Emerging mechanisms in the development of psychosis

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Emerging mechanisms in the development of psychosis

Post by trader32176 »

Dysregulation of complement and coagulation pathways:emerging mechanisms in the development of psychosis

published 7/5/21


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Early identification and treatment significantly improve clinical outcomes of psychotic disorders. Recent studies identified protein components of the complement and coagulation systems as key pathways implicated in psychosis. These specific protein alterations are integral to the inflammatory response and can begin years before the onset of clinical symptoms of psychotic disorder. Critically, they have recently been shown to predict the transition from clinical high risk to first-episode psychosis, enabling stratification of individuals who are most likely to transition to psychotic disorder from those who are not. This reinforces the concept that the psychosis spectrum is likely a central nervous system manifestation of systemic changes and highlights the need to investigate plasma proteins as diagnostic or prognostic biomarkers and pathophysiological mediators. In this review, we integrate evidence of alterations in proteins belonging to the complement and coagulation protein systems, including the coagulation, anticoagulation, and fibrinolytic pathways and their dysregulation in psychosis, into a consolidated mechanism that could be integral to the progression and manifestation of psychosis. We consolidate the findings of altered blood proteins relevant for progression to psychotic disorders, using data from longitudinal studies of the general population in addition to clinical high-risk (CHR) individuals transitioning to psychotic disorder. These are compared to markers identified from first-episode psychosis and schizophrenia as well as other psychosis spectrum disorders. We propose the novel hypothesis that altered complement and coagulation plasma levels enhance their pathways’ activating capacities, while low levels observed in key regulatory components contribute to excessive activation observed in patients. This hypothesis will require future testing through a range of experimental paradigms, and if upheld, complement and coagulation pathways or specific proteins could be useful diagnostic or prognostic tools and targets for early intervention and preventive strategies.


Psychotic disorders such as schizophrenia are among the most severe mental disorders, with large individual and societal costs [1]. Early identification and intervention are associated with improved symptomatic and functional outcomes [2, 3]. The liability to psychosis likely exists on a spectrum within the general population [4, 5].

Operationalized criteria for the clinical high-risk (CHR) state [6] serve to identify vulnerable groups at enhanced risk of psychotic disorders [3]. Identification of risk factors for development of psychosis in high-risk individuals is a key aspect of active research [7, 8]. Prognostication of risk is difficult based on clinical symptoms alone, with only ~20–35% of CHR individuals developing psychosis at 3 years. There is thus an urgent need to identify clinically translatable early biomarkers of psychosis risk [9]. Recently, baseline plasma proteomic biomarkers, predominantly components of the complement and coagulation pathways, have been found to accurately discriminate between CHR individuals who do and do not go on to develop a first psychotic episode [10]. This suggests that dysregulation of these systems could play a crucial role in early detection and may provide insights into the early pathophysiology of psychosis.

Here, we propose that the complement and coagulation systems have a central role in the development of psychosis phenotypes. We review existing evidence for immune and coagulation dysfunction in the blood associated with the psychosis phenotypic spectrum. We then focus on the physiological roles of complement and coagulation before examining how dysfunction of these pathways may give rise to pathology. We integrate novel findings into a refinement of the prevailing “two-hit” hypothesis, where early genetic and/or environmental developmental disruptions to the developing central nervous system (CNS) (“first-hit”) increase the vulnerability of the individual to subsequent, late environmental disruptions (“second-hit”), leading to the development of CNS manifestation [11,12,13]. This proposed theory integrates complement and coagulation dysregulation that can lead to immune activation, contributing to the development of psychotic disorder. Finally, we consider the potential implications in relation to treatment of psychotic disorders and propose directions for future research.

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There is now compelling evidence for a key role of complement and coagulation alterations in psychosis spectrum disorders and we propose that these changes lead to increased risk for psychosis. Intriguingly, the evidence may be most robust for dysregulation in early psychosis phenotypes, such as in advance of psychotic experiences among apparently well children, or prior to the onset of psychotic disorder among the high-risk population. The observed pattern of protein changes in these pathways has been consistent and points to the presence of chronic immune activation as a risk factor for psychosis. Critically, while the conceptualization of psychosis as an inflammatory condition and immune activation is not new, our data provide a novel understanding and refocus on the consolidated functions of the complement and coagulation pathways contributing to the progression to psychotic disorder. These pathways may provide objective biomarkers of psychosis, and enable identification of therapeutic targets for early and more effective intervention strategies and treatment.
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Re: Emerging mechanisms in the development of psychosis

Post by Howzitgoing »

Robin Williams’s son Zak says dad's misdiagnosis may have 'exacerbated' his symptoms: 'Those drugs are no joke'


... dementia with Lewy bodies (DLB), which Robin suffered from the last two years of his life.

DLB, as defined by the Alzheimer's Society, is a type of dementia that shares symptoms with both Alzheimer’s disease and Parkinson’s disease, and may account for 10 to 15 percent of all cases of dementia.

Two years before Robins died by suicide in 2014, he was mistakenly diagnosed with Parkinson’s disease. However, though his direct cause of death was asphyxia due to hanging, an examination of his brain issue suggested that his real diagnosis was DLB.

Williams, who suggests his dad's misdiagnosis "might have exacerbated the situation," adds the drugs to treat Parkinson's are "no joke. They put you through it."

"The diagnosis was different than the disease so I think it could be a situation where you’re taking stuff and experiencing purely the side effects of [the drug]," he explained. Still, "there’s a range of efficacy but what I found was they’re also really hard on the mind and body, so that was hard to see."

The disease had a profound impact on Robin's comedic timing, or his “lightening-quick recall," which was his signature. "That’s part of being excellent at improvisation. [But] all the symptoms… presented in one part or another," Williams said.

In a candid interview with Max Lugavere on his podcast The Genius Life, Williams opened up about his father’s misdiagnosis ...

https://www.yahoo.com/lifestyle/robin-w ... 29125.html
Robin Williams’s son Zak says dad's misdiagnosis may have 'exacerbated' his symptoms: 'Those drugs are no joke'
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