More threads by David Baxter PhD

David Baxter PhD

Late Founder
Increased Brain MAO-A Levels in Major Depressive Disorder
by Donald S. Robinson, MD
Primary Psychiatry, 2007;14(12):32-34

Deficiency of monoamine neurotransmitter levels was proposed as the underlying cause of depressive disorders over 40 years ago. Extensive biochemical studies and pharmacologic evidence show that all antidepressants modulate functional levels of monoamine neurotransmitters implicated in depression (ie, serotonin, norepinephrine, and dopamine). Evidence of norepinephrine, serotonin, and, more recently, dopamine?s key roles in the biology of depression is compelling; however, the primary mechanism of monoamine depletion in depression remains unresolved.

The leading targets for the cause of depression include deficient monoamine neurotransmitter synthesis and dysregulation of both monoamine neuroreceptors and monoamine neuronal transporters. Despite intense study, none of these etiologies have emerged as the primary factor underlying monoamine deficiency. Recently, investigators from the University of Toronto conducted a series of positron emission tomography (PET) studies providing compelling evidence that elevated brain monoamine oxidase A (MAO-A) levels could be the primary monoamine-lowering mechanism in major depressive disorder (MDD).1

Possible Causes of Monoamine Deficiency in Depression
Studies of postmortem brain tissues from patients with depression or suicidal behavior have failed to detect a deficiency in either tyrosine hydroxylase, the rate-limiting enzyme for norepinephrine synthesis, or tryptophan hydroxylase, the rate-limiting enzyme for serotonin synthesis.2-5 The post-mortem studies? results are inconsistent, either detecting no change or in some cases modest increases in enzymatic pathways for monoamine synthesis in brain tissues of affected individuals.

Since many studies find no decrement in monoamine transporter density indices in brain tissues of depressed and suicidal patients, loss of monoamine-releasing neurons appears to be an unlikely mechanism of neurotransmitter deficiency. Even those studies reporting a reduction found decreases in monoamine transporter indices of only modest magnitude (≤25%)5-8 in contrast to much greater monoamine transporter loss associated with the neurodegenerative disorders.9

In a comprehensive review of the evidence relating to mechanisms of serotonin (5-HT) depletion in depression, Stockmeier10 commented on the many sources of biologic variance in postmortem and brain imaging studies, which confound interpretation of results. In addition to postmortem degradation of brain monoamines and enzymes, other uncontrolled variables need to be considered, such as absent or retrospective diagnoses; exposure to smoking, drugs or alcohol; and other sources of biologic and demographic variance.

Extensive evidence supports the notion that a functional 5-HT deficiency plays a role in depression, but investigations still fail to identify the cause of this monoamine deficiency. A wealth of evidence documents that biochemical abnormalities are present in depression, including low 5-hydroxy-indoleacetic acid in the cerebrospinal fluid of patients with suicidal behavior, decreased 5-HT uptake and 5-HT transporter- (5-HTT) binding sites in brain and platelets of depressed subjects, and blunted neuroendocrine response to serotonergic stimuli. Alterations of 5-HT receptor densities have been documented in the prefrontal cortex of subjects with depression and suicide; 5-HT2A receptors were increased and 5-HT1A receptors decreased in cerebral cortical regions of both drug-free and antidepressant-treated patients.11

Assessing current understanding of the various biochemical abnormalities reported in postmortem and brain imaging studies, Stockmeier10 concluded that the methodologic heterogeneity of these investigations, with their often inconsistent and conflicting results, precludes attempts at identifying the underlying pathophysiology of serotonin dysfunction in depression.

5-HT Transporter in Depression
Neuroimaging studies utilizing an 11C-labeled specific ligand for monoamine transporter-binding sites now permit in vivo 5-HTT density measurement in brain regions of subjects experiencing a major depressive episode (MDE).12 Brain 5-HTT binding potential, which serves as an index of transporter-receptor density, may be a key function during an MDE because the monoamine transporter regulates extracellular 5-HT levels within the central nervous system (CNS). 5-HTT binding potential was assessed in 22 nonsmoking, medication-free (≥3 months) patients with MDEs and 20 age-matched controls. No overall group differences in binding potential between patients and healthy patients were observed in any of the brain regions studied by PET. However, a post hoc analysis of the data found a correlation between highly negativistic attitude and increased transporter-binding potential (mean increase=21%).12

PET Study of Brain MAO-A
This same group of investigators employed a positron emission tomography (PET) radiotracer selective for the monoamine oxidase (MAO)-A isozyme, 11C-labeled harmine, to assess the amount present of this enzyme, which serves as the major catabolic pathway in the CNS for the monoamine neurotransmitters serotonin and norepinephrine. Studies in animal models and in humans at clinically relevant doses indicate that harmine is a specific and reversible ligand for the MAO-A form of the enzyme.13-15 Harmine?s specific distribution volume, which is derived from the ratio of brain and plasma harmine concentrations at equilibrium, provides a measure of MAO-A enzyme density and serves as an index for the amount of enzyme present in various brain regions.

This milestone study found consistent and marked differences in the specific distribution volume of MAO-A in untreated, depressed patients with MDD and matched healthy controls in several areas of the brain.1 Methodologic strengths of this study include the fact that PET testing involved living, non-smoking, medication-free patients who were carefully diagnosed by structured interview for presence of MDE. The increase in MAO-A distribution volume in MDE patients was highly significant compared with normal controls, with a mean increase of 34% (P<0.001) and an effect size of two standard deviations. This difference in MAO-A levels represents a striking disparity between patients and healthy subjects. MAO-A enzyme levels were elevated in MDE patients throughout every brain region tested, including the prefrontal cortex, temporal cortex, anterior and posterior cingulated cortex, thalamus, caudate, putamen, hippocampus, and midbrain.

Since MAO-A metabolizes all three major monoamine neurotransmitters (selectively, for norepinephrine and serotonin) and serves as the major catabolic pathway in the CNS for each of these transmitters, it is plausible that elevated MAO-A density constitutes the primary factor leading to monoamine deficiency. No prior study has convincingly explained why monoamine levels are deficient in depression. The presence of elevated MAO-A levels, by enhancing the catabolism of monoamine neurotransmitters, may produce a basal state of monoamine depletion predisposing to depression. Other secondary influences, e.g., differences in monoamine transporters and receptor sensitivity, may further modulate extracellular monoamine concentrations, affecting symptom type, severity, and response to treatment.

It is postulated that a state of functional monoamine deficiency underlies depressive disorders, but the primary cause has not been elucidated despite extensive investigation. A recent PET neuroimaging study of brain MAO-A levels in patients with MDD found a marked increase in this catabolic enzyme compared with healthy subjects. Methodologic strengths of this study include the fact that measurements were conducted in living, nonsmoking, and medication-free patients carefully screened for presence of an MDE. Both the effect size and the ubiquitous nature of this increase in MAO-A enzyme levels in all brain regions studied suggest that elevated MAO-A levels may be the primary cause of monoamine depletion in depression.

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  13. Bergstrom M, Westerberg G, Langstrom B. 11C-harmine as a tracer for monoamine oxidase A (MAO-A): in vitro and in vivo studies. Nucl Med Biol. 1997;24(4):287-293.
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  15. Ginovart N, Meyer JH, Boovariwala A, et al. Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain. J Cereb Blood Flow Metab. 2005;26(3):330-344.
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