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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.

Keywords: schizophrenia, treatment-resistant, connectomics, dysconnectivity, gamma band oscillations, NMDA receptors, GABA interneurons

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Treatment-resistant schizophrenia (TRS) remains one of the greatest therapeutic challenges in psychiatry. Schizophrenia is a complex neurodevelopmental syndrome; with disease processes occurring in utero that may disrupt the formation of critical neural circuits and result in widespread brain dysconnectivity. Hints of altered neural circuitry, for example delays in gross and fine motor skill development, often evolve during childhood and may precede the first subtle signs of psychosis during late adolescence in those who will develop the illness (14). Adolescents with disrupted neural circuit development and circuit dysconnectivity related to the progression of the disease often begin to exhibit sub-threshold psychotic symptoms during developmental periods associated with increasing gray matter (GM) volume and refinement of cortical circuits including synaptic pruning, reinforcement, and neuronal synchronization (58). The gradual alterations in brain connectivity and subsequent symptoms can persist for years before psychosis emerges and diagnosis and antipsychotic medications are initiated. In most cases, individuals with schizophrenia progress with an illness that is characterized by periods of exacerbation and remission of psychosis. Recovery is dependent on compliance with and response to optimized antipsychotic medication, the development of a strong therapeutic alliance to treatment team members, and intensive social and vocational support (9). Even with the best antipsychotic treatments that are available today and access to full functional supports, a sub-population of patients with schizophrenia will never attain an optimal response to treatment and remain very ill. These are the patients who have treatment-refractory illness or in the case of non-response to clozapine, ultra-resistant disease (10, 11).

Identifying treatments that will benefit patients with TRS remains a significant challenge. Our understanding of personalized treatment response and resistance to medication is limited by an inability to accurately pinpoint the individual genetic, cellular and neural circuit drivers of psychoses. Investigations of neuronal ensembles and cortical networks at the micro-scale level are not possible using the clinical diagnostic and macro-scale imaging tools that are currently available. Moreover, inconsistent clinical definitions of positive, negative or cognitive symptom-specific differences in TRS lead to ambiguous treatment guideline recommendations and a wide variation in clinical approaches to treat TRS in practice. Different phenotypes of psychoses may respond to different targeted treatments that are cellular or neural circuit-specific, but at present we do not have the ability to identify the appropriate targeted therapies for different TRS phenotypes.

The Treatment Response and Resistance in Psychosis (TRRIP) working group recently addressed these challenges (12). Members are researchers and clinicians who have expertise in TRS and attended specific TRRIP working group meetings at international schizophrenia and neuropsychopharmacology research conferences to establish criteria to standardize the definition of treatment resistance in schizophrenia. In addition to capturing a core definition of treatment resistance that can be included and shared across all clinical treatment guidelines worldwide, recommendations were also made on the importance of identification of all clinical sub-specifiers or symptom phenotypes common to TRS (12). The standardization of clinical criteria of TRS has been an important advancement and will benefit future TRS research and clinical translation.

Treatment resistance has been most characterized in schizophrenia by how responsive the positive symptom domain is to antipsychotic medications. It is estimated that 70–80% of patients with schizophrenia have a phenotype of psychosis that is responsive to dopamine-blocking treatment (13). However, in over 100 years of treatment history and despite the improvements made to the functional selectivity and potency of antipsychotic medications, 60% of patients continue to fail to achieve symptom improvement after several weeks on drug therapy (14).

Many treatment-refractory patients present with a psychosis that is positive symptom domain responsive, but have symptoms that are non-responsive within the negative or cognitive symptom subdomains and associated circuits. It is now recommended that patients with symptom profiles that do not respond to antipsychotic medication and are considered treatment resistant be identified as: TRS-positive symptom domain-, TRS-negative symptom domain-, and TRS-cognitive symptom domain-specific. For those patients with combined treatment resistance in more than one domain (multidimensional resistance), identifying all of those specific symptom domains will provide further clarification (12).

Traditionally, for those patients who are unable to obtain adequate positive symptom control or sustain a response with at least 2 dopamine receptor-2 (D2)-blocking agents at therapeutic doses for at least 6 weeks, clozapine is the recommended drug of choice. An estimated 30–60% of these patients will respond to clozapine and have what can be described as a clozapine-responsive psychosis (10, 15, 16). Patients who do not have an optimal response to clozapine and continue to experience prominent positive symptoms have clozapine-resistant psychosis or an ultra-resistant psychotic disease (11). Currently, there are no therapies that address this most severe form of neural-dysconnectivity in schizophrenia.

In this review, we examine TRS from a circuit-based perspective. We start by highlighting the historical development of connectome science in schizophrenia, identifying those early pioneers in psychiatry who originally recognized the disease as an illness of widespread disconnectivity and their valuable contribution to the evolution of network science today. We then examine neuroimaging studies that support both systemic and circuit-level brain dysconnectivity specific to treatment resistance and attempt to explain underlying circuit biology and brain topology that may be unique to this most severe form of the illness. Within a connectome context, attempts to map on-off circuit connectivity synonymous with excitatory and inhibitory neuronal pathways are discussed. Functional correlates of dysconnectivity in schizophrenia are also considered with a focus on cortical network oscillations, giving particular emphasis to the role of gamma band oscillations (GBOs) and their ability to integrate information across large populations of neurons in the illness. Mechanistic models describing underlying neural circuitry and the complex relationship involved in the synchronized firing between excitatory pyramidal cells and inhibitory gamma-aminobutyric acid (GABA)-ergic interneurons are also reviewed to help visualize and understand the inter-relationship between neuronal ensembles within the brain and the complex mechanisms behind their dysfunctional communication in schizophrenia. Finally, we deconstruct how augmenting pharmacological treatments, such as glutamate N-methyl-D-aspartate (NMDA) receptor and GABA interneuron modulators as well as nitric oxide (NO)-based treatments may be applied within a circuit context to improve circuit integration and treatment response in TRS. Updates on neurosurgical and neuromodulation targets under investigation in TRS are also included and provide an overview of beneficial circuit-based targets that may improve treatment resistant symptoms in those patients that remain refractory to pharmacological approaches.

This review supports the idea that the mapping of cellular and system-level networks to both on (excitatory) and off (inhibitory) circuit phenotypes specific to treatment-resistant disease may be a productive strategy in expanding future research toward customized neural circuit-specific pharmacotherapeutics and directed neuromodulation treatments in schizophrenia. Targeted therapeutics that can improve particular areas of regional functional dysconnectivity that are found to be substantially affected in TRS is an intriguing approach to precision medicine in schizophrenia.

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History of connectomics in schizophrenia-the early connectionists

Theoretical models of disconnectivity and the investigation of connectomics and brain network organization have been examined in schizophrenia since the early nineteenth century. Historically, there have been a number of influential figures who have made major contributions to the development of modern day network-based science known as connectomics. One of the very first connectionist pioneers in psychiatry was Wilhelm Griesinger (1817–1868), a German neurologist and psychiatrist who initially proposed that mental illnesses are brain disorders with pathological and neuroanatomical origins similar to neurological disorders (17). From his teachings, his student Theodor Hermann Meynert (1833–1892), a German-Austrian neuropathologist, anatomist and psychiatrist, made further contributions to this biological model of mental illness (18). His work was based primarily on neuroanatomical and histological studies where he worked to characterize various afferent and efferent white matter (WM) fiber tracts of the cerebral cortex. Meynert believed that association fibers connecting regional areas of the brain are the most disrupted in psychiatric diseases, which has been consistently demonstrated by several structural and functional magnetic resonance imaging (MRI) studies of schizophrenia in recent times (1821).