The Neurochemistry of Pediatric Major Depressive Disorder

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.

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(Drug information on 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.

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.

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.