- Email: [email protected]
P.3.027 Mismatch negativity generation in the human serotonergic and antiglutamatergic model of psychosis
$466
P3 Psychotic disorders and antipsychotics
Methods: Outpatients with bipolar I disorder (DSM-IV-TR) responding inadequately to ongoing medications (anticonvulsants, traditional mood stabilizers, or atypical [excluding quetiapine] or typical antipsychotics) were observed prior to and following the addition of QTP. Severity of symptoms was evaluated using the Clinical Global Impression scale for bipolar disorder (CGI-BP). Patients were assessed at least once every two months, but no less than eight times a year. Scores > or 1 point lower than previous CGI-BP scores and/or adjustment of treatment were recorded as relapses. Efficacy was assessed by calculating the relative risk of relapse before and following QTP treatment. Results: 42 patients (22 males, mean age 42±18.0 years and 20 females, mean age 53± 18.44 years) were observed for an average of 9.5 months (range 3 18 months) before the addition of QTP at a mean daily dose of 535±54.5 mg. Patients were subsequently followed for an average of 18.1 months (range 6 42 months). Prior to the addition of QTP, an overall relapse rate of 0.11 episodes/month was recorded, which related to 0.05 depressive episodes/month and 0.06 manic or mixed episodes/month. Following the addition of QTP, overall relapse rates were reduced to 0.06 episodes/month, representing 0.01 depressive and 0.05 manic or mixed episodes/month. When compared with the period following QTP treatment, the relative risk of relapse prior to add-on therapy with QTP was 1.75 for all episodes (chi 2= 14.1, P < 0.001) 3.36 for depressive episodes (chi 2 =8.1, P < 0.001) and 1.5 for manic or mixed episodes (chi 2 =4.5, P < 0.05). Conclusions: This naturalistic follow-up study suggests the efficacy of add-on QTP in the long-term treatment of bipolar disorder, particularly in the prevention of depressive episodes. Supported by a grant from AstraZeneca.
•
Parenteral administration of olanzapine for schizophrenic patients with aggressive behaviour
D. Vasile*, M.D. Gheorghe, O. Vasiliu, A. Baloescu. Central Militaty Hospital, Department of Psychiatty, Bucharest, Romania Background: Management of acutely agitated patients with psychotic symptoms is a complex clinical challenge. Difficulty in taking complete history, medication noncompliance, lack of insight all these are important obstacles in the selection of an appropriate antipsychotic drug. Olanzapine has remarcable sedative properties and its parenteral form of administration has a fast onset of action. The lack of significant side effects is also a reason for its use in psychiatric emergencies. Objective: To evaluate the impact of olanzapine over haloperidol parenteral administration for aggressive and agitated behaviour in patients diagnosed with schizophrenia. Methods: Study group consisted in 52 patients, equal sex ratio, age between 29 and 56, with a known history of schizophrenia (DSM-IV-TR) admitted in our clinic for acute psychotic episode. All of these patients presented a score above 25 in selected items of PANSS ~ostility, excitement, uncooperativeness, tension and poor control. Patients were monitored for a week during which rhey received either olanzapine 12.3 mg/day im (29 patients) or haloperidol 17.8 mg/day (23 patients). Parenteral benzodiazepines (diazepam) and oral anticholinergic medication (trihexifenidil) was associated as needed. We realised an evaluation of these patients during the study using Simpson-Angus Scale, Barnes Akathisia Scale and selected items of PANSS mentioned above.
Results: Patients receiving olanzapine have had a faster decrease in PANSS selected items (7.5±1.5) than those with haloperidol (4.5±1.2) and a lack of neurological side effects. Less aditional treatment was required in the olanzapine treated patients. Conclusions: Olanzapine in parenteral administration prooves itself an efficient treatment for aggressive behaviour in schizophrenic patients due to its combined fast onset of sedative action and lack of extrapyramidal side effects.
•
Mismatch negativity generation in the human serotonergic and antiglutamatergic model of psychosis
K. Heekeren*, A. Neukirch, E. Gouzoulis-Mayfrank. University
of Cologne, Psychiatty and Psychotherapy, Kdln, Germany Rationale: Mismatch negativity (MMN) is an event-related component of the auditory evoked potentials that occurs after any discriminable change in an ongoing repetitive standard acoustic stimulation. Many studies have reported MMN deficits in schizophrenic patients (Javitt 2000). Based on animal experiments it is assumed that MMN depends on NMDA receptor functioning. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN in the NMDA antagonist model of psychosis with ketamine. The only study which investigated MMN in the 5HT2A agonist of psychosis so far, showed no effect of the serotonergic hallucinogen psilocybin on MNN. Objective: To study how the hallucinogens dimethyltryptamine (DMT) (5HT2a agonist) and S-ketamine (NDMA antagonist) in moderate and high doses influence the generation of MMN in humans. Methods: Fifteen healthy subjects with no current or previous history of neurological or psychiatric disorders participated in a randomized, double-blind, cross-over study with a low and a high dose of DMT and S-ketamine, which elicited subtle "prepsychotic" or full blown psychotic symptoms. The MMN to pitch and to duration deviant acoustic stimuli were obtained by a 96-channel electroencephalograph recording. A source analysis was performed on the basis of the 4 generators model of MMN which was described by Waberski et al. (2001) (SI: right superior temporal lobe; $2 left superior temporal lobe; $3 right inferior temporal lobe; $4 anterior cingulate gyrus). Results: Nine subjects completed both experimental days with the two doses of both drugs. Overall we found a decrease in generation of MMN under both substances. The MMN to the duration deviant was significantly reduced under both S-ketamine doses at the two temporal sources (S 1+$2) and under the high S-ketamine dose also at the frontal source ($4). The MMN reduction after DMT was only significant for the low dose at the right superior temporal source (S 1). Conclusions: The NMDA antagonist state (S-ketamine) which is a model for psychoses with negative and positive symptoms had a stronger influence on MMN than the 5HT2A agonist state (DMT) which is thought to be an appropriate model for psychoses with prominent positive symptoms. Our findings in human experimental psychoses are in line with clinical findings in patients with schizophrenia. Regarding the stronger effect of S-ketamine (i.e. the model for psychoses with negative symptoms) on MMN, it is noteworthy that a recent study reported an association between MMN deficits and poor functioning in schizophrenia (Light and Braff 2005).
P3 Psychotic disorders and antipsychotics
References [1] Javitt, D.C. (2000) Intracortical mechanisms of mismatch negativity dysfunction in schizophrenia. Audiol Neurootol 5, 207 215. [2] Light, G.A., Braff, D.L. (2005) Mismatch negativity deficits are associated with poor functioning in schizophrenia patients. Arch Gen PsychiatL'y 62, 127 136. [3] Waberski, T.D., Kreitschmann-Andermahr, I., Kawohl, W., Datwas, E, Ryang, Y., Gobbele, R., Buchner, H. (2001) Spatio-temporal source imaging reveals subcomponents of the human auditory mismatch negativity in the cingulum and right inferior temporal gyrus. Neurosci Lett 308, 107 110.
~ A
volumetric MRI study of thalamus and basal ganglia in patients with first-episode drug naive schizophrenia
M.H. Kang*, C.S. Lee, C.E. Kim, S.Y. Cho. Inha University Hospital, Psychiatry, Incheon, Republic of Korea Purpose: This study was performed to find out the structural brain abnormalities, especially thalamus and basal ganglia, in patients with schizophrenia. Method: Volumetric brain MRI study was performed on 24 patients with schizophrenia and 24 healthy control subjects. Images of regions of interest were defined as lateral ventricle, caudate nucleus, putamen, globus pallidus and thalamus. Their volumes were analyzed using the Stanford Brain Imaging Program. Repeated measure of ANCOVA with intracranial volume as covariance, and linear regresion analysis for each brain regions were used as statistics. Results: Volumes of posterior 20% of thalamus of patients were smaller than those of controls (F 5.736 p 0.021). Volumes of right thalamus of female patients and middle 40% of thalamus of female patients were smaller than those of controls (F 3.919 p 0.054). Volumes of the right caudate nucleus of female patients were greater than those of controls (F 3.746 p 0.060) The percent asymmetry index of caudate nucleus of female patients were greater than those of controls (F 4.264 p 0.045). The percent asymmetry index of putamen of female patients were smaller than those of controls (F 10.711 p 0.002). Significant correlation between globus pallidus volumes and caudate nucleus volumes in control group was not shown in patient group. Significant correlation between the volume of posterior 20% of thalamus and globus pallidus volume in control group was not shown in patient group. In patient group, right lateral ventricle volumes and right putamen volumes were negatively correlated (t 2.530 p 0.019). In male patient group, left lateral ventricle volume and left thalamus volume were negatively correlated (t 4.058 p 0.010). Conclusion: These results suggest that patients with firstepisode schizophrenia have structural change of thalamus, caudate nucleus, putamen, and glubus pallidus. These findings partially support the theory of abnormality in cortico-striato-pallidothalamic circuit in Schizophrenia.
~Long
term outcomes and atypical antipsychotic discontinuation rates. Do different methodologies give similar results?
R. Hodgson*. Lyme Brook Centre, Psychiatry, Stoke on Trent,
United Kingdom Introduction: RCTs are often seen as the gold standard for efficacy but do not necessarily inform the clinician about real world
$467
effectiveness. Observational studies, especially if well constructed and powered can fulfil this role as well as providing valuable information on drug usage. In the UK, The National Institute for Clinical Excellence (NICE) has recognised these conflicts and recommended long term outcome studies using a variety of methodologies. This paper specifically investigates whether consistent differential patterns of efficacy/effectiveness emerge between the atypical antipsychotics irrespective of methodology used. Method: A systematic review of English language papers reporting long term treatment outcomes/medication discontinuation rates in patients with schizophrenia treated with atypical antipsychotics. Long term was defined as one year or greater and search strategies incorporated Cochrane methodologies. Results: Over 20 studies were identified by March 2005. A range of methodologies were used with naturalistic studies being the most common. Statistical techniques varied within these studies, as did the precise measure of outcome. Relapse or medication discontinuation rates were the most frequently reported endpoints. RCTs were virtually non-existent for follow up periods greater than one year. Sample sizes varied significantly (range 37 to > 10,000) subjects) and follow up periods extended to 9 years. Clozapine, olanzapine and risperidone are the most commonly studied atypical antipsychotics. The majority of studies involved more than one drug. Given the nature of this review it is understandable that significant long term follow studies are only just being published. One of the largest (The Lily sponsored SOHO trial) with over 10,000 subjects has yet to report three year results but two year results are broadly similar to earlier reports. Two further observational studies from Finland and Britain (Tiihonen et al, 2004; Hodgson et al, 2005) mirror key SOHO results. These two studies were not directly sponsored by the pharmaceutical industry; have follow up periods of over seven years and substantial subject numbers (2230 and 486 respectively). Both sets of authors conclude that that clozapine is the most effective atypical in the long term with the lowest discontinuation rates and that olanzapine is significantly more effective than risperidone. Smaller follow up studies of clozapine from Australia and the United States show remarkably similar discontinuation rates to Hodgson et al (2005). A similar pattern emerges when medication discontinuation rates in RCTs are considered. For example, Purdon et al (2000) explored differences in cognitive function in patients with schizophrenia treated with olanzapine and risperidone. At 12 months, 43% of patients had discontinued olanzapine but 67% had discontinued risperidone. Data on more recently introduced atypicals is lacking. SOHO results indicate equivalence between risperidone and amisulpiride with quetiapine being less effective. These findings are in accord with a meta analysis of 142 RCTs. Conclusions: This systematic review suggests that atypical antipsychotics cannot be seen as homogeneous when real world effectiveness is considered. The long term studies identified in this investigation consistently demonstrate (irrespective of methodology) that clozapine is the most effective atypical followed by olanzapine and then risperidone.
References [1] Hodgson RE, Belgamwar R, Al-tawarah Y MacKenzie G., 2005. The use of atypical antipsychotics in the treatment of schizophrenia in North Staffordshire. Human Psychopharmacology (in press). [2] Purdon SE, Jones, BDW, Stip E, et al., 2000. Neuropsychological changes in early phase schizophrenia during 12 months treatment with olanzapine, risperidone or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Archives of General Psychiatt2¢ 154: 24%258.
P3 Psychotic disorders and antipsychotics
Methods: Outpatients with bipolar I disorder (DSM-IV-TR) responding inadequately to ongoing medications (anticonvulsants, traditional mood stabilizers, or atypical [excluding quetiapine] or typical antipsychotics) were observed prior to and following the addition of QTP. Severity of symptoms was evaluated using the Clinical Global Impression scale for bipolar disorder (CGI-BP). Patients were assessed at least once every two months, but no less than eight times a year. Scores > or 1 point lower than previous CGI-BP scores and/or adjustment of treatment were recorded as relapses. Efficacy was assessed by calculating the relative risk of relapse before and following QTP treatment. Results: 42 patients (22 males, mean age 42±18.0 years and 20 females, mean age 53± 18.44 years) were observed for an average of 9.5 months (range 3 18 months) before the addition of QTP at a mean daily dose of 535±54.5 mg. Patients were subsequently followed for an average of 18.1 months (range 6 42 months). Prior to the addition of QTP, an overall relapse rate of 0.11 episodes/month was recorded, which related to 0.05 depressive episodes/month and 0.06 manic or mixed episodes/month. Following the addition of QTP, overall relapse rates were reduced to 0.06 episodes/month, representing 0.01 depressive and 0.05 manic or mixed episodes/month. When compared with the period following QTP treatment, the relative risk of relapse prior to add-on therapy with QTP was 1.75 for all episodes (chi 2= 14.1, P < 0.001) 3.36 for depressive episodes (chi 2 =8.1, P < 0.001) and 1.5 for manic or mixed episodes (chi 2 =4.5, P < 0.05). Conclusions: This naturalistic follow-up study suggests the efficacy of add-on QTP in the long-term treatment of bipolar disorder, particularly in the prevention of depressive episodes. Supported by a grant from AstraZeneca.
•
Parenteral administration of olanzapine for schizophrenic patients with aggressive behaviour
D. Vasile*, M.D. Gheorghe, O. Vasiliu, A. Baloescu. Central Militaty Hospital, Department of Psychiatty, Bucharest, Romania Background: Management of acutely agitated patients with psychotic symptoms is a complex clinical challenge. Difficulty in taking complete history, medication noncompliance, lack of insight all these are important obstacles in the selection of an appropriate antipsychotic drug. Olanzapine has remarcable sedative properties and its parenteral form of administration has a fast onset of action. The lack of significant side effects is also a reason for its use in psychiatric emergencies. Objective: To evaluate the impact of olanzapine over haloperidol parenteral administration for aggressive and agitated behaviour in patients diagnosed with schizophrenia. Methods: Study group consisted in 52 patients, equal sex ratio, age between 29 and 56, with a known history of schizophrenia (DSM-IV-TR) admitted in our clinic for acute psychotic episode. All of these patients presented a score above 25 in selected items of PANSS ~ostility, excitement, uncooperativeness, tension and poor control. Patients were monitored for a week during which rhey received either olanzapine 12.3 mg/day im (29 patients) or haloperidol 17.8 mg/day (23 patients). Parenteral benzodiazepines (diazepam) and oral anticholinergic medication (trihexifenidil) was associated as needed. We realised an evaluation of these patients during the study using Simpson-Angus Scale, Barnes Akathisia Scale and selected items of PANSS mentioned above.
Results: Patients receiving olanzapine have had a faster decrease in PANSS selected items (7.5±1.5) than those with haloperidol (4.5±1.2) and a lack of neurological side effects. Less aditional treatment was required in the olanzapine treated patients. Conclusions: Olanzapine in parenteral administration prooves itself an efficient treatment for aggressive behaviour in schizophrenic patients due to its combined fast onset of sedative action and lack of extrapyramidal side effects.
•
Mismatch negativity generation in the human serotonergic and antiglutamatergic model of psychosis
K. Heekeren*, A. Neukirch, E. Gouzoulis-Mayfrank. University
of Cologne, Psychiatty and Psychotherapy, Kdln, Germany Rationale: Mismatch negativity (MMN) is an event-related component of the auditory evoked potentials that occurs after any discriminable change in an ongoing repetitive standard acoustic stimulation. Many studies have reported MMN deficits in schizophrenic patients (Javitt 2000). Based on animal experiments it is assumed that MMN depends on NMDA receptor functioning. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN in the NMDA antagonist model of psychosis with ketamine. The only study which investigated MMN in the 5HT2A agonist of psychosis so far, showed no effect of the serotonergic hallucinogen psilocybin on MNN. Objective: To study how the hallucinogens dimethyltryptamine (DMT) (5HT2a agonist) and S-ketamine (NDMA antagonist) in moderate and high doses influence the generation of MMN in humans. Methods: Fifteen healthy subjects with no current or previous history of neurological or psychiatric disorders participated in a randomized, double-blind, cross-over study with a low and a high dose of DMT and S-ketamine, which elicited subtle "prepsychotic" or full blown psychotic symptoms. The MMN to pitch and to duration deviant acoustic stimuli were obtained by a 96-channel electroencephalograph recording. A source analysis was performed on the basis of the 4 generators model of MMN which was described by Waberski et al. (2001) (SI: right superior temporal lobe; $2 left superior temporal lobe; $3 right inferior temporal lobe; $4 anterior cingulate gyrus). Results: Nine subjects completed both experimental days with the two doses of both drugs. Overall we found a decrease in generation of MMN under both substances. The MMN to the duration deviant was significantly reduced under both S-ketamine doses at the two temporal sources (S 1+$2) and under the high S-ketamine dose also at the frontal source ($4). The MMN reduction after DMT was only significant for the low dose at the right superior temporal source (S 1). Conclusions: The NMDA antagonist state (S-ketamine) which is a model for psychoses with negative and positive symptoms had a stronger influence on MMN than the 5HT2A agonist state (DMT) which is thought to be an appropriate model for psychoses with prominent positive symptoms. Our findings in human experimental psychoses are in line with clinical findings in patients with schizophrenia. Regarding the stronger effect of S-ketamine (i.e. the model for psychoses with negative symptoms) on MMN, it is noteworthy that a recent study reported an association between MMN deficits and poor functioning in schizophrenia (Light and Braff 2005).
P3 Psychotic disorders and antipsychotics
References [1] Javitt, D.C. (2000) Intracortical mechanisms of mismatch negativity dysfunction in schizophrenia. Audiol Neurootol 5, 207 215. [2] Light, G.A., Braff, D.L. (2005) Mismatch negativity deficits are associated with poor functioning in schizophrenia patients. Arch Gen PsychiatL'y 62, 127 136. [3] Waberski, T.D., Kreitschmann-Andermahr, I., Kawohl, W., Datwas, E, Ryang, Y., Gobbele, R., Buchner, H. (2001) Spatio-temporal source imaging reveals subcomponents of the human auditory mismatch negativity in the cingulum and right inferior temporal gyrus. Neurosci Lett 308, 107 110.
~ A
volumetric MRI study of thalamus and basal ganglia in patients with first-episode drug naive schizophrenia
M.H. Kang*, C.S. Lee, C.E. Kim, S.Y. Cho. Inha University Hospital, Psychiatry, Incheon, Republic of Korea Purpose: This study was performed to find out the structural brain abnormalities, especially thalamus and basal ganglia, in patients with schizophrenia. Method: Volumetric brain MRI study was performed on 24 patients with schizophrenia and 24 healthy control subjects. Images of regions of interest were defined as lateral ventricle, caudate nucleus, putamen, globus pallidus and thalamus. Their volumes were analyzed using the Stanford Brain Imaging Program. Repeated measure of ANCOVA with intracranial volume as covariance, and linear regresion analysis for each brain regions were used as statistics. Results: Volumes of posterior 20% of thalamus of patients were smaller than those of controls (F 5.736 p 0.021). Volumes of right thalamus of female patients and middle 40% of thalamus of female patients were smaller than those of controls (F 3.919 p 0.054). Volumes of the right caudate nucleus of female patients were greater than those of controls (F 3.746 p 0.060) The percent asymmetry index of caudate nucleus of female patients were greater than those of controls (F 4.264 p 0.045). The percent asymmetry index of putamen of female patients were smaller than those of controls (F 10.711 p 0.002). Significant correlation between globus pallidus volumes and caudate nucleus volumes in control group was not shown in patient group. Significant correlation between the volume of posterior 20% of thalamus and globus pallidus volume in control group was not shown in patient group. In patient group, right lateral ventricle volumes and right putamen volumes were negatively correlated (t 2.530 p 0.019). In male patient group, left lateral ventricle volume and left thalamus volume were negatively correlated (t 4.058 p 0.010). Conclusion: These results suggest that patients with firstepisode schizophrenia have structural change of thalamus, caudate nucleus, putamen, and glubus pallidus. These findings partially support the theory of abnormality in cortico-striato-pallidothalamic circuit in Schizophrenia.
~Long
term outcomes and atypical antipsychotic discontinuation rates. Do different methodologies give similar results?
R. Hodgson*. Lyme Brook Centre, Psychiatry, Stoke on Trent,
United Kingdom Introduction: RCTs are often seen as the gold standard for efficacy but do not necessarily inform the clinician about real world
$467
effectiveness. Observational studies, especially if well constructed and powered can fulfil this role as well as providing valuable information on drug usage. In the UK, The National Institute for Clinical Excellence (NICE) has recognised these conflicts and recommended long term outcome studies using a variety of methodologies. This paper specifically investigates whether consistent differential patterns of efficacy/effectiveness emerge between the atypical antipsychotics irrespective of methodology used. Method: A systematic review of English language papers reporting long term treatment outcomes/medication discontinuation rates in patients with schizophrenia treated with atypical antipsychotics. Long term was defined as one year or greater and search strategies incorporated Cochrane methodologies. Results: Over 20 studies were identified by March 2005. A range of methodologies were used with naturalistic studies being the most common. Statistical techniques varied within these studies, as did the precise measure of outcome. Relapse or medication discontinuation rates were the most frequently reported endpoints. RCTs were virtually non-existent for follow up periods greater than one year. Sample sizes varied significantly (range 37 to > 10,000) subjects) and follow up periods extended to 9 years. Clozapine, olanzapine and risperidone are the most commonly studied atypical antipsychotics. The majority of studies involved more than one drug. Given the nature of this review it is understandable that significant long term follow studies are only just being published. One of the largest (The Lily sponsored SOHO trial) with over 10,000 subjects has yet to report three year results but two year results are broadly similar to earlier reports. Two further observational studies from Finland and Britain (Tiihonen et al, 2004; Hodgson et al, 2005) mirror key SOHO results. These two studies were not directly sponsored by the pharmaceutical industry; have follow up periods of over seven years and substantial subject numbers (2230 and 486 respectively). Both sets of authors conclude that that clozapine is the most effective atypical in the long term with the lowest discontinuation rates and that olanzapine is significantly more effective than risperidone. Smaller follow up studies of clozapine from Australia and the United States show remarkably similar discontinuation rates to Hodgson et al (2005). A similar pattern emerges when medication discontinuation rates in RCTs are considered. For example, Purdon et al (2000) explored differences in cognitive function in patients with schizophrenia treated with olanzapine and risperidone. At 12 months, 43% of patients had discontinued olanzapine but 67% had discontinued risperidone. Data on more recently introduced atypicals is lacking. SOHO results indicate equivalence between risperidone and amisulpiride with quetiapine being less effective. These findings are in accord with a meta analysis of 142 RCTs. Conclusions: This systematic review suggests that atypical antipsychotics cannot be seen as homogeneous when real world effectiveness is considered. The long term studies identified in this investigation consistently demonstrate (irrespective of methodology) that clozapine is the most effective atypical followed by olanzapine and then risperidone.
References [1] Hodgson RE, Belgamwar R, Al-tawarah Y MacKenzie G., 2005. The use of atypical antipsychotics in the treatment of schizophrenia in North Staffordshire. Human Psychopharmacology (in press). [2] Purdon SE, Jones, BDW, Stip E, et al., 2000. Neuropsychological changes in early phase schizophrenia during 12 months treatment with olanzapine, risperidone or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Archives of General Psychiatt2¢ 154: 24%258.