- Email: [email protected]
P.2.b.012 Plasma cortisol levels and resilience in depressed patients
S338
P.2.b Affective disorders and antidepressants – Affective disorders (basic)
lower before treatment and approached the value observed within the control group (7.9±4.1 ng/ml) during 6 weeks of treatment with SSRIs. Conclusions: The blunted PRL response to a challenge with a single-dose of buspirone approaches normal value after 6-weeks SSRI treatment independently of clinical response. Our findings support a role for the 5-HT (1A) receptor in the etiology of MD, specifically at the postsynaptic site. References [1] Meltzer HY, Maes M, 1994, Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects. Biol Psychiatry 35, 316−23. [2] Moeller FG, Steinberg JL, Fulton M, Kramer G, Petty F, 1994, A preliminary neuroendocrine study with buspirone in major depression. Neuropsychopharmacology 10, 75−83. [3] Navines R, Martin-Santos R, Gomez-Gil E, Martinez de Osaba MJ, Luisa Imaz M, Gasto C, 2007, Effects of citalopram treatment on hypothermic and hormonal responses to the 5-HT(1A) receptor agonist buspirone in patients with major depression and therapeutic response. Psychoneuroendocrinology doi:10.1016/j.psyneuen.2007.01.006.
P.2.b.011 Antidepressant therapy and apoptosis of immnocompetent cells in patients with depressive disorders N. Vyalova1 ° , S. Ivanova1 , G. Simutkin1 , V. Semke2 . 1 Mental Health Research Institute, Laborratory of Cellular and MolecularBiological Investigations, Tomsk, Russia; 2 Mental Health Research Institute, Borderline States Department, Tomsk, Russia Introduction: In last years interdisciplinary investigations of psychoneuroimmunomodulation in clinic and therapy of stressrelated mental diseases are topical. Psychological stress and depressive disorder are associated with several immune alterations, including reduced cell proliferation and natural killer cell activity and disturbances of cytokine levels. Psychotropic (antidepressant) medications can be effect on various immune functions, including normal physiological programmed cell death of lymphocytes. Programmed death of cells by apoptosis is regarded as a protective mechanism of organism against an accumulation and spread of defective cells. Apoptosis is a normal physiological programmed cell death that can be enhanced by a variety of external stimuli, such as stress, viral infections, medications and pathological conditions. This phenomenon can be mediated via various pathways that cause condensation of the cytoplasm and chromatin, nuclear fragmentation, and ultimate sequestration of cellular contents into membrane-bound apoptotic bodies. The aim of this investigation was to study apoptosis of immunocompetent cells in the patients with depression in the process of the antidepressant therapy. Methods: We measured apoptosis in the mononuclears lymphocytes (MNLs) of peripheral blood) of 26 patients with depression and in 20 age- and gender-matched controls. The inclusion criterion was depression (diagnosed according to ICD10: F31 – bipolar affective disorder; F32 – depressive episode; F33 – recurrent affective disorder). The exclusion criteria were any other psychiatric disorder or any immunological disorder. The investigation was carried out in dynamics: before the beginning the pharmacotherapy against the background of depressive symptomatology and after the course of medication with selective serotonin re-uptake inhibitors (fluoxetine). We counted number of leukocytes, percent CD95+ lymphocytes and morphological changes characteristic of apoptosis in lymphocytes and neutrophils.
Results and Discussion: We observed significantly increased apoptosis in the MNLs of depressive patients: the percentage of lymphocytes with expression FAS-receptors was 19.47±1.02% (11.64±0.31% in control, p < 0.05). Level of spontaneous apoptosis of neutrophils in smears in patients with depressive disorder before treatment reliably differed from values observed in healthy persons (1.16±0.38% and 0.40±0.15%, respectively, p < 0.01). Also, we demonstrated a significant increase of lymphocytes with morphological changes characteristic of apoptosis (nuclear condensation, vacuolation, and blebbing) in the depressive patients (2.03±0.72% and 0.88±0.18% in control, p < 0.05). The normalisation of CD95+lymphocytes was observed after the conducted treatment with selective serotonin re-uptake inhibitors. After the treatment, number of neutrophils exposed to apoptosis significantly decreased up to 0.59±0.27%. Also, we demonstrated a significant decrease lymphocytes with fragmented nucleus in schizophrenic patients (0.23±0.08% and 0.88±0.18% in control, p < 0.05). Conclusion: Antidepressant therapy have potent immunomodulatory properties, resulting in decreased levels of expressing receptors to Fas-dependent death and apoptosis realization of immunocompetent cells. Our results can explain findings obtained by others that showed reduced NK activity and lower mitogen stimulation in depressed patients. Some of these observations can be attributed to the increased apoptosis in these cells. It is not yet clear whether this tendency could be attributed to a certain subpopulation of the MNLs or to the MNLs in general.
P.2.b.012 Plasma cortisol levels and resilience in depressed patients G. Camardese ° , F. Adamo, L. Mosca, A. Picello, G. Pizi, B. Mattioli, L. Pucci, P. Bria. University of the Sacred Heart, Institute of Psychiatry, Rome, Italy Introduction: In recent years a large body of evidence has emerged linking stressful life events with an increased vulnerability for affective and anxiety disorders. Stressful events often precede the onset of depression and stress has also been associated with the severity of the illness. Meantime there has been growing interest in the concept of resilience. A current theory views resilience as a measure of stress coping ability and its clinical significance may lie in its ability to function as an index of overall mental health. Resilience is a complex notion that incorporates such dimensions as coping mechanism and personality. Several critical factors are associated with a successful adaptation to stressful events: some of these include temperament, personality traits, cognitive factors, genetic traits, and other attribute, such a sense of humour and social support. Existing literature highlights a correlation between PTSD and low resilience. Furthermore, resilience can be used as a measure of treatment outcome in patients suffering of post-traumatic stress. Regarding mood disorders there is a lack of information on the correlation between resilience and treatment outcome. An analysis of the biological mechanisms underlying both resilience and depression shows the implication of common features. Several biochemical mediators of response to extreme stress may be related to resilience or vulnerability, and the release of cortisol may tend to undermine resilience. The present study analyses the correlation between resilience and plasma cortisol levels in depressed patients during treatment.
P.2.b Affective disorders and antidepressants – Affective disorders (basic) Methods: 38 outpatients (M/F = 13/25; mean age 43.09±15.01) with a Major Depressive Disorder (MDD) during a Major Depressive Episode (MDE) have been recruited at the Institute of Psychiatry of the Catholic University in Rome. Acute symptoms were measured with 21-HDRS (Hamilton Depression Rating Scale) and HARS (Hamilton Anxiety Rating Scale); CD-RISC (ConnorDavidson Resilience Scale) was used to measure resilience. A blood sample for the determination of plasma cortisol levels was collected. Psychopathological status and laboratory testing were assessed before the admission and after 12 weeks. Results: No significant correlation between plasma cortisol levels and HDRS, HARS or resilience scores at the baseline has been found in depressed patients. A significant inverse correlation between resilience scores and severity of symptoms has been observed (r = −0.428, p = 0.01). A significant decrease of plasma cortisol levels has been observed after antidepressant treatment (173.10±68.43 vs. 126.83±49.90, p = 0.014). A higher remission rate was observed among the patients having a better resilience. Conclusions: Recent studies are trying to determine which neurobiological responses are related to resilience, to psychological stress in general and in specific psychopathological forms. More specifically, the hyperactivity of the hypothalamic–pituitary– adrenal axis is a frequent finding in depressed patients. This same alteration has been correlated to a weak stress response and therefore to a low resilience. In our small sample plasma cortisol levels did not provide significant correlation to resilience scores. Nevertheless resilience seems to be inversely related to the severity of depressive episode and could offer a predictive value for treatment outcome.
S339
determined by analyzing whole blood samples. There were 14allele designations identified by the genotyping process. Plasma drug levels were measured using validated liquid chromatography/tandem mass spectrometry (LC/MS/MS). Phenotypes comparisons were calculated with ANOVA using logarithms of AUC and Cmax. The least squares geometric mean and 90% CI for AUC and Cmax were calculated. Results: Of the 63-screened subjects who were then genotyped, 42 (67.5%) were EMs; 11 (17%) intermediate metabolizers (IMs); 9 (14%) PMs; and 1 (1.5%) was an ultrarapid metabolizer (UM). Fourteen subjects (7 EMs, 7 PMs) were identified for enrollment. Following the administration of desvenlafaxine succinate, PK was not significantly different between the groups. Conversely, following venlafaxine ER administration, significant differences (p < 0.001) were observed between EMs and PMs in the PK of both venlafaxine and desvenlafaxine: higher concentrations of venlafaxine and lower concentrations of desvenlafaxine were observed in PMs compared with EMs. Common treatment emergent adverse events (TEAEs) included nausea (n = 5, 36%) and headache (n = 3, 21%). Treatment
Phenotype AUC (ng*h/mL) GEO mean 90% CI
VEN ER 75 mg: Venlafaxine PK EM vs PM p Value <0.001 VEN ER 75 mg: Desvenlafaxine PK EM vs PM p Value <0.0001 DVS 100 mg: Desvenlafaxine PK EM vs PM p Value =0.641
EM PM EM PM EM PM
559 2522 3013 772 5530 4899
390–804 1722–3587 2345–3871 585–1018 4063–7526 3488–6822
References [1] Connor KM, 2006, Assessment of resilience in the aftermath of trauma. J Clin Psychiatry 67(Suppl 2), 46−9. [2] Charney DS, 2004, Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 161, 195–216. [3] Yehuda R, 2004, Risk and resilience in posttraumatic stress disorder. J Clin Psychiatry 65(Suppl 1), 29−36.
P.2.b.013 A comparison of the pharmacokinetics of venlafaxine extended release and desvenlafaxine succinate in healthy subjects S. Preskorn1 , A. Patroneva2 ° , A. Nichols2 , H. Silman2 , R. Pedersen2 , J. Paul2 , S. Ahmed2 . 1 Clinical Research, Institute, Wichita, USA; 2 Wyeth Research, Global Medical Affairs, Philadelphia, USA Purpose: Metabolism for many antidepressants, including venlafaxine, is by the cytochrome (CYP) p450 2D6 enzyme. CYP2D6 polymorphisms unequivocally increase the PK variability of many psychiatric medications, which may increase interindividual variability in efficacy and/or tolerability. The metabolism of desvenlafaxine succinate is largely independent of the 2D6 system. This study evaluated the pharmacokinetics (PK) of single doses of venlafaxine extended release (ER) and desvenlafaxine succinate in healthy adults who are extensive or poor metabolizers (EMs or PMs, respectively) via CYP2D6. Methods: This open-label, randomized, crossover, single-dose study enrolled 14 subjects aged 19 to 36 years using single oral doses of venlafaxine ER 75 mg and desvenlafaxine succinate 100 mg. The CYP2D6 genotype of each screened subject was
Conclusions: Extensive metabolizers (67.5%) were the largest group of CYP2D6 polymorphism identified in subjects screened for inclusion in this study (N = 63). Amongst the 14 subjects enrolled in the study, significant differences in AUC and Cmax occur for venlafaxine between EMs (n = 7) and PMs (n = 7) following administration of venlafaxine ER. Conversely, following administration of desvenlafaxine succinate, the differences in AUC and Cmax for desvenlafaxine for the EM and PM subjects were not significant. Thus, the PK following the administration of venlafaxine ER is affected by the CYP2D6 polymorphisms, whereas exposure to desvenlafaxine following administration of desvenlafaxine succinate is not. This lack of effect may reduce variability in drug tolerance and efficacy. References [1] Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH, 2006, Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther 318(2), 657– 665. [2] Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J, Lanczik M, et al, 2004, CYP2D6 genotype: Impact on adverse effects and nonresponse during treatment with antidepressants – A pilot study. Clin Pharmacol Ther 75(5), 386–393.
P.2.b Affective disorders and antidepressants – Affective disorders (basic)
lower before treatment and approached the value observed within the control group (7.9±4.1 ng/ml) during 6 weeks of treatment with SSRIs. Conclusions: The blunted PRL response to a challenge with a single-dose of buspirone approaches normal value after 6-weeks SSRI treatment independently of clinical response. Our findings support a role for the 5-HT (1A) receptor in the etiology of MD, specifically at the postsynaptic site. References [1] Meltzer HY, Maes M, 1994, Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects. Biol Psychiatry 35, 316−23. [2] Moeller FG, Steinberg JL, Fulton M, Kramer G, Petty F, 1994, A preliminary neuroendocrine study with buspirone in major depression. Neuropsychopharmacology 10, 75−83. [3] Navines R, Martin-Santos R, Gomez-Gil E, Martinez de Osaba MJ, Luisa Imaz M, Gasto C, 2007, Effects of citalopram treatment on hypothermic and hormonal responses to the 5-HT(1A) receptor agonist buspirone in patients with major depression and therapeutic response. Psychoneuroendocrinology doi:10.1016/j.psyneuen.2007.01.006.
P.2.b.011 Antidepressant therapy and apoptosis of immnocompetent cells in patients with depressive disorders N. Vyalova1 ° , S. Ivanova1 , G. Simutkin1 , V. Semke2 . 1 Mental Health Research Institute, Laborratory of Cellular and MolecularBiological Investigations, Tomsk, Russia; 2 Mental Health Research Institute, Borderline States Department, Tomsk, Russia Introduction: In last years interdisciplinary investigations of psychoneuroimmunomodulation in clinic and therapy of stressrelated mental diseases are topical. Psychological stress and depressive disorder are associated with several immune alterations, including reduced cell proliferation and natural killer cell activity and disturbances of cytokine levels. Psychotropic (antidepressant) medications can be effect on various immune functions, including normal physiological programmed cell death of lymphocytes. Programmed death of cells by apoptosis is regarded as a protective mechanism of organism against an accumulation and spread of defective cells. Apoptosis is a normal physiological programmed cell death that can be enhanced by a variety of external stimuli, such as stress, viral infections, medications and pathological conditions. This phenomenon can be mediated via various pathways that cause condensation of the cytoplasm and chromatin, nuclear fragmentation, and ultimate sequestration of cellular contents into membrane-bound apoptotic bodies. The aim of this investigation was to study apoptosis of immunocompetent cells in the patients with depression in the process of the antidepressant therapy. Methods: We measured apoptosis in the mononuclears lymphocytes (MNLs) of peripheral blood) of 26 patients with depression and in 20 age- and gender-matched controls. The inclusion criterion was depression (diagnosed according to ICD10: F31 – bipolar affective disorder; F32 – depressive episode; F33 – recurrent affective disorder). The exclusion criteria were any other psychiatric disorder or any immunological disorder. The investigation was carried out in dynamics: before the beginning the pharmacotherapy against the background of depressive symptomatology and after the course of medication with selective serotonin re-uptake inhibitors (fluoxetine). We counted number of leukocytes, percent CD95+ lymphocytes and morphological changes characteristic of apoptosis in lymphocytes and neutrophils.
Results and Discussion: We observed significantly increased apoptosis in the MNLs of depressive patients: the percentage of lymphocytes with expression FAS-receptors was 19.47±1.02% (11.64±0.31% in control, p < 0.05). Level of spontaneous apoptosis of neutrophils in smears in patients with depressive disorder before treatment reliably differed from values observed in healthy persons (1.16±0.38% and 0.40±0.15%, respectively, p < 0.01). Also, we demonstrated a significant increase of lymphocytes with morphological changes characteristic of apoptosis (nuclear condensation, vacuolation, and blebbing) in the depressive patients (2.03±0.72% and 0.88±0.18% in control, p < 0.05). The normalisation of CD95+lymphocytes was observed after the conducted treatment with selective serotonin re-uptake inhibitors. After the treatment, number of neutrophils exposed to apoptosis significantly decreased up to 0.59±0.27%. Also, we demonstrated a significant decrease lymphocytes with fragmented nucleus in schizophrenic patients (0.23±0.08% and 0.88±0.18% in control, p < 0.05). Conclusion: Antidepressant therapy have potent immunomodulatory properties, resulting in decreased levels of expressing receptors to Fas-dependent death and apoptosis realization of immunocompetent cells. Our results can explain findings obtained by others that showed reduced NK activity and lower mitogen stimulation in depressed patients. Some of these observations can be attributed to the increased apoptosis in these cells. It is not yet clear whether this tendency could be attributed to a certain subpopulation of the MNLs or to the MNLs in general.
P.2.b.012 Plasma cortisol levels and resilience in depressed patients G. Camardese ° , F. Adamo, L. Mosca, A. Picello, G. Pizi, B. Mattioli, L. Pucci, P. Bria. University of the Sacred Heart, Institute of Psychiatry, Rome, Italy Introduction: In recent years a large body of evidence has emerged linking stressful life events with an increased vulnerability for affective and anxiety disorders. Stressful events often precede the onset of depression and stress has also been associated with the severity of the illness. Meantime there has been growing interest in the concept of resilience. A current theory views resilience as a measure of stress coping ability and its clinical significance may lie in its ability to function as an index of overall mental health. Resilience is a complex notion that incorporates such dimensions as coping mechanism and personality. Several critical factors are associated with a successful adaptation to stressful events: some of these include temperament, personality traits, cognitive factors, genetic traits, and other attribute, such a sense of humour and social support. Existing literature highlights a correlation between PTSD and low resilience. Furthermore, resilience can be used as a measure of treatment outcome in patients suffering of post-traumatic stress. Regarding mood disorders there is a lack of information on the correlation between resilience and treatment outcome. An analysis of the biological mechanisms underlying both resilience and depression shows the implication of common features. Several biochemical mediators of response to extreme stress may be related to resilience or vulnerability, and the release of cortisol may tend to undermine resilience. The present study analyses the correlation between resilience and plasma cortisol levels in depressed patients during treatment.
P.2.b Affective disorders and antidepressants – Affective disorders (basic) Methods: 38 outpatients (M/F = 13/25; mean age 43.09±15.01) with a Major Depressive Disorder (MDD) during a Major Depressive Episode (MDE) have been recruited at the Institute of Psychiatry of the Catholic University in Rome. Acute symptoms were measured with 21-HDRS (Hamilton Depression Rating Scale) and HARS (Hamilton Anxiety Rating Scale); CD-RISC (ConnorDavidson Resilience Scale) was used to measure resilience. A blood sample for the determination of plasma cortisol levels was collected. Psychopathological status and laboratory testing were assessed before the admission and after 12 weeks. Results: No significant correlation between plasma cortisol levels and HDRS, HARS or resilience scores at the baseline has been found in depressed patients. A significant inverse correlation between resilience scores and severity of symptoms has been observed (r = −0.428, p = 0.01). A significant decrease of plasma cortisol levels has been observed after antidepressant treatment (173.10±68.43 vs. 126.83±49.90, p = 0.014). A higher remission rate was observed among the patients having a better resilience. Conclusions: Recent studies are trying to determine which neurobiological responses are related to resilience, to psychological stress in general and in specific psychopathological forms. More specifically, the hyperactivity of the hypothalamic–pituitary– adrenal axis is a frequent finding in depressed patients. This same alteration has been correlated to a weak stress response and therefore to a low resilience. In our small sample plasma cortisol levels did not provide significant correlation to resilience scores. Nevertheless resilience seems to be inversely related to the severity of depressive episode and could offer a predictive value for treatment outcome.
S339
determined by analyzing whole blood samples. There were 14allele designations identified by the genotyping process. Plasma drug levels were measured using validated liquid chromatography/tandem mass spectrometry (LC/MS/MS). Phenotypes comparisons were calculated with ANOVA using logarithms of AUC and Cmax. The least squares geometric mean and 90% CI for AUC and Cmax were calculated. Results: Of the 63-screened subjects who were then genotyped, 42 (67.5%) were EMs; 11 (17%) intermediate metabolizers (IMs); 9 (14%) PMs; and 1 (1.5%) was an ultrarapid metabolizer (UM). Fourteen subjects (7 EMs, 7 PMs) were identified for enrollment. Following the administration of desvenlafaxine succinate, PK was not significantly different between the groups. Conversely, following venlafaxine ER administration, significant differences (p < 0.001) were observed between EMs and PMs in the PK of both venlafaxine and desvenlafaxine: higher concentrations of venlafaxine and lower concentrations of desvenlafaxine were observed in PMs compared with EMs. Common treatment emergent adverse events (TEAEs) included nausea (n = 5, 36%) and headache (n = 3, 21%). Treatment
Phenotype AUC (ng*h/mL) GEO mean 90% CI
VEN ER 75 mg: Venlafaxine PK EM vs PM p Value <0.001 VEN ER 75 mg: Desvenlafaxine PK EM vs PM p Value <0.0001 DVS 100 mg: Desvenlafaxine PK EM vs PM p Value =0.641
EM PM EM PM EM PM
559 2522 3013 772 5530 4899
390–804 1722–3587 2345–3871 585–1018 4063–7526 3488–6822
References [1] Connor KM, 2006, Assessment of resilience in the aftermath of trauma. J Clin Psychiatry 67(Suppl 2), 46−9. [2] Charney DS, 2004, Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 161, 195–216. [3] Yehuda R, 2004, Risk and resilience in posttraumatic stress disorder. J Clin Psychiatry 65(Suppl 1), 29−36.
P.2.b.013 A comparison of the pharmacokinetics of venlafaxine extended release and desvenlafaxine succinate in healthy subjects S. Preskorn1 , A. Patroneva2 ° , A. Nichols2 , H. Silman2 , R. Pedersen2 , J. Paul2 , S. Ahmed2 . 1 Clinical Research, Institute, Wichita, USA; 2 Wyeth Research, Global Medical Affairs, Philadelphia, USA Purpose: Metabolism for many antidepressants, including venlafaxine, is by the cytochrome (CYP) p450 2D6 enzyme. CYP2D6 polymorphisms unequivocally increase the PK variability of many psychiatric medications, which may increase interindividual variability in efficacy and/or tolerability. The metabolism of desvenlafaxine succinate is largely independent of the 2D6 system. This study evaluated the pharmacokinetics (PK) of single doses of venlafaxine extended release (ER) and desvenlafaxine succinate in healthy adults who are extensive or poor metabolizers (EMs or PMs, respectively) via CYP2D6. Methods: This open-label, randomized, crossover, single-dose study enrolled 14 subjects aged 19 to 36 years using single oral doses of venlafaxine ER 75 mg and desvenlafaxine succinate 100 mg. The CYP2D6 genotype of each screened subject was
Conclusions: Extensive metabolizers (67.5%) were the largest group of CYP2D6 polymorphism identified in subjects screened for inclusion in this study (N = 63). Amongst the 14 subjects enrolled in the study, significant differences in AUC and Cmax occur for venlafaxine between EMs (n = 7) and PMs (n = 7) following administration of venlafaxine ER. Conversely, following administration of desvenlafaxine succinate, the differences in AUC and Cmax for desvenlafaxine for the EM and PM subjects were not significant. Thus, the PK following the administration of venlafaxine ER is affected by the CYP2D6 polymorphisms, whereas exposure to desvenlafaxine following administration of desvenlafaxine succinate is not. This lack of effect may reduce variability in drug tolerance and efficacy. References [1] Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH, 2006, Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther 318(2), 657– 665. [2] Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J, Lanczik M, et al, 2004, CYP2D6 genotype: Impact on adverse effects and nonresponse during treatment with antidepressants – A pilot study. Clin Pharmacol Ther 75(5), 386–393.