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(11C)-N-Methylspiperone pet detects different levels of dopamine D2 receptor occupancy of an atypical neuroleptic than (11C)-raclopride pet
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XIII. Pharmacotherapy--Mechanism of Action A. Dopamine D2 Receptor Interactions D I F F E R E N T PATTERNS OF D2/D2-L1KE RECEPTOR B L O C K A D E IN THE TEMPORAL CORTEX A N D THE STRIATUM BY TYPICAL ANTIPSYCHOTICS: AN 123I-EPIDEPRIDE SPET S T U D Y Bigliani V. ~, Mulligan R.S. 2, Acton P.D. 2, Gacinovic S. 2, Ell p.j.2 Kerwin R.W. ~, Pilowsky L.S. ~ IbTstitute ~['Psyehiato', De Crespigny Park, London UK; Zblstitute o['Nuc[ear Medicine, University College London Medical School, London, UK Typical antipsychotics are thought to exert their therapeutic effect through blockade of D2/D2-1ike dopamine receptors in the limbic system. We used a high affinity radioligand ~-'31-epidepride and SPET to study striatal and limbic D2/Da-like receptors in 13 male schizophrenic patients (mean age 41.5, range 25 53) treated with different classes of typical antipsychotics (chlorpromazine equivalent range 37.5 1700 mg/day) and a group of 9 healthy volunteers (mean age 34.3, range 25-48). A dynamic sequence of SPET scans were taken up to 4 hours post injection (approx. 150 MBq iv) using a high resolution multi-detector brain dedicated scanner (SME 810). Region of interest analysis was performed on co-registered images to measure the mean counts in the striatum, temporal cortex and cerebellum. An approximation of saturable receptor binding in striatum and temporal cortex was calculated as a ratio to the cerebellum {background activity) for scans 180 minutes onwards. The reduction in available receptors in the drug-treated patients relative to the healthy control group showed a strong dosedependency in the striatum, with near total saturation ('100% occupancy') of available receptors at doses higher than 600 mg/d. However, there appears to be complete saturation of available receptors in the temporal cortex at all clinically efficacious doses, down to 37.5 mg. The differential binding observed between the temporal cortex and the straiatum may explain previous reports of therapeutic efficacy for low doses of typical antipsychotics.
D2-DENSITY, PERSONALITY TRAITS, A N D NEGATIVE SYMPTOMS OF SCHIZOPHRENIA L. Farde Karolhtska hlstitutet. Department ¢~fCl#tical Neuroscienee, Psychiatl3" section. Karolinska Ho,spital, S-171 76 Stockhohn, Sweden
Using Positron Emission Tomography ( PET ) and the radioligand [llC]raclopride, we recently described a pronounced variability in central D2-dopamine receptor density in normal subjects ( 1). This variability prompted a search for correlation's between D2-density and individual differences in personality traits using the Karolinska Scales of Personality. D2-density correlated strongly with irritability and with detachment, a trait that includes lack of closeness and warmth in personal relations (2). Neuroreceptor density may thus serve as measurable biochemical link in the chain of events that relate the genetic endowment to human personality traits. The detachment dimension resembles the social isolation, the indifference to people and the lack of intimate friendships that commonly characterize patients with schizophrenia and are included among the category of negative symptoms of schizophrenia. Importantly, negative symptoms respond poorly, or might even get worse, when treated with classical neuroleptic drugs that block D2-dopamine receptors and thereby reduces the density of available receptors. Thus, the finding of a strong negative correlation between detachment and D2-density suggests that new pharmacological principles, avoiding high D2-occupancy, must be explored for the treatment of negative symptoms. PET-studies on D2-dopamine receptors in schizophrenia has hitherto been focused primarily on patients with predominantly positive symptoms. Future explorations for low D2-density in schizotypal personality disorders and in schizophrenic patients with predominantly negative symptomatology are strongly motivated. References 1. Farde et al. (1995) Synapse, 20, 200 208. 2. Farde et al. (1997) Nature, 285, 590.
(t t C )-N-METHYLSPIPERONE PET DETECTS D I F F E R E N T LEVELS OF DOPAMINE D 2 RECEPTOR O C C U P A N C Y OF AN ATYPICAL NEUROLEPTIC T H A N (11C )-RACLOPRIDE PET G. Hagberg ~'4, O. Gefvert 3, M. Bergstr6m l's, I.-M. Wieselgren 2, L. Lindstr6m 3, F.-A. Wiesel 2, B. L~mgstr6m L4 I Uppsala Universi O' PET Centre, S-75185 U)~psakl. Sweden; 2Dept. P~3,chiato', UniversiO' Hospital Uppsala UniversiO', S-75017 Uppsala, Su,eden; adept. Psychiatric Research. UniversiO, ~f Uppsaht, Vgister~tsCentral Hospital, S-721 89 VOsterds, Sweden: 4'Sub-lemtomole hiorecognition pr~ject'. Research and Developnwnt corporation ¢~/Japan The De receptor binding potential of the PET tracers (~C)raclopride and (~lC)-N-methylspiperone was investigated in a group of five patients with schizophrenia, during treatment with an atypical neuroleptic, seroquel (quetiapine). A steady state condition was ensured by treating the patients with 750 mg seroquel during 3 weeks followed by a period of tapering off the dose. For each patient, two doses were chosen at random during the dose-descending period and for each of the two
166
doses. PET examinations were performed with both tracers. In parallel, a group of four healthy volunteers was investigated. The D 2 binding potential in the putamen and the caudate nucleus was determined by assuming a three-compartment model and by using the evaluation method proposed by Patlak and Blasberg, (J (i-r Blood Flow Metab (1985) 5:584 590). The occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing seroquel dose was detected with (' ~C )-raclopride (p < 0.01 ), no such trend was apparent for ( *~C )-N-methylspiperone (p > 0.09 ). The range of seroquel occupancy measured by 0~C)-raclopride was twice the (~ ~C )-N-methylspiperone range. In conclusion, (x 1C )-N M S in contrast to (nC)-RAC, fails to detect changes in D 2 receptor binding of the atypical neuroleptic, seroquel.
STRIATAL D O P A M I N E D2 R E C E P T O R O C C U P A N C Y IN PATIENTS T R E A T E D WITH O L A N Z A P I N E T.J. Raedler*, M.B. K n a b l e , T. Lafargue, D. Pickar, D.R. Weinberger
antipsychotics have much improved side effect profiles, but their impact on cognition is unclear. Thus, we have undertaken this study to evaluate the memory effects of a typical antipsychotic, two atypical antipsychotics and a muscarinic agonist and antagonist. The muscarinic antagonist scopolamine is known to cause decreased learning and memory in various paradigms in animal and man and thus served as a positive control. In experiment I, inhibition of apomorphine induced climbing in mice was used to generate functional antidopaminergic efficacy data (EDs0's) for olanzapine (0.42 mg/kg), clozapine (2.6 mg/kg), haloperidol (0.08 mg/kg), oxotremorine (0.08 mg/kg) and scopolamine (>0.3 mg/kg). In experiment 2, these data were used to select dose ranges for subsequent testing in one trial mouse passive avoidance in order to determine potential learning and memory deficits. Drugs were administered prior to training trial. 24 hours later, retention testing suggested learning and memory deficits at the following minimum effective doses: Olanzapine > 3 m g / k g , clozapine I mg/kg, haloperidol > 1 mg/kg, oxotremorine > 3 mg/kg and scopolamine 0.3 mg/kg. Although olanzapine had potent activity in the efficacy assay (apomorphine induced climbing), it did not have effects on learning and memory at seven fold higher doses. Clozapine produced significant learning and memory deficits in the same range as the ED~o for apomorphine induced climbing.
ETmical Bm#~ Disorders Branch. National hzstitute ~?l Mental Health, 2700 Martin Luther King Ave. SE, WashhTgton. DC20032, USA Four male patients (mean age-37.5 years) were studied with 1-123 IBZM-SPECT alter three weeks of treatment on a tow dose (5mg) and a high dose (20rag) of olanzapine without concomitant medications. Subjects received 7 mCi of 1-123 IBZM. Scans of thirty minutes duration were obtained ninety minutes alter the injection, when IBZM-uptake is at equilibrium. The ratio of specific to nonspecific binding in the basal ganglia ((BG-CBL)/CBL) was determined using M R I assisted placement of ROls. Receptor occupancy was calculated using a referencerange from a group of 16 normal volunteers. The mean D2 occupancy on olanzapine 5 mg was 58"/,, (range 52% to 62%): the mean D2 occupancy on olanzapine 20 mg was 83% (range 77% to 97%). Although the D2 occupancy rates on 5 mg and 20 mg olanzapine were significantly different (p<0.03), there were no significant differences in ratings for positive symptoms. negative symptoms or movement disorders on these two doses. The D2 occupancy rate was significantly correlated with olanzapine dose perkg body-weight (r=0.89: 11<0.05). In our small sample, high doses of olanzapine led to higher D2 receptor occupancy without apparent changes in clinical parameters. These findings need to be evaluated in a larger cohort.
OLANZAPINE: ANTIDOPAMINERGIC AND M E M O R Y EFFECTS IN M I C E T.R. R a s m u s s e n , M . D . B . Swedberg, F.P. B y m a s t e r *
*Lilly Research Laboratories, h~dkmapolis. IN 46285. USA Cognitive deficits are a serious problem in schizophrenia and impact the vocational ability of the patients. The new atypical
IN VIVO EFFECTS OF O L A N Z A P I N E ON R A D I O L I G A N D B I N D I N G , D O P A M I N E D2 AUTORECEPTOR BLOCKADE, AGONISTI N D U C E D IN VIVO P H O S P H O I N O S I T I D E HYDROLYSIS AND NEUROTRANSMITTER RELEASE W. Z h a n g , K . W . Perry, F.P. B y m a s t e r
Eli Lilly and Omlpany. bMianapolis, Lilly Corporate Center hTdiamt, 46285, USA Olanzapine is an efficacious atypical antipsychotic with high affinity in vitro for dopamine, serotonin_, (5HT2), 5HT~, muscarmic, a:adrenergic and histamine H1 receptor subtypes. However. side effects produced by blockade of these receptors, particularly muscarinic receptors, have not been prominent in clinical studies. Thus, we have investigated in rats the effect of olanzapine on in vivo receptor binding, functional blockade of receptors and neurotransmitter release. Olanzapine inhibited specific radioligand binding in vivo to 5HT 2 (spiperone in frontal cortex), DI (SCH23390 in neostriatum), D2 (raclopride in neostriatum), and muscarinic (QNB in hippocampus) receptors with EDso values of 0.15, 15, 0.6, and >10mg/kg, respectively. Agonist activation of 5HT, and muscarinic phosphoinositide coupled receptors ill vivo was determined by prelabeling phospholipid stores with intraventricularly injected -~H-myoinositoI and measuring phosphoinositide hydrolysis after administration of lithium. In studies utilizing this novel
XIII. Pharmacotherapy--Mechanism of Action A. Dopamine D2 Receptor Interactions D I F F E R E N T PATTERNS OF D2/D2-L1KE RECEPTOR B L O C K A D E IN THE TEMPORAL CORTEX A N D THE STRIATUM BY TYPICAL ANTIPSYCHOTICS: AN 123I-EPIDEPRIDE SPET S T U D Y Bigliani V. ~, Mulligan R.S. 2, Acton P.D. 2, Gacinovic S. 2, Ell p.j.2 Kerwin R.W. ~, Pilowsky L.S. ~ IbTstitute ~['Psyehiato', De Crespigny Park, London UK; Zblstitute o['Nuc[ear Medicine, University College London Medical School, London, UK Typical antipsychotics are thought to exert their therapeutic effect through blockade of D2/D2-1ike dopamine receptors in the limbic system. We used a high affinity radioligand ~-'31-epidepride and SPET to study striatal and limbic D2/Da-like receptors in 13 male schizophrenic patients (mean age 41.5, range 25 53) treated with different classes of typical antipsychotics (chlorpromazine equivalent range 37.5 1700 mg/day) and a group of 9 healthy volunteers (mean age 34.3, range 25-48). A dynamic sequence of SPET scans were taken up to 4 hours post injection (approx. 150 MBq iv) using a high resolution multi-detector brain dedicated scanner (SME 810). Region of interest analysis was performed on co-registered images to measure the mean counts in the striatum, temporal cortex and cerebellum. An approximation of saturable receptor binding in striatum and temporal cortex was calculated as a ratio to the cerebellum {background activity) for scans 180 minutes onwards. The reduction in available receptors in the drug-treated patients relative to the healthy control group showed a strong dosedependency in the striatum, with near total saturation ('100% occupancy') of available receptors at doses higher than 600 mg/d. However, there appears to be complete saturation of available receptors in the temporal cortex at all clinically efficacious doses, down to 37.5 mg. The differential binding observed between the temporal cortex and the straiatum may explain previous reports of therapeutic efficacy for low doses of typical antipsychotics.
D2-DENSITY, PERSONALITY TRAITS, A N D NEGATIVE SYMPTOMS OF SCHIZOPHRENIA L. Farde Karolhtska hlstitutet. Department ¢~fCl#tical Neuroscienee, Psychiatl3" section. Karolinska Ho,spital, S-171 76 Stockhohn, Sweden
Using Positron Emission Tomography ( PET ) and the radioligand [llC]raclopride, we recently described a pronounced variability in central D2-dopamine receptor density in normal subjects ( 1). This variability prompted a search for correlation's between D2-density and individual differences in personality traits using the Karolinska Scales of Personality. D2-density correlated strongly with irritability and with detachment, a trait that includes lack of closeness and warmth in personal relations (2). Neuroreceptor density may thus serve as measurable biochemical link in the chain of events that relate the genetic endowment to human personality traits. The detachment dimension resembles the social isolation, the indifference to people and the lack of intimate friendships that commonly characterize patients with schizophrenia and are included among the category of negative symptoms of schizophrenia. Importantly, negative symptoms respond poorly, or might even get worse, when treated with classical neuroleptic drugs that block D2-dopamine receptors and thereby reduces the density of available receptors. Thus, the finding of a strong negative correlation between detachment and D2-density suggests that new pharmacological principles, avoiding high D2-occupancy, must be explored for the treatment of negative symptoms. PET-studies on D2-dopamine receptors in schizophrenia has hitherto been focused primarily on patients with predominantly positive symptoms. Future explorations for low D2-density in schizotypal personality disorders and in schizophrenic patients with predominantly negative symptomatology are strongly motivated. References 1. Farde et al. (1995) Synapse, 20, 200 208. 2. Farde et al. (1997) Nature, 285, 590.
(t t C )-N-METHYLSPIPERONE PET DETECTS D I F F E R E N T LEVELS OF DOPAMINE D 2 RECEPTOR O C C U P A N C Y OF AN ATYPICAL NEUROLEPTIC T H A N (11C )-RACLOPRIDE PET G. Hagberg ~'4, O. Gefvert 3, M. Bergstr6m l's, I.-M. Wieselgren 2, L. Lindstr6m 3, F.-A. Wiesel 2, B. L~mgstr6m L4 I Uppsala Universi O' PET Centre, S-75185 U)~psakl. Sweden; 2Dept. P~3,chiato', UniversiO' Hospital Uppsala UniversiO', S-75017 Uppsala, Su,eden; adept. Psychiatric Research. UniversiO, ~f Uppsaht, Vgister~tsCentral Hospital, S-721 89 VOsterds, Sweden: 4'Sub-lemtomole hiorecognition pr~ject'. Research and Developnwnt corporation ¢~/Japan The De receptor binding potential of the PET tracers (~C)raclopride and (~lC)-N-methylspiperone was investigated in a group of five patients with schizophrenia, during treatment with an atypical neuroleptic, seroquel (quetiapine). A steady state condition was ensured by treating the patients with 750 mg seroquel during 3 weeks followed by a period of tapering off the dose. For each patient, two doses were chosen at random during the dose-descending period and for each of the two
166
doses. PET examinations were performed with both tracers. In parallel, a group of four healthy volunteers was investigated. The D 2 binding potential in the putamen and the caudate nucleus was determined by assuming a three-compartment model and by using the evaluation method proposed by Patlak and Blasberg, (J (i-r Blood Flow Metab (1985) 5:584 590). The occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing seroquel dose was detected with (' ~C )-raclopride (p < 0.01 ), no such trend was apparent for ( *~C )-N-methylspiperone (p > 0.09 ). The range of seroquel occupancy measured by 0~C)-raclopride was twice the (~ ~C )-N-methylspiperone range. In conclusion, (x 1C )-N M S in contrast to (nC)-RAC, fails to detect changes in D 2 receptor binding of the atypical neuroleptic, seroquel.
STRIATAL D O P A M I N E D2 R E C E P T O R O C C U P A N C Y IN PATIENTS T R E A T E D WITH O L A N Z A P I N E T.J. Raedler*, M.B. K n a b l e , T. Lafargue, D. Pickar, D.R. Weinberger
antipsychotics have much improved side effect profiles, but their impact on cognition is unclear. Thus, we have undertaken this study to evaluate the memory effects of a typical antipsychotic, two atypical antipsychotics and a muscarinic agonist and antagonist. The muscarinic antagonist scopolamine is known to cause decreased learning and memory in various paradigms in animal and man and thus served as a positive control. In experiment I, inhibition of apomorphine induced climbing in mice was used to generate functional antidopaminergic efficacy data (EDs0's) for olanzapine (0.42 mg/kg), clozapine (2.6 mg/kg), haloperidol (0.08 mg/kg), oxotremorine (0.08 mg/kg) and scopolamine (>0.3 mg/kg). In experiment 2, these data were used to select dose ranges for subsequent testing in one trial mouse passive avoidance in order to determine potential learning and memory deficits. Drugs were administered prior to training trial. 24 hours later, retention testing suggested learning and memory deficits at the following minimum effective doses: Olanzapine > 3 m g / k g , clozapine I mg/kg, haloperidol > 1 mg/kg, oxotremorine > 3 mg/kg and scopolamine 0.3 mg/kg. Although olanzapine had potent activity in the efficacy assay (apomorphine induced climbing), it did not have effects on learning and memory at seven fold higher doses. Clozapine produced significant learning and memory deficits in the same range as the ED~o for apomorphine induced climbing.
ETmical Bm#~ Disorders Branch. National hzstitute ~?l Mental Health, 2700 Martin Luther King Ave. SE, WashhTgton. DC20032, USA Four male patients (mean age-37.5 years) were studied with 1-123 IBZM-SPECT alter three weeks of treatment on a tow dose (5mg) and a high dose (20rag) of olanzapine without concomitant medications. Subjects received 7 mCi of 1-123 IBZM. Scans of thirty minutes duration were obtained ninety minutes alter the injection, when IBZM-uptake is at equilibrium. The ratio of specific to nonspecific binding in the basal ganglia ((BG-CBL)/CBL) was determined using M R I assisted placement of ROls. Receptor occupancy was calculated using a referencerange from a group of 16 normal volunteers. The mean D2 occupancy on olanzapine 5 mg was 58"/,, (range 52% to 62%): the mean D2 occupancy on olanzapine 20 mg was 83% (range 77% to 97%). Although the D2 occupancy rates on 5 mg and 20 mg olanzapine were significantly different (p<0.03), there were no significant differences in ratings for positive symptoms. negative symptoms or movement disorders on these two doses. The D2 occupancy rate was significantly correlated with olanzapine dose perkg body-weight (r=0.89: 11<0.05). In our small sample, high doses of olanzapine led to higher D2 receptor occupancy without apparent changes in clinical parameters. These findings need to be evaluated in a larger cohort.
OLANZAPINE: ANTIDOPAMINERGIC AND M E M O R Y EFFECTS IN M I C E T.R. R a s m u s s e n , M . D . B . Swedberg, F.P. B y m a s t e r *
*Lilly Research Laboratories, h~dkmapolis. IN 46285. USA Cognitive deficits are a serious problem in schizophrenia and impact the vocational ability of the patients. The new atypical
IN VIVO EFFECTS OF O L A N Z A P I N E ON R A D I O L I G A N D B I N D I N G , D O P A M I N E D2 AUTORECEPTOR BLOCKADE, AGONISTI N D U C E D IN VIVO P H O S P H O I N O S I T I D E HYDROLYSIS AND NEUROTRANSMITTER RELEASE W. Z h a n g , K . W . Perry, F.P. B y m a s t e r
Eli Lilly and Omlpany. bMianapolis, Lilly Corporate Center hTdiamt, 46285, USA Olanzapine is an efficacious atypical antipsychotic with high affinity in vitro for dopamine, serotonin_, (5HT2), 5HT~, muscarmic, a:adrenergic and histamine H1 receptor subtypes. However. side effects produced by blockade of these receptors, particularly muscarinic receptors, have not been prominent in clinical studies. Thus, we have investigated in rats the effect of olanzapine on in vivo receptor binding, functional blockade of receptors and neurotransmitter release. Olanzapine inhibited specific radioligand binding in vivo to 5HT 2 (spiperone in frontal cortex), DI (SCH23390 in neostriatum), D2 (raclopride in neostriatum), and muscarinic (QNB in hippocampus) receptors with EDso values of 0.15, 15, 0.6, and >10mg/kg, respectively. Agonist activation of 5HT, and muscarinic phosphoinositide coupled receptors ill vivo was determined by prelabeling phospholipid stores with intraventricularly injected -~H-myoinositoI and measuring phosphoinositide hydrolysis after administration of lithium. In studies utilizing this novel