- Email: [email protected]
P.3.d.012 The effects of single dose aripiprazole and haloperidol on resting blood flow in healthy volunteers
S560
P.3.d Psychotic disorders and antipsychotics - Antipsychotics (basic)
Conclusions: These results show that plasma levels of BDNF and glutamate are decreased at the onset of psychosis, therefore indicate that the psychotic episode affects to neurobiological substances. When the patients begin the pharmacological treatment the glutamate and BDNF levels increase significantly but it's necessary at least 6 months of treatment to obtain normal levels. These neurotransmitters could offer us a relevant key for the pharmacological treatment of psychotic diseases. The prognosis in children with a first psychotic episode is worse than prognosis in adults with the same diagnosis and is probable that neurotrophic factors could be implicated in these differences.
IP.3.d.0111 The immunomodulatory effects of atypical neuroleptics quetiapine and amisulpride in the dynamics of 6-week treatment
o.x. Lobacheva1 ., T.P. Vetlugina 1, A.V. Semke 2 . 1Mental Health Research Institute, Clinical Psychoneuroimmunology Laboratory, Tomsic, Russia; 2Mental Health Research Institute, Endogenous Disorders Department, Tomsic, Russia The objective of the conducted research was the estimation of immunomodulatory effects of atypical antipsychotics Quetiapine and Amisulprid in the dynamics of 6-week treatment. We examined 39 schizophrenic patients: 26 patients (F20.5) were treated by Quetiapine (Seroquel), 13 patients (F20.05, F20.0, F20.09) - by Amisulprid (Solian). The psychometric scale PANSS was used to estimate the dynamics of psychopathological symptomatology during atypical neuroleptics' treatment. The immunological examination included the definition of cellular immunity parameters (the phenotyping of surface receptors of immunocompetent cells with the use of homogeneous antibodies) and humoral immunity parameters (concentration of IgM, IgG, IgA; level of Cle). The research was carried out in two points: first - before the prescription of atypical neuroleptics, second - in 6 weeks of treatment. The most significant changes of psychopathological symptomatology according to the PANSS scale were observed during Amisulprid treatment: the average per cent of PANSS total number decrease was 29.2%; average per cent of number decrease according to the positive disorders' subscale was 34.9%; according to the negative disorders' subscale - 29.3%; according to the sychopathologic symptoms' subscale - 27.7%. During Quetiapine treatment: the average per cent of number decrease according to the PANSS subscales was 24.7%, 20.2%, 25.5% and 25.5% respectively. Before the atypical neuroleptics' therapy, T-immunodeficiency was diagnosed among the schizophrenic patients, which was kept within 6 weeks of treatment. We determined the following significant changes in comparison to the control group of healthy people: the decrease of T-Iymphocytes (CD2+), mature T-Iymphocytes (CD3+), helpers/inductors (CD4+); the increase ofB-lymphocytes and activated T-Iymphocytes (HLADR+), the increase of CIC level and the tendency to the increase of IgG concentration. Besides, blood analysis of the patients, who were prescribed with further Solian therapy, revealed higher quantity of natural killers' (CD16+). The peculiarities of immunomodulatory influence of atypical neuroleptics on the immunity were determined during 6-week therapy. Quetiapine normalized B-Iymphocytes and activated T-Iymphocytes (HLADR+), the number of natural killers CD16+ tended to the level of control group, loosing reliability. In the process of Amisulprid treatment we observed the normalization
of natural killers' (CD16+) number; the number ofB-lymphocytes and activated T-Iymphocytes (HLADR+) tended to the level of the control group followed by the clear tendency to the decrease of CIC level and IgM, IgG concentration. However, we observed further reduction of some cell immunity parameters (the decrease of T-Iymphocytes CD2+, B-Iymphocytes CD20+) in comparison to the 1st point of investigation. Thus, we estimated the immunomodulatory effects of atypical neuroleptics Quetiapine and Amisulprid. We received new data about their influence on immune parameters of schizophrenics. Immunosuppressive effect on T-part of the immunity during 6week treatment was observed. We determined that the favorable clinical dynamics was followed by the positive dynamics of some immune parameters, probably caused by the optimization of the psychoneuroimmunomodulation mechanisms under the atypical neuroleptics' influence.
1P.3.d.0121 The effects of single dose aripiprazole and haloperidol on resting blood flow in healthy volunteers R. Handley1., F. Zelaya/, AAT.S. Reinders", T. Marques", S. Kapur1, R. Murray1, P. McGuire 1, S. Williams2 , C. Pariante 1, P. Dazzan1. 1 Institute of Psychiatry, Psychological Medicine, London, United Kingdom; 2Institute of Psychiatry, Clinical Neuroscience, London, United Kingdom The direct effects of typical and atypical antipsychotics on blood flow remain unclear. PET, SPECT and cerebrography have been used to indirectly explore the effects of antipsychotic drugs on blood flow by studying metabolism. These studies suggest that typical and atypical antipsychotics may have differential effects in the striatal and frontal cortices but more similar effects on temporal cortex metabolism. Unfortunately, most studies have evaluated individuals with psychosis in which the pathology of the disorder and previous antipsychotic treatment history playa role in the findings. Furthermore, most studies have not directly compared the effects of typical and atypical antipsychotics. In this study we directly compare the differential effects of typical and atypical antipsychotics on resting blood flow in healthy individuals. Studying healthy individuals, in whom perfusion alterations are not confounded by pathophysiological factors, allows us to better estimate the direct effects of these drugs on brain physiology. Single doses of haloperidol (3 mg) and aripiprazole (10 mg) were administered to 17 healthy Caucasian, right handed males (mean age 23yrs, SD3) in a repeated measures, randomised, double-blind, placebo controlled design. Volunteers had no current or past psychiatric history themselves or in their first degree relatives. Volunteers abstained from substance use and smoking for at least 3 months prior to the study. Four hours post treatment, a continuous arterial spin labeling sequence was used to obtain a direct measure of blood flow using a 1.5 Tesla scanner. Sixty-four volumes were acquired with a slice thickness of 3.3 mm (including inter-slice gap) over 6 minutes. A perfusion-weighted image was produced via the subtraction of the image in which blood had been labeled from that in which it had not and co-registered with a high resolution structural image. Between-subject analysis was performed on global perfusion using a random effects model at the second level. Compared with placebo, haloperidol significantly increased perfusion in the putamen bilaterally, in the right parahippocampal gyrus and in the medial frontal cortex bilaterally (p < 0.001,
P.3.d Psychotic disorders and antipsychotics - Antipsychotics (basic) corrected; effect size=0.8). Compared with placebo, aripiprazole increased perfusion in the left putamen only (p < 0.001, corrected; effect size=0.6). Similar to the findings for metabolism in patients, striatal blood flow increased with both typical and atypical antipsychotics. This change was more widespread following haloperidol. Unexpectedly, haloperidol was also associated with increased blood flow in the frontal and temporal regions, whereas no such changes were found following aripiprazole. This study provides the first evidence that regional, antipsychotic-specific alterations in rCBF occur within 4 hours of administration of a single antipsychotic dose in healthy volunteers. Furthermore, these alterations in perfusion are independent from pathophysiological processes, and provide important insight into basal brain function in populations receiving different antipsychotic medications. The findings have important implications for the interpretation of functional and structural imaging findings in schizophrenia and for understanding the different side effect profiles for these drugs.
1P.3.d.0131 Reboxetine enhances cortical dopaminergic and glutamatergic transmission and the antipsychotic-like effect of olanzapine
S561
increase (873.5±168.0%, p < 0.001). The increased dopamine output in the NAC seen after olanzapine (1.25 mglkg; 272.5±53.2%) was in contrast not significantly enhanced by addition of reboxetine (302. 1±47.0%). We observed a small, but significant increase of NMDA-induced currents after bath application of a low concentration of reboxetine 20 nM (117.7±4.2, p
T.H. Svensson 1 • , K. Jardemark1, A. Malmerfelt1, C. Bjorkholm1, M.M. Marcus 1 . 1Karolinska Institutet, Department ofPhysiology and Pharmacology Section of Neuropsychopharmacology, Stockholm, Sweden Objective: Preclinical data show that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine to raclopride, a typical D2/3 antagonist, increases its antipsychotic efficacy and, in parallel, enhances dopamine output in the medial prefrontal cortex (mPFC)(I), generating in principle a clozapinelike profile. Subsequent clinical results have suggested that adding reboxetine to a stable treatment with various antipsychotic drugs (APDs) may indeed improve positive, negative and depressive symptoms in schizophrenia [2]. Therefore we have here, in rats, investigated the behavioral and neurobiological consequences of adding reboxetine to the second generation APD olanzapine. Methods: The antipsychotic efficacy was evaluated using the conditioned avoidance response (CAR) test, a preclinical test of clinical antipsychotic activity with high predictive validity. Using a catalepsy test, we assessed the propensity of these drugs, alone and in combination, to cause extrapyramidal side effects (EPS). We also measured dopamine output in two brain regions, the mPFC and the nucleus accumbens (NAC), respectively, using in vivo microdialysis in freely moving rats, and finally we assessed the effects of these drugs on cortical glutamatergic neurotransmission using in vitro electrophysiological intracellular recording techniques to measure N-methyl-D-aspartate {NMDA)-induced currents in pyramidal neurons of the mPFC. Results: Addition of reboxetine (6mglkg) to a low dose of olanzapine (1.25 mglkg), which by itself did not produce a significant suppression of CAR (90.5±38.5%; median±semiinterquartile range), markedly enhanced the suppression of CAR (47.0±40.0% (p < 0.05), yet without any concomitant catalepsy. However, addition of reboxetine to a higher dose of olanzapine (2.5 mglkg) did not enhance suppression of CAR. The low dose of olanzapine (1.25 mglkg) alone caused a moderate increase cortical dopamine [max effect 4l9.8±66.5% (mean±SEM, % of baseline)], whereas addition of reboxetine induced a markedly larger
[I] Linner L, Wiker C, Wadenberg ML, Schalling M, Svensson TH (2002). Noradrenalioe reuptake inhibition enhances the antipsychotic-like effect ofrac1opride and potentiates D2-blockage-induced dopamine release io the medial prefrontal cortex of the rat. Neuropsychopharmacology 27, 691--698. [2] Raedler TJ, Jalm H, Arlt J, Kiefer F, Schick M, Naber D, Wiedemann K (2004). Adjunctive use of reboxetine in schizophrenia. European Psychiatry: the Journal of the Association of European Psychiatrists 19, 366--369. 3. Poyurovsky M, Isaacs I, Fuchs C, Schneidrnan M, Faragian S, Weizrnan R, Weizrnan A (2003) Attenuation of olanzapineioduced weight gain with reboxetine io patients with schizophrenia: a double-blind, placebo-controlled study. Am J Psychiatry. 160(2):297302.
1P.3.d.0141 Modification of cortical inhibition by paliperidone or risperidone: preliminary results L. Ustoha11 . , R. Prikryl", H. Kucerova 1, L. Havlaskova 1, E. Ceskova 1 . 1FN Brno, Department ofPsychiatry, Brno, Czech Republic Introduction: Deficit of cortical inhibition in schizophrenia reflects the psychopathology of the cortical and subcortical brain areas. The reduced Cortical Silent Period (CSP) duration is a marker of impaired cortical inhibition. It is known from neurophysiological studies that the CSP is a function of GABA-B receptors. The CSP duration is invariably found to be shortened in patients with schizophrenia either without or with the use of antipsychotics compared to controls [1]. Antipsychotic therapy extends the CSP and therefore causes changes in abnormal cortical inhibition processes [2]. It was confirmed that clozapine cause prolongation of cortical inhibition [3]. Aim: Aim ofthis study was to assess the impact ofpaliperidone and risperidone on the CSP in drug-naive patients with first episode of schizophrenia using transcranial magnetic stimulation (TMS). Methodology: Three drug-naive patients with first episode of paranoid schizophrenia were included in the study. Prior to inclusion in the study and 28 days after paliperidone (one patient) or risperidone (two patients) monotherapy were
P.3.d Psychotic disorders and antipsychotics - Antipsychotics (basic)
Conclusions: These results show that plasma levels of BDNF and glutamate are decreased at the onset of psychosis, therefore indicate that the psychotic episode affects to neurobiological substances. When the patients begin the pharmacological treatment the glutamate and BDNF levels increase significantly but it's necessary at least 6 months of treatment to obtain normal levels. These neurotransmitters could offer us a relevant key for the pharmacological treatment of psychotic diseases. The prognosis in children with a first psychotic episode is worse than prognosis in adults with the same diagnosis and is probable that neurotrophic factors could be implicated in these differences.
IP.3.d.0111 The immunomodulatory effects of atypical neuroleptics quetiapine and amisulpride in the dynamics of 6-week treatment
o.x. Lobacheva1 ., T.P. Vetlugina 1, A.V. Semke 2 . 1Mental Health Research Institute, Clinical Psychoneuroimmunology Laboratory, Tomsic, Russia; 2Mental Health Research Institute, Endogenous Disorders Department, Tomsic, Russia The objective of the conducted research was the estimation of immunomodulatory effects of atypical antipsychotics Quetiapine and Amisulprid in the dynamics of 6-week treatment. We examined 39 schizophrenic patients: 26 patients (F20.5) were treated by Quetiapine (Seroquel), 13 patients (F20.05, F20.0, F20.09) - by Amisulprid (Solian). The psychometric scale PANSS was used to estimate the dynamics of psychopathological symptomatology during atypical neuroleptics' treatment. The immunological examination included the definition of cellular immunity parameters (the phenotyping of surface receptors of immunocompetent cells with the use of homogeneous antibodies) and humoral immunity parameters (concentration of IgM, IgG, IgA; level of Cle). The research was carried out in two points: first - before the prescription of atypical neuroleptics, second - in 6 weeks of treatment. The most significant changes of psychopathological symptomatology according to the PANSS scale were observed during Amisulprid treatment: the average per cent of PANSS total number decrease was 29.2%; average per cent of number decrease according to the positive disorders' subscale was 34.9%; according to the negative disorders' subscale - 29.3%; according to the sychopathologic symptoms' subscale - 27.7%. During Quetiapine treatment: the average per cent of number decrease according to the PANSS subscales was 24.7%, 20.2%, 25.5% and 25.5% respectively. Before the atypical neuroleptics' therapy, T-immunodeficiency was diagnosed among the schizophrenic patients, which was kept within 6 weeks of treatment. We determined the following significant changes in comparison to the control group of healthy people: the decrease of T-Iymphocytes (CD2+), mature T-Iymphocytes (CD3+), helpers/inductors (CD4+); the increase ofB-lymphocytes and activated T-Iymphocytes (HLADR+), the increase of CIC level and the tendency to the increase of IgG concentration. Besides, blood analysis of the patients, who were prescribed with further Solian therapy, revealed higher quantity of natural killers' (CD16+). The peculiarities of immunomodulatory influence of atypical neuroleptics on the immunity were determined during 6-week therapy. Quetiapine normalized B-Iymphocytes and activated T-Iymphocytes (HLADR+), the number of natural killers CD16+ tended to the level of control group, loosing reliability. In the process of Amisulprid treatment we observed the normalization
of natural killers' (CD16+) number; the number ofB-lymphocytes and activated T-Iymphocytes (HLADR+) tended to the level of the control group followed by the clear tendency to the decrease of CIC level and IgM, IgG concentration. However, we observed further reduction of some cell immunity parameters (the decrease of T-Iymphocytes CD2+, B-Iymphocytes CD20+) in comparison to the 1st point of investigation. Thus, we estimated the immunomodulatory effects of atypical neuroleptics Quetiapine and Amisulprid. We received new data about their influence on immune parameters of schizophrenics. Immunosuppressive effect on T-part of the immunity during 6week treatment was observed. We determined that the favorable clinical dynamics was followed by the positive dynamics of some immune parameters, probably caused by the optimization of the psychoneuroimmunomodulation mechanisms under the atypical neuroleptics' influence.
1P.3.d.0121 The effects of single dose aripiprazole and haloperidol on resting blood flow in healthy volunteers R. Handley1., F. Zelaya/, AAT.S. Reinders", T. Marques", S. Kapur1, R. Murray1, P. McGuire 1, S. Williams2 , C. Pariante 1, P. Dazzan1. 1 Institute of Psychiatry, Psychological Medicine, London, United Kingdom; 2Institute of Psychiatry, Clinical Neuroscience, London, United Kingdom The direct effects of typical and atypical antipsychotics on blood flow remain unclear. PET, SPECT and cerebrography have been used to indirectly explore the effects of antipsychotic drugs on blood flow by studying metabolism. These studies suggest that typical and atypical antipsychotics may have differential effects in the striatal and frontal cortices but more similar effects on temporal cortex metabolism. Unfortunately, most studies have evaluated individuals with psychosis in which the pathology of the disorder and previous antipsychotic treatment history playa role in the findings. Furthermore, most studies have not directly compared the effects of typical and atypical antipsychotics. In this study we directly compare the differential effects of typical and atypical antipsychotics on resting blood flow in healthy individuals. Studying healthy individuals, in whom perfusion alterations are not confounded by pathophysiological factors, allows us to better estimate the direct effects of these drugs on brain physiology. Single doses of haloperidol (3 mg) and aripiprazole (10 mg) were administered to 17 healthy Caucasian, right handed males (mean age 23yrs, SD3) in a repeated measures, randomised, double-blind, placebo controlled design. Volunteers had no current or past psychiatric history themselves or in their first degree relatives. Volunteers abstained from substance use and smoking for at least 3 months prior to the study. Four hours post treatment, a continuous arterial spin labeling sequence was used to obtain a direct measure of blood flow using a 1.5 Tesla scanner. Sixty-four volumes were acquired with a slice thickness of 3.3 mm (including inter-slice gap) over 6 minutes. A perfusion-weighted image was produced via the subtraction of the image in which blood had been labeled from that in which it had not and co-registered with a high resolution structural image. Between-subject analysis was performed on global perfusion using a random effects model at the second level. Compared with placebo, haloperidol significantly increased perfusion in the putamen bilaterally, in the right parahippocampal gyrus and in the medial frontal cortex bilaterally (p < 0.001,
P.3.d Psychotic disorders and antipsychotics - Antipsychotics (basic) corrected; effect size=0.8). Compared with placebo, aripiprazole increased perfusion in the left putamen only (p < 0.001, corrected; effect size=0.6). Similar to the findings for metabolism in patients, striatal blood flow increased with both typical and atypical antipsychotics. This change was more widespread following haloperidol. Unexpectedly, haloperidol was also associated with increased blood flow in the frontal and temporal regions, whereas no such changes were found following aripiprazole. This study provides the first evidence that regional, antipsychotic-specific alterations in rCBF occur within 4 hours of administration of a single antipsychotic dose in healthy volunteers. Furthermore, these alterations in perfusion are independent from pathophysiological processes, and provide important insight into basal brain function in populations receiving different antipsychotic medications. The findings have important implications for the interpretation of functional and structural imaging findings in schizophrenia and for understanding the different side effect profiles for these drugs.
1P.3.d.0131 Reboxetine enhances cortical dopaminergic and glutamatergic transmission and the antipsychotic-like effect of olanzapine
S561
increase (873.5±168.0%, p < 0.001). The increased dopamine output in the NAC seen after olanzapine (1.25 mglkg; 272.5±53.2%) was in contrast not significantly enhanced by addition of reboxetine (302. 1±47.0%). We observed a small, but significant increase of NMDA-induced currents after bath application of a low concentration of reboxetine 20 nM (117.7±4.2, p
T.H. Svensson 1 • , K. Jardemark1, A. Malmerfelt1, C. Bjorkholm1, M.M. Marcus 1 . 1Karolinska Institutet, Department ofPhysiology and Pharmacology Section of Neuropsychopharmacology, Stockholm, Sweden Objective: Preclinical data show that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine to raclopride, a typical D2/3 antagonist, increases its antipsychotic efficacy and, in parallel, enhances dopamine output in the medial prefrontal cortex (mPFC)(I), generating in principle a clozapinelike profile. Subsequent clinical results have suggested that adding reboxetine to a stable treatment with various antipsychotic drugs (APDs) may indeed improve positive, negative and depressive symptoms in schizophrenia [2]. Therefore we have here, in rats, investigated the behavioral and neurobiological consequences of adding reboxetine to the second generation APD olanzapine. Methods: The antipsychotic efficacy was evaluated using the conditioned avoidance response (CAR) test, a preclinical test of clinical antipsychotic activity with high predictive validity. Using a catalepsy test, we assessed the propensity of these drugs, alone and in combination, to cause extrapyramidal side effects (EPS). We also measured dopamine output in two brain regions, the mPFC and the nucleus accumbens (NAC), respectively, using in vivo microdialysis in freely moving rats, and finally we assessed the effects of these drugs on cortical glutamatergic neurotransmission using in vitro electrophysiological intracellular recording techniques to measure N-methyl-D-aspartate {NMDA)-induced currents in pyramidal neurons of the mPFC. Results: Addition of reboxetine (6mglkg) to a low dose of olanzapine (1.25 mglkg), which by itself did not produce a significant suppression of CAR (90.5±38.5%; median±semiinterquartile range), markedly enhanced the suppression of CAR (47.0±40.0% (p < 0.05), yet without any concomitant catalepsy. However, addition of reboxetine to a higher dose of olanzapine (2.5 mglkg) did not enhance suppression of CAR. The low dose of olanzapine (1.25 mglkg) alone caused a moderate increase cortical dopamine [max effect 4l9.8±66.5% (mean±SEM, % of baseline)], whereas addition of reboxetine induced a markedly larger
[I] Linner L, Wiker C, Wadenberg ML, Schalling M, Svensson TH (2002). Noradrenalioe reuptake inhibition enhances the antipsychotic-like effect ofrac1opride and potentiates D2-blockage-induced dopamine release io the medial prefrontal cortex of the rat. Neuropsychopharmacology 27, 691--698. [2] Raedler TJ, Jalm H, Arlt J, Kiefer F, Schick M, Naber D, Wiedemann K (2004). Adjunctive use of reboxetine in schizophrenia. European Psychiatry: the Journal of the Association of European Psychiatrists 19, 366--369. 3. Poyurovsky M, Isaacs I, Fuchs C, Schneidrnan M, Faragian S, Weizrnan R, Weizrnan A (2003) Attenuation of olanzapineioduced weight gain with reboxetine io patients with schizophrenia: a double-blind, placebo-controlled study. Am J Psychiatry. 160(2):297302.
1P.3.d.0141 Modification of cortical inhibition by paliperidone or risperidone: preliminary results L. Ustoha11 . , R. Prikryl", H. Kucerova 1, L. Havlaskova 1, E. Ceskova 1 . 1FN Brno, Department ofPsychiatry, Brno, Czech Republic Introduction: Deficit of cortical inhibition in schizophrenia reflects the psychopathology of the cortical and subcortical brain areas. The reduced Cortical Silent Period (CSP) duration is a marker of impaired cortical inhibition. It is known from neurophysiological studies that the CSP is a function of GABA-B receptors. The CSP duration is invariably found to be shortened in patients with schizophrenia either without or with the use of antipsychotics compared to controls [1]. Antipsychotic therapy extends the CSP and therefore causes changes in abnormal cortical inhibition processes [2]. It was confirmed that clozapine cause prolongation of cortical inhibition [3]. Aim: Aim ofthis study was to assess the impact ofpaliperidone and risperidone on the CSP in drug-naive patients with first episode of schizophrenia using transcranial magnetic stimulation (TMS). Methodology: Three drug-naive patients with first episode of paranoid schizophrenia were included in the study. Prior to inclusion in the study and 28 days after paliperidone (one patient) or risperidone (two patients) monotherapy were