Dataset Information

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia.

ABSTRACT: The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatment-resistance criteria.

SUBMITTER: White TP

PROVIDER: S-EPMC4793111 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia.

White Thomas P TP Wigton Rebekah R Joyce Dan W DW Collier Tracy T Fornito Alex A Shergill Sukhwinder S SS

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150909 5

The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, ...[more]

PMID: 26346637

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Project description:BackgroundTreatment-resistant depression (TRD) refers to patients with major depressive disorder who do not remit after 2 or more antidepressant trials. TRD is common and highly debilitating, but its neurobiological basis remains poorly understood. Recent neuroimaging studies have revealed cortical connectivity gradients that dissociate primary sensorimotor areas from higher-order associative cortices. This fundamental topography determines cortical information flow and is affected by psychiatric disorders. We examined how TRD impacts gradient-based hierarchical cortical organization.MethodsIn this secondary study, we analyzed resting-state functional magnetic resonance imaging data from a mindfulness-based intervention enrolling 56 patients with TRD and 28 healthy control subjects. Using gradient extraction tools, baseline measures of cortical gradient dispersion within and between functional brain networks were derived, compared across groups, and associated with graph theoretical measures of network topology. In patients, correlation analyses were used to associate measures of cortical gradient dispersion with clinical measures of anxiety, depression, and mindfulness at baseline and following the intervention.ResultsCortical gradient dispersion was reduced within major intrinsic brain networks in patients with TRD. Reduced cortical gradient dispersion correlated with increased network degree assessed through graph theory-based measures of network topology. Lower dispersion among default mode, control, and limbic network nodes related to baseline levels of trait anxiety, depression, and mindfulness. Patients' baseline limbic network dispersion predicted trait anxiety scores 24 weeks after the intervention.ConclusionsOur findings provide preliminary support for widespread alterations in cortical gradient architecture in TRD, implicating a significant role for transmodal and limbic networks in mediating depression, anxiety, and lower mindfulness in patients with TRD.

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

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia.

Publications

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia.

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