- Email: [email protected]
S.06.03 Is dopamine a variable in PET-studies on drug induced receptor occupancy?
S.06.
PET
assessment
of neurotransmitter
release
coutributiug to explain the syuergistic effect of the two treatmeuts. Moreover, recent observations about clock genes aud their role in the regulation of mammalian circadiau rhythmicity raised iuterest about the possible role of genetic mechanisms in iuflueuciug the circadiau rhythms abnormalities that characterize major depressive episodes Followiug this liue of reasoning, we recently studied variants of genes pertaiuiug to the molecular clock (CLOCK aud GSK3-b), aud found them to iuflueuce core features of the disorder, such as age at ouset aud recurrence of illness.
in human
[2]
[3]
Benedetti et al. (2003) Morning light treatment hastens the antidepressant effect of citalopram: a placebo controlled trial. Journal of Clinical Psychiatry, in press. Benedetti et al. (2003) Antidepressant effects of light therapy combined with sleep deprivation are influenced by a functional polymorphism within the promoter of the serotonin transporter gene. Biological Psychiatry, in press. Benedetti et al. (2003) Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression. American Journal of Medical Genetics, in press.
S.06. PET assessment of neurotransmitter release in human brain: Progress and pitfalls IS.06.021
Imaging
dopamine
M. Laruelle. Columbia Univ. Surgeons, Associate Professor York. i2S.A.
synaptic
activity
with
College of Physicians and of Psychiatry and Radiology,
PET
New
Several groups have recently provided evidence that PET aud SPECT ueuroreceptor imaging techniques might be applied to measure acute fluctuations in dopamiue syuaptic couceutratiou in the living humau brain Competitiou betweeu DA aud radioligauds for biudiug to D2 receptor is the principle uuderlyiug this approach. This uew application of ueuroreceptor imaging provides a dyuamic measurement of ueurotrausmissiou that is very iuformative to our uuderstaudiug of neuropsychiatric conditions. In this presentation, we review aud discuss the body of data supporting the feasibility aud poteutial of this imaging paradigm. Eudogeuous competition studies performed in rodents, uouhumau primates, aud humaus will be summarized. Followiug this overview, the validity of the model uuderlyiug the iuterpretatiou of these imaging data will be assessed. The curreut reference model is defined as the occupancy model, since chauges in radiotracer biudiug poteutial are assumed to be directly caused by chauges in occupancy of D2 receptors by DA. A munber of experimental data supporting this model are preseuted. On the other baud, a number of observations remail1 uuexplaiued. First, the amphetamine-induced chauges in the BP of D2 receptor autagouists [ 123IlIBZM aud [ 1 lC]raclopride last louger thau amphetamine-induced chauges in DA extracellular couceutration Second, uoubeuzamides D2 receptor amagonists such as spiperoue aud pimozide are uot affected by chauges in DA release, or are affected in a direction opposite to that predicted by the occupancy model. Similar observations were reported with Dl radiotracers. These results suggest that the chauges in BP followiug chauges in DA couceutratiou might uot be fully accounted by a simple occupaucy model. Specifically, we will review the data supporting that agonist-mediated receptor iuterualizatiou might play au important
Progress
and pitfalls
s109
role in characterizing receptor-ligaud iuteractious. A better uuderstaudiug of the mechanism uuderlyiug the effects observed with beuzamides will be essential to develop this imaging technique to other receptor systems.
I S 06 03
L. Farde. Sweden [l]
Drain:
Is dopamine a variable in PET-studies induced receptor occupancy? Karolinska
Institute&
Clinical
Neuroscience,
on
drug
Stockholm,
PET -studies of typical autipsychotics have showu that D2dopamiue receptor occupancy of about 70% is required to achieve autipsychotic effect whereas occupancy exceeding 80% is associated with a risk of extrapyramidal side effects (EPS). These fiudiugs have major implications for clinical dose recommeudatious aud for the developmeut of uew autipsychotic drugs. Most calculations of D2-dopamiue receptor occupancy have however beeu based 011 the assumption that the couceutratiou of eudogeuous dopamiue (DA) is the same in all braiu regions aud does uot chauge with disease or treatment conditions. The present paper aims at a discussion 011 the role of eudogeuous DA in relation to drug-induced D2-receptor occupancy. Experimental studies in animals aud mau have demo&rated that radioligaud biudiug to D2-receptors is sensitive to the couceutratiou of eudogeuous DA. To iuterpret measurements where a radiolabeled ligaud aud DA compete for the same biudiug site the followiug equilibrium equatiou cau be used B*=[(Bmax - B)F*]/[Kd*(l + FKd)], B* aud F* are specifically bound aud free couceutratious of a radioligaud with the affinity Kd*. F aud Kd are the free couceutratiou aud affinity of a competing ligaud like dopamiue. In its simple fonn, the equation assumes biudiug competition for the same receptor populatiou aud does uot account for the suggested existence of high aud low affinity states for agonist binding. The concentration aud D2-occupancy levels by eudogeuous DA at physiological couditious is a basis for the discussion In au experimental PET-study we examined [ 11 Clraclopride biudiug in cyuomolgus monkeys at baseline aud after DA-depletion with reserpiue 1 mgkg (Giuovart et al, 1997). The biudiug was 50 % higher after reserpiue. A 50 % iucrease in [l lC]raclopride biudiug after reserpiue corresponds to 33 % occupancy by DA at baseline. According to the equation above the free DA-couceutratiou may thus be about 0.5 Kd at baseline. This iufonnatiou cau be used to recalculate “traditional” occupancy values. At a representative value for typical autipsychotics of about 80 %, the recalculated occupancy will be 79 %. This small difference indicate a miuor error in the calculations wheu uot taking eudogeuous DA iuto account. However, the calculations also provide iufonnatiou with regard to chauges in occupancy by DA during treatment. At a drug occupancy of 80 % the occupancy by DA will be reduced from 33% to 9 %. This iudirect effect of autipsychotic drugs points to the first in a series of subsequent biochemical eveuts related to autipsychotic effect. The calculations are based 011 the assumption that there is 110 chauge in eudogeuous DA couceutratiou during drug treatment. Typical autipsychotics may however iucrease the extra cellular couceutratiou of dopamiue as has beeu demo&rated with braiu dialysis in the rat striatum. The iucrease is dose-dependeut aud at most two-fold followiug both single aud repeated administration of a narcoleptic drug. As seeu from the equation above it cau uot be excluded that such iucreases in dopamiue concentration during high dose treatment may have au effect 011 radioligaud binding. Currently used PET-radioligauds have differeut affinity values for
SllO
S.07.
The impact
of genomics
the D2-dopamiue receptor. A critical question is if the differences correspond to differeut sensitivity to eudogeuous DA. Importantly, as seeu from the equation, the specific biudiug of tracer doses of auy radioligaud will be reduced to the same relative extent despite the fact that radioligauds may have differeut affiuities. The relative reduction in B* is determiued ouly by the ratio FiKd for unlabeled DA aud uot by radioligaud affinity. It has beeu suggested that the autipsychotic effect is mediated by drug biudiug to D2receptors in limbic or cortical regions. New radioligauds with high affinity have a poteutial for determiuatiou of extrastriatal D2dopamiue receptor occupancy (Olssou aud Farde, 200 1). Further advaucemeuts of the methodology may thus allow for detection of small regional differences in D2-occupancy that may correspond to regional differences in eudogeuous DA. References
Ginovart, N., Farde, L., Halldin, C. and Swahn, C.-G., 199 Effects of reseipine-induced depletion of synaptic dopamine on [l lC]raclopride binding to DZdopamine receptors in the monkey brain, Synapse, 25, 321-325. [2] Olsson, H. and Farde, L., 2001, Striatal and extrastriatal drug occupancy - a simulation study with the high affinity radioligand [l lClFLB457, Neuroimage, 14, 93&945.
in schizophrenia
aud 5-HT2A receptor by 5-HT in vivo, a low proportiou of high affinity sites to which eudogeuous 5-HT binds, or in the case of llC-MDL 100907, the high concentration of 5-HT2A receptors located iutracellularly aud heuce beyond iuteractiou with syuaptic 5-HT. A similar lack of sensitivity of other serotouergic radioligauds (1 SF-Altauseriu, 1 SF-MPPF) has beeu observed in some other PET ceutres. In summary, the characteristics of the 5-HT ueurotrausmitter system, rather thau the radioligauds per se, may partly explain the curreut difficulties in imaging 5-HT release. References
[l] [2] [3] [4] [5]
Lamelle, J Cereb Blood Flow Metab 20: 4233451 (2000). Rabiner et al, NeuroImage 15: 62&632 (2002). Rabiner et al, J Psychopharmacol 16: 195-199 (2002). Hume et al, Synapse 41:15&159 (2001). Hirani et al, submitted (2003).
[l]
S.07. The impact of genomics in schizophrenia IS
IS 06 04
Can
we
measure
5-HT
release
with
07 01
Functional Alterations
genomics of specific
of schizophrenia: pathways
PET?
P.M. Grasby’ , E. Hiram’, S. Hume’ , P Coweu2, E. Rabiuer3, T. Sharp4. ‘Cyclotron Unit, Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom; 2 University of Oxford, Psychopharmacology Unit, Oxford, United Kingdom; 3GlaxoSmithKline Pharmaceuticals, Experimental Medicine, Camlwidge, United Kingdom; 4 University of Oxford, Department of Pharmacology, Oxford, United Kingdom Imaging of eudogeuous ueurotrausmitter release using PET is au exciting aud valuable technique in uuderstaudiug human in vivo neurochemistry (1). Eudogeuous ueurotrausmitter imaging has beeu demonstrated for dopamiue aud possibly for eudogeuous opioids, however the exteusiou of this technique to other ueurotransmitter systems remaius to be established. The exact reasons why the biudiug of select radiotracers appear to be sensitive to eudogeuous neurotransmitter are uot established although simple competitive occupancy or receptor iuterualisatiou models are predomiuaut theories. Presently, we are iuvestigatiug the possibility of imaging eudogeuous 5-HT release using selective PET radiotracers. In studies in mau we have established that neither acute tryptophau depletiou or tryptophau iufusiou (to putatively lower aud raise central 5-HT respectively) had auy effect ou 1 lC-WAY 100635 biudiug to 5-HT 1A receptors (2). Furthermore, acute aud chrouic treatment with SSRIs (expected to raise iutrasyuaptic 5HT levels) did uot alter 1 lC-WAY 100635 binding. Similarly, 5-HTlA occupancy by exogenous 5-HT agonist drugs has proved difficult to image in mau (3). However, such mauipulatious in mau may be sub-optimal for altering central 5-HT levels aud therefore the effect of substantial iucreases of eudogeuous serotouiu ou 1 lCWAY 100635 aud 1 lC-MDL 100907 biudiug was investigated in rat braiu in vivo (4, 5). Biudiug studies were complemented by in vivo microdialysis to monitor 5-HT levels in similarly treated isofluraue-auaesthetised rats aud by early geue expression studies. llC-WAY 100635 aud llC-MDL 100907 proved to be geuerally iuseusitive to iucreased syuaptic 5-HT in our rodeut models. Theoretically, such minimal effects may be explaiued by mauy factors iucludiug a low baseline occupancy of the 5-HTlA
K. Mimics. Pittsburgh,
University US.A.
of Pittsburgh,
Department
of Psychiatry,
Recent advances in DNA microarray technology have euabled scielitists to simultaneously assess complex geue expression chauges for the majority of the humau geuome, making this au optimal approach for studying the molecular bases of complex braiu disorders. The observed geue expression patterus are already uucoveriug uew iufonnatiou about the pathophysiology of disease states, ofteu suggesting that previously uuknowu molecular cascades may play a critical role in acquiring the disease. In the future, geue expression profiliug (trauscriptome analysis) aud geuotypiug may lead to iudividualizatiou of diagnosis, ultimately liukiug molecular phenotypes to specific clinical profiles. This kuowledge will drive a much improved aud personalized application of phannacogeuomics, where compounds will be screened for their ability to modulate the trauscripts that are chauged in a diagnosis-specific mamrer. Microarray studies do uot require precisely fonnulated hypotheses. Using these exploratory approaches, hypotheses are uot proveu or discarded, rather they emerge from the dataset. Microarray technology is a true data-driven approach, where the question asked is broad (“What is the trauscriptome difference betweeu the two conditions?“) aud the answer (provided by the dataset) is most ofteu unexpected aud uot associated with au a priori hypothesis. In our recent cDNA microarray studies of altered geue expressiou patterus in the prefroutal cortex of individuals with schizophrenia, we uncovered a munber of iutriguiug trauscriptome chauges. First, complex data miuiug procedures uncovered a dowuregulatiou of trauscripts eucodiug proteins that regulate presyuaptic fuuctiou, postsyuaptic signaling cascades aud a munber of metabolic pathways. At the ueurotrausmitter system level, we ideutified a number of known genes that showed cousisteutly chauged expression in schizophrenia that belonged to GABAergic aud glutamiuergic signaling, coufinniug previous reports which associated the dysregulatiou of these geue products with schizophrenia. In addition, we also ideutified altered expression
PET
assessment
of neurotransmitter
release
coutributiug to explain the syuergistic effect of the two treatmeuts. Moreover, recent observations about clock genes aud their role in the regulation of mammalian circadiau rhythmicity raised iuterest about the possible role of genetic mechanisms in iuflueuciug the circadiau rhythms abnormalities that characterize major depressive episodes Followiug this liue of reasoning, we recently studied variants of genes pertaiuiug to the molecular clock (CLOCK aud GSK3-b), aud found them to iuflueuce core features of the disorder, such as age at ouset aud recurrence of illness.
in human
[2]
[3]
Benedetti et al. (2003) Morning light treatment hastens the antidepressant effect of citalopram: a placebo controlled trial. Journal of Clinical Psychiatry, in press. Benedetti et al. (2003) Antidepressant effects of light therapy combined with sleep deprivation are influenced by a functional polymorphism within the promoter of the serotonin transporter gene. Biological Psychiatry, in press. Benedetti et al. (2003) Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression. American Journal of Medical Genetics, in press.
S.06. PET assessment of neurotransmitter release in human brain: Progress and pitfalls IS.06.021
Imaging
dopamine
M. Laruelle. Columbia Univ. Surgeons, Associate Professor York. i2S.A.
synaptic
activity
with
College of Physicians and of Psychiatry and Radiology,
PET
New
Several groups have recently provided evidence that PET aud SPECT ueuroreceptor imaging techniques might be applied to measure acute fluctuations in dopamiue syuaptic couceutratiou in the living humau brain Competitiou betweeu DA aud radioligauds for biudiug to D2 receptor is the principle uuderlyiug this approach. This uew application of ueuroreceptor imaging provides a dyuamic measurement of ueurotrausmissiou that is very iuformative to our uuderstaudiug of neuropsychiatric conditions. In this presentation, we review aud discuss the body of data supporting the feasibility aud poteutial of this imaging paradigm. Eudogeuous competition studies performed in rodents, uouhumau primates, aud humaus will be summarized. Followiug this overview, the validity of the model uuderlyiug the iuterpretatiou of these imaging data will be assessed. The curreut reference model is defined as the occupancy model, since chauges in radiotracer biudiug poteutial are assumed to be directly caused by chauges in occupancy of D2 receptors by DA. A munber of experimental data supporting this model are preseuted. On the other baud, a number of observations remail1 uuexplaiued. First, the amphetamine-induced chauges in the BP of D2 receptor autagouists [ 123IlIBZM aud [ 1 lC]raclopride last louger thau amphetamine-induced chauges in DA extracellular couceutration Second, uoubeuzamides D2 receptor amagonists such as spiperoue aud pimozide are uot affected by chauges in DA release, or are affected in a direction opposite to that predicted by the occupancy model. Similar observations were reported with Dl radiotracers. These results suggest that the chauges in BP followiug chauges in DA couceutratiou might uot be fully accounted by a simple occupaucy model. Specifically, we will review the data supporting that agonist-mediated receptor iuterualizatiou might play au important
Progress
and pitfalls
s109
role in characterizing receptor-ligaud iuteractious. A better uuderstaudiug of the mechanism uuderlyiug the effects observed with beuzamides will be essential to develop this imaging technique to other receptor systems.
I S 06 03
L. Farde. Sweden [l]
Drain:
Is dopamine a variable in PET-studies induced receptor occupancy? Karolinska
Institute&
Clinical
Neuroscience,
on
drug
Stockholm,
PET -studies of typical autipsychotics have showu that D2dopamiue receptor occupancy of about 70% is required to achieve autipsychotic effect whereas occupancy exceeding 80% is associated with a risk of extrapyramidal side effects (EPS). These fiudiugs have major implications for clinical dose recommeudatious aud for the developmeut of uew autipsychotic drugs. Most calculations of D2-dopamiue receptor occupancy have however beeu based 011 the assumption that the couceutratiou of eudogeuous dopamiue (DA) is the same in all braiu regions aud does uot chauge with disease or treatment conditions. The present paper aims at a discussion 011 the role of eudogeuous DA in relation to drug-induced D2-receptor occupancy. Experimental studies in animals aud mau have demo&rated that radioligaud biudiug to D2-receptors is sensitive to the couceutratiou of eudogeuous DA. To iuterpret measurements where a radiolabeled ligaud aud DA compete for the same biudiug site the followiug equilibrium equatiou cau be used B*=[(Bmax - B)F*]/[Kd*(l + FKd)], B* aud F* are specifically bound aud free couceutratious of a radioligaud with the affinity Kd*. F aud Kd are the free couceutratiou aud affinity of a competing ligaud like dopamiue. In its simple fonn, the equation assumes biudiug competition for the same receptor populatiou aud does uot account for the suggested existence of high aud low affinity states for agonist binding. The concentration aud D2-occupancy levels by eudogeuous DA at physiological couditious is a basis for the discussion In au experimental PET-study we examined [ 11 Clraclopride biudiug in cyuomolgus monkeys at baseline aud after DA-depletion with reserpiue 1 mgkg (Giuovart et al, 1997). The biudiug was 50 % higher after reserpiue. A 50 % iucrease in [l lC]raclopride biudiug after reserpiue corresponds to 33 % occupancy by DA at baseline. According to the equation above the free DA-couceutratiou may thus be about 0.5 Kd at baseline. This iufonnatiou cau be used to recalculate “traditional” occupancy values. At a representative value for typical autipsychotics of about 80 %, the recalculated occupancy will be 79 %. This small difference indicate a miuor error in the calculations wheu uot taking eudogeuous DA iuto account. However, the calculations also provide iufonnatiou with regard to chauges in occupancy by DA during treatment. At a drug occupancy of 80 % the occupancy by DA will be reduced from 33% to 9 %. This iudirect effect of autipsychotic drugs points to the first in a series of subsequent biochemical eveuts related to autipsychotic effect. The calculations are based 011 the assumption that there is 110 chauge in eudogeuous DA couceutratiou during drug treatment. Typical autipsychotics may however iucrease the extra cellular couceutratiou of dopamiue as has beeu demo&rated with braiu dialysis in the rat striatum. The iucrease is dose-dependeut aud at most two-fold followiug both single aud repeated administration of a narcoleptic drug. As seeu from the equation above it cau uot be excluded that such iucreases in dopamiue concentration during high dose treatment may have au effect 011 radioligaud binding. Currently used PET-radioligauds have differeut affinity values for
SllO
S.07.
The impact
of genomics
the D2-dopamiue receptor. A critical question is if the differences correspond to differeut sensitivity to eudogeuous DA. Importantly, as seeu from the equation, the specific biudiug of tracer doses of auy radioligaud will be reduced to the same relative extent despite the fact that radioligauds may have differeut affiuities. The relative reduction in B* is determiued ouly by the ratio FiKd for unlabeled DA aud uot by radioligaud affinity. It has beeu suggested that the autipsychotic effect is mediated by drug biudiug to D2receptors in limbic or cortical regions. New radioligauds with high affinity have a poteutial for determiuatiou of extrastriatal D2dopamiue receptor occupancy (Olssou aud Farde, 200 1). Further advaucemeuts of the methodology may thus allow for detection of small regional differences in D2-occupancy that may correspond to regional differences in eudogeuous DA. References
Ginovart, N., Farde, L., Halldin, C. and Swahn, C.-G., 199 Effects of reseipine-induced depletion of synaptic dopamine on [l lC]raclopride binding to DZdopamine receptors in the monkey brain, Synapse, 25, 321-325. [2] Olsson, H. and Farde, L., 2001, Striatal and extrastriatal drug occupancy - a simulation study with the high affinity radioligand [l lClFLB457, Neuroimage, 14, 93&945.
in schizophrenia
aud 5-HT2A receptor by 5-HT in vivo, a low proportiou of high affinity sites to which eudogeuous 5-HT binds, or in the case of llC-MDL 100907, the high concentration of 5-HT2A receptors located iutracellularly aud heuce beyond iuteractiou with syuaptic 5-HT. A similar lack of sensitivity of other serotouergic radioligauds (1 SF-Altauseriu, 1 SF-MPPF) has beeu observed in some other PET ceutres. In summary, the characteristics of the 5-HT ueurotrausmitter system, rather thau the radioligauds per se, may partly explain the curreut difficulties in imaging 5-HT release. References
[l] [2] [3] [4] [5]
Lamelle, J Cereb Blood Flow Metab 20: 4233451 (2000). Rabiner et al, NeuroImage 15: 62&632 (2002). Rabiner et al, J Psychopharmacol 16: 195-199 (2002). Hume et al, Synapse 41:15&159 (2001). Hirani et al, submitted (2003).
[l]
S.07. The impact of genomics in schizophrenia IS
IS 06 04
Can
we
measure
5-HT
release
with
07 01
Functional Alterations
genomics of specific
of schizophrenia: pathways
PET?
P.M. Grasby’ , E. Hiram’, S. Hume’ , P Coweu2, E. Rabiuer3, T. Sharp4. ‘Cyclotron Unit, Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom; 2 University of Oxford, Psychopharmacology Unit, Oxford, United Kingdom; 3GlaxoSmithKline Pharmaceuticals, Experimental Medicine, Camlwidge, United Kingdom; 4 University of Oxford, Department of Pharmacology, Oxford, United Kingdom Imaging of eudogeuous ueurotrausmitter release using PET is au exciting aud valuable technique in uuderstaudiug human in vivo neurochemistry (1). Eudogeuous ueurotrausmitter imaging has beeu demonstrated for dopamiue aud possibly for eudogeuous opioids, however the exteusiou of this technique to other ueurotransmitter systems remaius to be established. The exact reasons why the biudiug of select radiotracers appear to be sensitive to eudogeuous neurotransmitter are uot established although simple competitive occupancy or receptor iuterualisatiou models are predomiuaut theories. Presently, we are iuvestigatiug the possibility of imaging eudogeuous 5-HT release using selective PET radiotracers. In studies in mau we have established that neither acute tryptophau depletiou or tryptophau iufusiou (to putatively lower aud raise central 5-HT respectively) had auy effect ou 1 lC-WAY 100635 biudiug to 5-HT 1A receptors (2). Furthermore, acute aud chrouic treatment with SSRIs (expected to raise iutrasyuaptic 5HT levels) did uot alter 1 lC-WAY 100635 binding. Similarly, 5-HTlA occupancy by exogenous 5-HT agonist drugs has proved difficult to image in mau (3). However, such mauipulatious in mau may be sub-optimal for altering central 5-HT levels aud therefore the effect of substantial iucreases of eudogeuous serotouiu ou 1 lCWAY 100635 aud 1 lC-MDL 100907 biudiug was investigated in rat braiu in vivo (4, 5). Biudiug studies were complemented by in vivo microdialysis to monitor 5-HT levels in similarly treated isofluraue-auaesthetised rats aud by early geue expression studies. llC-WAY 100635 aud llC-MDL 100907 proved to be geuerally iuseusitive to iucreased syuaptic 5-HT in our rodeut models. Theoretically, such minimal effects may be explaiued by mauy factors iucludiug a low baseline occupancy of the 5-HTlA
K. Mimics. Pittsburgh,
University US.A.
of Pittsburgh,
Department
of Psychiatry,
Recent advances in DNA microarray technology have euabled scielitists to simultaneously assess complex geue expression chauges for the majority of the humau geuome, making this au optimal approach for studying the molecular bases of complex braiu disorders. The observed geue expression patterus are already uucoveriug uew iufonnatiou about the pathophysiology of disease states, ofteu suggesting that previously uuknowu molecular cascades may play a critical role in acquiring the disease. In the future, geue expression profiliug (trauscriptome analysis) aud geuotypiug may lead to iudividualizatiou of diagnosis, ultimately liukiug molecular phenotypes to specific clinical profiles. This kuowledge will drive a much improved aud personalized application of phannacogeuomics, where compounds will be screened for their ability to modulate the trauscripts that are chauged in a diagnosis-specific mamrer. Microarray studies do uot require precisely fonnulated hypotheses. Using these exploratory approaches, hypotheses are uot proveu or discarded, rather they emerge from the dataset. Microarray technology is a true data-driven approach, where the question asked is broad (“What is the trauscriptome difference betweeu the two conditions?“) aud the answer (provided by the dataset) is most ofteu unexpected aud uot associated with au a priori hypothesis. In our recent cDNA microarray studies of altered geue expressiou patterus in the prefroutal cortex of individuals with schizophrenia, we uncovered a munber of iutriguiug trauscriptome chauges. First, complex data miuiug procedures uncovered a dowuregulatiou of trauscripts eucodiug proteins that regulate presyuaptic fuuctiou, postsyuaptic signaling cascades aud a munber of metabolic pathways. At the ueurotrausmitter system level, we ideutified a number of known genes that showed cousisteutly chauged expression in schizophrenia that belonged to GABAergic aud glutamiuergic signaling, coufinniug previous reports which associated the dysregulatiou of these geue products with schizophrenia. In addition, we also ideutified altered expression