Functional brain connectivity phenotypes for schizophrenia drug discovery

Abstract

While our knowledge of the pathophysiology of schizophrenia has increased dramatically this has not translated into the development of new and improved drugs to treat this disorder. Human brain imaging and electrophysiological studies have provided dramatic new insight into the mechanisms of brain dysfunction in the disease, with a swathe of recent studies highlighting the differences in functional brain network and neural system connectivity present in the disorder. Only recently has the value of applying these approaches in preclinical rodent models relevant to the disorder started to be recognised.Here we highlight recent findings of altered functional brain connectivity in preclinical rodent models and consider their relevance to those alterations seen in the brains of schizophrenia patients. Furthermore, we highlight the potential translational value of using the paradigm of functional brain connectivity phenotypes in the context of preclinical schizophrenia drug discovery, as a means both to understand the mechanisms of brain dysfunction in the disorder and to reduce the current high attrition rate in schizophrenia drug discovery.3

An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

“…Increasingly, psychiatric disorders are being conceptualized in terms of dysregulation of extended brain networks, and aberrant connectivity between brain regions, as measured by electrophysiological or functional imaging methods, is emerging as an important biomarker (Dawson et al, 2015). Dysfunctional connectivity indicates a disruption of information flow and interaction between distinct brain regions and is thought to underlie specific symptoms.…”

Average spectral power changes at the hippocampal electroencephalogram in schizophrenia model induced by ketamine

“…) only at the lowest dose, both on the 1st day (5 min: P < 0.01; 10 min: P < 0.001; 15 min: P < 0.05) as on the 10th day of treatment (5 min: P < 0.01; 10 min: P < 0.01; 15 min: P < 0.001; 20 min: P < 0.01) when compared to the control group [1st day(5 min: 4.87 AE 0.12; 10 min: 4.84 AE 0.12; 15 min: 4.88 AE 0.16) [F 3,58 = 23.63; Treatment protocol with saline (Control), ketamine 10 mg/kg (Ket 10), ketamine 50 mg/kg (Ket 50), or ketamine 100 mg/kg (Ket 100).ª 2017 Soci et e Franc ßaise de Pharmacologie et de Th erapeutique Fundamental & Clinical Pharmacology 32 (2018) Specimen recording in the hippocampal EEG of rats filtered between 0-4 Hz (delta); 4-8 Hz (theta); >8-13 Hz (alpha); 30-50 Hz (gamma low); and 50-100 Hz (gamma high), after acute treatment (Figure 2a) or repeated treatment for 10 days (Figure 2b) with ketamine (10, 50 or 100 mg/kg). All EEG traces had calibration scale in mV, and polygraphic records were cut in 10-s epochs.…”

Different serum protein factor levels in first‐episode drug‐naive patients with schizophrenia characterized by positive and negative symptoms

“…[3][4][5] Understanding the relation between the neuropathological findings and clinical symptom domains of schizophrenia could help in the development of novel drug treatments that target the different characteristics of the illness. 4,6 Additionally, improved understanding of the pathophysiology of schizophrenia may enable the definition of more specific potential diagnostic or therapeutic targets. 7,8 The future development of antipsychotic drugs may also be disease-specific and target the core pathologies of schizophrenia-like positive and negative symptom domains.…”