Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression.
BACKGROUND
Adult neurogenesis is coupled to angiogenesis in neurogenic niches in the dentate gyrus (DG) and increased by antidepressants in rodents. We hypothesized that, in major depressive disorder (MDD), antidepressants increase neural progenitor cells (NPCs) and capillaries in the human DG.


METHODS
Neural progenitor cells and capillaries, detected on hippocampal sections by immunohistochemistry for neural stem cell protein, were quantified by stereology in matched MDDs (untreated, n = 12), MDD treated with selective serotonin reuptake inhibitors (MDD*SSRI, n = 6) or tricyclic antidepressants (MDD*TCA, n = 6), and nonpsychiatric control subjects (n = 12), all confirmed by psychological autopsy.


RESULTS
The MDD*SSRI had a larger capillary area and more NPCs versus MDDs (p = .034 and p = .008, respectively) and control subjects (p = .010 and p = .002, respectively) in the whole DG, more NPCs in the anterior (pes, p = .042) and central (midbody, p = .004) DG, and greater capillary area in the pes (p = .002) and midbody (p = .021). The NPC number and capillary area correlated positively in the whole sample (R2 = .454, p < .001) and in treated subjects (R2 = .749, p = .001). We found no NPCs or antidepressant-related angiogenesis in CA1 and parahippocampal gyrus. The DG volume correlated positively with NPC number (p = .004) and capillary area (p < .001) and differed between groups in whole hippocampus (p = .013) and midbody (p = .036). Age negatively correlated with NPC number (p = .042), capillary area (p = .037), and bifurcations (p = .030). No gender effect was detected.


CONCLUSIONS
Antidepressants increase human hippocampal NPCs and angiogenesis selectively in the anterior and mid DG. These results raise the possibility of a causal relationship between angiogenesis and neurogenesis, as seen in other proliferating tissues, and support their possible role in the mechanism of action of antidepressants.
Department of Psychiatry, Columbia University, Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York 10032, USA. mb928@columbia.edu
Maura
M
Boldrini
René
R
Hen
Mark D
MD
Underwood
Gorazd B
GB
Rosoklija
Andrew J
AJ
Dwork
J John
JJ
Mann
Victoria
V
Arango
D000328:Adult; D053687:Adult Stem Cells / Q000187:drug effects*; D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011180:Postmortem Changes
D000928:Antidepressive Agents; D007381:Intermediate Filament Proteins; D019394:Ki-67 Antigen; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; D019408:Platelet Endothelial Cell Adhesion Molecule-1