Dataset Information

Persistent ?2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder.

ABSTRACT: Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the ?2 subunit, may be effective in treating patients with major depressive disorder. Using [123I]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of ?2-subunit-containing nAChRs (?2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied ?2*-nAChR binding in postmortem brain samples from depressed subjects.The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one [123I]5-I-A-85380 SPECT scan and an MRI scan. The availability of ?2*-nAChRs was quantified as VT/fP. Postmortem analysis of ?2*-nAChR binding was conducted with [123I]5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects.The ?2*-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, ?2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in ?2*-nAChR number between groups in the postmortem study.Depressed patients have lower ?2*-nAChR availability than do healthy subjects. The difference between ?2*-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine.

SUBMITTER: Saricicek A

PROVIDER: S-EPMC3494404 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder.

Saricicek Aybala A Esterlis Irina I Maloney Kathleen H KH Mineur Yann S YS Ruf Barbara M BM Muralidharan Anjana A Chen Jason I JI Cosgrove Kelly P KP Kerestes Rebecca R Ghose Subroto S Tamminga Carol A CA Pittman Brian B Bois Frederic F Tamagnan Gilles G Seibyl John J Picciotto Marina R MR Staley Julie K JK Bhagwagar Zubin Z

The American journal of psychiatry 20120801 8

<h4>Background</h4>Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the β2 subunit, may be effective in treating patients with major depressive disorder. Using [123I]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of β2-subunit-containing nAChRs (β2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied β2*-nAChR binding in postmortem brain samples from depressed subje ...[more]

PMID: 22772158

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Dataset Information

Persistent ?2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder.

Publications

Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder.

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