Substantia nigra ultrastructural pathology in schizophrenia

Walker, Courtney K.; Roche, Joy K.; Sinha, Vidushi; Roberts, Rosalinda C.

doi:10.1016/j.schres.2017.12.004

Cited by 27 publications

(12 citation statements)

References 64 publications

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“…In another recent study (87) authors reported that a greater decrease of myelination in substantia nigra was observed in cases of schizophrenia with a poor response to treatment in comparison with responders and healthy controls. This finding does not allow to conclude that substantia nigra aberrations may be considered as predictors of treatment resistance.…”

Section: Resultsmentioning

confidence: 93%

Predictive Factors of Treatment Resistance in First Episode of Psychosis: A Systematic Review

2019

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Background: Clinical and functional outcome improvement in psychotic disorders is a challenge for the investigators. Recent advances offered opportunities for ameliorating the course of the illness during its early stages and for identifying treatment-resistant patients. Patients who had not response to two different antipsychotics, administered at correct doses for a sufficient period, can be operationally considered treatment-resistant. Available evidence suggested that the response's trajectory to the antipsychotic treatment revealed that a small proportion of subjects are poor responders (8.2%), the majority of patients have a moderate response (76.4%), and only 15.4% can be considered rapid responders with the greatest magnitude of response. Patients with first episode of psychosis generally obtain a more favorable response profile. Nevertheless, in around 25% of these patients symptoms of psychosis persist with a worse long-term course of illness. Objectives: The aim of this review is to report current evidences on the main predictors of treatment non-response in patients at early stage of psychosis. Methods: We used a specific string that guaranteed a high sensitive search in pubmed. We included the following types of publications: randomized-controlled trials, observational studies, longitudinal studies, retrospective studies, case-control studies, open-label investigations, cohort studies, and reviews. Publications must concern predictors of treatment resistance in early psychosis. Results: Forty-seven records were included: 5 reviews, 3 meta-analyses, 22 longitudinal studies, 2 retrospective studies, 1 naturalistic study, 6 randomized controlled trials, 2 open-label studies, 2 case-control studies, 4 cohort studies, 2 retrospective studies. Several factors were identified as predictors of treatment resistance: lower premorbid functioning; lower level of education; negative symptoms from first psychotic episode; comorbid substance use; younger age at onset; lack of early response; non-adherence to treatment; and longer duration of untreated psychosis. The role of gender and marital status is still controversial. More evidences are needed about neurobiological, genetic, and neuroimaging factors. Conclusions: The identification of specific predictive factors of treatment resistance in patients with first episode of psychosis ameliorates the quality of clinical management of these patients in the critical early phase of schizophrenia.

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Section: Resultsmentioning

confidence: 93%

Predictive Factors of Treatment Resistance in First Episode of Psychosis: A Systematic Review

2019

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“…Notably, post-mortem analysis performed in the prefrontal cortex of schizophrenic patients revealed oligodendrocyte ultrastructural abnormalities [183]. Similarly, cytoskeletal derangements within nigro-striatal DA neurons and axons were recently evidenced in another cohort of schizophrenic brains [184]. Remarkably, a very recent neuropathological examination provided evidence for TDP-43-positive cytosolic inclusions and dystrophic neurites in the brain of a patient diagnosed with FTLD presenting brief psychotic episodes and catatonia, which is a syndrome related to schizophrenia [120].…”

Section: Cytoskeletal Abnormalities and Neuronal Inclusions In Schmentioning

confidence: 99%

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Ryskalin

Limanaqi

Frati

et al. 2018

IJMS

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The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations.

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“…Exposure of C57BL/6 mice to cuprizone results in demyelination and behaviors that resemble some of those seen in schizophrenia. Cuprizone is a copper chelating agent that when included in the rodent diet for weeks will result in mice developing widespread demyelination, oligodendrocyte loss and myelin breakdown which is similar to changes seen in post-mortem brains of individuals who had schizophrenia (Gudi et al, 2014 ; Walker et al, 2018 ). This model was used to test the effects of haloperidol, clozapine, quetiapine on WM recovery and remyelination (Xu et al, 2011 ).…”

Section: Pharmacological Wm Targets In Treatment Resistant Schizophrementioning

confidence: 93%

“…Six samples were from treatment resistant subjects and 6 samples were from treatment responsive individuals (a further 2 samples were unknown for treatment response) and these were compared to 9 normal controls. Though this is a small sample size study, tissue from the substantia nigra of treatment resistant patients showed aberrant myelination characterized by increased G ratio (associated with decreased myelin thickness), axons without cytoplasm, and protrusions into the myelin sheath (Walker et al, 2018 ). The patients in both groups had an average duration of disease of 24 years so while treatment exposure is likely to have been different between groups, these results suggest cellular level changes that may be integral to treatment resistance.…”

Section: What Evidence Do We Have For Wm Changes In Schizophrenia Beimentioning

confidence: 99%

Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia

Crocker

Tibbo

2018

Front. Pharmacol.

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Despite development of comprehensive approaches to treat schizophrenia and other psychotic disorders and improve outcomes, there remains a proportion (approximately one-third) of patients who are treatment resistant and will not have remission of psychotic symptoms despite adequate trials of pharmacotherapy. This level of treatment response is stable across all stages of the spectrum of psychotic disorders, including early phase psychosis and chronic schizophrenia. Our current pharmacotherapies are beneficial in decreasing positive symptomology in most cases, however, with little to no impact on negative or cognitive symptoms. Not all individuals with treatment resistant psychosis unfortunately, even benefit from the potential pharmacological reductions in positive symptoms. The existing pharmacotherapy for psychosis is targeted at neurotransmitter receptors. The current first and second generation antipsychotic medications all act on dopamine type 2 receptors with the second generation drugs also interacting significantly with serotonin type 1 and 2 receptors, and with varying pharmacodynamic profiles overall. This focus on developing dopaminergic/serotonergic antipsychotics, while beneficial, has not reduced the proportion of patients experiencing treatment resistance to date. Another pharmacological approach is imperative to address treatment resistance both for response overall and for negative symptoms in particular. There is research suggesting that changes in white matter integrity occur in schizophrenia and these may be more associated with cognition and even negative symptomology. Here we review the evidence that white matter abnormalities in the brain may be contributing to the symptomology of psychotic disorders. Additionally, we propose that white matter may be a viable pharmacological target for pharmacoresistant schizophrenia and discuss current treatments in development for schizophrenia that target white matter.

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Substantia nigra ultrastructural pathology in schizophrenia

Cited by 27 publications

References 64 publications

Predictive Factors of Treatment Resistance in First Episode of Psychosis: A Systematic Review

Predictive Factors of Treatment Resistance in First Episode of Psychosis: A Systematic Review

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia

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