spectroscopy and its application to neuropsychiatric disorders. Can J Psychiatry 2002;47:315-26. |
|33.||Tsai G, Coyle JT. N-acetylaspartate in neuropsychiatric disorders. Prog Neurobiol 1995;46:531-40. |
|34.||Glitz DA, Manji HK, Moore GJ. Mood disorders: Treatment-induced changes in brain neurochemistry and structure. Semin Clin Neuropsychiatry 2002;7:269-80. |
|35.||Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ. A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972;2:632-5. |
|36.||Barkai AI, Dunner DL, Gross HA, Mayo P, Fieve RR. Reduced myo-inositol levels in cerebrospinal fluid from patients with affective disorder. Biol Psychiatry 1978;13:65-72. |
|37.||Levine J, Barak Y, Gonzalves M, Szor H, Elizur A, Kofman O, et al. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 1995;152:792-4. |
|38.||Chang L, Cloak CC, Ernst T. Magnetic resonance spectroscopy studies of GABA in neuropsychiatric disorders. J Clin Psychiatry 2003;64:7-14. |
|39.||Brambilla P, Perez J, Barale F, Schettini G, Soares JC. GABAergic dysfunction in mood disorders. Mol Psychiatry 2003;8:721-37, 715. |
|40.||Petrie RX, Reid IC, Stewart CA. The N-methyl-D-aspartate receptor, synaptic plasticity, and depressive disorder. A critical review. Pharmacol Ther 2000;87:11-25. |
|41.||Sanacora G, Mason GF, Rothman DL, Krystal JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 2002;159:663-5. |
|42.||Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth F, Sule A, et al. Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 2007;61:806-12. |
|43.||Bhagwagar Z, Wylezinska M, Taylor M, Jezzard P, Matthews PM, Cowen PJ. Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am J Psychiatry 2004;161:368-70. |
|44.||Streeter CC, Hennen J, Ke Y, Jensen JE, Sarid-Segal O, Nassar LE, et al. Prefrontal GABA levels in cocaine-dependent subjects increase with pramipexole and venlafaxine treatment. Psychopharmacology (Berl) 2005;182:516-26. |
|45.||Renshaw PF, Parow AM, Hirashima F, Ke Y, Moore CM, Frederick Bde B, et al. Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression. Am J Psychiatry 2001;158:2048-55. |
|46.||Henry ME, Moore CM, Kaufman MJ, Michelson D, Schmidt ME, Stoddard E, et al. Brain kinetics of paroxetine and fluoxetine on the third day of placebo substitution: A fluorine MRS study. Am J Psychiatry 2000;157:1506-8. |
Naren P Rao
Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore - 560 029, Karnataka