Harris A. Eyre

Neuroplastic changes in depression: a role for the immune system.

Accumulating evidence suggests that there is a rich cross-talk between the neuroimmune system and neuroplasticity mechanisms under both physiological conditions and pathophysiological conditions in depression. Anti-neuroplastic changes which occur in depression include a decrease in proliferation of neural stem cells (NSCs), decreased survival of neuroblasts and immature neurons, impaired neurocircuitry (cortical-striatal-limbic circuits), reduced levels of neurotrophins, reduced spine density and dendritic retraction. Since both humoral and cellular immune factors have been implicated in neuroplastic processes, in this review we present a model suggesting that neuroplastic processes in depression are mediated through various neuroimmune mechanisms. The review puts forward a model in that both humoral and cellular neuroimmune factors are involved with impairing neuroplasticity under pathophysiological conditions such as depression. Specifically, neuroimmune factors including interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, CD4⁺CD25⁺T regulatory cells (T reg), self-specific CD4⁺T cells, monocyte-derived macrophages, microglia and astrocytes are shown to be vital to processes of neuroplasticity such as long-term potentiation (LTP), NSC survival, synaptic branching, neurotrophin regulation and neurogenesis. In rodent models of depression, IL-1, IL-6 and TNF are associated with reduced hippocampal neurogenesis; mechanisms which are associated with this include the stress-activated protein kinase (SAPK)/Janus Kinase (JNK) pathway, hypoxia-inducible factors (HIF)-1α, JAK-Signal Transducer and Activator of Transcription (STAT) pathway, mitogen-activated protein kinase (MAPK)/cAMP responsive element binding protein (CREB) pathway, Ras-MAPK, PI-3 kinase, IKK/nuclear factor (NF)-κB and TGFβ activated kinase-1 (TAK-1). Neuroimmunological mechanisms have an active role in the neuroplastic changes associated with depression. Since therapies in depression, including antidepressants (AD), omega-3 polyunsaturated fatty acids (PUFAs) and physical activity exert neuroplasticity-enhancing effects potentially mediated by neuroimmune mechanisms, the immune system might serve as a promising target for interventions in depression.

Neuroimmunological effects of physical exercise in depression

The search for an extended understanding of the causes of depression, and for the development of additional effective treatments is highly significant. Clinical and pre-clinical studies suggest stress is a key mediator in the pathophysiology of depression. Exercise is a readily available therapeutic option, effective as a first-line treatment in mild to moderate depression. In pre-clinical models exercise attenuates stress-related depression-like behaviours. Cellular and humoral neuroimmune mechanisms beyond inflammation and oxidative stress are highly significant in understanding depression pathogenesis. The effects of exercise on such mechanisms are unclear. When clinical and pre-clinical data is taken together, exercise may reduce inflammation and oxidation stress via a multitude of cellular and humoral neuroimmune changes. Astrocytes, microglia and T cells have an antiinflammatory and neuroprotective functions via a variety of mechanisms. It is unknown whether exercise has effects on specific neuroimmune markers implicated in the pathogenesis of depression such as markers of immunosenescence, B or T cell reactivity, astrocyte populations, self-specific CD4+ T cells, T helper 17 cells or T regulatory cells.

Exercising the worry away: how inflammation, oxidative and nitrogen stress mediates the beneficial effect of physical activity on anxiety disorder symptoms and behaviours.

Regular physical activity exerts positive effects on anxiety disorder symptoms, although the biological mechanisms underpinning this effect are incompletely understood. Numerous lines of evidence support inflammation and oxidative and nitrogen stress (O&NS) as important in the pathogenesis of mood and anxiety disorders, and physical activity is known to influence these same pathways. This paper reviews the inter-relationships between anxiety disorders, physical activity and inflammation and O&NS, to explore whether modulation of inflammation and O&NS may in part underpin the positive effect of physical activity on anxiety disorders. Numerous studies support the notion that physical activity operates as an anti-inflammatory and anti-O&NS agent which potentially exerts positive effects on neuroplasticity, the expression of neurotrophins and normal neuronal functions. These effects may therefore influence the expression and evolution of anxiety disorders. Further exploration of this area may elicit a deeper understanding of the pathogenesis of anxiety disorders, and inform the development of integrated programmes including PA specifically suited to the treatment and prevention of anxiety disorders and symptoms.

A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis.

Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype-the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders.

Treating Depression and Depression-Like Behavior with Physical Activity: An Immune Perspective

The increasing burden of major depressive disorder makes the search for an extended understanding of etiology, and for the development of additional treatments highly significant. Biological factors may be useful biomarkers for treatment with physical activity (PA), and neurobiological effects of PA may herald new therapeutic development in the future. This paper provides a thorough and up-to-date review of studies examining the neuroimmunomodulatory effects of PA on the brain in depression and depression-like behaviors. From a neuroimmune perspective, evidence suggests PA does enhance the beneficial and reduce the detrimental effects of the neuroimmune system. PA appears to increase the following factors: interleukin (IL)-10, IL-6 (acutely), macrophage migration inhibitory factor, central nervous system-specific autoreactive CD4+ T cells, M2 microglia, quiescent astrocytes, CX3CL1, and insulin-like growth factor-1. On the other hand, PA appears to reduce detrimental neuroimmune factors such as: Th1/Th2 balance, pro-inflammatory cytokines, C-reactive protein, M1 microglia, and reactive astrocytes. The effect of other mechanisms is unknown, such as: CD4+CD25+ T regulatory cells (T regs), CD200, chemokines, miRNA, M2-type blood-derived macrophages, and tumor necrosis factor (TNF)-α [via receptor 2 (R2)]. The beneficial effects of PA are likely to occur centrally and peripherally (e.g., in visceral fat reduction). The investigation of the neuroimmune effects of PA on depression and depression-like behavior is a rapidly developing and important field.

A critical review of the efficacy of non-steroidal anti-inflammatory drugs in depression.

Non-steroidal anti-inflammatory drugs (NSAIDs) require further investigation given mixed results regarding efficacy. We critically and systematically reviewed the literature to determine whether selective COX-2 and non-selective COX inhibitor NSAIDs as adjuncts or monotherapy affect depressive symptoms. Electronic databases including Embase, PsycINFO, Ovid Medline, ScienceDirect, Google Scholar and the Cochrane Central Register of Controlled Trials database were searched up to September 2013. We utilised randomised controlled trials (RCTs), cohort studies and an open label study examining the efficacy of NSAIDs as adjuncts or monotherapy on depressive symptoms in subjects without major comorbidities. There were a total of 6 studies exploring the efficacy of selective COX-2 inhibitor NSAIDs on depressive symptoms with a total of 2706 subjects from 6 RCTs. 4 of the RCTs showed a significant effect of NSAIDs; 2 demonstrated no effect. There were a total of 5 studies exploring the efficacy of non-selective COX inhibitor NSAIDs on depressive symptoms with a total of 7978 subjects. There was 1 RCT, 3 cohort studies and 1 open label pilot study. The RCT failed to show a significant result. 1 of the retrospective cohort studies showed a positive result, with the other 2 showing no effect. The pilot study showed a positive result for NSAIDs. These studies demonstrated significant methodological heterogeneity (i.e. age range, sex, presence of antidepressant use, method of depression measure, severity of depressive symptoms, duration and study design (RCT vs. cohort)). The efficacy of NSAIDs on depressive symptoms appears negligible, however firm conclusions are difficult given the inconsistent findings and substantial methodological heterogeneity. Further high quality research is needed to explore NSAID efficacy in clinical and biological subtypes of depression, as monotherapy and adjunct with various antidepressants, and across various ages.

Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

BackgroundTumour necrosis factor - alpha (TNF-α) is a pro-inflammatory cytokine that combines a plethora of activities in the early stages of an immune response. TNF-α has gained increasing importance given TNF-α upregulation in multiple brain pathologies like neuropsychiatric conditions such as depression, schizophrenia, as well as neuroinflammatory disorder like multiple sclerosis (MS).AimThe aim of this review is to critically analyse neurobiological, immunological and molecular mechanisms through which TNF-α influences the development of cognitive dysfunction.Principal findings/resultsThe review presents several lines of original research showing that the immunological properties of TNF-α exacerbate inflammatory responses in the central nervous system such as microglial and endothelial activation, lymphocytic and monocytic infiltration and the expression of downstream pro-inflammatory cytokines and apoptotic factors. Depression, schizophrenia, and MS all manifest symptoms of activated immune response along with cognitive dysfunction, with TNF-α overexpression as a central clinical feature common to these disorders. Furthermore, TNF-α acts negatively on neuroplasticity and the molecular mechanisms of memory and learning (i.e., long-term potentiation and long-term depression). TNF-α also exerts influence over the production of neurotrophins (i.e., nerve growth factor and brain-derived neurotrophic factor), neurogenesis, and dendritic branching.Conclusions/significanceThis review outlines that TNF-α and its receptors have a substantial yet underappreciated influence on the development and progression of neuropsychiatric symptoms across several disease entities. An improved understanding of these underlying mechanisms may help develop novel therapeutic targets in the form of drugs specifically targeting downstream products of TNF-α activation within the central nervous system.

A meta-analysis of chemokines in major depression

Chemokines are increasingly recognised as playing a role in depression. Here we meta-analyse the data on concentrations of all chemokines in patients diagnosed with a major depression versus healthy controls. We included studies which utilised Diagnostic and Statistical Manual (DSM)-IV diagnostic criteria for major depression, participants free from major medical conditions, studies with healthy controls, and unstimulated measurements of chemokines. We only included chemokines which had ≥3 studies performed. Two chemokines and 15 studies in total met criteria for this meta-analysis; 8 for Monocyte Chemotactic Protein (MCP)-1/CCL2 (n=747), and 7 for Interleukin (IL)-8/CXCL8 (n=560). There were significantly higher concentrations of CCL2/MCP-1 in depressed subjects compared with control subjects - overall mean difference of 36.43pg/mL (95% CI: 2.43 to 70.42). There was significant heterogeneity across these studies (I2=98.5%). The estimates of mean difference between the control and depression groups did not remain significant when the trim-and-fill procedure was used to correct for publication bias. There was no significant difference in concentrations of IL-8/CXCL8 in depressed subjects compared with control subjects. Significant heterogeneity was found across these studies (I2=96.7%). The estimates of mean difference between the control and depression groups remained non-significant when the trim-and-fill procedure was used to correct for publication bias. This meta-analysis reports significantly heterogeneity in this field among studies. There are higher concentrations of the chemokine MCP-1/CCL2 in depressed subjects compared with control subjects, and no differences for IL-8/CXCL8. More high quality research and consistent methodologies are needed in this important area of enquiry.

A phase-specific neuroimmune model of clinical depression

Immune dysfunction and pro-inflammatory states in particular have been implicated in the aetiology and pathogenesis of depression. Whilst the onset of an episode and certain symptoms of depression appear well explained by this inflammatory model, the underpinnings of the episodic and progressive nature, as well as relapse and remission status in depression require attention. In this review it is suggested that additional immune factors beyond pro- and anti-inflammatory cytokines may effectively contribute to the understanding of the neurobiology of clinical depression. Considering neurobiological effects of immunomodulatory factors such as T cells, macrophages, microglia and astrocytes relevant to depression, we suggest a neuroimmune model of depression underpinned by dynamic immunomodulatory processes. This perspective paper then outlines a neuroimmune model of clinical phases of depression in an attempt to more adequately explain depression-like behaviours in pre-clinical models and the dynamic nature of depression in clinical populations. Finally, the implications for immunomodulatory treatments of depression are considered.

Altered resting-state functional connectivity in late-life depression: A cross-sectional study

BACKGROUND Disrupted brain connectivity is implicated in the pathophysiology of late-life depression (LLD). There are few studies in this area using resting-state functional magnetic resonance imaging (rs-fMRI). In this pilot case-control study, we compare rs-fMRI data between age-matched depressed and non-depressed older adults. METHODS Older participants (≥55 years) with current major depressive disorder (MDD) were recruited to participate in an ongoing study of LLD, and were compared to the age-matched, non-depressed controls. Rs-fMRI data were collected using a 3-Tesla MRI system. In this study, a data-driven approach was chosen and an independent component analysis (ICA) was performed. RESULTS Seventeen subjects with MDD were compared to 31 controls. The depressed group showed increased connectivity in three main networks compared to the controls (p(corr)<0.05), including connectivity between the default mode network (DMN) and the posterior superior temporal sulcus (pSTS). Increased connectivity was also observed within the visual network in the medial, lateral and ventral regions of the occipital lobes, and within the auditory network throughout the right superior temporal cortex. CONCLUSION This data-driven, pilot study finds patterns of increased connectivity that may be unique to LLD in the DMN, as well as visual and auditory networks. The functional implications of this aberrant connectivity remains to be determined. These findings should be further explored in larger samples.