CANCELLED - TO BE RESCHEDULED - Animal models for drug discovery in schizophrenia: promises and pitfalls

Antipsychotic drugs alleviate certain psychotic symptoms of schizophrenia, however cognitive deficit and negative symptoms remain an unmet clinical need (Keefe et al. Arch Gen Psychiatry 2007; 64:633-647). In spite of significant efforts by the Pharmaceutical Industry and academic groups, no drug has yet received a license for these indications (see Talpos, Drug Discov Today, 2017; doi: 10.1016/j.drudis.2017.04.014 for recent review). Several key issues remain unresolved, for example, the failure of positive results with new drug candidates in preclinical to Phase II clinical trials to translate into success in large Phase III trials (Bespalov et al. Nat Rev Drug Discov 2016; 15(7):516) and the impact of long-term antipsychotic drug treatment on brain function. Recent work by Carol Tamminga and colleagues has identified subgroups of patients according to brain based biomarkers not in accordance with their clinical diagnoses (Clementz et al. Am J Psychiatry 2016; 173:373-384). The authors suggest that these subtypes of patients are likely to benefit from differential treatment strategies. The key to development of improved therapies is improved animal models that mimic the human condition in terms of behaviour and pathology and that predict efficacy of novel treatments in patients. The benefit of using animals is development of different models that can represent these separate clinical biotypes, and assessing therapeutic potential of novel and appropriate treatments for each of these. Long-standing research in our laboratory shows that sub-chronic treatment (2 mg/kg ip for 7 days followed by 7 days wash-out) with the un-competitive NMDAR antagonist PCP (Phencyclidine) mimics cognitive and negative symptoms in female Lister Hooded rats, and produces associated pathological changes (Neill et al. Pharmacol & Ther 2010;128(3): 419-432; Neill et al. Eur Neuropsych 2014; 24:822-835; Cadinu et al. Neuropharmacology 2018; 142: 41-62). These effects are attenuated by atypical antipsychotics, specifically low dose risperidone and novel targets but not by classical antipsychotics. An emerging project in our laboratory shows that maternal immune activation (mIA) induces pathological and behavioural deficits in the offspring that are sex and time dependent and may represent the developmental trajectory of the illness (Murray et al. Brain Behavior and Immunity, 2018, Very recent work suggests that the mechanism through which mIA does this is at least partly via effects on placental transport. Our latest results with new drug targets, specifically a novel and selective Kv3.1/3.2 channel modulator, AUT00206, in the scPCP model will be evaluated in this presentation, and recent work with the mIA model.