Elevated Monoamine Oxidase A Levels in the Brain - Medizin ...

ORIGINAL ARTICLE 

Elevated Monoamine Oxidase A Levels in the Brain 

An Explanation for the Monoamine Imbalance of Major Depression 

Jeffrey H. Meyer, MD, PhD; Nathalie Ginovart, PhD; Anahita Boovariwala, BSc; Sandra Sagrati, BSc; 

Doug Hussey, BSc; Armando Garcia, BSc; Trevor Young, MD, PhD; Nicole Praschak-Rieder, MD; 

Alan A. Wilson, PhD; Sylvain Houle, MD, PhD 

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 

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). 

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. 3-11 

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%. 3-8,12,13 Even the largest reported re- 

emission tomography, was used to measure MAO-A DV S 

(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 DV S 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. 

Arch Gen Psychiatry. 2006;63:1209-1216 

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, NOV 2006 WWW.ARCHGENPSYCHIATRY.COM 

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©2006 American Medical Association. All rights reserved. 

ductions 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 Studies 9 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 investigation 16 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 depres-

Activity, kBq/mL 


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Prefrontal Cortex 

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Time, min 

Anterior Cingulate Cortex 

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sion 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, 18-23 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 DV S (specific distribution volume), an index 

of MAO-A density, is measurable in vivo in the brain 

using harmine labeled with carbon 11 ([ 11 C]harmine) posi- 



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Thalamus 

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Temporal Cortex 

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Figure 1. Time activity curves for harmine labeled with carbon 11 ([ 11 C]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) DV S (an index of MAO-A density) values within 10% of their group mean, and these 2 participants have near identical areas under their 

[ 11 C]harmine plasma input curves (within 1%). 

tron emission tomography (PET). 25,26 [ 11 C]Harmine is a 

selective, reversible PET radiotracer for MAO-A, and 

MAO-A DVS is an index of specifically bound [ 11 C]harmine. 

25-27 [ 11 C]Harmine PET demonstrates the requisite 

properties of a PET radiotracer for measurement of MAO- 

A 25-27 : harmine has a high affinity (Ki=2nM) and a selective 

affinity for the MAO-A enzyme. [ 11 C]Harmine shows 

high brain uptake in humans with the greatest uptake in 

regions with the highest MAO-A density. 25-27 [ 11 C]Harmine 

also shows reversible kinetics in all regions with specific 

binding in humans 25-27 (Figure 1). The MAO-A inhibitors 

can fully displace specific binding of [ 11 C]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 

[ 11 C]harmine over clorgyline labeled with carbon 11 

([ 11 C]clorgyline) is that [ 11 C]harmine has reversible brain 


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©2006 American Medical Association. All rights reserved.

kinetics, whereas [ 11 C]clorgyline shows slowly reversible 

brain kinetics. 29 The main advantage of [ 11 C]harmine over 

deuterium-substituted [ 11 C]clorgyline is that deuteriumsubstituted 

[ 11 C]clorgyline has substantial non–MAO-A 

binding in humans in some brain regions. 29 

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. 3-6,8,30 

METHODS 

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 [ 11 C]harmine PET scan. Participants were between 

20 and 49 years of age. Healthy participants were age 

matched within 4 years to depressed patients (Table). 

Allstudyparticipants(MDEandhealthy)werephysicallyhealthy 

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 

borderlineandantisocialpersonalitydisorderusingtheStructured 

Clinical Interview for DSM-IV for Axis II disorders. 33 All participants 

underwent a urine drug screen on the day of the [ 11 C]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 disorders 32 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. 

Table. Sample Demographics 

Demographic 

Healthy 

Group 

(n = 17) 

Depressed 

Group 

(n = 17) 

Age, mean ± SD, y 34 ± 8 34 ± 8 

Women, No. 7 9 

Men, No. 10 8 

Education, mean ± SD, y 15 ± 2 15 ± 2 

Psychiatric diagnosis* None Major depressive episode; 

major depressive disorder 

First major depressive episode NA 8 

Second major depressive episode NA 5 

Third major depressive episode NA 4 

No previous antidepressant 

treatment 

NA 11 

Previous antidepressant 

treatment† 

NA 6 

Abbreviation: NA, not applicable. 

*Study participants did not have comorbid Axis I disorders, borderline 

personality disorder, or antisocial personality disorder. 

†No study participant with depression had received antidepressant 

treatment within the past 5 months. 

IMAGE ACQUISITION AND ANALYSIS 

A dose of 370 MBq of intravenous [ 11 C]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. [ 11 C]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 

[ 11 C]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 [ 11 C]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 


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MAO-A DVs 

40 

30 

20 

10 

0 

Healthy Participants 

Depressed Participants 

Prefrontal 

Cortex ∗ 

Temporal 

Cortex ∗ 

Anterior 

Cingulate Cortex† 

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 [ 11 C]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 

DV S. 26 The DV S 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, 

DV S was referred to as DVB. 26 ) The DVS can be expressed 

in terms of kinetic rate parameters as: 

where K 1 and k 2 are influx and efflux rates for radiotracer passage 

across the blood-brain barrier and k 3 and k 4 describe the radioligand 

transfer between the free and nonspecific compartment 

and the specific binding compartment. K 1/k2 is similar among 

different individuals (for further details see Ginovart et al 26 ). 

The [ 11 C]harmine PET measure of the MAO-A DV S was previously 

found to be reliable. Under test-retest conditions, for 

the regions evaluated in this study, the mean absolute difference 

in MAO-A DV S, expressed as a percentage of MAO-A DV S, 

ranged from 5% to 17% (n=6 individuals) (J.H.M., A.A.W., S.H., 

et al, unpublished data, 2005). 

STATISTICAL ANALYSIS 

Posterior 

Cingulate Cortex ∗ 

The primary analysis was an independent-sample t test comparingMAO-ADV 

Sbetweendepressedandhealthyindividualsforeach 

brain region, since it was expected that MAO-A DV S would be significantly 

elevated in each brain region in the depressed group. We 

chose to examine each individual region because it would also be 

ofinterestwhethertherewerenodifferencesinsomebrainregions. 

Thalamus ∗ Caudate† Putamen† Hippocampus† Midbrain‡ 

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 

DV S was 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. 

DVs = K1 × 

k2 k3 k4 RESULTS 

As expected, given the previous report of no relationship 

between age or sex with MAO-A density, 37 there was no 

relationship between age or sex and regional MAO-A DV S 

in our sample (analysis of covariance; effect of age, F 1,32=0.3 

to 0.001; P=.50 to .98; analysis of variance; effect of sex, 

F1,32=0.4 to 0.001; P=.50 to .98). 

There was a highly significant elevation in MAO-A DVS 

in all regions in the depressed group compared with the 

healthy group (independent-sample t test, P=.001 to 

�.001; mean difference in MAO-A DVS between groups, 

34%; mean effect size, 2) (Figure 2). Because this was 

not the situation of a single significant finding among a 

number of nonsignificant findings, a correction for multiple 

comparisons was not performed. A multiple analysis 

of variance was also performed, with regional MAO-A 

DVS as the dependent variable and diagnosis as a predictor 

variable (effect of diagnosis: F 9,24=5.8; P� .001). 

To examine whether MAO-A DVS is related to particular 

clinical characteristics in addition to diagnosis, 

secondary post hoc analyses were performed using the 

Pearson correlation coefficient, correlating regional 

MAO-A DVS with the following clinical characteristics: 

duration of illness, episode number, duration of episode, 

illness severity based on the 17-item Hamilton 

Depression Rating Scale Score, 34 and lifetime history of 

antidepressant treatment. None of the correlations 

reached the trend level (P�.10). 

COMMENT 

The main finding was that MAO-A DVS, the index of 

MAO-A density, was elevated throughout the brain on 

average by 34% (2 SDs). Monoamine oxidase A metabo- 


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A B 

MAO-A 

Vesicle Containing 

Monoamine 

C D 

MAO-A 

Presynaptic 

Transporter 



Postsynaptic 

Receptor 

lizes all 3 major monoamines (serotonin, norepinephrine, 

and dopamine) 17 in the brain, and no previous study 

has convincingly explained why monoamine levels may 

be low during MDEs; therefore, it is plausible that an elevation 

in brain MAO-A density is the primary monoamine-lowering 

process during MDEs. 

Elevated brain MAO-A density during MDEs has important 

implications for the monoamine theory of depression 

when combined with previous neuroimaging results 

in medication-free depressed patients 4,8,36,38 (ie, no 

medication for �3 months). An advanced monoamine 

theory (Figure 3A-D) can be conceptualized: During 

an MDE, elevated MAO-A levels increase the metabolism 

of monoamines such as serotonin, norepinephrine, 

and dopamine. Thereafter, individual monoamine transporter 

densities have a secondary influence on specific 

extracellular monoamine levels. If the monoamine transporter 

density for a particular monoamine is low, the effect 

of greater monoamine metabolism on extracellular monoamine 

levels is somewhat attenuated, resulting in a moderate 

monoamine loss. Long-term, moderate loss of a particular 

monoamine in specific brain regions eventually 

results in moderate severity of particular symptoms. If 

the monoamine transporter density for a particular monoamine 

is not low during an MDE, then the extracellular 

concentration of the monoamine is severely reduced and 

symptoms associated with long-term regional loss of that 

particular monoamine eventually become severe. In short, 

MAO-A 

MAO-A 

Presynaptic 

Transporter 



Postsynaptic 

Receptor 

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 norepinephrinereleasing 

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. 

elevated MAO-A levels can be viewed as a general monoamine-lowering 

process (with no relationship to particular 

symptoms), whereas the regional density of monoamine 

transporters has a selective influence on particular 

monoamines (with a strong relationship with particular 

symptoms). 

Data to support this advancement of the monoamine 

model are found in investigations of drug-free (ie, no 

medication for �3 months), depressed individuals with 

early-onset depression who do not have comorbid psychiatric 

or medical illnesses. 4,8,36,38 This includes 4 earlier 

PET brain imaging studies 4,8,36,38 in addition to the present 

study. The binding potential (BP) is often measured 

in PET studies and is an index of receptor density. During 

MDEs, greater regional serotonin transporter BP is 

associated with more severely pessimistic thinking (dysfunctional 

attitudes), 8 and greater striatal dopamine 

transporter BP is associated with more severe motor 

retardation. 4 In addition, during MDEs, increased cortex 

serotonin 2 BP occurs when severe pessimism is 

present, 36 and increased striatal dopamine 2 BP occurs 

when severe motor retardation is present. 38 Increased 

serotonin 2 receptor density can occur when serotonin 

is lowered in the long term, 39-42 and increased dopamine 

2 BP (as measured with PET with raclopride labeled 

with carbon 11) can occur when the extracellular dopamine 

level is low. 38 These studies 4,8,36,38 argue that 

patients with MDEs and greater monoamine transporter 


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density are additionally vulnerable to monoamine loss, 

show up-regulation (or increase in BP) of receptors sensitive 

to monoamine loss, and have greater severity of 

particular symptoms. 

This advancement in monoamine theory relies on the 

principle that a single explanation for the findings that 

directly support it is likely to be the correct explanation. 

Although one could conceive of different explanations 

for individual findings, 4,8,36,38 it would be extremely 

difficult to generate an alternative, single, cohesive 

explanation for the entire study series. The statistical significance 

of the comparison of mean regional MAO-A DVS 

for the current study was P=3�10 −6 , and the statistical 

significances of the previous 4 studies were high (P=.003 

for elevations in prefrontal serotonin 2 BP in depression 

with severe pessimistic thinking, P=.005 for elevation in 

striatal dopamine 2 BP for depressed individuals with motor 

retardation, P�.001 for correlation between prefrontal 

serotonin transporter BP and pessimistic thinking, and 

P=.006 for correlation between striatal dopamine transporter 

BP and motor retardation). Each study sample was 

gathered separately. In general, the probability of multiple 

independent chance events occurring together can 

be estimated by multiplying the probability of each separate 

event occurring. For each study, the significance reflects 

the likelihood of the finding occurring by chance 

alone. If one took the specific viewpoint that the findings 

of these studies are unrelated, independent chance 

events (ie, there is no common model to explain them), 

then the probability of all of these findings occurring together 

results in a P value of 2.7�10 −16 . Given the resulting 

statistical significance, it is exceedingly unlikely 

that these findings represent independent chance events. 

In addition, the entire sample consisted of 89 depressed 

and 103 healthy individuals. Depressed patients were drug 

free for at least 3 months plus 5 half-lives of medication. 

None had comorbid medical illnesses or Axis I psychiatric 

illness, 4,8,36,38 and 94% of the sample was nonsmoking. 

The collective set of highly significant findings in 

unbiased samples across a series of studies to support a 

common theory must be considered strongly. 

Our monoamine model of depression is consistent with 

many other findings of monoamine research in depression. 

This modern model views elevated MAO-A levels 

as a pathologic process that results in excessive loss of 3 

major monoamines, since increasing monoamine levels 

through antidepressant inhibition of MAO-A or inhibition 

of monoamine transporter function are longstanding 

therapeutic treatments. 30 This model also predicts 

that indices of monoamine loss should be best 

detected in subgroups with high severity of particular 

symptoms. Therefore, investigations that compare monoamine 

abnormalities between depressed and healthy individuals 

and do not selectively sample individuals with 

severe symptom clusters should find abnormalities in depression 

at a rate exceeding chance but not at a frequency 

near 100%, as is observed. 3-8,30,38 

In this advanced monoamine model, it is proposed that 

long-term rather than short-term monoamine loss is important 

for several reasons. First, the period for which 

monoamine receptor abnormalities are found in the studies 

directly supporting this model 4,8,36,38 spans the months 

to years an MDE is typically present before treatment. 1 Second, 

long-term increasing of monoamine levels reduces 

symptoms substantially more than short-term increasing 

of monoamine levels. 30 Third, monoamine levels increased 

in the long term, consequent to antidepressant administration, 

influence secondary and tertiary messenger 

system targets, such as cyclic adenosine monophosphate 

response element binding protein and brain-derived neurotrophic 

factor, particularly in animal models. 43 Available 

evidence demonstrates that these targets are abnormal 

during MDEs. 43 An advanced model of long-term 

monoamine loss has the advantage of potentially being consistent 

with secondary and tertiary messenger theories of 

depression if long-term monoamine loss influences the 

same secondary and tertiary messenger targets as monoamine 

levels increased in the long term. 

An important facet of this advanced monoamine model 

is that, depending on the combinations of long-term serotonin, 

norepinephrine, or dopamine loss, one would expect 

different combinations of the associated symptoms 

during depressive episodes. This is entirely consistent with 

the particular definition of an MDE that requires 5 of 9 

symptoms. 44 In addition, this advanced monoamine model 

proposes that variable levels of long-term monoamine loss 

result in variable levels of symptom severity across individuals, 

as is commonly observed. 

A significant problem in depression research is a lack 

of valid animal models. 43 An important implication of this 

study is that new animal models of major depression can 

be created that have chronic monoaminergic abnormalities 

similar to what is found in untreated depressive episodes. 

For example, dexamethasone administration to 

older Sprague-Dawley rats can increase MAO-A density 

in the brain by 300%, 45 and Wistar rats can be genetically 

selected to breed high platelet serotonin transporter 

density and low platelet serotonin density sublines. 

46 Breeding of rat sublines with high brain 

monoamine transporter density and exposing these animals 

to an MAO-A–increasing paradigm could generate 

a new animal model of depression with long-term monoamine 

loss. 

There are some limitations in this work. Our study has 

the major advantage of measuring MAO-A DVS in vivo. On 

the other hand, there are some disadvantages with PET. 

The resolution of PET does not permit detailed localization 

of MAO-A at the cellular level. For example, an increase 

in MAO-A density could be attributed to a greater 

density of MAO-A per mitochondrion or an increase in mitochondrial 

density within MAO-A–containing neurons. 

A second issue is that, although MAO-A DVS is an index 

of MAO-A density, it also reflects 2 other parameters, namely 

free and nonspecific binding and MAO-A affinity for the 

radioligand. These other parameters are unlikely to influence 

the interpretations of this study. The estimates of free 

and nonspecific binding in the present study (found by obtaining 

the difference between total distribution volume 26 

and specific distribution volume) were similar in patients 

and healthy controls, and an elevation in MAO-A affinity 

would be expected to have a similar functional effect of increasing 

monoamine removal through increased binding 

to monoamines. We also acknowledge in the interpretation 

of this study that there are other neurochemical and 


1214 


neuropathologic models of depression (which may be interrelated). 

In addition, this article is not intended to argue 

that other neurochemical and neuropathologic processes 

do not play a role in antidepressant treatment. Finally, 

we acknowledge that scientific models of disease are typically 

replaced with more complicated scientific models of 

disease, and it is possible that this new theory of monoamine 

dysregulation in untreated MDEs will be replaced 

by a more complicated theory at a future date. 

Future study should investigate why MAO-A levels are 

elevated during MDEs. It is well known that the plasma 

cortisol concentration is elevated during depression, 30,43 

and it was demonstrated that dexamethasone administration 

can substantially increase MAO-A activity in 

19-month-old Sprague-Dawley rats. 45 Since dexamethasone 

and cortisol both have agonist effects on glucocorticoid 

receptors, it is possible (should this animal model 

be representative of adult humans) that greater cortisol 

agonist effects during depressive episodes contribute to 

an elevation in MAO-A levels. It would also be interesting 

to explore a relationship between genotypes and 

MAO-A levels through complex models such as geneenvironment 

interaction designs in large samples. 47 It 

seems unlikely that a simple, single genotype to MAO-A 

activity relationship will be explanatory, since Balciuniene 

et al 48 did not find any simple, single-genotype relationship 

to MAO-A activity in a postmortem study of 

humans. 

This is the first study, to our knowledge, to measure 

MAO-A levels in the brain in medication-free individuals 

during MDEs secondary to major depressive disorder. 

An index of MAO-A density, the MAO-A DVS, was 

elevated by 34% (or 2 SDs) in depressed individuals. The 

sizable magnitude of this finding and the absence of other 

compelling explanations for a primary monoaminelowering 

process during MDEs led to the conclusion that 

elevated MAO-A density should be viewed as the primary 

monoamine-lowering process during untreated major 

depression. This finding has major implications for 

modernizing the monoamine theory of depression. Taken 

in conjunction with other studies of serotonin and dopamine 

receptors in medication-free depressed individuals, 

4,8,36,38 it can be argued that monoamine transporter 

density has a secondary role to influence long-term loss 

of specific monoamines, resulting in a model of variable 

severity of long-term monoamine loss during untreated 

major depression. Important implications of the new 

monoamine theory of depression are that different combinations 

of severe long-term monoamine loss can explain 

the variety of symptom cluster presentations found 

in MDEs and that great potential exists to generate more 

complex animal models of persistent monoamine loss that 

may closely resemble the monoaminergic abnormalities 

of untreated depression. 

Submitted for Publication: January 1, 2006; final revision 

received February 22, 2006; accepted February 23, 2006. 

Correspondence: Jeffrey H. Meyer, MD, PhD, College 

Street Site, Centre for Addiction and Mental Health, PET 

Centre, 250 College St, Toronto, Ontario, Canada M5T 

1R8 (jeff.meyer@camhpet.ca). 

Financial Disclosure: Dr Meyer has received grant sup- 

port for other projects from Eli Lilly, GlaxoSmithKline, 

and Lundbeck. 

Funding/Support: This research received project support 

from the Canadian Institutes of Health Research 

(FRN-69052). 

Additional Information: To be presented in part at a symposia 

at the Society of Biological Psychiatry; May 19, 2006; 

Toronto, Ontario. 

Acknowledgment: We thank technicians Alvina Ng, BSc, 

and Ken Singh, BSc, research assistant Irina Vitcu, BSc, 

chemist Alexandra Chestakova, MSc, and engineers Terry 

Bell, BTech, and Ted Brandts-Harris, BASc, for their assistance 

with this project. We thank Stephen Kish, PhD, 

for his suggestions regarding the manuscript. 

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