Background: Dopamine D2 receptors are the primary target ofantipsychotic treatment; antagonism at this receptor is thought to becritical to antipsychotic function. The D3 dopamine receptor hasemerged as a possible pharmacological target, in part because of itshigh density in the ventral striatum, a core area involved inschizophrenia pathology. In animal models, D3-selective antagonismappears tomodulate motor disturbances and improve cognition. Theaddition of significant D3 antagonism to D2 antagonism is hypothe-sized to offer reduced risk for extrapyramidal symptoms, cognitiveenhancement, and improvement in the negative symptoms ofschizophrenia. Cariprazine is a novel D3/D2 antagonist-partialagonist in clinical development for the treatment of schizophreniaand acute mania. The pharmacological profile of cariprazine asdetermined by in vitro, ex vivo, and in vivo evaluation is reported.Methods: In vitro studies: receptor binding profile and D3/D2

functional activity were evaluated. Behavioral assays: cariprazinewas tested in a battery of standard antipsychotic assays supple-mented with a cognitive test. Receptor occupancy studies: [3H]cariprazine binding in rat brain sections was determined byautoradiography. In vivo occupancy of striatal and limbic dopamineD3/D2 receptors was measured by displacement of [3H]raclopride(D2/D3 receptor antagonist) in mice. In cynomolgus monkeys, PETscanning measured D3/D2 occupancy using [11C]MNPA (D2/D3

agonist) and [11C]raclopride; occupancy at 5-HT1A receptors wasmeasured by [11C]WAY-100635 (selective 5-HT1A antagonist).Results: Cariprazine displayed high affinity for human D3 receptors, 5-to 8-fold selectivity over D2, 5-HT2B, and 5-HT1A receptors, and >200-fold selectivity over other targets studied. In functional assays,cariprazine showed both antagonist and partial agonist activity at D3

andD2 receptors. Cariprazine potently inhibited apomorphine-inducedclimbing, psychostimulant-induced hypermotility, and conditionedavoidance response (CAR). Cariprazine produced no catalepsy up todoses 100-fold its CAR ED50 value and inhibited haloperidol-inducedcatalepsy. Cariprazine significantly improved the learning performanceof scopolamine-impaired rats in the water-labyrinth. [3H]Cariprazinebinds to striatum, nucleus accumbens, islands of Calleja, and to lesserdegree, hippocampus, indicating its primary sites of action. Cariprazinedose dependently and almost completely displaced [3H]raclopridebinding from striatal and olfactory tubercle D3/D2 receptors in mice.PET primate studies showed significant D3/D2 occupancy with muchhigher affinity for these receptors compared with 5-HT1A.Discussion: Cariprazine has high affinity for D3/D2 receptors with D3

preference and demonstrates antagonist- partial agonist character-istics in vitro and in vivo. In a battery of behavioral tests, cariprazineshows potent antipsychotic-like activitywith cognitive enhancing-likeeffects and low risk of catalepsy. Autoradiography and PET studiesindicated that cariprazine strongly binds to dopaminergic regions;receptor occupancy iswithin the effective range predicted by currentlyused atypical antipsychotics. Cariprazine has a unique pharmacologi-cal profile thatmay provide benefits in the treatment of schizophrenia,bipolar mania, and depression. Further clinical development isplanned based on positive results in recent Phase II trials inschizophrenia and bipolar mania.

doi:10.1016/j.schres.2010.02.680

Poster 186LARGE EFFECT OF BASELINE TREATMENT WITH LONG ACTINGANTIPSYCHOTIC DRUGS ON RANDOMIZED TREATMENT OUTCOMES

Thomas Barnes1, Peter Jones2, Graham Dunn3, Karen Hayhurst3,Richard Drake3, Shon Lewis31Imperial College London, United Kingdom; 2University Of Cambridge,Cambridge, United Kingdom; 3University Of Manchester, Manchester,United Kingdom

Background: In the CUtLASS 1 Trial (Jones et al., 2006) patientswith an inadequate clinical response or intolerance were rando-mised to either a first generation antipsychotic (FGA) drug or a(non-clozapine) second generation antipsychotic (SGA) withassessments at baseline, 12, 26 and 52 weeks following randomisa-tion. The primary outcome was quality of life (QOL) measured usingthe QLS, with secondary outcome measures including symptoms(PANSS), depression (CDSS), overall functioning (GAF), drugattitude (DAI) and adherence (Kemp). Non-neurological side effects(ANNSERS) and neurological side effects (Simpson-Angus, AIMS,Barnes) were also assessed. Would outcome during the course ofthe trial be affected by the delivery route of the antipsychotic drugprescribed at trial entry?Methods: Forty per cent (N=90) of the 227 patients entering theCUtLASS 1 Trial were being treated with a depot FGA antipsychoticprior to randomisation.Results: Fitting multi-level mixed-effects models using Stata 11 andincluding demographic variables and baseline attitudes to medica-tion as predictors showed that: QLS was significantly reduced (-5.7points; CI -10.1, -1.4) at final visit in those receiving depot beforerandomisation. There was no significant difference in this effectbetween those who were randomised to first or second generationantipsychotics during the trial. The same pattern of results held forPANSS total score and GAF. Modelling centre as a separate level hadlittle effect on coefficients of baseline covariates. Baseline DAI scoreindicating adherent attitudes predicted better outcome on all threemeasures (p<0.001).Discussion: Participants randomised from depot medication atbaseline had a significantly worse one-year outcome regardless ofsubsequent allocation to FGA or SGA than those taking oralmedication at baseline. This may be due to reduced adherence.Once participants were randomised into the study, adherentattitudes were predictive of outcome. The effect was presentwhether the patient was randomised to a first or second generationantipsychotic during the course of the trial.

doi:10.1016/j.schres.2010.02.681

Poster 187THE ADDITION OF TIAGABINE TO ANTIPSYCHOTIC MEDICATIONIN THE TREATMENT OF RECENT-ONSET SCHIZOPHRENIA BYMODIFICATION OF DEVELOPMENTAL PRUNING OF PREFRONTALCIRCUITRY

Hannah M. Liebman2, Wilson Woo11Harvard Medical School, Boston, MA, USA; 2Beth Israel DeaconessMedical Center, Boston, MA, USA

Background: The overt symptoms and deficits of schizophrenia(SZ) typically begin to emerge during late adolescence and earlyadulthood, followed by a period of post-onset functional deteriora-tion. This peri-onset period temporally coincides with the finalmaturation of the prefrontal cortex (PFC), which is characterized bya process of extensive pruning of synaptic connectivities. Increasingevidence suggests that upregulation of GABA (gamma aminobutyricacid) neurotransmission may play an important role in regulatingthe onset and duration of peri-adolescent synaptic pruning. It ispostulated that deficient GABA neurotransmission, especially onethat is mediated by the inhibitory neurons that contain the calciumbuffer protein parvalbumin (PV), may disturb the synaptic pruningprocess and hence contribute to the onset of schizophrenia.Enhancement of GABA neurotransmission may therefore restorethe integrity of PFC neural circuits, which may then lead to lastingimprovement in cognitive deficits and clinical symptoms.

Abstracts380