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Multidimensional Connectomics and Treatment-Resistant Schizophrenia: Linking Phenotypic Circuits to Targeted Therapeutics.

ABSTRACT: Schizophrenia is a very complex syndrome that involves widespread brain multi-dysconnectivity. Neural circuits within specific brain regions and their links to corresponding regions are abnormal in the illness. Theoretical models of dysconnectivity and the investigation of connectomics and brain network organization have been examined in schizophrenia since the early nineteenth century. In more recent years, advancements have been achieved with the development of neuroimaging tools that have provided further clues to the structural and functional organization of the brain and global neural networks in the illness. Neural circuitry that extends across prefrontal, temporal and parietal areas of the cortex as well as limbic and other subcortical brain regions is disrupted in schizophrenia. As a result, many patients have a poor response to antipsychotic treatment and treatment failure is common. Treatment resistance that is specific to positive, negative, and cognitive domains of the illness may be related to distinct circuit phenotypes unique to treatment-refractory disease. Currently, there are no customized neural circuit-specific and targeted therapies that address this neural dysconnectivity. Investigation of targeted therapeutics that addresses particular areas of substantial regional dysconnectivity is an intriguing approach to precision medicine in schizophrenia. This review examines current findings of system and circuit-level brain dysconnectivity in treatment-resistant schizophrenia based on neuroimaging studies. Within a connectome context, on-off circuit connectivity synonymous with excitatory and inhibitory neuronal pathways is discussed. Mechanistic cellular, neurochemical and molecular studies are included with specific emphasis given to cell pathology and synaptic communication in glutamatergic and GABAergic systems. In this review we attempt to deconstruct how augmenting treatments may be applied within a circuit context to improve circuit integration and treatment response. Clinical studies that have used a variety of glutamate receptor and GABA interneuron modulators, nitric oxide-based therapies and a variety of other strategies as augmenting treatments with antipsychotic drugs are included. This review supports the idea that the methodical mapping of system-level networks to both on (excitatory) and off (inhibitory) cellular circuits specific to treatment-resistant disease may be a logical and productive approach in directing future research toward the advancement of targeted pharmacotherapeutics in schizophrenia.

SUBMITTER: MacKay MB

PROVIDER: S-EPMC6218602 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Multidimensional Connectomics and Treatment-Resistant Schizophrenia: Linking Phenotypic Circuits to Targeted Therapeutics.

MacKay Mary-Anne B MB Paylor John W JW Wong James T F JTF Winship Ian R IR Baker Glen B GB Dursun Serdar M SM

Frontiers in psychiatry 20181030

Schizophrenia is a very complex syndrome that involves widespread brain multi-dysconnectivity. Neural circuits within specific brain regions and their links to corresponding regions are abnormal in the illness. Theoretical models of dysconnectivity and the investigation of connectomics and brain network organization have been examined in schizophrenia since the early nineteenth century. In more recent years, advancements have been achieved with the development of neuroimaging tools that have pro ...[more]

PMID: 30425662

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Project description:Schizophrenia is a severe neuropsychiatric disorder that affects approximately 0.5-1% of the population. Response to antipsychotic therapy is highly variable, and it is not currently possible to predict those patients who will or will not respond to antipsychotic medication. Furthermore, a high percentage of patients, approximately 30%, are classified as treatment-resistant (treatment-resistant schizophrenia; TRS). TRS is defined as a non-response to at least two trials of antipsychotic medication of adequate dose and duration. These patients are usually treated with clozapine, the only evidence-based pharmacotherapy for TRS. However, clozapine is associated with severe adverse events. For these reasons, there is an increasing interest to identify better targets for drug development of new compounds and to establish better biomarkers for existing medications. The ability of antipsychotics to improve psychotic symptoms is dependent on their antagonist and reverse agonist activities at different neuroreceptors, and some genetic association studies of TRS have focused on different pharmacodynamic factors. Some genetic studies have shown an association between antipsychotic response or TRS and neurodevelopment candidate genes, antipsychotic mechanisms of action (such as dopaminergic, serotonergic, GABAergic, and glutamatergic) or pharmacokinetic factors (i.e., differences in the cytochrome families). Moreover, there is a growing body of literature on the structural and functional neuroimaging research into TRS. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify resistant patients earlier. Studies examining the neuropharmacological mechanisms of antipsychotics, including clozapine, can help to improve our knowledge of their action on the central nervous system, with further implications for the discovery of biomarkers and the development of new treatments. The identification of the underlying mechanisms of TRS is a major challenge for developing personalized medicine in the psychiatric field for schizophrenia treatment. The main goal of precision medicine is to use genetic and brain-imaging information to improve the safety, effectiveness, and health outcomes of patients via more efficiently targeted risk stratification, prevention, and tailored medication and treatment management approaches. The aim of this review is to summarize the state of art of pharmacogenetic, pharmacogenomic and neuroimaging studies in TRS.

Dataset Information

Multidimensional Connectomics and Treatment-Resistant Schizophrenia: Linking Phenotypic Circuits to Targeted Therapeutics.

Publications

Multidimensional Connectomics and Treatment-Resistant Schizophrenia: Linking Phenotypic Circuits to Targeted Therapeutics.

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