- Email: [email protected]
P.3.22 Predictive factors of resistance to antidepressant treatment: results from a European multicentre study
868
Clinical Neuropsychopharmacology
changed by elozapine treatment. There was no correlation between elozapine blood levels and insulin (p=0.5), GH (p=0.7), IGF-1 (p=0.5), or IGFBP-1 (Io=0.5) levels on elozapine. Conclusions: Clozapine treatment is associated with the development of new onset abnormal glucose control in 55% of subjects within 3 months of initiation, which was not associated with weight gain. Fasting glucose levels are increased, and a prolonged hyperglycaemic peak is seen following clozapine initiation. Patients showed evidence of insulin resistance at baseline, which may be related to prior treatment with antipsychotics or the disease process seen in refractory schizophrenia. Clozapine treatment was not associated with alterations in insulin, GH, IGF, or IGFBP-1. The absence of the expected hormonal compensatory response to increased glucose levels is concerning and suggests that alterations in glucoregulation are occurring proximal to the hormonal regulation of glt~ose levels. Clozapine has been found to inhibit glucose transport into neuronal cell lines [1]. We hypothesise that clozapine impairs glucose transport into the glucose sensing neurones, thereby increasing the threshold for initiation of the hormonal homeostatic mechanisms. This mechanism would explain the rapid increase in plasma glt~ose level independent of changes in hormonal levels.
References [1] Dwyer DS, Pink&sky HB, Liu Y, Bradley RJ. Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells. Prog Neuropsychopharmacol Biol Psychiatr 1999; 23: 69-80.
IP.3.221 Predictive factors of resistance to antidepressant treatment: results from a European multicentre study P. O s w a l d 1 , D. S o u e r y 1 , S. K a s p e r 2, Y. Lecrubier 3,
J. Zohar 4, J. Mendlewicz 1. On behalf of the Group for
the Study of Resistant Depression (GSRD). 1Department of Psychiatry, Unioersity Clinics of Brussels, Erasme Hospital, Free Unioersity of Brussels, Brussels, Belgium; 2Department of General Psychiatry, Unioersity Hospital for Psychiatry, Vienna, Austria; 3INSERM, Hdpital de la Salpgtri~re, Paris, France; 4Chaim Sheba Medical Centre, Dioision of Psychiatry, Tel Hashomer, Israel When adequately treated, up to half of all patients with major depression do not respond adequately to first-line antidepressant (AD). However, research on resistance to AD treatment has been marked with inconsistent findings, mainly due to the plethora of definitions of treatment
resistant depression (TRD) (Rush et al., 2003). During the last decade, a consensus has been raised defining TRD as the failure to respond to at least two consecutive adequate A D from different classes (Souery et al., 1999). This definition allows the investigation of clinical predicting factors of TRD. We initiated a study including seven European centres: Brussels, Sint-Truiden, Leuven, TelAviv, Paris, Vienna and Milan. A total of 996 patients with major unipolar depression having received at least one adequate AD treatment for the current episode were recruited. All patients were evaluated using the MINI (Mini International Neuropsychiatric Interview, a validated structured diagnostic interview, providing an accurate DSM-IV diagnosis (Sheehan et al., 1998). An exhaustive questionnaire was applied investigating more than 200 factors including: 1) demographic and psychosocial characteristics, 2) data on the current depressive episode, including psychiatric comorbidities, personality dimensions and somatic comorbidities, 3) personal and family history of psychiatric disorders, 4) data on current and past antidepressant and other psychotropic treatments. According to the definition of TRD, a logistic regression model was applied for which we excluded a sample of 112 patients, because they were non responder to a single and unique AD treatment, and another sample of 254 patients, because of partial missing data used for the categorization in resistant or non resistant patients. 276 unipolar patients were considered as resistant and 354 as non resistant (responder to a first or single A D or non responder to a first A D but responder to a second AD). We found that current melancholia (p=0.01), severe intensity (p=.006), current suicide risk (p<0.0001), current panic disorder (p<0.0001), current anxiety disorder (p<0.0001), a low educational level (p=0.01), personality disorder (p=0.05), current hospitalization (p=0.001), family history &bipolar disorder (p=0.05) and suicide (p=0.05), absence of response to a first antidepressant lifetime (p=0.02) and early age at onset (<16 yo, p<0.001; <18 yo, p<0.001) predict the occurrence of TRD in our unipolar sample. In a multifactorial logistic regression model, a current panic disorder, a current suicide risk and an early age at onset (<16 yo and <18 yo) were found to be the major risk factors in TRD. This is, to our knowledge, the first study investigating a large number &potential predictive factors of TRD in a multicentre European study, involving a large sample of patients with major unipolar depression. Supported by an tw~restricted grant from Lundbeck.
References [1] Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview
Clinical Neuropsychopharmacology (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33. [2] Souery D, Amsterdam J, de Montigny C, Lecrubier Y, Montgomery S, Lipp O, Racagni G, Zohar J, Mendlewicz J.Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999 Jan;9(1-2):83-91. [3] Rush A J, Thase ME, Dube S. Research issues in the study of difficult-to-treat depression. Biol Psychiatr. 2003 Apr 15; 53(8): 743-53.
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Naltrexone for treatment of heroin dependence in Russia
V Egorova, E.M. Krupitsky, E.E. Zvartau, D.V. Masalov, M.V Tsoi, A.M. Burakov, T.Y. Didenko, T.N. Romanova, E.B. Ivanova, A.Y. Bespalov, E. Verbitskaya, N.G. Neznanov, A.Y. Grinenko, G. Woody. Valdman
Institute of Pharmacology, Paoloo Medical Unioersity, St Petersburg, Russian Federation Clinical trials previously done with naltrexone in the USA demonstrated that its clinical efficacy is limited by a poor compliance with the medication. Naltrexone might be more effective in Russia due to two major reasons: 1. Major alternative to naltrexone - opioid agonists maintenance is prohibited in Russia by the law thus naltrexone is the only available pharmacotherapy, and 2. Heroin addicts in Russia are mostly young people who live with their parents because of financial limitations, and parents are usually those who initiate treatment and can control the everyday process of taking the naltrexone (compliance). The aim of the study was to evaluate clinical efficacy of naltrexone for relapse prevention in detoxified heroin addicts in Russian cultural settings. Methods: 52 recently detoxified heroin addicts after passing a naloxone challenge were randomly assigned to one of two groups. Subjects of the first group (N=27, age 22.8-t-0.8) had been administered naltrexone (50 mg/day) in combination with twice-a-month drug counseling for 6 months. Subjects of the second group (N=25, age 20.7-t-0.8) took placebo with twice-a-month drug counseling. All subjects had been twice-a-month controlled for drug use with urine drug testing, for compliance with the medication by measuring riboflavine in the urine, and for psychiatric symptoms by brief evaluations with the rating scales for depression, anxiety, anhedonia, and craving for heroin; more extensive evaluations with Addiction Severity Index and Risk Assessment Battery measuring HIV risk behavior were
$69
done at 3 and 6 months. The study design was double blind placebo controlled and randomized. All data were examined by analysis of variance (AN©VA) for continuous variables and by t-tests for categorical variables. Survival analysis (Kaplan-Meier Survival Functions) was employed to compare the relapse free proportion in naltrexone and placebo groups. Results: The rate of abstinence in naltrexone group had been significantly higher than in placebo group starting since the end of the first months and throughout the six months of the study, while the corresponding rate of relapse was much lower. To the end of the six months treatment in the naltrexone group 12 subjects (44.4%) were abstinent and 15 (55.6%) dropped out of the study, while in placebo group 4 subjects (16%) were abstinent and 21 (84%) dropped out (io<0.05). The level of compliance with the study medication among those patients who remained in the study was varying within 85-95% interval. Naltrexone reduced craving for heroin significantly more effectively than placebo within the first two months of the study. Naltrexone did not influence directly psychiatric status (anxiety, depression, anhedonia, and other psychiatric symptoms), overall social functioning and HIV risk behavior in abstinent heron addicts. The number of side effects were very limited in both groups. Conclusion: Naltrexone is effective and safe medication for stabilization and relapse prevention in heroin addicts in Russia. Cultural factors unique to Russia are associated with greater interest and compliance with naltrexone than in USA.
IP.3241 Volumes of brain structures in twins discordant for bipolar disorder A.C. van der Schot1, R_ Vonk1,2, H.E. Hulshoff Pol 1, V. Nuboer 1, W. Nolen 1'3, R.S. Kahn 1. 1Rudolf Magnus
Institute of Neuroscience, Department of Psychia#y, Unioersity Medical Center Utrecht, The Netherlands; 2GGZ ~-Hertogenbosch, The Netherlands; 3Unioersitair Medisch Centrum Groningen, The Netherlands Background: several magnetic resonance imaging (MRI) studies have demonstated structural brain abnormalities in bipolar disorder, e.g. smaller volumes of the subgenual prefrontal cortex and larger volumes of the amygdala, caudate nucleus and thalamus. However, so far the reported abnormalities are inconsistent (Lochhead et al., 2004). For example the amygdala has been found enlarged (Strakowski et al., 1999) but also decreased (Blumberg et al., 2003). Also, the anterior cingulate has been found to be decreased in adolescents with bipolar disorder but
Clinical Neuropsychopharmacology
changed by elozapine treatment. There was no correlation between elozapine blood levels and insulin (p=0.5), GH (p=0.7), IGF-1 (p=0.5), or IGFBP-1 (Io=0.5) levels on elozapine. Conclusions: Clozapine treatment is associated with the development of new onset abnormal glucose control in 55% of subjects within 3 months of initiation, which was not associated with weight gain. Fasting glucose levels are increased, and a prolonged hyperglycaemic peak is seen following clozapine initiation. Patients showed evidence of insulin resistance at baseline, which may be related to prior treatment with antipsychotics or the disease process seen in refractory schizophrenia. Clozapine treatment was not associated with alterations in insulin, GH, IGF, or IGFBP-1. The absence of the expected hormonal compensatory response to increased glucose levels is concerning and suggests that alterations in glucoregulation are occurring proximal to the hormonal regulation of glt~ose levels. Clozapine has been found to inhibit glucose transport into neuronal cell lines [1]. We hypothesise that clozapine impairs glucose transport into the glucose sensing neurones, thereby increasing the threshold for initiation of the hormonal homeostatic mechanisms. This mechanism would explain the rapid increase in plasma glt~ose level independent of changes in hormonal levels.
References [1] Dwyer DS, Pink&sky HB, Liu Y, Bradley RJ. Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells. Prog Neuropsychopharmacol Biol Psychiatr 1999; 23: 69-80.
IP.3.221 Predictive factors of resistance to antidepressant treatment: results from a European multicentre study P. O s w a l d 1 , D. S o u e r y 1 , S. K a s p e r 2, Y. Lecrubier 3,
J. Zohar 4, J. Mendlewicz 1. On behalf of the Group for
the Study of Resistant Depression (GSRD). 1Department of Psychiatry, Unioersity Clinics of Brussels, Erasme Hospital, Free Unioersity of Brussels, Brussels, Belgium; 2Department of General Psychiatry, Unioersity Hospital for Psychiatry, Vienna, Austria; 3INSERM, Hdpital de la Salpgtri~re, Paris, France; 4Chaim Sheba Medical Centre, Dioision of Psychiatry, Tel Hashomer, Israel When adequately treated, up to half of all patients with major depression do not respond adequately to first-line antidepressant (AD). However, research on resistance to AD treatment has been marked with inconsistent findings, mainly due to the plethora of definitions of treatment
resistant depression (TRD) (Rush et al., 2003). During the last decade, a consensus has been raised defining TRD as the failure to respond to at least two consecutive adequate A D from different classes (Souery et al., 1999). This definition allows the investigation of clinical predicting factors of TRD. We initiated a study including seven European centres: Brussels, Sint-Truiden, Leuven, TelAviv, Paris, Vienna and Milan. A total of 996 patients with major unipolar depression having received at least one adequate AD treatment for the current episode were recruited. All patients were evaluated using the MINI (Mini International Neuropsychiatric Interview, a validated structured diagnostic interview, providing an accurate DSM-IV diagnosis (Sheehan et al., 1998). An exhaustive questionnaire was applied investigating more than 200 factors including: 1) demographic and psychosocial characteristics, 2) data on the current depressive episode, including psychiatric comorbidities, personality dimensions and somatic comorbidities, 3) personal and family history of psychiatric disorders, 4) data on current and past antidepressant and other psychotropic treatments. According to the definition of TRD, a logistic regression model was applied for which we excluded a sample of 112 patients, because they were non responder to a single and unique AD treatment, and another sample of 254 patients, because of partial missing data used for the categorization in resistant or non resistant patients. 276 unipolar patients were considered as resistant and 354 as non resistant (responder to a first or single A D or non responder to a first A D but responder to a second AD). We found that current melancholia (p=0.01), severe intensity (p=.006), current suicide risk (p<0.0001), current panic disorder (p<0.0001), current anxiety disorder (p<0.0001), a low educational level (p=0.01), personality disorder (p=0.05), current hospitalization (p=0.001), family history &bipolar disorder (p=0.05) and suicide (p=0.05), absence of response to a first antidepressant lifetime (p=0.02) and early age at onset (<16 yo, p<0.001; <18 yo, p<0.001) predict the occurrence of TRD in our unipolar sample. In a multifactorial logistic regression model, a current panic disorder, a current suicide risk and an early age at onset (<16 yo and <18 yo) were found to be the major risk factors in TRD. This is, to our knowledge, the first study investigating a large number &potential predictive factors of TRD in a multicentre European study, involving a large sample of patients with major unipolar depression. Supported by an tw~restricted grant from Lundbeck.
References [1] Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview
Clinical Neuropsychopharmacology (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33. [2] Souery D, Amsterdam J, de Montigny C, Lecrubier Y, Montgomery S, Lipp O, Racagni G, Zohar J, Mendlewicz J.Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999 Jan;9(1-2):83-91. [3] Rush A J, Thase ME, Dube S. Research issues in the study of difficult-to-treat depression. Biol Psychiatr. 2003 Apr 15; 53(8): 743-53.
~-~
Naltrexone for treatment of heroin dependence in Russia
V Egorova, E.M. Krupitsky, E.E. Zvartau, D.V. Masalov, M.V Tsoi, A.M. Burakov, T.Y. Didenko, T.N. Romanova, E.B. Ivanova, A.Y. Bespalov, E. Verbitskaya, N.G. Neznanov, A.Y. Grinenko, G. Woody. Valdman
Institute of Pharmacology, Paoloo Medical Unioersity, St Petersburg, Russian Federation Clinical trials previously done with naltrexone in the USA demonstrated that its clinical efficacy is limited by a poor compliance with the medication. Naltrexone might be more effective in Russia due to two major reasons: 1. Major alternative to naltrexone - opioid agonists maintenance is prohibited in Russia by the law thus naltrexone is the only available pharmacotherapy, and 2. Heroin addicts in Russia are mostly young people who live with their parents because of financial limitations, and parents are usually those who initiate treatment and can control the everyday process of taking the naltrexone (compliance). The aim of the study was to evaluate clinical efficacy of naltrexone for relapse prevention in detoxified heroin addicts in Russian cultural settings. Methods: 52 recently detoxified heroin addicts after passing a naloxone challenge were randomly assigned to one of two groups. Subjects of the first group (N=27, age 22.8-t-0.8) had been administered naltrexone (50 mg/day) in combination with twice-a-month drug counseling for 6 months. Subjects of the second group (N=25, age 20.7-t-0.8) took placebo with twice-a-month drug counseling. All subjects had been twice-a-month controlled for drug use with urine drug testing, for compliance with the medication by measuring riboflavine in the urine, and for psychiatric symptoms by brief evaluations with the rating scales for depression, anxiety, anhedonia, and craving for heroin; more extensive evaluations with Addiction Severity Index and Risk Assessment Battery measuring HIV risk behavior were
$69
done at 3 and 6 months. The study design was double blind placebo controlled and randomized. All data were examined by analysis of variance (AN©VA) for continuous variables and by t-tests for categorical variables. Survival analysis (Kaplan-Meier Survival Functions) was employed to compare the relapse free proportion in naltrexone and placebo groups. Results: The rate of abstinence in naltrexone group had been significantly higher than in placebo group starting since the end of the first months and throughout the six months of the study, while the corresponding rate of relapse was much lower. To the end of the six months treatment in the naltrexone group 12 subjects (44.4%) were abstinent and 15 (55.6%) dropped out of the study, while in placebo group 4 subjects (16%) were abstinent and 21 (84%) dropped out (io<0.05). The level of compliance with the study medication among those patients who remained in the study was varying within 85-95% interval. Naltrexone reduced craving for heroin significantly more effectively than placebo within the first two months of the study. Naltrexone did not influence directly psychiatric status (anxiety, depression, anhedonia, and other psychiatric symptoms), overall social functioning and HIV risk behavior in abstinent heron addicts. The number of side effects were very limited in both groups. Conclusion: Naltrexone is effective and safe medication for stabilization and relapse prevention in heroin addicts in Russia. Cultural factors unique to Russia are associated with greater interest and compliance with naltrexone than in USA.
IP.3241 Volumes of brain structures in twins discordant for bipolar disorder A.C. van der Schot1, R_ Vonk1,2, H.E. Hulshoff Pol 1, V. Nuboer 1, W. Nolen 1'3, R.S. Kahn 1. 1Rudolf Magnus
Institute of Neuroscience, Department of Psychia#y, Unioersity Medical Center Utrecht, The Netherlands; 2GGZ ~-Hertogenbosch, The Netherlands; 3Unioersitair Medisch Centrum Groningen, The Netherlands Background: several magnetic resonance imaging (MRI) studies have demonstated structural brain abnormalities in bipolar disorder, e.g. smaller volumes of the subgenual prefrontal cortex and larger volumes of the amygdala, caudate nucleus and thalamus. However, so far the reported abnormalities are inconsistent (Lochhead et al., 2004). For example the amygdala has been found enlarged (Strakowski et al., 1999) but also decreased (Blumberg et al., 2003). Also, the anterior cingulate has been found to be decreased in adolescents with bipolar disorder but