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

Can autism be identified early using a simple smell test? Current Biology.July 2015.

08 07 2015

Early diagnosis of autism is important to maximise the benefit of  interventions. A test that does not involve lengthy observations or language & communication assessment could be really useful in early and easy identification of autism.  Autistic individuals  have impairments in sensory motor coordination. Defects in  Internal Action Models (IAM) are considered significant in this. The relationship between IAM and  social communication is still unclear.

Sniff response is an IAM important in olfaction. Sniff response  depends on large-scale connectivity between ventral temporal olfactory cortex where odor valence is processed.  It also depends on cerebellar circuits where the response is likely actuated. It is interesting to note that ventral temporal and cerebellar substrates of olfaction are the key neural substrates specifically implicated in ASD. 

Sniff response modulates the sniff magnitude automatically in relation to the odor valence. i.e. the automatic response is to take deep sniffs when exposed to nicer smells compared with bad ones. Would autistic children  show a different pattern? Could this be useful in early detection?

Liron Rozenkrantz et al from Weizmann Institute in Israel measured the sniff response in autistic children. Children were exposed to different odours and their sniff response were recorded using olfactometer and a special nasal cannula that delivered odors and measured the airflow. 18 autistic children and matched controls participated in this study.The procedure was completed in 10 minutes.


Normal children altered their sniff response  to account for odour properties. Autistic children did not show this ability to modulate sniff response.They also found that the differences in pleasant versus unpleasant sniff duration along with the sniff volume for unpleasant odours effectively distinguished TD from ASD children with 81% accuracy. Children with more severe autism showed  more aberrant sniffing i.e. longer sniff duration for unpleasant odors.They also found that aberrant sniffing correlated with social impairment scores and not  with motor impairments .

The study suggest that altered olfaction can be a novel early diagnostic test for Autism. Autistic children fail to modulate their sniff response according to the odour. It  has the specific advantage that this test is non verbal and non task dependent .

Limitations: It needs to be seen whether the  observed defects are specific for Autism or whether same defects are seen in other neuro developmental disorders.

Summary of the article

Mechanistic Link between Olfaction and Autism Spectrum Disorder.

Rozenkrantz L, Zachor D, Heller I, Plotkin A, Weissbrod A, Snitz K, Secundo L, Sobel N. Curr Biol. 2015 Jul. in Press.

Is cognitive function related to plasma ratio of Clozapine to N-Desmethylclozapine? AM J Psych.June,2015


Working memory is defective in patients with schizophrenia. Poor working memory is associated with poor functional outcome. Though muscarinic neurotransmission is postulated to play a significant role in this, improving cholinergic transmission do not seem to improve working memory. Large individual variability in cholinergic status is mentioned as an explanation. clozapine also show a range of effects on cognition ( improve, neutral, deleterious effect on cognition). Is this difference due to differential actions of clozapine and its metabolite,  N-des methyl clozapine (NDMC)?

Clozapine has antimuscarinic actions at M1,M3 and M5 while NDMC is a potent partial agonist at these sites. Plasma concentrations of NDMC can vary from 20% to 150% of clozapine concentrations. It is likely that the ratios clozapine and NDMC will have an effect on cholinergic tone and thus on cognition.

Tarek K. Rajj et al from Toronto explored the relationships between serum anticholinergic activity (SAA), clozapine concentration, NDMC concentration, and cognition. 30 adult patients with schizophrenia/ schizoaffective disorder on stable clozapine monotherapy  participated in this study.Cognition was assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB).


Working memory  was negatively correlated with clozapine/NDMC ratio. Working memory   was not correlated with age, gender, education, PANSS score, clozapine concentration, or NDMC concentration. SAA levels correlated with clozapine level but not with working memory.The association between clozapine/NDMC ratio and cognition is specific to working memory,

Limitations: This is cross sectional study. We do not know the baseline cognitive functioning of the participants. Duration of treatment with clozapine is another factor to consider,as benefits of clozapine may not be accrued if less than 6 months.

Comments: This opens several interesting clinical possibilities and precautions.  If we can inhibit the metabolism of NDMC, ( but not clozapine ) we can expect improvement in working memory. Patients with high clozapine /NDMC ratio would need special attention, they may have more working memory problems and can also experience  delirious states.

Summary of the article: 

Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine.

Rajji TK, Mulsant BH, Davies S, Kalache SM, Tsoutsoulas C, Pollock BG, Remington G.

Am J Psychiatry. 2015 Jun 1;172(6):579-85.

Do risk of dementia increase substantially when depression and diabetes occur together? JAMA Psych. June, 2015.

16 06 2015

Diabetes (DM) affects up to 14% of Western population. 25% of women and 16% of men will have  depression during their life time. Depression and diabetes  often co occur . The link between DM and depression is bidirectional. It is also known that both disorders contribute to an increased risk for vascular complications.

Depression and DM – both are  strong independent risk factors for dementia. DM increase risk for all cause dementia by 47%. Depression  doubles the subsequent risk for all-cause dementia. What about the combination of DM and depression?
Studies on patients with DM have shown that those who also have depression are at a high risk of dementia. Further clarity on this would be gained if large cohorts of individuals could be studied for risk for all-cause dementia among persons with DM, depression, or both compared with persons who had neither illness.

A Danish study ( by researchers from Seattle and Copenhagen) using national cohort of 2.4 million people has done just this.All living Danish citizens 50 years or older who were free of dementia at January 2007  were followed up until  December, 2013 .Danish psychiatric central register identified individuals with a diagnosis of depression or who have been prescribed with antidepressants. National diabetes register identified those diagnosed with DM .


19 % had a diagnosis of depression. 9 % received a diagnosis of DM, and 4%  had  comorbid depression and DM.The mean age at the initial diagnosis of DM was 63  years. Mean age  at the initial diagnosis of depression was 59  years. 2.4% developed  dementia, of this, 26% had depression alone,11% had DM alone, and 7%  had comorbid depression and DM.

Depression alone, contributed  83% greater risk of dementia. DM alone was associated with a 20% greater risk for all-cause dementia.  Depression and DM the risk was higher:  a 117% greater risk. This combined effect is more pronounced  in younger people. The combined effect of these two  illness exposures on all-cause dementia risk was larger than the sum of the 2 individual diseases.

One  limitation is  the lack of information on possible confounders such as health-risk behaviors ( smoking, obesity, and sedentary  lifestyle) .These can well be mediators of the association.

Comments: Depression alone is associated with the highest relative risk for all-cause dementia. Individuals with depression and DM need to consider engaging in neuro protective activities.  Physical activity is  increasingly well established as an effective strategy. It have  anti-inflammatory effects and it promotes  neurovascular health.

Summary of the article:

Effect of depression and diabetes mellitus on the risk for dementia: a national population-based cohort study.

Katon W, Pedersen HS, Ribe AR, Fenger-Grøn M, Davydow D, Waldorff FB, Vestergaard M.

JAMA Psychiatry. 2015 Jun 1;72(6):612-9