A novel TMS-EEG study of GABAergic and glutamatergic neurotransmission in antipsychotic treatment response in schizophrenia

People who suffer from schizophrenia experience a wide range of symptoms, including delusions (fixed, false beliefs) hallucinations (e.g. hearing voices), cognitive symptoms (e.g. difficulties with memory, concentration, slow thinking) and negative symptoms (e.g. lack of motivation). The available pharmacological treatment for schizophrenia, the antipsychotic medications, are working through the reduction of a brain chemical called dopamine. However, a third to half of the patients still experience significant symptoms despite treatment with antipsychotics. This results in patients having side effects without improvement of their symptoms, including delusions, hallucinations and cognitive symptoms. Dopamine reduction is therefore not working for all patients and for all symptoms of schizophrenia and that's why other brain chemicals, such as GABA and glutamate, are being studied in the hope that alternative medications can be made available for those patients who do not respond to the current antipsychotics. In conjunction with the brain chemicals, a cognitive ability of the brain called cognitive control, may also play a role in the non-response of the symptoms to dopamine reducing antipsychotics. Cognitive control synchronises the internal and external realities by helping us to change and adapt our behaviour based on information from the environment and comparing this information with our own internal goals, rules or intentions. This internal-external synchronisation is thought to protect us from symptoms of mental illness by acting as the "immune system of brain" and dealing with the symptoms of mental illness as they arise. This ability is impaired in schizophrenia. In this research proposal we will study how GABA and glutamate chemicals in the brain change in patients who take antipsychotics and respond to them and in patients who take antipsychotics but have not responded to them. We will use a non-invasive, simple and safe stimulation of the brain called transcranial magnetic stimulation (TMS), which has been used for years in clinical practice as treatment for depression and research in schizophrenia, to stimulate these brain chemicals. TMS applies magnetic pulses to the brain via a 'coil" placed on specific areas on the scalp. An electric current is delivered to the coil, which acts as the magnetic field generator in the procedure. The generated magnetic field induces an electrical current in the brain. We will record the response of the brain to the TMS stimulation with electroencephalogram (EEG). EEG detects electrical activity in the brain using small, metal discs (electrodes) attached to the scalp and the activity shows up as wavy lines on an EEG recording. The differences in GABA and glutamate between the two groups will provide information on the likelihood of a patient to respond to the current antipsychotics. We will also study if cognitive control plays a role in the differences in GABA and glutamate between the two groups. This information will ultimately help to predict which patient will respond to which medication as soon as possible after the diagnosis. It may also contribute to the research for development of new medications acting on GABA and glutamate, so that patients will be able to take the mediations that work for them and improve their symptoms and quality of life without having to try ineffective medications and suffer side effects for years.

Treatment non-response to antipsychotics (APs) is a major unmet medical need in schizophrenia (SCZ), with as many as a third to half of the patients experiencing significant positive symptoms (i.e. delusions and hallucinations) despite optimal treatment with APs. Patients are exposed to trials of APs and their side effects, as there are no robust predictors of non-response. All available APs act through dopamine D2 receptor blockade but their ineffectiveness to treat positive psychotic symptoms in all patients but also the cognitive symptoms of SCZ, which are almost ubiquitous across patients with SCZ, and negative symptoms, has led to the implication of glutamatergic and GABAergic neurotransmission dysfunction in the emergence and persistence of SCZ symptoms. Among the cognitive symptoms of SCZ, cognitive control (CC) is thought to play a central role in the formation and persistence of psychotic symptoms. The underlying mechanisms of response to APs are still poorly understood. The combination of transcranial magnetic stimulation with electroencephalography (TMS-EEG) is a powerful clinical research tool that directly probes cortical properties, such as excitability, inhibition and oscillatory activity and provides direct functional neurotransmission indices. We propose to use TMS-EEG to measure the effects of APs on GABAergic and glutamatergic neurotransmission and study their association with CC in 40 responders and 40 non-responders to APs with SCZ. The study will develop our understanding on the pathophysiological mechanisms of AP response in SCZ and will contribute to the identification of candidate neurophysiological biomarkers predictive of response to APs, which can guide treatment in a more effective and safe, patient-centred manner as soon as possible after the initial diagnosis and ultimately aid the development of novel candidate therapies modulating the GABA and glutamatergic systems.