Targeting Serotonin With Common Antidepressants Induces Rapid Recovery From Cytopenia

Abstract

The hematopoietic system uses several, yet undiscovered, factors to adapt to stresses such as chemotherapy, infections, or bleeding. Serotonin is commonly known as a neurotransmitter but is also produced and used in peripheral organs. In particular, we have shown that serotonin synthesized in the bone marrow is necessary for erythroid progenitors' survival and proliferation. Serotonin levels can be increased by FDA approved antidepressants called selective serotonin reuptake inhibitors (SSRI). In this work, we report a previously unknown role of SSRI in the recovery of cytopenia, after autologous hematopoietic stem cell transplantation in patients and after sub-lethal irradiation in mice. We also observed an unexpected cooperation between SSRI and G-CSF on the improvement of the 3 hematopoietic lineages. Of note, SSRI do not seem to affect blood cells production in the absence of stress-induced hematopoiesis. We propose that the serotonergic system could be a valuable therapeutic target in stress-induced cytopenia, especially as a rescue after radiation or chemotherapy.

Keywords: G-CSF; antidepressants; autologous hematopoietic stem cell transplantation; chemotherapy; cytopenia; serotonin.

Targeting the serotonergic system as a novel strategy for reducing chemotherapy-induced cytopenia and their complications in human.

Figure 1.

SSRIs hasten recovery from ASCT-related cytopenia in humans. (A) Recovery from neutropenia after ASCT in retrospective cohort of 22 patients treated with SSRIs and 66 paired controls. Mean number of days elapsed before reaching neutrophil count of > 500/mm³ was 12.2 in SSRI group and 14.3 in control group (P = .0216). (B) Recovery from neutropenia after ASCT in same cohort, according to treatment received: G-CSF, SSRI without G-CSF, or none (control without G-CSF). (C) Days of hospitalization, (D) progression-free survival, and (E) overall survival after ASCT in same cohort, for SSRI and control groups. (F) Number of days CD34 + cells were collected (left graph) and number of CD34 + cells collected (right graph), prior to ASCT, in second retrospective cohort, for SSRI and control groups. Abbreviations: ASCT, autologous stem cell transplant; G-CSF, granulocyte colony-stimulating factor; ns, not significant.

Figure 2.

SSRI (fluoxetine), alone or with G-CSF, hastens recovery from irradiation-induced cytopenia in mice. (A), (B), (D): Horizontal lines represent lower limit of normal range for hemoglobin (11 g/dL), platelets (300 × 10³/mm³), and neutrophils (0.5 × 10³/mm³), and threshold for profound anemia (8 g/dL), in mice.^, (A) In vivo rescue experiments with fluoxetine: hemoglobin (g/dL), platelet (10³/mm³), and neutrophil (10³/mm³) levels in WT mice (n = 7) treated with fluoxetine or placebo (control) from D − 1 (ie, 1 day before sublethal irradiation) until end of experiment; data from 3 independent experiments. (B) In vivo rescue experiments with G-CSF, alone or with fluoxetine: hemoglobin (g/dL), platelet (10³/mm³), and neutrophil (10³/mm³) levels in WT mice (n = 5) treated with G-CSF, alone or with fluoxetine, from D − 1 before sublethal irradiation until end of experiment; data from 3 independent experiments. (C) Flow cytometry analysis of hematopoietic progenitor cells in bone marrow of WT mice (n = 5) treated with fluoxetine or placebo (control) from D − 1 before sublethal irradiation. Change over time for erythroid progenitors shown on left; D13 data for all progenitors shown on right. Erythroid progenitors: cKIT⁺, Ter119^+/int, CD71^+/−; proerythroblasts: cKIT⁺, CD71⁺, Ter119^int; EryA: cKIT⁺, Ter119^+/int, CD71⁺, FSC-A^high; EryB: cKIT⁺, Ter119^+/int, CD71^+/int, FSC-A^low.; EryC: cKIT⁺, Ter119^+/int, CD71⁻, FSC-A^low.; megakaryocytes: Ter119⁻, cKIT^+,CD41⁺; granulocyte progenitors: lineage-negative, removal of cKIT⁺CD34⁻cells, maturation from myeloblasts to neutrophils according to cKIT and Ly6G markers (see Supplimentary Fig. 1A). (D) Timing of fluoxetine treatment in rescue experiments in mice: hemoglobin (g/dL), platelet (10³/mm³), and neutrophil (10³/mm³) levels in WT mice (n = 5) treated with placebo (control) or fluoxetine from D − 7 to D0 (ie, day of irradiation), from D − 7 on, or from D − 1 on; data from 3 independent experiments. (E) Hemoglobin, platelet, and neutrophil levels in WT mice (n = 7) treated with placebo (control) or fluoxetine for 0 days, 7 days, 3 weeks, 4 weeks, or 6 weeks, at steady state without any other intervention. (F) Flow cytometry analysis of hematopoietic stem and progenitor cells in bone marrow of WT mice (n = 7) treated with placebo (control) or fluoxetine for 4 weeks, at steady state without any other intervention. Abbreviations: LSK, Lin⁻, Sca1⁺, CD117⁺cells; LT-HSC and ST-HSC, long-term (LSK, CD150⁺, CD48⁻) and short-term (LSK, CD150⁺, CD48⁺) hematopoietic stem cells; LRP, lineage-restricted progenitors (LSK, CD150⁻, CD48⁺); CMP, common myeloid progenitors (LK, CD34⁺, CD16/32^int); GMP, granulocyte macrophage progenitors (Lin⁻, Sca1⁻, CD117⁺, CD34⁺, CD16/32^high); MEP, megakaryocyte erythroid progenitors (Lin⁻, Sca1⁻, CD117⁺, CD34⁻, CD16/32^low) (see Supplementary Fig. 1B); G-CSF, granulocyte colony-stimulating factor; W, week; WT, wild type.