Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior.

Major depressive disorder (MDD) is one of the most common and debilitating neuropsychiatric illnesses. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of MDD. The complement system represents one of the major effector mechanisms of the innate immune system, and plays a critical role in inflammation. However, the role of complement components in MDD is not well understood. Here, we found significant increase in component 3 (C3) expression in the prefrontal cortex (PFC) of depressed suicide subjects. We tested the role of altered C3 expression in mouse model of depression and found that increased C3 expression in PFC as a result of chronic stress causes depressive-like behavior. Conversely, mice lacking C3 were resilient to stress-induced depressive-like behavior. Moreover, selective overexpression of C3 in PFC was sufficient to cause depressive-like behavior in mice. We found that C3a (activated product of C3) receptor, C3aR+ monocytes were infiltrated into PFC following chronic stress. However, C3aR knockout mice displayed significantly reduced monocyte recruitment into PFC and reduced levels of the proinflammatory cytokine IL-1ß in PFC after chronic stress. In addition, C3aR knockout mice did not exhibit chronic stress-induced behavior despair. Similarly, chronic stress-induced increases in C3aR+ monocytes and IL-1ß in PFC, and depressive-like behavior were attenuated by myeloid cell depletion. These postmortem and preclinical studies identify C3aR signaling as a key factor in MDD pathophysiology.

Can epigenetic biomarkers lead us to precision medicine in predicting treatment response and remission for patients being considered for ECT?

While electroconvulsive therapy (ECT) is the gold standard for the treatment of depression, there is currently a lack of clinically useful biomarkers predictive of treatment response. Epigenetics provides reasonable potential as a biomarker for treatment response for ECT, given that the study of epigenetics combines both the impact of biology and environment in the shaping of psychopathology. Initial limited studies are promising. Further studies to establish precision medicine in term of ECT treatment response using epigenetics predictors can provide great benefit to both patients and physicians in saving time, money, and frustration.

Longitudinal study of inflammatory markers and psychopathology in schizophrenia.

OBJECTIVE: Schizophrenia is associated with abnormal levels of blood inflammatory markers, which may be correlated with levels of psychopathology. Few previous studies have explored whether baseline inflammatory marker levels predict longitudinal changes in psychopathology. In the present study, we explored this association in a cohort of patients with schizophrenia. METHOD: We investigated inflammatory markers and psychopathology after 3, 6, and 12 months of antipsychotic treatment for subjects with baseline and follow-up data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. Linear regression models, controlling for multiple potential confounding factors, were used to investigate these associations. RESULTS: There was a significant decrease in monocyte, ICAM, and adiponectin levels between baseline and 12 months. Higher baseline blood interleukin-6 (IL-6) predicted greater reduction in PANSS total and general subscale scores at 3 and 6 months, and PANSS negative subscale scores at 3 months (ß = -0.10 to -0.16, p < 0.05 for each). Higher baseline blood leptin levels predicted greater reduction in PANSS total, negative and general subscale scores at 6 months (ß = -0.09 to -0.11, p < 0.05 for each). In post-hoc analyses, associations between baseline IL-6 levels and symptom reduction were strongest in patients treated with either ziprasidone or quetiapine. Changes in blood inflammatory markers were generally not associated with changes in psychopathology. CONCLUSIONS: Our findings provide additional support that measuring blood inflammatory markers may be relevant to the clinical care of patients with schizophrenia. Specifically, these markers may help guide selection of antipsychotic treatment towards more personalized medicine approaches for patients with schizophrenia.

Inflammatory Pathways in Psychiatric Disorders: The case of Schizophrenia and Depression.

PURPOSE OF REVIEW: A better understanding of the key molecules/pathways underlying the pathophysiology of depression and schizophrenia may contribute to novel therapeutic strategies. In this review, we have discussed the recent developments on the role of inflammatory pathways in the pathogenesis of depression and schizophrenia. RECENT FINDINGS: Inflammation is an innate immune response that can be triggered by various factors, including pathogens, stress and injury. Under normal conditions, the inflammatory responses quiet after pathogen clearance and tissue repair. However, abnormal long-term or chronic inflammation can lead to damaging effects. Accumulating evidence suggest that dysregulated inflammation is linked to the pathogenesis of neuropsychiatric disorders. In this review, we have discussed the roles of complement system, infiltration of peripheral immune cells into the central nervous system (CNS), the gut-brain axis, and the kynurenine pathway in depression and schizophrenia. SUMMARY: There is a large body of compelling evidence on the role of inflammatory pathways in depression and schizophrenia. Although most of these findings show their roles in the pathophysiology of the above disorders, additional studies are warranted to investigate the therapeutic potential of various immune signaling targets discussed in this article.

Complement component 3 levels in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder.

Late-life major depression (LLMD) is a risk factor for the development of mild cognitive impairment and dementia, including Alzheimer's disease (AD) and vascular dementia. Immune dysregulation and changes in innate immune responses in particular, have been implicated in the pathophysiology of both LLMD and AD. Complement system, a key component of the innate immune mechanism, is known to play an important role in synaptic plasticity and cognitive functions. However, its role in LLMD remains unknown. In the present study, we examined the levels of complement component 3 (C3, the convergence point of all complement activation pathways) in the cerebrospinal fluid (CSF) of elderly depressed subjects compared to healthy controls; as well as the relationship of CSF C3 levels with amyloid-beta (Aß42 and Aß40), total tau (T-tau) and phosphorylated tau (P-tau) proteins and cognition scores. CSF was obtained from 50 cognitively intact volunteers (major depression group, N = 30; comparison group, N = 20) and analyzed for levels of C3 by ELISA. C3 levels were marginally lower in the major depression group relative to the comparison group. We did not find any significant association of C3 with the AD biomarkers Aß42 reflecting plaque pathology, P-tau related to tau pathology or the neurodegeneration biomarker T-tau. In contrast, C3 was positively correlated with CSF Aß40, which may reflect Aß deposition in cerebral vessel walls. We observed a negative correlation between C3 levels and Total Recall on the Buschke Selective Reminding Test (BSRT) for memory performance in the depressed subjects when controlling for education. This initial evidence on C3 status in LLMD subjects may have implications for our understanding of the pathophysiology of major depression especially in late life.