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

Do brain cortical thickness differ according to income ? Psychological Science.June, 2015

15 06 2015

Educational achievement is highly correlated with socio economic status. The difference in academic achievement between students from higher and lower income groups  (income achievement gap) is increasing in many countries. There are various ( social, psychological, biological) reasons for this. Are there neuroanatomical differences between higher and lower income children ? Do these differences explain the income achievement gap?

Allyson P. Mackey and team of researchers from USA related cortical structure parameters ( cortical grey and white matter volumes, cortical surface area)  to family income and performance on standardized tests of academic skills. Eligibility for free/ reduced price lunch at school was the criterion for classifying as poor SES. Participants, 58 school children ( 15 yrs age on average) participated in this study. They completed Massachusetts Comprehensive Assessment System (MCAS) for academic performance measure.All underwent MRI to measure the cortical parameters.


Academic performance scores were significantly lower in lower income group.Cortical gray-matter volume was significantly greater in the higher-income group than in the lower-income group. Cortical thickness in all lobes of the brain was greater in students from higher-income than lower-income backgrounds. Greater cortical thickness, particularly in temporal and occipital lobes, was associated with better test performance. Cortical white-matter volume and total cortical surface area did not differ significantly between groups.

It is possible that these differences are due to less gray-matter formation early in development  or could be due to accelerated thinning. Higher levels of stress and less enrichment in the environment may have influenced brain development.

It needs to be highlighted that a thicker cortex is not inherently better. relationship between cortical thickness and cognitive performance is still unclear. Educational interventions in lower income children have proven to enhance performance as well as neural connectivity.

comments: It is well established that income and SES play a crucial role in academic achievement. Growing body of research indicate that brain suffer from inequality and poverty in many different ways.

Summary of the article:

Neuroanatomical correlates of the income-achievement gap. Mackey AP, Finn AS, Leonard JA, Jacoby-Senghor DS, West MR, Gabrieli CF, Gabrieli JD. Psychol Sci. 2015 Jun;26(6):925-33

Is inhalation antipsychotic safe and useful? Annals Gen psych. 2015.April.


Controlling acute agitation early on is important to avoid serious and harmful consequences. Oral and IM medications are the main pharmacological routes available now to achieve this. Inhalation route is another possibility opened with the licensing of the first inhalation antipsychotic medication.

Loxapine is a typical antipsychotic in use since 1970’s. It is  widely used in France and Canada. Inhalation form is approved  ( US & EU) for acute treatment of agitation in adults with schizophrenia / bipolar disorder. Maximum plasma concentration is achieved in approximately 2 minutes. Half-life for the 5- and 10-mg doses is approximately 6 hours.

Dina Popovic, Philippe Nuss and Eduard Vieta review efficacy and safety of  loxapine in this article.

Loxapine is structurally similar to clozapine. It has actions on D2 as well as 5 HT 2A receptors. It has atypical characteristics. A 2007 Cochrane review showed that loxapine  ( oral) is as effective as other typical and atypical antipsychotics. As expected,  EPS is the main side effect of medications like loxapine. There have been no trials assessing the efficacy of the oral or intramuscular formulation of loxapine in acute treatment of manic episode, but is still widely prescribed in the treatment of mania.

Effect on  acute agitation ( inhalation loxapine)

In two phase III studies (one in subjects with schizophrenia, the other in subjects with bipolar disorder) inhaled loxapine doses of 5 and 10 mg were both superior to placebo 10 min after administration. Pooled data suggest  that NNT  is  comparable to that observed for intramuscular administration of other antipsychotics.

Interestingly,  no clinically relevant extrapyramidal side effects or akathisia have emerged following administration of loxapine 10 mg or 5 mg. There is no apparent QT prolongation . Most common adverse event was short-term dysgeusia.

 Active airways disease (asthma and chronic obstructive pulmonary disease)  is a contraindication due to the risk of bronchospasm .

Limitations:  Data sets available are small .  The inhaler is single use only . The recommended use of  10 mg administration ( only a single dose  in 24 hrs) raises the issue of further medication choices if agitation is not controlled. Screening for chest conditions  ( including auscultation ) may be difficult when patients are agitated. 

Comments: If  the favourable side effects profile is established in large data sets, loxapine inhalation may be a preferred  option in early stages of agitation in cooperative patients.  This is particularly the case as ECG is  recommended/ required before administering  haloperidol, which is   commonly used to control agitation.

 Summary of the article:

Revisiting loxapine: a systematic review. Popovic D, Nuss P, Vieta E. Ann Gen Psychiatry. 2015 Apr 1;14:15. doi: 10.1186/s12991-015-0053-3

Do antipsychotics differ in weight gain during first episode treatment? Early Inter Psy.2015.Epub, June, 2015


Obesity contributes significantly to poor cardiac health among individuals with psychosis. Cardiovascular risk doubles in first year of treatment with antipsychotics.  Antipsychotics (AP) contribute heavily to this weight gain. Prevention of rapid weight gain during the early period of psychosis should be a major aim.

Meta analysis suggest that anti histaminic antipsychotics (clozapine, olanazapine, chlorpromazine, quetiapine) and 5HT2C blockers ( risperidone, paliperidone) are more likely to cause weight gain compared to pure D2 blockers like haloperidol. Contributing factors/ mechanisms involved in weight gain chronic schizophrenia while on AP may be different  from first episode cases.

Tel C et al conducted a meta-analysis of all AP studies in first- episode patients looking at weight changes during  short-term (≤12 weeks) and long-term (>12 weeks) treatment. Studies on first episode psychosis patients ( minimum age of 15, less than 16 weeks AP treatment in life time or AP naive at entry, treatment provided in OP settings) were included. Short term AP treatment was defined as less than 12 weeks, long term was defined as  13-52 weeks. Since there is no placebo controlled study in first episode patients, study sample with prodromal patients were used to calculate placebo controlled group outcomes.


From 3059 studies identifies initially, 28 studies that met all inclusion criteria were analysed.  Majority (22) of these were open label studies.

Mean weight gain difference was 3.22 kg in AP group compared to placebo.  The mean weight difference was significantly higher in Western countries (4.17 kg, CI = 3.38–4.96) than in Asian countries (1.36 kg, CI = −0.25 to 2.99).

Long term effect on weight : 5.30 kg  mean gain difference  between AP medications and placebo ( CI = 2.87–7.74, P < 0.001)

Olanzapine (n = 6, 9.34 kg (CI = 5.55– 13.12), P < 0.001) and clozapine (n = 2, 7.19 kg (CI = 0.28–14.09), P = 0.041) were the interventions associated with the highest weight gain compared to placebo. The only one intervention with perphenazine reported weight loss (−0.41 kg)

Ziprasidone maintains weight benefit effect in first episode samples. (This is already shown in chronic schizophrenia samples). This might be down to  noradrenaline re uptake blocking effects. Individual risk even with  Ziprasidone is not negligible. Ziprasidone registration studies showed that 7-16% participants gained significant weight. Olanzapine and  Clozapine consistently show increase in weight irrespective of stage of illness.

Haloperidol, unlike in studies of chronic schizophrenia patients, was associated with both short- and long-term weight gains in this analysis. Aripiprazole’s advantage shown in previous studies was not observed in this. Long term studies of aripiprazole on weight are lacking.

There seems to be no advantage in selecting Olanzapine as first or second agent in first episode patients, though studies still show that this medication continue to be  the commonly used antipsychotic.

Medication studies need to ensure that baseline weight, BMI and percentage increase  as well as dose -weight relationship are reported  routinely.

Comment: Weight gain need to be monitored closely and choice of AP should consider this effect. This is more so important during early stage of AP treatment.

Summary of article:

Antipsychotic-induced weight gain in first-episode psychosis patients: a meta-analysis of differential effects ofantipsychotic medications.

Tek C, Kucukgoncu S, Guloksuz S, Woods SW, Srihari VH, Annamalai A.

Early Interv Psychiatry. 2015 May 12. doi: 10.1111/eip.12251. [Epub ahead of print]