Genotype-controlled analysis of plasma dopamine beta-hydroxylase activity in psychotic unipolar major depression.
BACKGROUND
Plasma activity of dopamine beta-hydroxylase (DbetaH), the enzyme that converts dopamine to norepinephrine, is reportedly lower in patients with unipolar major depression with psychotic features (UDPF) than in those with nonpsychotic unipolar major depression (UD). Plasma DbetaH is under genetic control by the structural locus encoding DbetaH protein, DBH. This study tested the hypothesis that diagnosis-specific allelic variation at DBH accounts for lower plasma DbetaH in UDPF.


METHODS
Plasma DbetaH activity was measured in samples from patients with UDPF (n = 33) and UD (n = 45). Genotypes were determined at several functional DBH polymorphisms, including C-1021T, a single nucleotide polymorphism (SNP) in the proximal 5' region that associates with variation in plasma DbetaH activity.


RESULTS
Mean plasma DbetaH activity was significantly lower in UDPF than in UD. Genotyping at DBH did not reveal genetic associations distinguishing UDPF from UD. A two-way analysis of variance showed significant effects of genotype and diagnostic group but no significant interaction.


CONCLUSIONS
Although the effects of the diagnosis of UDPF, and of DBH allele status, on plasma DbetaH activity were replicated, the lower plasma DbetaH in patients with UDPF was not accounted for by DBH genotype. Several explanations for this result are possible. First, other variants at DBH, or at other loci, could account for the findings. Second, nongenetic factors could account for the differences in plasma DbetaH. In this regard, we hypothesize that abnormal regulation of hypothalamic-pituitary-adrenal function in UDPF lowers expression of DbetaH protein, which could in turn alter the ratio of dopamine and norepinephrine in noradrenergic neurons, thereby promoting development of psychotic symptoms.
Cubells
Joseph F
JF
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
Price
Lawrence H
LH
Meyers
Barnett S
BS
Anderson
George M
GM
Zabetian
Cyrus P
CP
Alexopoulos
George S
GS
Nelson
J Craig
JC
Sanacora
Gerard
G
Kirwin
Paul
P
Carpenter
Linda
L
Malison
Robert T
RT
Gelernter
Joel
J
D000328:Adult; D000368:Aged; D000483:Alleles; D002874:Chromosome Mapping; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D004299:Dopamine beta-Hydroxylase / Q000097:blood / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*
D004299:Dopamine beta-Hydroxylase; D006854:Hydrocortisone