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Original Article |

Elevated Monoamine Oxidase A Levels in the Brain:  An Explanation for the Monoamine Imbalance of Major Depression FREE

[+] Author Affiliations

Author Affiliations: Vivian M. Rakoff PET Imaging Centre (Drs Meyer, Ginovart, Praschak-Rieder, Wilson, and Houle, Mss Boovariwala and Sagrati, and Messrs Hussey and Garcia) and Mood and Anxiety Disorders Division (Drs Meyer and Young), Clarke Division, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario; and Department of General Psychiatry, Medical University of Vienna, Vienna, Austria (Dr Praschak-Rieder).


Arch Gen Psychiatry. 2006;63(11):1209-1216. doi:10.1001/archpsyc.63.11.1209.
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Published online

Context  The monoamine theory of depression proposes that monoamine levels are lowered, but there is no explanation for how monoamine loss occurs. Monoamine oxidase A (MAO-A) is an enzyme that metabolizes monoamines, such as serotonin, norepinephrine, and dopamine.

Objective  To determine whether MAO-A levels in the brain are elevated during untreated depression.

Setting  Tertiary care psychiatric hospital.

Patients  Seventeen healthy and 17 depressed individuals with major depressive disorder that met entry criteria were recruited from the care of general practitioners and psychiatrists. All study participants were otherwise healthy and nonsmoking. Depressed individuals had been medication free for at least 5 months.

Main Outcome Measure  Harmine labeled with carbon 11, a radioligand selective for MAO-A and positron emission tomography, was used to measure MAO-A DVS(specific distribution volume), an index of MAO-A density, in different brain regions (prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, caudate, putamen, thalamus, anterior temporal cortex, midbrain, hippocampus, and parahippocampus).

Results  The MAO-A DVS was highly significantly elevated in every brain region assessed (t test; P = .001 to 3×10−7). The MAO-A DVS was elevated on average by 34% (2 SDs) throughout the brain during major depression.

Conclusions  The sizable magnitude of this finding and the absence of other compelling explanations for monoamine loss during major depressive episodes led to the conclusion that elevated MAO-A density is the primary monoamine-lowering process during major depression.

Figures in this Article

Major depressive disorder is an important illness because it has a 1-year prevalence of 2% to 5% and ranks fourth among causes of death or injury.1 For more than 30 years, it has been theorized that levels of monoamines, such as serotonin, norepinephrine, and dopamine, are generally low in the brain during untreated major depressive episodes (MDEs).2 However, no convincing mechanism of monoamine loss has ever been found.311

Previous investigations of monoamine transporters and monoamine synthesis enzymes have not identified a prominent monoamine-lowering process during untreated depressive episodes. Loss of monoamine-releasing neurons is an unlikely mechanism of monoamine loss, since some investigations report no reduction in monoamine transporters and the largest reported reductions in monoamine transporter density indices range from 14% to 25%.38,12,13 Even the largest reported reductions in monoamine transporter indices in depression are low compared with monoamine transporter loss observed in symptomatic neurodegenerative disease.14 Moreover, no abnormality in an index of serotonin transporter density was found in vivo in untreated depressed individuals.8 Decreased monoamine synthesis is unlikely during depression because investigations of monoamine synthesis enzymes in monoamine nuclei tend to find no change or modest increases in depressed individuals.10,11,15 Studies9 attempting to determine whether monoamine precursor uptake is reduced in depression are inconclusive because they are typically confounded by recent antidepressant use. Abnormally elevated monoamine oxidase B density seems less likely to occur in depression, as one investigation16 of monoamine oxidase B density in the amygdala found no significant difference in depressed individuals.

Monoamine oxidase A (MAO-A) is a logical enzyme to investigate in depression because it regulates levels of all 3 major monoamines (serotonin, norepinephrine, and dopamine) in the brain.17 Whether MAO-A levels in the brain are abnormal during MDEs is unknown because each previous investigation of MAO-A in the brain has had at least 2 critical confounders and/or limitations,1823 including complete nonspecificity of technique for MAO-A vs monoamine oxidase B, enrollment of study participants who had recently taken medication, unclear diagnosis of individuals who committed suicide, small sample size, and lack of differentiation between early-onset depression and late-onset depression. In contrast to the typical, early-onset depression before the age of 40 years, late-onset depression probably has a different pathophysiologic mechanism attributable to lesions and/or degenerative disease.24

The MAO-A DVS(specific distribution volume), an index of MAO-A density, is measurable in vivo in the brain using harmine labeled with carbon 11 ([11C]harmine) positron emission tomography (PET).25,26 [11C]Harmine is a selective, reversible PET radiotracer for MAO-A, and MAO-A DVS is an index of specifically bound [11C]harmine.2527 [11C]Harmine PET demonstrates the requisite properties of a PET radiotracer for measurement of MAO-A2527: harmine has a high affinity (Ki = 2nM) and a selective affinity for the MAO-A enzyme. [11C]Harmine shows high brain uptake in humans with the greatest uptake in regions with the highest MAO-A density.2527 [11C]Harmine also shows reversible kinetics in all regions with specific binding in humans2527 (Figure 1). The MAO-A inhibitors can fully displace specific binding of [11C]harmine in animal models,25,27 and MAO-A inhibitors at clinically tolerable doses can displace 80% of specific binding in humans.26 The metabolites of harmine are polar and do not cross the blood-brain barrier.28 The main advantage of [11C]harmine over clorgyline labeled with carbon 11 ([11C]clorgyline) is that [11C]harmine has reversible brain kinetics, whereas [11C]clorgyline shows slowly reversible brain kinetics.29 The main advantage of [11C]harmine over deuterium-substituted [11C]clorgyline is that deuterium-substituted [11C]clorgyline has substantial non–MAO-A binding in humans in some brain regions.29

Place holder to copy figure label and caption
Figure 1

Time activity curves for harmine labeled with carbon 11 ([11C]harmine) demonstrating reversible kinetics. Time activity curves for a representative depressed individual (closed circles) and a healthy individual (open circles) are shown. This pair of study participants was chosen because each has monoamine oxidase A (MAO-A) DVS (an index of MAO-A density) values within 10% of their group mean, and these 2 participants have near identical areas under their [11C]harmine plasma input curves (within 1%).

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The hypothesis of the present study is that the MAO-A DVS will be elevated throughout the brain during MDEs in medication-free individuals with major depressive disorder and typical early-onset illness. An elevation in MAO-A density is hypothesized because greater MAO-A could excessively lower brain monoamine levels.17 The location of elevated MAO-A density was hypothesized to be throughout the brain because monoamine receptor abnormalities in depression consistent with lowered monoamine levels have been reported in several brain regions, including the prefrontal cortex, striatum, and midbrain.36,8,30

PARTICIPANTS

Twenty individuals with an MDE and major depressive disorder were recruited, and 17 depressed individuals completed the protocol (mean ± SD age, 34 ± 8 years; 8 men and 9 women). Seventeen age-matched healthy individuals were recruited (mean ± SD age, 34 ± 8 years; 10 men and 7 women). Each underwent an [11C]harmine PET scan. Participants were between 20 and 49 years of age. Healthy participants were age matched within 4 years to depressed patients (Table).

All study participants (MDE and healthy) were physically healthy and nonsmoking and had no history of neurotoxin use. Participants were nonsmoking because it is reported that smoking can lower MAO-A levels, which could create greater variance in measurement.31 Women in perimenopause or menopause were excluded. Healthy participants were screened to rule out any Axis I disorders, and depressed participants were screened to rule out any comorbid Axis I disorders using the Structured Clinical Interview for DSM-IV.32 All participants were screened to rule out borderline and antisocial personality disorder using the Structured Clinical Interview for DSM-IV for Axis II disorders.33 All participants underwent a urine drug screen on the day of the [11C]harmine PET scan. All depressed patients underwent common blood tests to rule out medical causes of disturbed mood (thyroid function, electrolyte levels, and complete blood cell count).

For depressed patients, the mean ± SD age at onset of illness was 23 ± 10 years. Patients were in their first (n = 8), second (n = 5), or third (n = 4) MDE. No patient with depression had received antidepressant treatment within the past 5 months, and 11 depressed patients had never received antidepressant treatment. For depressed patients, a diagnosis of MDE secondary to major depressive disorder was based on the Structured Clinical Interview for DSM-IV for Axis I disorders32 and a consultation with a psychiatrist (J.H.M.). For patients with MDE, the minimum severity for enrollment was based on a cutoff score of 17 on the 17-item Hamilton Depression Rating Scale.34 The mean ± SD Hamilton Depression Rating Scale score for participants with MDE was 22 ± 3. Additional exclusion criteria included MDE with psychotic symptoms, bipolar disorder (type I or II), history of self-harm or suicidality outside episodes of depression, and history of alcohol or other drug abuse.

For each study participant, written consent was obtained after the procedures had been fully explained. The study and recruitment procedures were approved by the Research Ethics Board for Human Subjects at the Centre for Addiction and Mental Health, University of Toronto.

IMAGE ACQUISITION AND ANALYSIS

A dose of 370 MBq of intravenous [11C]harmine was administered as a bolus for each PET scan. An automatic blood sampling system was used to measure arterial blood radioactivity continuously for the first 10 minutes. Manual samples were obtained at 5, 10, 15, 20, 30, 45, 60, and 90 minutes. The radioactivity in whole blood and plasma was measured as described previously.26 Frames were acquired as follows: 15 frames of 1 minute, then 15 frames of 5 minutes. [11C]Harmine was of high radiochemical purity (>96%; mean ± SD, 98.4% ± 0.8%; n = 34) and high specific activity (mean ± SD, 43 ± 18 terabecquerels/mmol at the time of injection). The PET images were obtained using a GEMS 2048-15B camera (intrinsic in-plane resolution; full width at half maximum, 5.5 mm; Scanditronix Medical, General Electric, Uppsala, Sweden). All images were corrected for attenuation using a germanium 68/gallium 68 transmission scan and reconstructed by filtered back projection using a Hanning filter.

For the region of interest (ROI) method, each participant underwent magnetic resonance imaging (GE Signa 1.5-T scanner; spin-echo sequence, T1-weighted image; x, y, z voxel dimensions, 0.78, 0.78, and 3 mm, respectively; GE Medical Systems, Milwaukee, Wis). The ROIs were drawn on magnetic resonance images that were coregistered to each summed [11C]harmine PET image using a mutual information algorithm.35 The location of the ROI was verified by visual assessment of the ROI on the summated [11C]harmine PET image. The ROIs were drawn to sample the prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, caudate, putamen, thalamus, anterior temporal cortex, midbrain, and a hippocampal and parahippocampal region. The definitions of the ROIs were similar to our previous investigations.8,36 The prefrontal cortex regions (left and right) were drawn in transverse planes extending 32.5 mm in the z-axis and included Brodmann areas 9, 10, 46, and part of 8 and 47. The anterior cingulate cortex (Brodmann areas 24 and part of 32) was sampled from adjacent transverse planes extending 26 mm in the z-axis. The putamen and thalamus were drawn within adjacent transverse planes to maximally sample the individual structures. These planes extended 13 mm in the z-axis. The remaining regions were sampled from adjacent transverse planes that extended 19.5 mm in the z-axis. For the temporal cortex, the anterior third of the temporal cortex was sampled, and this included Brodmann area 38 and part of 20, 21, and 22. The anterior cingulate cortex and the posterior cingulate cortex (part of Brodmann areas 23 and 30) were drawn in transverse planes relative to the corpus callosum.

The kinetics of [11C]harmine can be described with an unconstrained 2-tissue compartment model (described as method B in our previous publication).26 Highly identifiable fits with the unconstrained 2-tissue compartment model are obtainable for the DVS.26 The DVS is an index of specific binding and represents the concentration of the specifically bound radiotracer in tissue relative to plasma concentration at equilibrium. (In previous publications, DVS was referred to as DVB.26) The DVS can be expressed in terms of kinetic rate parameters as:

Figures

Place holder to copy figure label and caption
Figure 1

Time activity curves for harmine labeled with carbon 11 ([11C]harmine) demonstrating reversible kinetics. Time activity curves for a representative depressed individual (closed circles) and a healthy individual (open circles) are shown. This pair of study participants was chosen because each has monoamine oxidase A (MAO-A) DVS (an index of MAO-A density) values within 10% of their group mean, and these 2 participants have near identical areas under their [11C]harmine plasma input curves (within 1%).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2

Comparison of monoamine oxidase A (MAO-A) DVS(an index of MAO-A density) between depressed and healthy study participants. On average, MAO-A DVSwas elevated by 34% or 2 SDs in depressed individuals. The hippocampal region also samples the parahippocampus. Differences between groups were highly statistically significant in each region. *P<1×10−5; †P<1×10−4; ‡P = .001.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3

Modernization of monoamine theory of depression. A, Description of monoamine release in a synapse in a healthy person. B, During a major depressive episode, monoamine oxidase A (MAO-A) density is elevated, resulting in greater metabolism of monoamines, such as serotonin, norepinephrine, and dopamine, in the brain. C and D, Range of outcomes. If the monoamine transporter density for a particular monoamine is low during a major depressive episode (C), the effect of an elevated MAO-A level on reducing that particular monoamine in the extracellular space is somewhat attenuated, resulting in a moderate loss of monoamine. This eventually results in a moderate severity of symptoms associated with long-term loss of that particular monoamine. If the monoamine transporter density for a particular monoamine is not low during a major depressive episode (D), then there is no protection against the effect of elevated MAO-A levels. The extracellular concentration of the monoamine is severely reduced, and symptoms associated with long-term loss of that particular monoamine eventually become severe. Some postsynaptic receptors increase in density when their endogenous monoamine level is low in the long term. Mostly, MAO-A is found in norepinephrine-releasing neurons but is reported to be detectable in other cells, such as serotonin-releasing neurons and glia. Even so, MAO-A metabolizes serotonin, norepinephrine, and dopamine in vivo.

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