Rajeev Krishnadas

Depression: an inflammatory illness?

Major depressive disorder (MDD) is associated with significant morbidity and mortality. Findings from preclinical and clinical studies suggest that psychiatric illnesses, particularly MDD, are associated with inflammatory processes. While it is unlikely that MDD is a primary ‘inflammatory’ disorder, there is now evidence to suggest that inflammation may play a subtle role in the pathophysiology of MDD. Most of the evidence that links inflammation to MDD comes from three observations: (a) one-third of those with major depression show elevated peripheral inflammatory biomarkers, even in the absence of a medical illness; (b) inflammatory illnesses are associated with greater rates of MDD; and (c) patients treated with cytokines are at greater risk of developing major depressive illness. We now know that the brain is not an immune privileged organ. Inflammatory mediators have been found to affect various substrates thought to be important in the aetiopathogenesis of MDD, including altered monoamine and glutamate neurotransmission, glucocorticoid receptor resistance and adult hippocampal neurogenesis. At a higher level, inflammation is thought to affect brain signalling patterns, cognition and the production of a constellation of symptoms, termed ‘sickness behaviour’. Inflammation may therefore play a role in the aetiology of depression, at least in a ‘cohort’ of vulnerable individuals. Inflammation may not only act as a precipitating factor that pushes a person into depression but also a perpetuating factor that may pose an obstacle to recovery. More importantly, inflammatory markers may aid in the diagnosis and prediction of treatment response, leading to the possibility of tailored treatments, thereby allowing stratification of what remains a heterogenous disorder.

Localized connectivity in depression: A meta-analysis of resting state functional imaging studies

Resting-state fMRI studies investigating the pathophysiology of depression have identified prominent abnormalities in large-scale brain networks. However, it is unclear if localized dysfunction of specialized brain regions contribute to network-level abnormalities. We employed a meta-analytical procedure and reviewed studies conducted in China investigating changes in regional homogeneity (ReHo), a measure of localized intraregional connectivity, from resting-state fMRI in depression. Exploiting the statistical power gained from pooled analysis, we also investigated the effects of age, gender, illness duration and treatment on ReHo. The medial prefrontal cortex (MPFC) showed the most robust and reliable increase in ReHo in depression, with greater abnormality in medication-free patients with multiple episodes. Brain networks that relate to this region have been identified previously to show aberrant connectivity in depression, and we propose that the localized neuronal inefficiency of MPFC exists alongside wider network level disruptions involving this region.

Nicotine dependence and illness severity in schizophrenia

BACKGROUND Reasons for the increased prevalence of cigarette smoking in schizophrenia are unclear. Studies assessing clinical symptoms have sampled heterogeneous populations, with discrepant findings. AIMS To examine the relationship between clinical features, social adjustment and nicotine dependence in a geographically defined population of people with schizophrenia. METHOD Cross-sectional clinical study of 131 people with schizophrenia in Nithsdale, Scotland. RESULTS Smokers were younger, mostly males and three times more likely to be unemployed. Those with severe nicotine dependence had greater scores on the positive subscale of the Positive and Negative Syndrome Scale (PANSS), and were prescribed higher doses of antipsychotic. Those with mild-moderate dependence had greater scores on the PANSS negative subscale. Greater symptom severity was associated with poorer social adjustment. Psychopathology and social adjustment were similar in quitters and never-smokers. CONCLUSIONS Our findings indicate an association between nicotine dependence, clinical symptoms and social adjustment in schizophrenia. Although causal links cannot be inferred, identifying the relationship between nicotine dependence and psychopathology may have some value in the management of smoking in schizophrenia. Further longitudinal studies are required to explore this relationship.

Attitudes towards mental illness in Malawi: a cross-sectional survey.

BackgroundStigma and discrimination associated with mental illness are strongly linked to suffering, disability and poverty. In order to protect the rights of those with mental disorders and to sensitively develop services, it is vital to gain a more accurate understanding of the frequency and nature of stigma against people with mental illness. Little research about this issue has been conducted in Sub- Saharan Africa. Our study aimed to describe levels of stigma in Malawi.MethodsA cross-sectional survey of patients and carers attending mental health and non-mental health related clinics in a general hospital in Blantyre, Malawi. Participants were interviewed using an adapted version of the questionnaire developed for the “World Psychiatric Association Program to Reduce Stigma and Discrimination Because of Schizophrenia”.Results210 participants participated in our study. Most attributed mental disorder to alcohol and illicit drug abuse (95.7%). This was closely followed by brain disease (92.8%), spirit possession (82.8%) and psychological trauma (76.1%). There were some associations found between demographic variables and single question responses, however no consistent trends were observed in stigmatising beliefs. These results should be interpreted with caution and in the context of existing research. Contrary to the international literature, having direct personal experience of mental illness seemed to have no positive effect on stigmatising beliefs in our sample.ConclusionsOur study contributes to an emerging picture that individuals in Sub-Saharan Africa most commonly attribute mental illness to alcohol/ illicit drug use and spirit possession. Our work adds weight to the argument that stigma towards mental illness is an important global health and human rights issue.

Relationship of cognitive function in patients with schizophrenia in remission to disability: a cross-sectional study in an Indian sample.

BackgroundCognitive deficits in various domains have been consistently replicated in patients with schizophrenia. Most studies looking at the relationship between cognitive dysfunction and functional disability are from developed countries. Studies from developing countries are few. The purpose of the present study was to compare the neurocognitive function in patients with schizophrenia who were in remission with that of normal controls and to determine if there is a relationship between measures of cognition and functional disability.MethodsThis study was conducted in the Psychiatric Unit of a General Hospital in Mumbai, India. Cognitive function in 25 patients with schizophrenia in remission was compared to 25 normal controls. Remission was confirmed using the brief psychiatric rating scale (BPRS) and scale for the assessment of negative symptoms (SANS). Subjects were administered a battery of cognitive tests covering aspects of memory, executive function and attention. The results obtained were compared between the groups. Correlation analysis was used to look for relationship between illness factors, cognitive function and disability measured using the Indian disability evaluation and assessment scale.ResultsPatients with schizophrenia showed significant deficits on tests of attention, concentration, verbal and visual memory and tests of frontal lobe/executive function. They fared worse on almost all the tests administered compared to normal controls. No relationship was found between age, duration of illness, number of years of education and cognitive function. In addition, we did not find a statistically significant relationship between cognitive function and scores on the disability scale.ConclusionThe data suggests that persistent cognitive deficits are seen in patients with schizophrenia under remission. The cognitive deficits were not associated with symptomatology and functional disability. It is possible that various factors such as employment and family support reduce disability due to schizophrenia in developing countries like India. Further studies from developing countries are required to explore the relationship between cognitive deficits, functional outcome and the role of socio-cultural variables as protective factors.

Socioeconomic deprivation and cortical morphology: psychological, social, and biological determinants of ill health study.

Objective Neighborhood-level socioeconomic deprivation has been associated with poor cognitive function pertaining to language and the executive control. Few studies have explored the cortical morphology of regions most commonly associated with these functions. The aim of this study was to examine the association between neighborhood-level deprivation and the morphology of cortical regions associated with language and executive control in adults. Methods Using a cross-sectional study design, we compared the cortical morphology of 42 neurologically healthy adult men from the least deprived and most deprived neighborhoods of Glasgow. We performed surface-based morphometry on 3-T structural magnetic resonance imaging (MRI) images to extract the cortical morphology—volume, thickness (CT), and surface area (SA) of regions commonly associated with language and executive control. Cortical morphology was compared between the two groups. We used mediation analysis to examine whether cardiometabolic risk factors mediated the relationship between deprivation status and cortical morphology. Results Intracranial volume and mean total CT did not differ between groups. The deprived group had significantly smaller left posterior parietal cortex SA (Cohen d = 0.89) and fusiform cortex SA (Cohen d = 1.05). They also had thinner left Wernicke’s area (Cohen d =0.93) and its right homologue (Cohen d = 1.12). Among the cardiometabolic markers, a composite factor comprising inflammatory markers mediated the relationship between deprivation status and Wernicke’s area CT. Conclusions A group of neurologically healthy men from deprived neighborhoods showed significantly smaller cortical morphology—both SA and CT—in regions of the brain pertaining to language and executive function. We provide additional evidence of a relationship between socioeconomic deprivation and cortical morphology.

Tardive dyskinesia and deficit schizophrenia.

Telfer S, Shivashankar S, Krishnadas R, McCreadie RG, Kirkpatrick B. Tardive dyskinesia and deficit schizophrenia.

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans

Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression.

Socioeconomic Status and the Cerebellar Grey Matter Volume. Data from a Well-Characterised Population Sample

The cerebellum is highly sensitive to adverse environmental factors throughout the life span. Socioeconomic deprivation has been associated with greater inflammatory and cardiometabolic risk, and poor neurocognitive function. Given the increasing awareness of the association between early-life adversities on cerebellar structure, we aimed to explore the relationship between early life (ESES) and current socioeconomic status (CSES) and cerebellar volume. T1-weighted MRI was used to create models of cerebellar grey matter volumes in 42 adult neurologically healthy males selected from the Psychological, Social and Biological Determinants of Ill Health study. The relationship between potential risk factors, including ESES, CSES and cerebellar grey matter volumes were examined using multiple regression techniques. We also examined if greater multisystem physiological risk index—derived from inflammatory and cardiometabolic risk markers—mediated the relationship between socioeconomic status (SES) and cerebellar grey matter volume. Both ESES and CSES explained the greatest variance in cerebellar grey matter volume, with age and alcohol use as a covariate in the model. Low CSES explained additional significant variance to low ESES on grey matter decrease. The multisystem physiological risk index mediated the relationship between both early life and current SES and grey matter volume in cerebellum. In a randomly selected sample of neurologically healthy males, poorer socioeconomic status was associated with a smaller cerebellar volume. Early and current socioeconomic status and the multisystem physiological risk index also apparently influence cerebellar volume. These findings provide data on the relationship between socioeconomic deprivation and a brain region highly sensitive to environmental factors.

Possible rheumatoid arthritis subtypes in terms of rheumatoid factor, depression, diagnostic delay and emotional expression: an exploratory case-control study

IntroductionDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathology of rheumatoid arthritis (RA), particularly as vulnerable personality types are exposed to chronic stress. Emotions are powerful modulators of stress responses. However, little is known about whether patients with RA process emotions differently to matched controls. In this study we: 1) assessed whether the trait emotional intelligence (trait EI) scores of patients with RA differ from healthy controls at the facet level; 2) explored any subgroups in RA, in terms of trait EI and common risk factors.MethodsA total of 637 patients with RA were compared to 496 controls on the trait EI Questionnaire (TEIQue). RA subgroups were explored in terms of trait EI, rheumatoid factor status (RF+/-), depression and time from onset of symptoms until diagnosis (diagnostic delay).ResultsThe RA group rated themselves lower on Adaptability, Stress-management, Emotion management, Self-esteem, Sociability, Assertiveness, Impulsiveness and Well-being, and higher on Empathy and Relationships than healthy controls. The RF- subtype reported more time with depression (25.2 vs. 11.3 months), a longer diagnostic delay (3.0 vs. 1.7 years), and greater emotional expression (5.15 vs. 4.72), than the RF+ subtype. These differences were significant at the P <0.05 level, but not following strict Bonferroni corrections and should therefore be treated as indicative only. RF- patients with a longer diagnostic delay reported depression lasting three times longer (42.7 months), when compared to three other subtypes (11.0 to 12.7 months).ConclusionsRA patients and controls differ in their emotion-related personality traits, as operationalized by trait EI. These differences may make people with RA more susceptible to chronic stress and HPA-axis dysregulation. RA may be a highly heterogeneous illness where at least two subtypes may be characterized by personality, psychiatric and immunological differences. RF- status, as well as diagnostic delay and emotional expression, may predict future risk of depression. Research on the causes of RA could benefit from a systems science approach.