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Hippocampal Angiogenesis and Progenitor Cell Proliferation Are Increased with Antidepressant Use in Major Depression

  • Maura Boldrini
    Correspondence
    Address correspondence to Maura Boldrini, M.D., Ph.D., Assistant Professor, Department of Psychiatry, Columbia University, Research Scientist V, Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10032
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York

    Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York

    Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
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  • René Hen
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York

    Departments of Neuroscience and Pharmacology, Columbia University, New York, New York

    Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York
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  • Mark D. Underwood
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York

    Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York
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  • Gorazd B. Rosoklija
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York

    Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York

    Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia
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  • Andrew J. Dwork
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York

    Department of Pathology and Cell Biology, Columbia University, New York, New York

    Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York
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  • J. John Mann
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York

    Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York
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  • Victoria Arango
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York

    Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York
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      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.

      Key Words

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