Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies

Mongan, David; Sabherwal, Sophie; Susai, Subash Raj; Föcking, Melanie; Cannon, Mary; Cotter, David

doi:10.1016/j.schres.2020.05.036

Cited by 33 publications

(27 citation statements)

References 94 publications

(217 reference statements)

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“…In circulation, the complement system interacts with pathogens to mark them for destruction by phagocytes 45 . The literature regarding findings in patients with SZ is inconclusive: while some studies have shown increased peripheral complement protein concentration in patients with SZ 46 , 47 , a recent meta-analysis has concluded that the evidence regarding complement system dysregulation is mixed 48 . In addition, recent evidence has suggested that the complement cascade is involved in several central nervous system processes, including neurogenesis and synaptic pruning, and has specifically been implicated in SZ 49 , 50 .…”

Section: Discussionmentioning

confidence: 99%

Increased random exploration in schizophrenia is associated with inflammation

et al. 2021

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One aspect of goal-directed behavior, which is known to be impaired in patients with schizophrenia (SZ), is balancing between exploiting a familiar choice with known reward value and exploring a lesser known, but potentially more rewarding option. Despite its relevance to several symptom domains of SZ, this has received little attention in SZ research. In addition, while there is increasing evidence that SZ is associated with chronic low-grade inflammation, few studies have investigated how this relates to specific behaviors, such as balancing exploration and exploitation. We therefore assessed behaviors underlying the exploration–exploitation trade-off using a three-armed bandit task in 45 patients with SZ and 19 healthy controls (HC). This task allowed us to dissociate goal-unrelated (random) from goal-related (directed) exploration and correlate them with psychopathological symptoms. Moreover, we assessed a broad range of inflammatory proteins in the blood and related them to bandit task behavior. We found that, compared to HC, patients with SZ showed reduced task performance. This impairment was due to a shift from exploitation to random exploration, which was associated with symptoms of disorganization. Relative to HC, patients with SZ showed a pro-inflammatory blood profile. Furthermore, high-sensitivity C-reactive protein (hsCRP) positively correlated with random exploration, but not with directed exploration or exploitation. In conclusion, we show that low-grade inflammation in patients with SZ is associated with random exploration, which can be considered a behavioral marker for disorganization. hsCRP may constitute a marker for severity of, and a potential treatment target for maladaptive exploratory behaviors.

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Section: Discussionmentioning

confidence: 99%

Increased random exploration in schizophrenia is associated with inflammation

et al. 2021

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“…This is also consistent with our results, as C4-ana is an in vivo by-product of C4 protein activation. Furthermore, several studies observed increased levels of a C4 protein inhibitor, C4-binding protein, in individuals with schizophrenia, implying an active compensatory mechanism [ 13 , 27 ]. Together, these findings suggest that plasma C3-ana may play a role in acute psychosis, whereas plasma C4-ana may contribute in a more chronic manner.…”

Section: Discussionmentioning

confidence: 99%

“…In healthy individuals, peripheral blood C4A and C4B protein concentrations correlate with the C4A and C4B gene copy number but also depend on age and sex [ 31 , 32 ]. The literature on the serological complement system in schizophrenia is large but characterized by small samples, variable methodological approaches, clinical diversity of cohorts, failure to assay C4A and C4B separately in most studies, and inconsistent results [ 2 , 3 , 27 ]. A recent meta-analysis of 10 studies of C4 protein concentration (mostly in serum) included 468 individuals with schizophrenia and 440 controls.…”

Section: Discussionmentioning

confidence: 99%

Increased activation product of complement 4 protein in plasma of individuals with schizophrenia

et al. 2021

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Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood–brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.

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“…A recent meta-analysis compared plasma complement protein levels and activity between SCZ patients and HC. Pooled estimated means did not reveal differences between the two groups in 11 studies of C3 and 10 studies of C4, even though individual studies reported significant increases in C3 and C4 in SCZ compared to HC [ 23 ]. Two more recent studies (not included in the meta-analysis) added to these inconsistencies.…”

Section: Microglial Synaptic Pruningmentioning

confidence: 99%

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders

Germann

Brederoo²,

Sommer

2021

Current Opinion in Psychiatry

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Purpose of review Excessive synaptic pruning has first been suggested by Irwin Feinberg (1982) as an important pillar in the pathophysiology in schizophrenia (SCZ). This article reviews recent developments highlighting factors implicated in aberrant synaptic pruning and its contribution to disease onset and emergence of cognitive symptoms in SCZ. Unraveling these factors provides new insights for potential prevention and treatment strategies for psychotic disorders. Recent findings Increased pruning in SCZ was recently confirmed by a positron emission tomography-study employing the novel tracer [11C]UCB-J, demonstrating the consequential loss of synaptic density. Recent evidence supports the contributing role of astrocytes and increased complement-mediated microglial pruning in disease onset and cognitive symptoms in SCZ. Increased microglial pruning is mediated specifically by C4. Furthermore, environmental factors (e.g., infections and stress) can lead to dysbiosis which was recently linked to microglial activation and pruning in SCZ. Summary Recent findings render the pruning machinery a potential target for early treatment and prevention in individuals at high risk for SCZ. Minocycline can improve cognition in SCZ, probably by reducing excessive pruning. Probiotics might also have beneficial effects on cognition, although recent findings are not encouraging. N-acetyl-cysteine recovers functional connectivity in SCZ both in vitro and in vivo, making it an interesting candidate.

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Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies

Cited by 33 publications

References 94 publications

Increased random exploration in schizophrenia is associated with inflammation

Increased random exploration in schizophrenia is associated with inflammation

Increased activation product of complement 4 protein in plasma of individuals with schizophrenia

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders

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