Abstract for presentation at 6th World Congress on Stress

Clomipramine and glucocorticoid function in depressed patients and healthy volunteers

  • Livia Carvalho, Stress, Psychiatry and Immunology Laboratory (SPI-Lab) Institute of Psychiatry, King's College London, United Kingdom
  • Mario Juruena, Section of Neurobiology of Mood Disorders and Stress, Psychiatry and Immunology (SPI-Lab). Institute of Psychiatry, United Kingdom
  • Dr Andrew Papadopoulos, Affective Disorders Unit, South London and Maudsley Trust, United Kingdom
  • Mrs Lucia Poon, Affective Disorders Unit, South London and Maudsley Trust, United Kingdom
  • R Kerwin, Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College London, United Kingdom
  • Dr Anthony Cleare, Institute of Psychiatry, United Kingdom
  • Dr Carmine Pariante, Division of Psychological Medicine, Institute of Psychiatry, King's College London, United Kingdom

    • Background: Impairment of glucocorticoid receptor mediated negative feedback on the hypothalamic-pituitary-adrenal axis has been demonstrated in patients with major depression in a phenomenon called glucocorticoid resistance. Interestingly, in vitro and in vivo data agree that this resistance can be overcome by the use of antidepressants, although the mechanism of action is still unclear. Our group and others have hypothesised that antidepressants overcome glucocorticoid resistance by inhibiting the steroid transporter p-glycoprotein - the transporter that limits steroids access to the brain. Methods: To further clarify the effect of antidepressants on glucocorticoid function, and its molecular mechanisms, we evaluated the effect of clomipramine on the in vitro glucocorticoid sensitivity of whole blood cells from 12 treatment resistant depressed patients and 21 controls. Whole blood was coincubated for 24hs with LPS 1ng/mL, clomipramine 10 μM and one of the following glucocorticoids: dexamethasone (100, 10 nM), prednisolone (1, 0.1 μM), cortisol (100 - 0.1 μM) or corticosterone (100 - 1 μM). Plasma was then separated by centrifugation and assayed for interleukin (IL)-6 by IMMULITE®. Results: Depressed patients had a trend towards higher unstimulated (unstimulated in ng/mL: 37.9 ± 12.4 in patients vs 11.9 ± 6.9 in controls, p=0.060) and significantly higher LPS-stimulated IL-6 levels than controls (stimulated in ng/mL: 919.0 ± 84.3 in patients vs 659.9 ± 39.4, in controls, p<0.005). In both groups, all glucocorticoids inhibited IL-6 production in a concentration dependent manner. Only in controls, however, clomipramine decreased glucocorticoid sensitivity. The difference reached statistical significance for all concentrations of dexamethasone and prednisolone and for cortisol on the concentration of 10 μM. As an example, compared to LPS-stimulated levels, IL-6 with dexamethasone 100 nM alone was 10.1 ± 1% in controls and 7.9 ± 0.5% in depressed; while with dexamethasone and clomipramine was 14.2 ± 2.2% in controls and 8.8 ± 0.7% in patients (P<0.005). Interestingly, the effect of clomipramine was not seen after coincubation with corticosterone - the only glucocorticoid tested that is not transported by p-glycoprotein. Conclusion: Depressed patients showed immune system activation compared to controls. Moreover, depressed patients who were resistant to antidepressant in vivo were also resistant to the effect of antidepressant in vitro. Our findings further support the notion that antidepressants have some effect in HPA axis activity that might be related to the transporter p-glycoprotein. These effects might be relevant for the mechanism of action of antidepressants. This study was funded by the UK MRC and the NARSAD.

    Conference Organiser - ICMS Pty Ltd