The Neurochemistry of Pediatric Major Depressive Disorder

Mar 01, 2008

Major depressive disorder (MDD) in pediatric populations represents a significant public health concern. Rates of MDD rise dramatically in adolescence, with an estimated lifetime prevalence of 15% in adolescents aged 15 to 18.

Major depressive disorder (MDD) in pediatric populations represents a significant public health concern. Rates of MDD rise dramatically in adolescence, with an estimated lifetime prevalence of 15% in adolescents aged 15 to 18.1 MDD is associated with severe consequences, including deterioration in academic functioning, increased risk of substance use and other mental disorders, and most critically, attempted and completed suicides-the third leading cause of death in this age group. Furthermore, adolescent MDD is a strong predictor of MDD in adulthood, which carries its own burden of disadvantage.2

The importance of specific neurobiological research in pediatric MDD has been recognized in the past decade. Recent studies of the pathophysiology of MDD have suggested that alteration of both neuroplasticity and cellular resilience play a critical role in the pathogenesis of MDD.3 This notion is supported by neuroimages showing significant reductions in regional CNS volume and number and/or size of neurons and glia, along with abnormalities in metabolic rate in specific brain regions. Complex mechanisms involving stress, the hypothalamic-pituitary-adrenal axis, excessive glutamatergic neurotransmission, and decreased expression of neurotrophic factors (such as brain-derived neurotrophic factor and Bcl-2 proteins) are believed to result in cell atrophy and cell death.3

Proton magnetic resonance spectroscopy (1H-MRS) allows for the assessment of certain brain chemicals that reflect neuronal activity and integrity, thus providing a noninvasive "window" into neuroplasticity. This article briefly reviews new research and presents current scientific data on the neurochemistry of pediatric MDD.

MrS: General Aspects

Safety concerns regarding radiation exposure in pediatric populations have limited the use of imaging techniques such as computed tomography, positron emission tomography, or single-photon emission computed tomography. Fortunately, MR imaging technology does not involve radiation exposure, thus alleviating safety concerns. MRS is a technique that provides metabolic assays of neuronal cells, cell energetics, density, membrane turnover, gliosis, and glycolysis through their respective surrogate markers, N-acetyl-l-aspartate (NAA), creatine, choline, myo-inositol (mI), and lactate levels.4,5

1H-MRS is frequently used to map the tissue-specific distribution of metabolites with 1-, 2-, or 3-dimensional localized spectra. These molecular images can be overlaid for reference on the anatomy from the structural MRI.6-9

NAA is the second most abundant amino acid in the CNS, and it is almost exclusively present in neuronal cell bodies and axons and is considered a putative marker of neuronal integrity and density.10,11 Its decrease may reflect axonal impairment (white matter abnormalities) or damage secondary to reduced glial support.12 Because oligodendrocytes play a crucial role in axonal myelination, NAA decline may reflect oligodendrocyte loss or dysfunction.

Choline is an essential component of membrane lipids, phosphatidylcholine, and sphingomyelin.13 The contribution of free choline to the signal is less than 5% and the contribution of acetylcholine is negligible.14 Elevated choline is attributed to abnormal cell membrane metabolism, myelin breakdown, or change in glial density.15 Choline also involves the second messenger system.

The creatine resonance is a composite peak comprising overlapping creatine and phosphocreatine resonances, representing the high-energy phosphate reserves in the cytosol of neurons and glia.16,17 Its elevation has been attributed to synergetic effects of oligodendrocytic remyelination and astrocytic microgliosis. It is believed to be relatively stable throughout the brain and therefore is used as a reference to gauge changes in other metabolites. However, not all MRS laboratories have followed this approach.

mI is considered to be a glial marker.18-20 Inositol is presumed to play a role in cerebral metabolism, but its precise mechanism remains unclear. mI is a precursor of the phosphatidyl-inositol second messenger system and has been implicated in MDD. Also, the mood-stabilizing agent lithium inhibits the enzyme inositol monophosphatase, which is involved in the catalytic conversion of inositol monophosphate into mI.

g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS and is integral in managing brain excitability. Glutamate, on the other hand, is an excitatory neurotransmitter that has been implicated in the pathogenesis of MDD. The resonances arising from glutamate, glutamine, and GABA are overlapping at 2.3 ppm and are often indistinguishable; this is referred to as Glx.

1

H-MRS in pediatric MDD

MRS research in MDD is still in its infancy and inconsistencies are rife. The discrepant findings may be attributed, in part, to methodology; for example, use of single voxel localization, which is susceptible to partial volume effects, given the small size and irregular shape of the striatum and thalamus; ratios to creatine instead of absolute quantification, which increase variability; and a lower, 1.5 Tesla magnetic field of lower sensitivity, spatial, and spectral resolutions. The variations may also reflect differing subject selection criteria (eg, age range, depression severity, medication status, and family history). Nonetheless, 1H-MRS studies in pediatric MDD have revealed new information about the neurochemistry of the disorder.

Accumulating evidence shows that MDD is associated with disturbances in pathways linking cortical, subcortical, and limbic sites. These regions include the anterior cingulate cortex, orbital cortex, striatum, amygdala, and hippocampus.21 These brain regions are linked and are believed to be critical in modulating emotional responses.

In general, MRS studies in pediatric MDD tend to confirm findings in adults implicating these regions. Seven studies have focused on the frontal cortex, 2 focused on the striatum, 1 focused on the thalamus, and 1 focused on the amygdala.

The frontal lobe

Several regions have been examined within the frontal lobe. These are regions that have been highly implicated in adult depression and include the anterior cingulate cortex, the dorsolateral prefrontal cortex, the left orbitofrontal cortex, and the prefrontal cortex.

Anterior cingulate cortex. A large body of evidence has linked the anterior cingulate cortex to MDD. The anterior cingulate cortex is placed anterior and ventral to the genu of the corpus callosum (termed "pregenual" and "subgenual"). In adults, striking reductions of up to 42% in mean gray matter volume of the subgenual prefrontal cortex were reported in several neuroimaging studies of familial MDD.22 A postmortem study of adults with familial MDD attributed gray matter reduction to reduced glial cell density in the subgenual prefrontal cortex.23 These findings suggest the potential role of 1H-MRS in identifying neurochemical alterations of MDD in this brain region.

Two separate 1H-MRS studies examined Glx and glutamate levels in the anterior cingulate cortex. In one study of 13 psychotropically naive adolescents with MDD and 13 healthy controls (aged 13 to 18), lower Glx levels in the anterior cingulate cortex of the MDD group were reported.24 Another study reported the same results in 14 children and adolescents with MDD (all medication-naive) and 14 matched comparisons (aged 10 to 19).25 In a later analysis of the same study, reduced Glx was found to contribute to glutamate but not to glutamine.26

Dorsolateral prefrontal cortex. Two 1H-MRS studies focused on the dorsolateral prefrontal cortex in pediatric MDD. These studies reported significant findings in the left dorsolateral prefrontal cortex but with conflicting results. One study reported increased absolute choline concentrations in the left dorsolateral prefrontal cortex,27 while a later study reported decreased choline and increased mI in the same region.28

It is important to note that these studies differed in the imaging technique used; 3-dimensional versus single-voxel, 0.8 cm3 voxel size versus 8 cm3, respectively. In addition, while in the first study all patients were psychotropically naive, in the second study, treatment with psychotropic agents was allowed at the time of the scan.

Left orbitofrontal cortex. There is only one study identified that focused on the left orbitofrontal cortex.29 Seventeen adolescents with MDD were compared with 28 healthy controls (aged 13 to 17). Patients with MDD were allowed to take psychotropic medications. Significant results showed higher ratios of choline/creatine and choline/NAA in the left orbitofrontal cortex of the group with MDD.

Prefrontal cortex. One study examined the prefrontal cortex of 12 children and adolescents who had MDD and 12 control subjects (aged 10 to 18). Patients were psychotropic medication-naive. The group with MDD was found to have increased choline/creatine in the right prefrontal cortex.30

Subcortical regions

Amygdala. The amygdala, part of the limbic system, is central to activating emotional responses and has been the focus of many imaging studies in MDD. Only one 1H-MRS study of adolescents with MDD (aged 14 to 18) examined this region. Decreased choline/creatine ratios were found in the left amygdala region of the MDD group (n = 11) compared with controls (n = 11).31

Thalamus and striatum (caudate and putamen). There are few studies that focus on these regions in pediatric MDD. The relationship between the basal ganglia and MDD has been inferred from the high comorbidity between MDD and Parkinson and Huntington disease, both basal ganglia-related disorders. In addition, morphometric and functional neuroimaging studies have documented a smaller caudate, putamen, and thalamus, as well as impaired metabolism and blood flow in the striatum and thalamus of patients with MDD.32-34

No significant metabolic alterations were found in choline and creatine levels of 18 children and adolescents with MDD and 18 controls. All patients were psychotropically naive.35,36

Our group recently completed a study that focused on the striatum and thalamus of adolescents with MDD (n = 13) compared with 10 controls. We identified increased choline and creatine only in the left caudate in patients with MDD.37

Conclusion

1H-MRS studies provide additional scientific support that impaired neuroplasticity may play a role in pediatric MDD as it does in adult MDD. In addition, findings of several studies reporting chemical changes only in the left hemisphere correlate with mounting evidence that implicates the left hemisphere in depression.38

Most studies found choline concentration or ratios to be significantly different between groups with MDD and healthy comparisons. Choline has been consistently implicated in adult MDD as well. Alterations in choline levels most likely reflect accelerated cell membrane turnover caused by glial impairment that has been linked to MDD.23,39

Another possible mechanism for choline elevation involves the second messenger system. Phosphocholine, which is a major choline signal contributor and a metabolite of phosphatidylcholine, is an important source of the second messenger, diacylglycerol, known to participate in intracellular signal transduction pathways13,40,41 that are thought to contribute to MDD pathogenesis.42

The findings of impaired Glx levels in the anterior cingulate cortex add neurochemical evidence to the role of impaired neuroplasticity in pediatric and adult patients with MDD. The findings also suggest that pediatric MDD does not entail neuronal loss, because none of the studies documented decreased NAA.

MRS research in pediatric MDD has great potential. It could allow for the early detection of neurochemical alterations, contribute to the identification of at-risk individuals, foster preventive therapeutic options, and provide biological markers for treatment response. Methodological inconsistencies and low statistical power limit current 1H-MRS findings. Future studies should enroll larger cohorts of medication-naive patients, comprise longitudinal follow-up, and strive to focus on specific clinical subgroups such as familial MDD and specific ages at onset (adolescent-onset vs childhood-onset). Such refinements in study design would improve the yield of this powerful, noninvasive neuroimaging technology.

References:

References


1.

Kessler RC, Walters EE. Epidemiology of

DSM-III-R

major depression and minor depression among adolescents and young adults in the National Comorbidity Survey.

Depress Anxiety.

1998;7:3-14.

2.

Weissman MM, Wolk S, Goldstein RB, et al. Depressed adolescents grown up.

JAMA.

1999;281: 1707-1713.

3.

Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression.

Nat Med.

2001;7:541-547.

4.

Danielsen EA, Ross B.

Magnetic Resonance Spectroscopy Diagnosis of Neurological Diseases.

New York: Marcel Dekker; 1999.

5.

Christiansen P, Toft P, Larsson HB, et al. The concentration of

N

-acetyl aspartate, creatine + phosphocreatine, and choline in different parts of the brain in adulthood and senium.

Magn Reson Imaging.

1993;11:799-806.

6.

Segebarth CM, Baleriaux DF, Luyten PR, den Hollander JA. Detection of metabolic heterogeneity of human intracranial tumors in vivo by

1

H NMR spectroscopic imaging.

Magn Reson Med.

1990;13:62-76.

7.

Duyn JH, Gillen J, Sobering G, et al. Multisection proton MR spectroscopic imaging of the brain.

Radiology.

1993;188:277-282.

8.

Duyn JH, Moonen CT. Fast proton spectroscopic imaging of human brain using multiple spin-echoes.

Magn Reson Med.

1993;30:409-414.

9.

Davie CA, Hawkins CP, Barker GJ, et al. Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions.

Brain.

1994;117:49-58.

10.

Simmons ML, Frondoza CG, Coyle JT. Immunocytochemical localization of

N

-acetyl-aspartate with monoclonal antibodies.

Neuroscience.

1991;45:37-45.

11.

Moffett JR, Namboodiri MA, Cangro CB, Neale JH. Immunohistochemical localization of

N

-acetylaspartate in rat brain.

Neuroreport.

1991;2:131-134.

12.

Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis.

N Engl J Med.

1998;338:278-285.

13.

Loffelholz K, Klein J, Koppen A. Choline, a precursor of acetylcholine and phospholipids in the brain.

Prog Brain Res.

1993;98:197-200.

14.

Miller DH, Albert PS, Barkhof F, et al. Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force.

Ann Neurol.

1996;39:6-16.

15.

Urenjak J, Williams SR, Gadian DG, Noble M. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types.

J Neurosci.

1993;13:981-989.

16.

Kemp GJ. Non-invasive methods for studying brain energy metabolism: what they show and what it means.

Dev Neurosci.

2000;22:418-428.

17.

Inglese M, Li BS, Rusinek H, et al. Diffusely elevated cerebral choline and creatine in relapsing-remitting multiple sclerosis.

Magn Reson Med.

2003; 50:190-195.

18.

Kim JP, Lentz MR, Westmoreland SV, et al. Relationships between astrogliosis and

1

H MR spectroscopic measures of brain choline/creatine and

myo

-inositol/creatine in a primate model.

AJNR.

2005; 26:752-759.

19.

Cecil KM. MR spectroscopy of metabolic disorders.

Neuroimaging Clin N Am.

2006;16:87-116, viii.

20.

Arnold DL, De Stefano N. Magnetic resonance spectroscopy in vivo: applications in neurological disorders.

Ital J Neurol Sci.

1997;18:321-329.

21.

Drevets WC. Neuroimaging studies of mood disorders.

Biol Psychiatry.

2000;48:813-829.

22.

Drevets WC, Price JL, Simpson JR Jr, et al. Subgenual prefrontal cortex abnormalities in mood disorders.

Nature.

1997;386:824-827.

23.

Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders.

Proc Natl Acad Sci U S A.

1998;95:13290-13295.

24.

Mirza Y, Tang J, Russell A, et al. Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression.

J Am Acad Child Adolesc Psychiatry.

2004;43:341-348.

25.

Rosenberg DR, Mirza Y, Russell A, et al. Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls.

J Am Acad Child Adolesc Psychiatry.

2004; 43:1146-1153.

26.

Rosenberg DR, MacMaster FP, Mirza Y, et al. Reduced anterior cingulate glutamate in pediatric major depression: a magnetic resonance spectroscopy study.

Biol Psychiatry.

2005;58:700-704.

27.

Farchione TR, Moore GJ, Rosenberg DR. Proton magnetic resonance spectroscopic imaging in pediatric major depression.

Biol Psychiatry.

2002;52:86-92.

28.

Caetano SC, Fonseca M, Olvera RL, et al. Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients.

Neurosci Lett.

2005;384:321-326.

29.

Steingard RJ, Yurgelun-Todd DA, Hennen J, et al. Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy.

Biol Psychiatry.

2000;48:1053-1061.

30.

MacMaster FP, Kusumakar V. Choline in pediatric depression.

McGill J Med.

2006:24-27.

31.

Kusumakar V, MacMaster FP, Gates L, et al. Left medial temporal cytosolic choline in early onset depression.

Can J Psychiatry.

2001;46:959-964.

32.

Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression.

J Neuropsychiatry Clin Neurosci.

1997;9:471-481.

33.

Tremblay LK, Naranjo CA, Graham SJ, et al. Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe.

Arch Gen Psychiatry.

2005;62: 1228-1236.

34.

Lacerda AL, Nicoletti MA, Brambilla P, et al. Anatomical MRI study of basal ganglia in major depressive disorder.

Psychiatry Res.

2003;124:129-140.

35.

Smith EA, Russell A, Lorch E, et al. Increased medial thalamic choline found in pediatric patients with obsessive-compulsive disorder versus major depression or healthy control subjects: a magnetic resonance spectroscopy study.

Biol Psychiatry.

2003;54: 1399-1405.

36.

Mirza Y, O'Neill J, Smith EA, et al. Increased medial thalamic creatine-phosphocreatine found by proton magnetic resonance spectroscopy in children with obsessive-compulsive disorder versus major depression and healthy controls.

J Child Neurol.

2006;21: 106-111.

37.

Gabbay V, Broody R, Nishawala M, et al. Proton magnetic resonance spectroscopy in adolescents with major depressive disorder. Presented at: American Academy of Child and Adolescent Psychiatry 53rd Annual Meeting; October 24-29, 2006; San Diego.

38.

Vataja R, Leppavuori A, Pohjasvaara T, et al. Poststroke depression and lesion location revisited.

J Neuropsychiatry Clin Neurosci.

2004;16:156-162.

39.

Hamidi M, Drevets WC, Price JL. Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes.

Biol Psychiatry.

2004;55:563-569.

40.

Exton JH. Signaling through phosphatidylcholine breakdown.

J Biol Chem.

1990;265:1-4.

41.

Exton JH. Phosphatidylcholine breakdown and signal transduction.

Biochim Biophys Acta.

1994; 1212:26-42.

42.

Manji HK, Chen G. Post-receptor signaling pathways in the pathophysiology and treatment of mood disorders.

Curr Psychiatry Rep.

2000;2:479-489.

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