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P.2.091 Cytochrome P450 2D6 and antidepressant toxicity and response: preliminary results
P2 Affective disorders and antidepressants
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Cytochrome P450 2D6 and antidepressant toxicity and response: preliminary results
D. Esposito 1 *, C. Verstuyft 2, P. Hardy 1 , L. Becquemont 2, E. Corruble 1 . ICHU de Bicetre, Psychiatty, Le Kremlin Bicetre,
France; 2CHU de Bicetre, Pharmacology, France Statement of the study: Several of the currently used antidepressants are at least partially metabolised by cytochrome P450 (CYP) 2D6. Among these are both classical nonselective reuptake inhibitors (NSRIs) and newer selective serotonin reuptake inhibitors (SSRIs). The activity of this enzyme markedly varies among individuals from poor to ultrarapid metabolism on the basis of the polymorphism of the CYP2D6 gene. The impact of genetically determined variations of CYP2D6 on plasma concentrations of antidepressants is moderately well established. In contrast, the clinical relevance in terms of adverse effects or response remains far less defined (Rau et al. 2004). Only a limited number of studies have assessed the effects of CYP2D6 genotypes or phenotypes on the clinical outcome in patients treated with antidepressants, and the results have been controversial (de Leon et al. 1998). This study investigated whether CYP2D6 genetic variability influences drug-induced adverse effects and outcomes among patients treated with CYP2D6-dependent antidepressants. Methods used: In this 4-week prospective study, CYP2D6 was genotyped in 60 depressed inpatients treated with CYP2D6dependent antidepressants. CYP2D6-dependent antidepressants were defined as those for which an impact of a poor metaboliser phenotype or coadministration of a CYP2D6 inhibitor on the plasma concentration was documented in the literature (Rau et al. 2004). Main outcome measures included Hamilton Depression Rating Scale-17, Beck Depression Inventory, and severity of adverse effects. CYP2D6 genotyping was performed using allelic discrimination assays based on fluorescent TaqMan probes. Poor and intermediate metaboliser alleles, as well as allelic duplications of CYP2D6, were detected. S u m m a r y of results: Outcome measures were stratified according to CYP2D6 genotypes. Preliminary results will be shown at the congress. Conclusion: At present, sufficient date are lacking that would allow the prediction of adverse effects or the efficacy of an antidepressant in a particular patient. This study tried to shed light on the question of whether the variations in metabolic capacity translate into clinically important parameters such as the predisposition to have adverse effects or to be nonresponsive during treatment with antidepressants.
References [1] de Leon, J., Barnhill, J., Rogers, T., Boyle, J., Chou, W.H. and Wedlund, RJ. (1998) Pilot study of the cytochrome P450 2D6 genotype in a psychiatric state hospital. Am. J. Psychiatry. 155, 1278 80. [2] Rau, T., Wohlleben, G., Wuttke, H., Thuerauf, N., Lunkenheimer, J., Lanczik, M. and Eschenhagen, T. (2004) CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants a pilot study. Clin. Pharmacol. Ther. 75: 38(:~93.
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Electroconvulsive seizures induce endothelial cell proliferation in specific hypothalamic nuclei
L. Jansson*, J. Hellsten, A. Tingstr6m. University of Lurid, Unit
for Molecular Psychiatty, Lurid, Sweden The patophysiology of affective disorders is often associated with a disturbance in basal biological functions regulated from the
$431
hypothalamus. Electroconvulsive stimulation (ECS) is an efficient antidepressant treatment and has been demonstrated to alter the activity of hypothalamic neurons. We have previously shown an increased proliferation of endothelial cells in response to ECS in specific areas of rat hippocampus and amygdala. To investigate whether ECS induce endothelial cell proliferation also in the hypothalamus, we treated adult male Wistar rats with 1 ECS daily for five days. For detection of proliferating cells bromodeoxyuridine (BrdU) was injected and the animals were allowed to survive for 2 0 h before perfusion. The number of hypothalamic cells double-labelled for BrdU and the endothelial cell marker Rat Endothelial Cell Antigen-1 (RECA-1) was then determined. To also investigate the hypothalamic pattern of neuronal activation in response to ECS, we stained for c-fos in rats allowed to survive for 2 h after a single ECS-treatment. Results: The results demonstrate a correlated pattern of increased endothelial cell proliferation and neuronal activation following ECS, in the paraventricular nucleus, the supraoptic nucleus and the ventromedial hypothalamic nucleus of the hypothalamus.
~ T h e early diagnose of the psychiatric side effects of interferon-alpha A. Kovacs 1 *, Z. Szabo 2, G. Gazdag 2. ]Pecsi Tudomanyegyetem
OEC, Department of psychiatty, Pecs, Hungaty; 2Szt. Laszlo Hospital, Consultation-Liason Psychiatric Setvice, Hungaty Background: Interferon-alfa (IFN-alfa) is an effective therapy of a variety of oncological and viral disorders. The CNS effects of IFN-alfa are based on the induction of the cytokine-cascade and the neuroendocrine system, as well as the modulation of the several neurotransmitter pathways. It is well-known fact, that mood and anxiety disorders are common psychiatric sequelaes of the IFN-alfa treatment, the incidence rate of these complications can be as high as 40%. Purpose: The objective of this study was to evaluate the clinical usefulness of a questionnaire developed for the screening of the psychiatric side-effects of IFN-alfa. It was expected that the questionnaire can support the cooperation between physicians and psychiatrists. Method: 28 patients, affected by HCV-infection, were evaluated before and during the IFN-alfa treatment. The psychiatric evaluation consisted of a structured psychiatric interview employing the DSM-IV criteria and a questionnaire developed by the authors for the physicians to support the early recognition and follow-up of the IFN-alfa side-effects. The questionnaire is consisting of two parts: 13 yes/no questions concerned with the psychic and 13 others with the somatic side-effects of the IFN-alfa. Patients completed the questionnaire monthly. The results were compared with the data of another HCV-infected IFN-alfa treated patientgroup (n 22) the members of which were referred to psychiatric examination because of mental deterioration, with no previous evaluation. Results: Out of the 28 cases, in 20 patients significant psychiatric syndromes were observed prospectively during the IFNalfa treatment. Anxiety disorders developed in 6 cases, depressive disorders in 9 cases, mixed (anxiety-and-depressive) disorders in 5 cases. Anxiety disorders appeared earlier (mean: 1.8 months) than depressions (mean:2.6 months). 9 patients showed depressive or anxiety symptoms before the start of the IFN-alfa administration. Out of these 9 patients, in 8 cases the mental symptoms markedly worsened during the IFN-alfa treatment. The questionnaire scores
•
Cytochrome P450 2D6 and antidepressant toxicity and response: preliminary results
D. Esposito 1 *, C. Verstuyft 2, P. Hardy 1 , L. Becquemont 2, E. Corruble 1 . ICHU de Bicetre, Psychiatty, Le Kremlin Bicetre,
France; 2CHU de Bicetre, Pharmacology, France Statement of the study: Several of the currently used antidepressants are at least partially metabolised by cytochrome P450 (CYP) 2D6. Among these are both classical nonselective reuptake inhibitors (NSRIs) and newer selective serotonin reuptake inhibitors (SSRIs). The activity of this enzyme markedly varies among individuals from poor to ultrarapid metabolism on the basis of the polymorphism of the CYP2D6 gene. The impact of genetically determined variations of CYP2D6 on plasma concentrations of antidepressants is moderately well established. In contrast, the clinical relevance in terms of adverse effects or response remains far less defined (Rau et al. 2004). Only a limited number of studies have assessed the effects of CYP2D6 genotypes or phenotypes on the clinical outcome in patients treated with antidepressants, and the results have been controversial (de Leon et al. 1998). This study investigated whether CYP2D6 genetic variability influences drug-induced adverse effects and outcomes among patients treated with CYP2D6-dependent antidepressants. Methods used: In this 4-week prospective study, CYP2D6 was genotyped in 60 depressed inpatients treated with CYP2D6dependent antidepressants. CYP2D6-dependent antidepressants were defined as those for which an impact of a poor metaboliser phenotype or coadministration of a CYP2D6 inhibitor on the plasma concentration was documented in the literature (Rau et al. 2004). Main outcome measures included Hamilton Depression Rating Scale-17, Beck Depression Inventory, and severity of adverse effects. CYP2D6 genotyping was performed using allelic discrimination assays based on fluorescent TaqMan probes. Poor and intermediate metaboliser alleles, as well as allelic duplications of CYP2D6, were detected. S u m m a r y of results: Outcome measures were stratified according to CYP2D6 genotypes. Preliminary results will be shown at the congress. Conclusion: At present, sufficient date are lacking that would allow the prediction of adverse effects or the efficacy of an antidepressant in a particular patient. This study tried to shed light on the question of whether the variations in metabolic capacity translate into clinically important parameters such as the predisposition to have adverse effects or to be nonresponsive during treatment with antidepressants.
References [1] de Leon, J., Barnhill, J., Rogers, T., Boyle, J., Chou, W.H. and Wedlund, RJ. (1998) Pilot study of the cytochrome P450 2D6 genotype in a psychiatric state hospital. Am. J. Psychiatry. 155, 1278 80. [2] Rau, T., Wohlleben, G., Wuttke, H., Thuerauf, N., Lunkenheimer, J., Lanczik, M. and Eschenhagen, T. (2004) CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants a pilot study. Clin. Pharmacol. Ther. 75: 38(:~93.
•
Electroconvulsive seizures induce endothelial cell proliferation in specific hypothalamic nuclei
L. Jansson*, J. Hellsten, A. Tingstr6m. University of Lurid, Unit
for Molecular Psychiatty, Lurid, Sweden The patophysiology of affective disorders is often associated with a disturbance in basal biological functions regulated from the
$431
hypothalamus. Electroconvulsive stimulation (ECS) is an efficient antidepressant treatment and has been demonstrated to alter the activity of hypothalamic neurons. We have previously shown an increased proliferation of endothelial cells in response to ECS in specific areas of rat hippocampus and amygdala. To investigate whether ECS induce endothelial cell proliferation also in the hypothalamus, we treated adult male Wistar rats with 1 ECS daily for five days. For detection of proliferating cells bromodeoxyuridine (BrdU) was injected and the animals were allowed to survive for 2 0 h before perfusion. The number of hypothalamic cells double-labelled for BrdU and the endothelial cell marker Rat Endothelial Cell Antigen-1 (RECA-1) was then determined. To also investigate the hypothalamic pattern of neuronal activation in response to ECS, we stained for c-fos in rats allowed to survive for 2 h after a single ECS-treatment. Results: The results demonstrate a correlated pattern of increased endothelial cell proliferation and neuronal activation following ECS, in the paraventricular nucleus, the supraoptic nucleus and the ventromedial hypothalamic nucleus of the hypothalamus.
~ T h e early diagnose of the psychiatric side effects of interferon-alpha A. Kovacs 1 *, Z. Szabo 2, G. Gazdag 2. ]Pecsi Tudomanyegyetem
OEC, Department of psychiatty, Pecs, Hungaty; 2Szt. Laszlo Hospital, Consultation-Liason Psychiatric Setvice, Hungaty Background: Interferon-alfa (IFN-alfa) is an effective therapy of a variety of oncological and viral disorders. The CNS effects of IFN-alfa are based on the induction of the cytokine-cascade and the neuroendocrine system, as well as the modulation of the several neurotransmitter pathways. It is well-known fact, that mood and anxiety disorders are common psychiatric sequelaes of the IFN-alfa treatment, the incidence rate of these complications can be as high as 40%. Purpose: The objective of this study was to evaluate the clinical usefulness of a questionnaire developed for the screening of the psychiatric side-effects of IFN-alfa. It was expected that the questionnaire can support the cooperation between physicians and psychiatrists. Method: 28 patients, affected by HCV-infection, were evaluated before and during the IFN-alfa treatment. The psychiatric evaluation consisted of a structured psychiatric interview employing the DSM-IV criteria and a questionnaire developed by the authors for the physicians to support the early recognition and follow-up of the IFN-alfa side-effects. The questionnaire is consisting of two parts: 13 yes/no questions concerned with the psychic and 13 others with the somatic side-effects of the IFN-alfa. Patients completed the questionnaire monthly. The results were compared with the data of another HCV-infected IFN-alfa treated patientgroup (n 22) the members of which were referred to psychiatric examination because of mental deterioration, with no previous evaluation. Results: Out of the 28 cases, in 20 patients significant psychiatric syndromes were observed prospectively during the IFNalfa treatment. Anxiety disorders developed in 6 cases, depressive disorders in 9 cases, mixed (anxiety-and-depressive) disorders in 5 cases. Anxiety disorders appeared earlier (mean: 1.8 months) than depressions (mean:2.6 months). 9 patients showed depressive or anxiety symptoms before the start of the IFN-alfa administration. Out of these 9 patients, in 8 cases the mental symptoms markedly worsened during the IFN-alfa treatment. The questionnaire scores