OBJECTIVE: Monoamine oxidase-A (MAO-A) is a key mitochondrial enzyme that 
metabolizes biogenic amine neurotransmitters such as dopamine and serotonin. 
Individuals with atypical depression (AD) are particularly responsive to 
treatment with MAO inhibitors (MAOIs). Biomarker tests are essential for prompt 
diagnosis of AD, and to identify those with an altered brain neurotransmitter 
metabolism who may selectively respond to MAOI therapy.
METHODS: In a sample of 118 Scandinavian patients with treatment-resistant 
depression who are naive to MAOI therapy, we investigated the associations 
between a common MAOA functional promoter polymorphism (MAOA-uVNTR), 
cerebrospinal fluid (CSF) neurotransmitter metabolites, and AD susceptibility. 
The metabolites for dopamine (homovanillic acid, HVA), serotonin 
(5-hydroxyindoleacetic acid) and noradrenaline (3-methoxy-4-hydroxyphenylglycol) 
were measured in the CSF.
RESULTS: AD was associated with the female sex and a higher HVA in CSF 
(P=0.008). The carriers of the MAOA-uVNTR short allele were significantly 
overrepresented among women with AD (P=0.005; odds ratio=4.76; 95% confidence 
interval=1.5-13.1; statistical power=80.0%). Moreover, the MAOA-uVNTR genotype 
significantly influenced the HVA concentration (P=0.01) and showed a strong 
trend in relation to 5-hydroxyindoleacetic acid concentration (P=0.057) in 
women. The mediational statistical analyses showed the CSF-HVA concentration as 
a key driver of the relationship between MAOA-uVNTR genotype and AD.
CONCLUSION: The association of the MAOA-uVNTR with both susceptibility to AD and 
dopamine metabolite (HVA) concentration lends further biological plausibility 
for high MAO-A enzyme activity as a mechanistic factor for genetic 
predisposition to AD through altered dopamine turnover. Our observations provide 
new evidence on the in-vivo functional significance of the MAOA-uVNTR short 
allele as a high activity variant.