- Email: [email protected]
P.3.e.017 Brain activation preceding auditory verbal hallucinations
S576
P.3.e Psychotic disorders and antipsychotics - Others (clinical)
Methods. This analysis was performed within the scope of the CLAMORS study (a nation-wide cross-sectional multicentre study carried out between years 2005 and 2006), which included consecutive outpatients meeting DSM-IV criteria for schizophrenia, schizophreniform or schizoaffective disorder. Smoking history was assessed by patient's interview, and checked with partners and/or relative when available. Apart from psychiatric history, physical examination and fasting analytical parameters determination, data on usual healthy life-style habits included current exercise, saturated-fat sparing diet, low-caloric diet, and daily dietary fibre, salt, caffeine and alcohol consumption. The lO-year CVE risk was computed by means of the Framingham function. Descriptive statistics, odds ratios with its 95% confidence intervals calculated with binary logistic regression and analysis of covariance (ANCOVA) to adjust for confounding variables were used to ascertain statistical association. Results. A total of 1,704 patients (61.1% male), 18 to 74 years (mean age: 40.2±12.3 years) were examined. The overall prevalence of current daily smoking was 54.54% (95% CI: 52.16%-56.90%). After controlling by age, sex, total cholesterol, HDL-cholesterol, blood pressure and diabetes diagnosis, smokers showed a lO-year CVE risk excess versus non-smokers of 2.63 (2.16-3.09), P < 0.001. Smoking cessation would reduce the likely of high/very high lO-year CVE risk (above 10%) by 90% [OR = 0.10 (0.06-0.18), P < 0.0001]. After adjusting by age and sex, smokers were more likely to consume daily alcohol [OR =4.13 (3.07-5.54), P < 0.0001] and caffeine [OR=3.39 (2.72-4.23), p
IP.3.e.0161 Effectiveness of repetitive transcranial magnetic stimulation repetitive TMS for depression in schizophrenia N. Maslenikov 1 ., E. Tsukarzi", S. Mosolov 1 . 1Moscow Research Institute of Psychiatry, Department for treatment of mental disorders, Moscow, Russia Background: Depression is an important co-occurring syndrome in schizophrenia and is associated with increased morbidity and mortality [1]. Pharmacological treatment of this condition has certain difficulties and stimulation techniques of the brain may be considered in the management of such patients [2]. The aim of the study was to estimate the effectiveness of rTMS for the treatment of depression in schizophrenia patients.
Methods: 97 patients with schizophrenia (ICD-lO) stabilized on antipsychotic medication and without exacerbation of psychotic symptoms were included in the study. All the patients had major depression (Calgary Depression Scale for Schizophrenia (CDSS) score ~ 6). Negative symptoms were prevalent in all patients. Mean PANSS composite index was - 11. 66 patients were randomly divided in 2 groups. 32 patients of the 1st group received 15-Hz rTMS on the left dorsolateral prefrontal cortex (100% intensity, 6-second trains, 60-second intervals, and 20-train session). Sessions were given 5 times a week during 3 weeks. 34 patients of the 2nd group were treated with antidepressant (SSRI) which was added to antipsychotic therapy and this group was an active control for the 1st group. 31 patients of the 3rd group were pharmacoresistant and received antipsychotic + antidepressant combination for at least 3 weeks prior to the study. 13 of them were non-responders from the 2nd group. Patients of the 3rd group underwent rTMS with the same parameters as the in the 1st group and they continued to receive their antipsychotic and antidepressant medication at the same doses. Patients were assessed weekly with CDSS, PANSS, Hamilton Depression Scale (HAMD), Clinical Global Impression for Schizophrenia (CGI-S) and with the battery of cognitive tests. Results: The responders rate (50% CDSS score reduction) was 20 (62.5%) in the 1st group, in the control group this number was 18 (52.9%). The number of responders in the 3rd group (resistant depressions in schizophrenia) was 20 (64.5%). Good tolerability, rapid onset of antidepressive effect and more potent reduction of negative symptoms in comparison with the control group were the prominent features of rTMS action. The disadvantage of rTMS was unstable effect, in 35% of responders in the 1st group depressive symptoms relapsed in two weeks after discontinuation of the therapy. Also there was increase in some of cognitive test results, which reflects improvement in executive functions and in attention switching. These changes were bigger in groups where rTMS was performed. We found no significant changes in verbal and visual memory. Conclusion: Our results have shown that antidepressive effect of rTMS in schizophrenia is comparable to conventional methods of pharmacological treatment. rTMS by itself or in combination with antidepressant is an effective for treatment of pharmacoresistant depression associated with schizophrenia. rTMS as an "add-on therapy" could be an optimal treatment of severe pharmacoresistant depression in schizophrenic patients without actual psychotic symptoms. References [1] Addington D.E., Addington 1M. Attempted suicide and depression in schizophrenia. Acta Psychiatr. Scand. 1992, 85(4), 288-291. [2] Rollnik ID. et al. High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients. Neuroreport. 2000, 11(18), 4013--4015.
1P.3.e.0171 Brain activation preceding auditory verbal hallucinations 1. Sommer1 ., K.M. Diederen 1 , R.S. Kahn 1 . 1Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, The Netherlands
Objective: Auditory verbal hallucinations (AVH) or 'hearing voices' constitute a cardinal feature of psychosis. The pathophysiology of AVH is still unknown, but several indications exist. First, AVH in schizophrenia are responsive to antipsychotic medication
P.3.e Psychotic disorders and antipsychotics - Others (clinical)
in approximately 70% ofpatients. The antipsychotic effect ofthese agents is most likely mediated by antagonism at the D2 receptors. Therefore, a dopaminergic component can be presumed to be involved in the genesis of AVH. A second line of evidence is derived from neuroimaging studies aiming at visualizing brain activation during AVH. These studies demonstrated consistent activation of bilateral language-related areas during AVH, with most prominent activation in the right homologues of Broca's and Wernicke's area. However, as these language-related areas barely have any D2 innervations, this finding cannot easily be linked to the suspected dopaminergic component. Moreover, although functional imaging of cerebral activity during AVH is helpful to understand which cerebral functions are involved in the experience of AVH, they cannot explain how and where these experiences originate in the brain. As AVH arise without an external source i.e. the experience of an actual voice, they must be triggered internally. Studying brain activation in the time period preceding AVH may reveal this trigger. Method: Twenty-fourpsychotic patients indicated the presence of AVH during 3T fMRI scanning by squeezing a small hand-held balloon. Functional scans of 15 patients could be included in a tailored 'selective averaging' method to enable analysis of brain activation from 6 to 0 seconds prior to the AVH without any a priori assumptions. To control for motor related activation, 15 control subjects squeezed this balloon at matched time intervals. Results: Activity during AVH was observed in bilateral language-related areas, predominantly in the right hemisphere. In the six seconds preceding AVH prominent deactivation was observed in the left parahippocampal gyrus. In addition, significant deactivation was found in the left superior temporal, right inferior frontal and left middle frontal gyri as well as in the right insula and left cerebellum. No significant signal changes were revealed prior to the matched balloon-squeezing in the control subjects. Conclusions: Most prominent deactivation preceding AVH was observed in the parahippocampal gryus. As the parahippocampus is dopamine D2 innervated, this finding may be the missing link between dopaminergic overactivity and inadequate activation of bilateral language-related areas. The parahippocampus plays a central role in recognition and memory, as it receives complex analysed perceptual information from association cortices such as the language areas and forwards this information to the hippocampus in order to be ''recognized''. The recognized perceptual information is then passed back to the parahippocampal gyrus and from there redistributed to the association cortices involved in the original perception. Indeed, activation of association cortices originally involved in the perception has consistently been shown by neuroimaging studies during memory retrieval. In the case of AVH, increased dopaminergic stimulation from the mid-brain may enhance the redistribution function of the parahippocampal gyrus, leading to erroneous activation of association cortex and hence to incorrect recognition. Disinhibition of the parahippocampal gyrus, demonstrated as deactivation preceding AVH, then triggers the bilateral language-related areas which were originally involved in the perception of speech fragments as shown in the bilateral activation of language-related cortices during the AVH.
S577
1P.3.e.0181 The effects of psychopathology on subjective experience of side effects of anti psychotics in patients with schizophrenia
D.C. Jung" ", S.S. Hwang", S.H. Kim 1, N.Y. Lee 1, H.Y. Jung", Y.M. Ahn 1 , Y.S. Kim 1 . 1 Seoul National University Hospital, Department of Psychiatry and Behavioral Science and Institute ofHuman Behavioral Medicine, Seoul, South-Korea The subjective side effects could be described as mental or physical states which patients report regardless of etiological attributions or the antipsychotics. The patients' unfavorable antipsychotics-related expectation and affect may result in the expression of psychological and somatic manifestations, a phenomenon largely studied as the nocebo effect. Thus, it could be hypothesized that there may exist certain psychopathological conditions that make patients more prone to negative expectation of antipsychotics, which may in tum adversely affect their subjective experience and evaluation of side effects. The aim of this study is to delineate the relationship between self-reported side effects and psychopathology in schizophrenia patients. Clinical data of 175 participants were collected at the baseline of two antipsychotic trials; one is to start or switch to amisulpride, and the other is to switch to olanzapine. The participants completed the Liverpool University Neuroleptic Side Effects Rating Scale (LUNSERS) for subjective side effects and were evaluated with the Positive and Negative Syndrome Scale (PANSS) for their psychopathology. Red Herring (RH) items of the LUNSERS consist of symptoms which are not directly related to known antipsychotic side effects, which have been suggested to be associated with the over-reporting tendency of side effects. Based on a series of multiple linear regression analyses, we derived a model accounting for the relationships among the specific domains of psychopathology and RH items of the LUNSERS in predicting subjective side effects. The fitness of the model was tested using the structural equation modeling (SEM) method. The model with anxiety/depressive symptoms and RH serving as mediators between positive symptoms and subjective side effects was found to show good fitness. Positive symptoms caused mostly anxiety symptoms and tendency to report RH items, whereby resulting in over-generalized reporting of subjective side effects. However, a large proportion of variance of side effects was explained by RH, which was only partially explained by positive symptoms alone. We applied the above model to the amisulpride and olanzapine samples separately. The model with the amisulpride group showed excellent fit consistent with that of the combined group, but the olanzapine group showed poor fit. In the olanzapine group, only RH emerged as the significant predictor, which in tum was predicted by only anxiety/depressive factor. The amisulpride group had significantly higher positive factor and marginally higher negative factor scores, although overall severity of psychopathology was similar to that of the olanzapine group. Such differences may reflect the differences in sample recruitment. The amisulpride trial required acute exacerbation of symptoms, while the olanzapine trial mostly included chronic patients showing inefficacy of previous medication. This can be interpreted as reflecting the differences between the acute and chronic stages of schizophrenia, signifying that higher levels ofpositive symptoms in acute stage of schizophrenia are likely to make the patients vulnerable to nocebo effects and cause them to make over-generalized report of side effects. Studies that include acute stage patients presenting severe levels of these symptoms should not rely only on the subjective report of side effects but also apply objective measures.
P.3.e Psychotic disorders and antipsychotics - Others (clinical)
Methods. This analysis was performed within the scope of the CLAMORS study (a nation-wide cross-sectional multicentre study carried out between years 2005 and 2006), which included consecutive outpatients meeting DSM-IV criteria for schizophrenia, schizophreniform or schizoaffective disorder. Smoking history was assessed by patient's interview, and checked with partners and/or relative when available. Apart from psychiatric history, physical examination and fasting analytical parameters determination, data on usual healthy life-style habits included current exercise, saturated-fat sparing diet, low-caloric diet, and daily dietary fibre, salt, caffeine and alcohol consumption. The lO-year CVE risk was computed by means of the Framingham function. Descriptive statistics, odds ratios with its 95% confidence intervals calculated with binary logistic regression and analysis of covariance (ANCOVA) to adjust for confounding variables were used to ascertain statistical association. Results. A total of 1,704 patients (61.1% male), 18 to 74 years (mean age: 40.2±12.3 years) were examined. The overall prevalence of current daily smoking was 54.54% (95% CI: 52.16%-56.90%). After controlling by age, sex, total cholesterol, HDL-cholesterol, blood pressure and diabetes diagnosis, smokers showed a lO-year CVE risk excess versus non-smokers of 2.63 (2.16-3.09), P < 0.001. Smoking cessation would reduce the likely of high/very high lO-year CVE risk (above 10%) by 90% [OR = 0.10 (0.06-0.18), P < 0.0001]. After adjusting by age and sex, smokers were more likely to consume daily alcohol [OR =4.13 (3.07-5.54), P < 0.0001] and caffeine [OR=3.39 (2.72-4.23), p
IP.3.e.0161 Effectiveness of repetitive transcranial magnetic stimulation repetitive TMS for depression in schizophrenia N. Maslenikov 1 ., E. Tsukarzi", S. Mosolov 1 . 1Moscow Research Institute of Psychiatry, Department for treatment of mental disorders, Moscow, Russia Background: Depression is an important co-occurring syndrome in schizophrenia and is associated with increased morbidity and mortality [1]. Pharmacological treatment of this condition has certain difficulties and stimulation techniques of the brain may be considered in the management of such patients [2]. The aim of the study was to estimate the effectiveness of rTMS for the treatment of depression in schizophrenia patients.
Methods: 97 patients with schizophrenia (ICD-lO) stabilized on antipsychotic medication and without exacerbation of psychotic symptoms were included in the study. All the patients had major depression (Calgary Depression Scale for Schizophrenia (CDSS) score ~ 6). Negative symptoms were prevalent in all patients. Mean PANSS composite index was - 11. 66 patients were randomly divided in 2 groups. 32 patients of the 1st group received 15-Hz rTMS on the left dorsolateral prefrontal cortex (100% intensity, 6-second trains, 60-second intervals, and 20-train session). Sessions were given 5 times a week during 3 weeks. 34 patients of the 2nd group were treated with antidepressant (SSRI) which was added to antipsychotic therapy and this group was an active control for the 1st group. 31 patients of the 3rd group were pharmacoresistant and received antipsychotic + antidepressant combination for at least 3 weeks prior to the study. 13 of them were non-responders from the 2nd group. Patients of the 3rd group underwent rTMS with the same parameters as the in the 1st group and they continued to receive their antipsychotic and antidepressant medication at the same doses. Patients were assessed weekly with CDSS, PANSS, Hamilton Depression Scale (HAMD), Clinical Global Impression for Schizophrenia (CGI-S) and with the battery of cognitive tests. Results: The responders rate (50% CDSS score reduction) was 20 (62.5%) in the 1st group, in the control group this number was 18 (52.9%). The number of responders in the 3rd group (resistant depressions in schizophrenia) was 20 (64.5%). Good tolerability, rapid onset of antidepressive effect and more potent reduction of negative symptoms in comparison with the control group were the prominent features of rTMS action. The disadvantage of rTMS was unstable effect, in 35% of responders in the 1st group depressive symptoms relapsed in two weeks after discontinuation of the therapy. Also there was increase in some of cognitive test results, which reflects improvement in executive functions and in attention switching. These changes were bigger in groups where rTMS was performed. We found no significant changes in verbal and visual memory. Conclusion: Our results have shown that antidepressive effect of rTMS in schizophrenia is comparable to conventional methods of pharmacological treatment. rTMS by itself or in combination with antidepressant is an effective for treatment of pharmacoresistant depression associated with schizophrenia. rTMS as an "add-on therapy" could be an optimal treatment of severe pharmacoresistant depression in schizophrenic patients without actual psychotic symptoms. References [1] Addington D.E., Addington 1M. Attempted suicide and depression in schizophrenia. Acta Psychiatr. Scand. 1992, 85(4), 288-291. [2] Rollnik ID. et al. High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients. Neuroreport. 2000, 11(18), 4013--4015.
1P.3.e.0171 Brain activation preceding auditory verbal hallucinations 1. Sommer1 ., K.M. Diederen 1 , R.S. Kahn 1 . 1Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, The Netherlands
Objective: Auditory verbal hallucinations (AVH) or 'hearing voices' constitute a cardinal feature of psychosis. The pathophysiology of AVH is still unknown, but several indications exist. First, AVH in schizophrenia are responsive to antipsychotic medication
P.3.e Psychotic disorders and antipsychotics - Others (clinical)
in approximately 70% ofpatients. The antipsychotic effect ofthese agents is most likely mediated by antagonism at the D2 receptors. Therefore, a dopaminergic component can be presumed to be involved in the genesis of AVH. A second line of evidence is derived from neuroimaging studies aiming at visualizing brain activation during AVH. These studies demonstrated consistent activation of bilateral language-related areas during AVH, with most prominent activation in the right homologues of Broca's and Wernicke's area. However, as these language-related areas barely have any D2 innervations, this finding cannot easily be linked to the suspected dopaminergic component. Moreover, although functional imaging of cerebral activity during AVH is helpful to understand which cerebral functions are involved in the experience of AVH, they cannot explain how and where these experiences originate in the brain. As AVH arise without an external source i.e. the experience of an actual voice, they must be triggered internally. Studying brain activation in the time period preceding AVH may reveal this trigger. Method: Twenty-fourpsychotic patients indicated the presence of AVH during 3T fMRI scanning by squeezing a small hand-held balloon. Functional scans of 15 patients could be included in a tailored 'selective averaging' method to enable analysis of brain activation from 6 to 0 seconds prior to the AVH without any a priori assumptions. To control for motor related activation, 15 control subjects squeezed this balloon at matched time intervals. Results: Activity during AVH was observed in bilateral language-related areas, predominantly in the right hemisphere. In the six seconds preceding AVH prominent deactivation was observed in the left parahippocampal gyrus. In addition, significant deactivation was found in the left superior temporal, right inferior frontal and left middle frontal gyri as well as in the right insula and left cerebellum. No significant signal changes were revealed prior to the matched balloon-squeezing in the control subjects. Conclusions: Most prominent deactivation preceding AVH was observed in the parahippocampal gryus. As the parahippocampus is dopamine D2 innervated, this finding may be the missing link between dopaminergic overactivity and inadequate activation of bilateral language-related areas. The parahippocampus plays a central role in recognition and memory, as it receives complex analysed perceptual information from association cortices such as the language areas and forwards this information to the hippocampus in order to be ''recognized''. The recognized perceptual information is then passed back to the parahippocampal gyrus and from there redistributed to the association cortices involved in the original perception. Indeed, activation of association cortices originally involved in the perception has consistently been shown by neuroimaging studies during memory retrieval. In the case of AVH, increased dopaminergic stimulation from the mid-brain may enhance the redistribution function of the parahippocampal gyrus, leading to erroneous activation of association cortex and hence to incorrect recognition. Disinhibition of the parahippocampal gyrus, demonstrated as deactivation preceding AVH, then triggers the bilateral language-related areas which were originally involved in the perception of speech fragments as shown in the bilateral activation of language-related cortices during the AVH.
S577
1P.3.e.0181 The effects of psychopathology on subjective experience of side effects of anti psychotics in patients with schizophrenia
D.C. Jung" ", S.S. Hwang", S.H. Kim 1, N.Y. Lee 1, H.Y. Jung", Y.M. Ahn 1 , Y.S. Kim 1 . 1 Seoul National University Hospital, Department of Psychiatry and Behavioral Science and Institute ofHuman Behavioral Medicine, Seoul, South-Korea The subjective side effects could be described as mental or physical states which patients report regardless of etiological attributions or the antipsychotics. The patients' unfavorable antipsychotics-related expectation and affect may result in the expression of psychological and somatic manifestations, a phenomenon largely studied as the nocebo effect. Thus, it could be hypothesized that there may exist certain psychopathological conditions that make patients more prone to negative expectation of antipsychotics, which may in tum adversely affect their subjective experience and evaluation of side effects. The aim of this study is to delineate the relationship between self-reported side effects and psychopathology in schizophrenia patients. Clinical data of 175 participants were collected at the baseline of two antipsychotic trials; one is to start or switch to amisulpride, and the other is to switch to olanzapine. The participants completed the Liverpool University Neuroleptic Side Effects Rating Scale (LUNSERS) for subjective side effects and were evaluated with the Positive and Negative Syndrome Scale (PANSS) for their psychopathology. Red Herring (RH) items of the LUNSERS consist of symptoms which are not directly related to known antipsychotic side effects, which have been suggested to be associated with the over-reporting tendency of side effects. Based on a series of multiple linear regression analyses, we derived a model accounting for the relationships among the specific domains of psychopathology and RH items of the LUNSERS in predicting subjective side effects. The fitness of the model was tested using the structural equation modeling (SEM) method. The model with anxiety/depressive symptoms and RH serving as mediators between positive symptoms and subjective side effects was found to show good fitness. Positive symptoms caused mostly anxiety symptoms and tendency to report RH items, whereby resulting in over-generalized reporting of subjective side effects. However, a large proportion of variance of side effects was explained by RH, which was only partially explained by positive symptoms alone. We applied the above model to the amisulpride and olanzapine samples separately. The model with the amisulpride group showed excellent fit consistent with that of the combined group, but the olanzapine group showed poor fit. In the olanzapine group, only RH emerged as the significant predictor, which in tum was predicted by only anxiety/depressive factor. The amisulpride group had significantly higher positive factor and marginally higher negative factor scores, although overall severity of psychopathology was similar to that of the olanzapine group. Such differences may reflect the differences in sample recruitment. The amisulpride trial required acute exacerbation of symptoms, while the olanzapine trial mostly included chronic patients showing inefficacy of previous medication. This can be interpreted as reflecting the differences between the acute and chronic stages of schizophrenia, signifying that higher levels ofpositive symptoms in acute stage of schizophrenia are likely to make the patients vulnerable to nocebo effects and cause them to make over-generalized report of side effects. Studies that include acute stage patients presenting severe levels of these symptoms should not rely only on the subjective report of side effects but also apply objective measures.