Benzodiazepines and the potential trophic effect of antidepressants on dentate gyrus cells in mood disorders

Abstract

Modest antidepressant response rates of mood disorders (MD) encourage benzodiazepine (BZD) co-medication with debatable benefit. Adult hippocampal neurogenesis may underlie antidepressant responses, but diazepam co-administration impairs murine neuron maturation and survival in response to fluoxetine. We counted neural progenitor cells (NPCs), mitotic cells, and mature granule neurons postmortem in dentate gyrus (DG) from subjects with: untreated DSM-IV MD (n=17); antidepressant-treated MD (MD*ADT, n=10); benzodiazepine-antidepressant-treated MD (MD*ADT*BZD, n=7); no psychopathology or treatment (controls, n=18). MD*ADT*BZD had fewer granule neurons vs. MD*ADT in anterior DG and vs. controls in mid DG, and did not differ from untreated-MD in any DG subregion. MD*ADT had more granule neurons than untreated-MD in anterior and mid DG and comparable granule neuron number to controls in all dentate subregions. Untreated-MD had fewer granule neurons than controls in anterior and mid DG, and did not differ from any other group in posterior DG. MD*ADT*BZD had fewer NPCs vs. MD*ADT in mid DG. MD*ADT had more NPCs vs. untreated-MD and controls in anterior and mid DG. MD*ADT*BZD and MD*ADT had more mitotic cells in anterior DG vs. controls and untreated-MD. There were no between-group differences in mid DG in mitotic cells or in posterior DG for any cell type. Our results in mid-dentate, and to some degree anterior dentate, gyrus are consistent with murine findings that benzodiazepines counteract antidepressant-induced increases in neurogenesis by interfering with progenitor proliferation. We also confirmed, in this expanded sample, our previous finding of granule neuron deficit in untreated MD.

Early survival and delayed death of developmentally‐born dentate gyrus neurons

“…Altered production and survival of developmentally‐born DG neurons is also relevant for a number of disorders that are associated with large‐scale structural changes in the hippocampus, and sometimes the DG in particular, such as autism (Saitoh, Karns, & Courchesne, ; Schumann et al, ), schizophrenia (Lodge & Grace, ; Tamminga, Stan, & Wagner, ) and depression (McKinnon, Yucel, Nazarov, & MacQueen, ). For example, recent reports indicate that depressed patients have fewer total DG neurons in the anterior hippocampus, which can be restored by SSRI antidepressants (Boldrini et al, ; Mahar et al, ). While antidepressant treatments are often cited for their proneurogenic properties, our findings indicate that changes in the developmentally‐born cell population could also contribute to changes in total granule cell number.…”

Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood

“…The human anterior hippocampus, which is analogous to the ventral hippocampus in rodents, is smaller in unmedicated patients with depression and larger in antidepressant-treated patients than in healthy individuals 15 . Non-human primates with increased anxiety-like behaviour and neuroendocrine activity also show an increase in metabolism in the anterior hippocampus 16,17 .…”

The current state of the neurogenic theory of depression and anxiety

“…In contrast to the inconsistent results from counts of progenitor cells and dividing cells, postmortem studies consistently show an increase in total dentate granule cell number and dentate gyrus size in medicated depressed patients as compared to non-medicated patients [28,62]. This may be a better integrated measure of AHN than counts of progenitor cells.…”