Neuro inflammation and psychosis: new evidence


Patho-etiology of psychosis is not well understood. Neuro inflammation is one possibility. Studies have suggested that microglia, the immune cells of  the CNS, are involved. Pro inflammatory cytokines ( peripheral markers) are elevated in psychosis. Grey matter volume reductions are seen parallel to such elevations.These changes are seen in both schizophrenia and in ultra high risk groups.

Can we measure the microglial activity in the brain ? PET imaging using radioligands specific for a protein  (18kD translocator-protein (TSPO)) which is expressed on microglia is one possibility. This method of enquiry has shown increased microglial activity in individuals with schizophrenia. Severe symptoms of schizophrenia is often proceeded by a prodromal phase of attenuated symptoms. One third of individuals who meet high risk criteria develop psychosis within 2 yr follow up period. Would Ultra High Risk individuals also show  elevated microglial activity ?

Peter Bloomfield and team from Imperial College London studied this in 58 subjects. This included 14 ultrahigh risk patients & 14 controls, 14 schizophrenia patients & their  14 controls.Ultra-high-risk individuals were assessed with the Comprehensive Assessment of the At-Risk Mental States. All subjects underwent MRI and PET study.


There were no demographic differences between different groups. The binding ratio of the ligand [11C]PBR2 was elevated in Ultra high risk group and schizophrenia group.The elevation in ultra high risk group was specific to the subclinical psychotic symptoms. These high risk individuals were not on any medications and were new to services, we could assume that the observed changes are not due to medications or  previous illness. During the study, one participant developed  psychosis and this patient had the highest binding of ligand.

This study show that elevated microglial activity predates diagnosable , frank psychosis.

Limitations: Researchers used a relative quantification method ( ie binding expressed as ratio of binding in cortical grey matter to whole brain) and it is not clear whether high binding ratio is due to higher TSPO expression in cortical grey matter or lower expression elsewhere. We do not now know the predictive power of such high binding . i.e. does high binding mean more transition to florid psychosis? The association of high bidding ratio with high prodromal symptom severity observed in this study point to the higher chance of tradition with high binding.

It is unclear whether the   18kD translocator-protein (TSPO)  activity expressed by microglia is a protective mechanism triggered by disease process or it is a primary neuro inflammatory process linked to risk factors for psychosis and the development of subclinical symptoms.

The observation that anti inflammatory medications may reduce negative symptoms (for example: Minocycline reduce symptoms early in illness) and that some antipsychotics possess some degree of anti-inflammatory activity add to to the idea that  neuro inflammatory process is involved in psychosis.


Neuro inflammation is emerging as a consistent finding in psychosis. It needs to be seen how microglial activity changes over the time when individual’s mental state /diagnosis changes.

Summary of the article

Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study. Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, Bloomfield MA, Bonoldi I, Kalk N, Turkheimer F, McGuire P, de Paola V, Howes OD.Am J Psychiatry. 2016 Jan 1;173(1):44-52.

Can anxiety damage your heart?


Mind and Heart work in an interconnected way, perhaps more than between any other organs . Allgulander reviews the relationship between anxiety and cardiac heath in this article

Anxiety is a risk  factor for cardiac morbidity. A large scale study ( with 52 095 participants in 19 countries) reported in 2013 that after adjusting for comorbidity,  diagnoses of depression,panic disorder, specific phobia, posttraumaticstress disorder, and alcohol use disorders were associated with heart disease onset [odds ratios(ORs) 1.3–1.6]. (Scott et al 2013 ).  Associations with anxiety were greater in magnitude than those with depression.

A swedish military conscript study showed that anxiety state at age 18- 20 increased the risk of MI at follow up ( average 37 years) by more than 2 fold (Janzsky ,2008). A Taiawanse study found that nearly 5% of those with panic disorder were to develop MI in the next year ( compared to control rate of nearly 3%).

Prospective studies have shown that individuals with cardiac disorders do worse when they also suffer from anxiety.

What about acute physiological changes related to anxiety?

Takotsubo cardiomyopathy ( ‘broken heart’ syndrome) was first reported in Japan. Takotsubo is a trap used to catch octopus and  has a narrow neck and a round bottom. Left ventricle temporarily become weak and its shape changes. Majority of people with this ‘heart attack’ have experienced emotional stress. The condition is temporary and reversible. Left ventricle will return to normal shape in days/weeks. Pre existing  anxiety and depression are reported more often among sufferers.

White coat hypertension is tother condition to be considered here. Reports suggest that this may not be benign, i.e. it is associated with other pathological changes.It may have a social anxiety component , but there are no studies to delineate different contributors.

Exposure to both acute and chronic mental stress is associated with an increased incidence of adverse cardiac events. Imminent missile attacks, natural disasters, football match days, start of working week especially after holidays – all are shown to  increase cardiac events. Mental stress induced myocardial schema (MSMI) is an important current area of research.Mental stress triggers transient myocardial ischaemia in 30–70% of patients withpre-existing CAD. A 2014 metaanalysis (Wei et al 2014) showed that MSIMI was associated with a twofold increased risk of a combined end point of cardiac events or total mortality.


Anxiety is a risk factor for cardiac morbidity. Anxiety adversely affects cardiac patients. Recognition and treatment of anxiety is important in improving the outcomes in cardiac disorders.

Summary of the article :

Anxiety as a risk factor in cardiovascular disease. Allgulander C.

Curr Opin Psychiatry. 2016 Jan;29(1):13-17.

Can anxiety damage human brain? Current Opinion Psy.Jan.2016


Occasional and temporary anxiety is a normal part of life.It helps to direct our attentional resources to pertinent information in the environment and mobilise appropriate behaviour in response.Persistent or excessive anxiety is pathological. Would such anxiety cause any deleterious effects on brain? Linda Mah and colleagues ( Canada) review the present evidence to answer this question.

Amygdala is key in threat detection.Prefrontal cortex play crucial role in threat appraisal. Hippocampus helps to build the contextual sense of the event. Balanced activities in these systems result in emotional regulation.

In anxiety disorders, detection threshold is low, amygdala become hyperactive and  PFC control over amygdala is poor.Hippocampus fails to discriminate between threat and safety cues (impaired discriminative conditioning) and this lead to  overgeneralisation of fear stimulus.

It is well known that anxiety is a risk factor for disorders like depression.Significant psychosocial stress in middle age is shown to increase the risk for developing Alzheimer’s disease 20 years later.Presence of anxiety among those with Mild cognitive impairment can also increase the risk of conversion to dementia.

Anxiety increase glucocorticoids and this lead to hippocampal atrophy and diminished neurogenesis. This may explain the cognitive dysfunctions associated with anxiety. Persistent anxiety can cause loss of dendrites and spines in Pre frontal cortex.

Stress-induced damage to the hippocampus and PFC is not completely irreversible. Antidepressants ( desipramine, SSRI) and Lithium as well as CBT  can restore some of the above brain changes.There is a range of evidence ( mostly animal studies) to support this idea.


Pathological anxiety can cause  damages  (structural and functional) to brain. Interventions can mitigate these changes. It is not known whether anxiety interventions can reduce the risk of developing neuropsychiatric conditions (dementia/depression).

Summary of the article

Can anxiety damage the brain? Mah L, Szabuniewicz C, Fiocco AJ. Curr Opin Psychiatry. 2016 Jan;29(1):56-63.PMID: 26651008


Is inflammation the key factor in psychosis? AJP: Ahead of print: Oct, 2015.


Patho etiology of schizophrenia is not understood to any sufficient degree. Neuro inflammation is one of the  theories that is gaining momentum. Role of microglia in schizophrenia is supported by some evidence. Direct and indirect evidence for microglial activation ( PET studies, postmortem studies) is gradually emerging.

van Berckel BN et al in 2008 reported the first PET study showing elevated microglial activity in psychosis.Studies so far were done on patients who already have the disorder. What about those at higher risk for psychosis? We already know that , more than one third of individuals in high risk category would develop psychosis in near future.

Would inflammation be more marked  in ultra high risk for psychosis  individuals as compared to control? Peter S. Bloomfield ( imperial college, London) and team of researchers  addressed this key question.

56 individuals ( from London) participated in this study. 14 met criteria for ultra high risk. 14 age matched control individuals and 14 patients with schizophrenia were also studied. Ultra-high-risk individuals were assessed with the Comprehensive Assessment of the At-Risk Mental States. All participants underwent Brain MRI and PECT imaging.


Distribution volume ratios  of the ligand (= elevated microglial activity) was significantly high  ultra-high-risk individuals when compared with matched comparison subject. This was seen in total gray matter and frontal lobe and temporal lobe gray matter. More symptom score ( in ultra high risk group) meant that they have more microglial activation in grey matter (total). The effect observed is large ( Cohen’s d > 1.2). Microglial activity did not correlate with depressive symptoms , suggesting that it is specific to psychosis. Ultra high risk individuals were not on medications and the effect cannot be attributed to previous illness or treatment. The study also show that  microglial activity is elevated in  people with schizophrenia relative to comparison subjects, with a large effect size (Cohen’s d .1.7).

This is the first evidence  of  elevated brain microglial activity in people at ultra high risk of psychosis. It also show that greater microglial activity is associated with greater symptom severity.


Relatively small study. It is not known whether such changes persist over time.


There has been interest in anti-inflammatory agents as beneficial agents in psychotic disorders. The question here is: Would control of inflammatory activity in high risk stage prevent the onset of psychosis? It would also be interesting to see whether general anti inflammatory drugs or  target specific agents are required to test this hypothesis.

Summary of the article 

Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study.Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, Bloomfield MA, Bonoldi I, Kalk N, Turkheimer F, McGuire P, de Paola V, Howes OD. Am J Psychiatry. 2015 Oct 16:appiajp201514101358. [Epub ahead of print]

Can depressive symptoms increase risk of mortality ? Psychol Med.Oct.2015


Depressive disorder is well known to be associated with increased mortality. Few previous studies have shown that presence of depressive symptoms ( not meeting the threshold for diagnosis of depression) is associated with increased mortality.

White and colleagues from UK looked at the association of mortality with depressive symptoms across full range of severity. ELSA (English longitudinal study of ageing) is on ongoing longitudinal ,prospective cohort study started in 2002. This is a nationally representative sample of participants with age 50 or more . Participants were interviewed to assess depressive symptoms on the 8 item CES-D ( Centre for Epidemiological Studies) scale. Social ( e.g.socio economic class) , life style ( e.g. physical activity), clinical  ( e.g. all physical health disorders ) and demographic information were also available. Mortality data for 9 year period was used to study the association.


60% of people reported at least one depressive symptom.People reporting a greater severity of depressive symptoms were more likely to be female, older, non-white, have lower wealth,live alone, have impaired physical functioning, a smoker,hardly ever engage in physical activity, use antidepressants, and report a doctor-diagnosed health condition than those with lower scores. 20% died during the 9 yr period.

Relative to study members with no symptoms, an increased risk of mortality was found in people with depressive symptoms. Socio economic position, physical disorders, heath behaviours, functional impairements- all contributed to the observed association between depressive symptoms and mortality. Physical activity and functional impairments alone accounted for 73% of the depressive symptom mortality association.

It can be that depressive symptoms lead to inactivity and functional impairment and this lead to increased mortality ( = Meditational Association) . It is also possible that inactivity and functional impairments lead to depressive symptoms as well as increased mortality ( = Confounding Assn). The third possibility is depressive symptoms exerting a direct physiological effect ( e.g. immune mediated)  that increase mortality (= direct effect).

Limitations: CES-D  cannot generate diagnosis of depression. The tool ask  for the presence of depressive symptoms for one week only.

Conclusions: The study shows that there is an association between depressive symptoms and mortality. This association exist across all severity range.

Comments: Depressive symptoms are clinically important indicator of increased mortality. Clinical  and social factors may explain the links. Clinicians need to look at any depressive symptoms closely to identify potential, modifiable factors and offer interventions.

Summary of the article:

Severity of depressive symptoms as a predictor of mortality: the English longitudinal study of ageing.

White J, Zaninotto P, Walters K, Kivimäki M, Demakakos P, Shankar A, Kumari M, Gallacher J, Batty GD.

Psychol Med. 2015 Oct;45(13):2771-9.

Is experience of being bullied in childhood associated with midlife obesity?


Stressful experiences influence how one’s immune and metabolic systems function. Stress and  maltreatment in childhood lead to persistent changes in  immune and inflammatory systems  can lead to adult disorders ( physical and psychological).Evidence show that maltreated children grow up to have higher inflammatory proteins and higher risk of obesity. Understanding the role of childhood stressors are key in preventing many adult disorders.

Bullying is a  common stressor  in childhood. Bullying occurs in the context of power imbalance.Victims show higher levels of anxiety ,depression, self harming  behaviour and even psychotic symptoms. Victim’s cognitive and socio economic outcomes are also negatively affected.

R. Takizawa, A. Danese1, B. Maughan and L. Arseneault ( from UK and Japan) explored whether being bullied in childhood increase the risk of midlife inflammation and adiposity.


They used a 50 yr  prospective British cohort ( national child development study 1958)  to examine this relationship.Exposure to bullying was assessed via parental interviews when participants were 7 and 11 yrs. 28% of children had been exposed to occasional bullying with 15% bullied frequently. Inflammatory markers and BMI were assessed at age 45.

Childhood BMI, IQ, childhood adversity and  adult life style factors ( e.g. smoking) were likely to confound the relationship and hence such data were also collected.


Individuals who had been frequently bullied in childhood showed higher levels of inflammation  ( CRP levels) at mid-life than non-bullied participants.

Individuals (both men and women)  who had been bullied in childhood showed greater waist:hip ratio at mid-life than non bullied individuals.

Those who were bullied  had lower birth weight and BMI at age 7 years than those who had not been bullied.  They also had lower IQ scores; and they experienced greater socio-economic disadvantage as they were growing up.

Those bullied in childhood were in lower social class occupations  and showed higher rates of affective disorders than their non-bullied peers

Bullying in childhood was still associated with higher CRP levels in middle age after adjusting for the  confounders.   Higher obesity and BMI in women who were bullied also remained significant after such adjustments.


Those who experienced bullying  in childhood  have higher inflammation levels than non-bullied peers.

Women who had been bullied are more likely to be obese decades later.


This study adds to the growing literature on the role of childhood adversity on adult outcomes.The study strengthen our understanding of biological routes through which psychosocial adversity exerts its toxic influence. This also ask a serious question: Are we doing enough to prevent bullying in schools and homes? 

Summary of the article:

Bullying victimization in childhood predicts inflammation and obesity at mid-life: a five-decade birth cohort study. Takizawa R, Danese A, Maughan B, Arseneault L. Psychol Med. 2015 Oct;45(13):2705-15

Can ‘green walks’ reduce the urbanisation related risk for mental disorders? PNAS.July.2015


Increasing urbanisation is considered to be contributing to the aetiology of mental disorders. Our species is moving away from natural environments in an unprecedented way, that too in a short period of time. Proximity to green space is demonstrated to have positive effect on health. Even ‘window views’ of natural elements can atleast temporarily boost memory and attention and provide better impulse control. Urban green spaces also provide such positive effects.

Nature experience repeatedly show positive effect on many functions of our minds. The next question is:  How does that work?

One theory is about rumination which may either create a vulnerability  for mental disorders or generate mental dysfunction directly. Rumination is a self referential thought and is demonstrated to be associated  with negative effect on mental health. The increased attentional focus on negative ideas is maladaptive.  The area in the brain associated with rumination is subgenual prefrontal cortex (sgPFC).

Is it that nature exposure/ experience  make us less self focused? ( like being ‘lost in nature’ around us)?  Would nature experience   reduce rumination and thus improve mental functioning?

Gregory N. Bratmana, J. Paul Hamiltonb, Kevin S. Hahnc, Gretchen C. Dailyd, and James J. Grossc   from Stanford University did an interesting piece of work to answer this question.

38 healthy urban residents with no mental disorders  participated in this study. Baseline rumination measure was collected using  Rumination Questionnaire (RRQ).Regional blood flow was studied using arterial spin labelling (ASL). After baseline measures, each participant was randomly assigned to a 90-min walk in either a natural environment (19 participants) or urban environment (19 participants). After the walk, each participant returned to the laboratory and provided a second, follow-up self-report of levels of rumination  and underwent a second resting-state ASL scan.


Self reported rumination decreased significantly in nature walk group. Perfusion study show that neural activity in the selected brain area was decreased  in nature walk group . This study show that nature experience reduce both rumination and  sgPFC activation.

It is interesting to note that researchers found changes in activity in perigenual anterior cingulate cortex (pACC) also. This area is considered to have increased reactivity during social information processing in individuals born in urban areas. We already know that risk of psychosis is high with urban birth.   


Being in natural environments perhaps bring a sense of belonging  and a state of being one with surroundings which is hard-wired in us. What ever be the mechanisms, it adds to the strength of the idea that we need more green spaces in growing cities. Perhaps all facilities where people are recovering should have green spaces.

The authors argue that  policies that aim to increase the ‘ mental capital’  of our cities would help to  reduce population level mental dysfunctions.

Summary of the article:

Nature experience reduces rumination and subgenual prefrontal cortex activation.

Bratman GN, Hamilton JP, Hahn KS, Daily GC, Gross JJ. Proc Natl Acad Sci U S A. 2015 Jun 29