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Comparative Study
. 2010 Jun;20(6):379-87.
doi: 10.1016/j.euroneuro.2010.02.006. Epub 2010 Mar 15.

Antidepressants, but not antipsychotics, modulate GR function in human whole blood: an insight into molecular mechanisms

L A Carvalho  1 , B A Garner, T Dew, H Fazakerley, C M Pariante
Affiliations
Comparative Study

Antidepressants, but not antipsychotics, modulate GR function in human whole blood: an insight into molecular mechanisms

L A Carvalho et al. Eur Neuropsychopharmacol. 2010 Jun.

Abstract

Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Recently, we showed that this impairment is indeed due to a dysfunction of GR in depressed patients (Carvalho et al., 2009), and that the ability of the antidepressant clomipramine to decrease GR function in peripheral blood cells is impaired in patients with major depression who are clinically resistant to treatment (Carvalho et al. 2008). To further investigate the effect of antidepressants on GR function in humans, we have compared the effect of the antidepressants clomipramine, amytriptiline, sertraline, paroxetine and venlafaxine, and of the antipsychotics, haloperidol and risperidone, on GR function in peripheral blood cells from healthy volunteers (n=33). GR function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. Compared to vehicle-treated cells, all antidepressants inhibited dexamethasone (DEX, 10-100nM) inhibition of LPS-stimulated IL-6 levels (p values ranging from 0.007 to 0.1). This effect was specific to antidepressants, as antipsychotics had no effect on DEX-inhibition of LPS-stimulated IL-6 levels. The phosphodiesterase (PDE) type 4 inhibitor, rolipram, potentiated the effect of antidepressants on GR function, while the GR antagonist, RU-486, inhibited the effect of antidepressants on GR function. These findings indicate that the effect of antidepressants on GR function are specific for this class of psychotropic drugs, and involve second messenger pathways relevant to GR function and inflammation. Furthermore, it also points towards a possible mechanism by which one maybe able to overcome treatment-resistant depression. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.

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Figures

Figure 1
Figure 1
Tricyclic antidepressants clomipramine (n=16) and Amitryptiline (n=8) inhibited LPS-stimulated IL-6 levels. Results are expressed by MEAN±SEM of IL-6 levels (ng/mL). *p<0.05.
Figure 2
Figure 2
SSRI/SNRI sertraline (n=10, venlafaxine n=9, and paroxetine n=14) do not inhibit LPS-stimulated IL-6 levels. Results are expressed by MEAN±SEM of IL-6 levels (ng/mL). *p<0.05.
Figure 3
Figure 3
Dexamethasone (1–1000 nM) suppression of LPS-stimulated IL-6 levels in whole blood from healthy subjects (n=5–20) IC50DEX=4.5nM.
Figure 4
Figure 4
Dexamethasone (100 and 10 nM) suppression of LPS-stimulated IL-6 levels in healthy subjects (n = 9) with (hashed columns) or without (white columns) clomipramine (10 μM) and amitryptiline (10 μM). Results are expressed by MEAN ± SEM of the % dexamethasone suppression (LPS-stimulated IL-6 levels with glucocorticoid divided by LPS-stimulated IL-6 levels without glucocorticoids). *p<0.05.
Figure 5
Figure 5
Dexamethasone (100 and 10 nM) inhibition of LPS-stimulated IL-6 levels in healthy subjects with (hashed columns) or without (white columns) A) Sertraline (10 μM, n = 10), B) Venlafaxine (10 μM, n = 9, and C) Paroxetine (10 μM=14). Results are expressed by MEAN ± SEM of the % dexamethasone suppression (LPS-stimulated IL-6 levels with glucocorticoid divided by LPS-stimulated IL-6 levels without glucocorticoids). *p<0.05.
Figure 6
Figure 6
A) Dexamethasone (100 and 1 nM) inhibition of LPS-stimulated IL-6 levels in whole blood from healthy subjects (n = 17–19) with (hashed/dark columns) or without (white columns) haloperidol 10 μM or risperidone (10 μM). Results are expressed by MEAN ± SEM of the % dexamethasone inhibition (LPS-stimulated IL-6 levels with glucocorticoid divided by LPS-stimulated IL-6 levels without dexamethasone).
Figure 7
Figure 7
A) LPS-stimulated IL-6 levels in whole blood of healthy subjects (n = 8–14) in the presence or absence of Dexamethasone (100 nM), RU-486 (40 μM) and clomipramine 10 μM. Results are expressed by MEAN ± SEM of the % glucocorticoid inhibition (LPS-stimulated IL-6 levels with glucocorticoid divided by LPS-stimulated IL-6 levels without glucocorticoids). *p<0.05.
Figure 8
Figure 8
A) LPS-stimulated IL-6 levels in whole blood of healthy subjects (n = 5–20) in the presence or absence of dexamethasone (10 nM), clomipramine 10 μM or rolipram (10 μM). Results are expressed by MEAN ± SEM of the % dexamethasone inhibition (LPS-stimulated IL-6 levels with glucocorticoid divided by LPS-stimulated IL-6 levels without dexamethasone). *p<0.05.
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References

    1. Aihara M, Ida I, Yuuki N, Oshima A, Kumano H, Takahashi K, Fukuda M, Oriuchi N, Endo K, Matsuda H, Mikuni M. HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions. Psychiatry Res. 2007;155:245–256. - PubMed
    1. Allen JA, Halverson-Tamboli RA, Rasenick MM. Lipid raft microdomains and neurotransmitter signalling. Nat. Rev. Neurosci. 2007;8:128–140. - PubMed
    1. Augustyn M, Otczyk M, Budziszewska B, Jagla G, Nowak W, Basta-Kaim A, Jaworska-Feil L, Kubera M, Tetich M, Leskiewicz M, Lason W. Effects of some new antidepressant drugs on the glucocorticoid receptor-mediated gene transcription in fibroblast cells. Pharmacol. Rep. 2005;57:766–773. - PubMed
    1. Avella J, Lehrer M, Katz M, Minden E. Two cases involving clomipramine intoxication. J. Anal. Toxicol. 2004;28:504–508. - PubMed
    1. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Kunzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Kohnlein O, Dabitz H, Bruckl T, Muller N, Pfister H, Lieb R, Mueller JC, Lohmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller-Myhsok B. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat. Genet. 2004;36:1319–1325. - PubMed

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