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.
Highlights
Treatment-resistant schizophrenia (TRS) remains one of the greatest therapeutic challenges in psychiatry
Meynert’s student Carl Wernicke (1848–1905) further developed the disconnectivity theory of schizophrenia. He was best known for his theories regarding the neural circuits involved in higher cognitive functions and the neuropathology of aphasia, he studied the neuroanatomical and functional aspects of schizophrenia. In his textbook Grundriss der Psychiatrie (Outlines of Psychiatry 1900) which was written based on detailed reviews of his clinical cases, he outlined his hypothesis that there is a deficiency in association fiber connectivity in schizophrenia that contributes to an overactivation of cortical sensory regions that can lead to the development of psychosis [22]
The excessive stimulation of pyramidal ventral tegmental area (VTA) neurons leads to the inhibition of mesocortical dopamine neurons and insufficient dopamine release in the PFC and subsequent negative and cognitive symptoms in schizophrenia [130, 131]. In those patients who fail to respond to antipsychotic medication, it has been demonstrated that dopamine receptor-2 (D2) receptor occupancy is identical to treatment-responsive patients, the lack of efficacy from D2-blocking medication may indicate that hyperdopaminergia may not be related to the symptoms associated with non-response to medications [132]
Summary
Treatment-resistant schizophrenia (TRS) remains one of the greatest therapeutic challenges in psychiatry. He was best known for his theories regarding the neural circuits involved in higher cognitive functions and the neuropathology of aphasia, he studied the neuroanatomical and functional aspects of schizophrenia In his textbook Grundriss der Psychiatrie (Outlines of Psychiatry 1900) which was written based on detailed reviews of his clinical cases, he outlined his hypothesis that there is a deficiency in association fiber connectivity in schizophrenia that contributes to an overactivation of cortical sensory regions that can lead to the development of psychosis [22]. Kraepelin was the first to develop a classification system of psychiatric disorders and divided endogenous psychoses into two distinct forms based on disease course and outcome He described the psychosis involved in schizophrenia as a dementia praecox, a term that combined the cognitive symptoms (dementia) of the illness with an early development of the disorder (praecox) vs the episodic nature of manic depressive (affective) psychosis [23]. Through these methods they are able to create a “connectome,” the neuronal map of the brain’s anatomical and functional connectivity architecture, and elucidate the complex organization of the neuronal elements that underlies brain function [31,32,33,34]
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