Do childhood trauma lead to early detectable changes in BDNF and cytokines? Act Psy.May.2015

27 05 2015

Childhood trauma contribute enormously to mental health problems in the society. Understanding the brain /psychological mechanisms  mediating such effects are  crucial to help us develop interventions.  Low BDNF levels are associated with childhood trauma among adults with  mental disorders. It is also noted that trauma interact with BDNF val66 met polymorphism,  where met allele carriers  are at higher risk. Another pathway to consider is cytokines, where  trauma might be activating and maintaining  elevated levels of inflammatory cytokines.

Adults with a history of childhood trauma and psychiatric disorders show decrease in BDNF  and  increase in cytokines levels. A history of childhood trauma may set in changes in immune system functioning i.e.  leading to a permanent chronic inflammatory state . Lower BDNF expression in adulthood is related to poorer cognitive performance smaller hippocampal volumes , and increased psychiatric comorbidity . 

Do trauma lead to early detectable changes  in BDNF and cytokines?  Bucker J et al  report the results of a study asking this question.

Children who experienced  early trauma ( i.e.  trauma before age 4) were recruited from a foster home and child protection programme in South Brazil. They were between the ages of 3 and 12. A matching control group was also recruited. A structured interview identified psychiatric diagnosis (  in accordance with DSM-IV criteria (K-SADS-E)). Socio demographic variables as well  as trauma history were collected in detail. BDNF plasma levels were measured by ELISA. Concentration of plasma cytokines were determined by flow cytometry.

There were 36 children with trauma and 26 children without trauma. Both groups were comparable in age gender, IQ and education years. Trauma groups BMI was higher. Half of the children in trauma group  had been exposed to more than one type of trauma. 20% reported sexual abuse. 75% of trauma group had subsyndromal psychiatric symptoms.

Results

Trauma group showed significant high levels of BDNF and TNF Alpha, when controlled for previous infection status. This is in contrast to the finding of lower BDNF in adults  who experienced child hood trauma. This may be a compensatory mechanism that is activated in response to trauma. It is  possible that it may reflect the resilience mechanims,  given that the children are away from traumatic environment and that they currently do to have any psychiatric diagnosis. To check whether being in a safer environment was the reason for higher BDNF, authors checked  the relationship between the ‘ time since trauma cessation’  and BDNF levels . No relationship was observed between these two.

The small sample size means that study lacks  statistical power  for subanalyses.  Absence of a specific instrument to quantify aspects such as the severity and intensity of trauma is another limitation.  The control group can be described as  ‘supernormal’  due to the fact that they included only children without psychiatric symptoms.

Conclusions:

Trauma during childhood  sets in motion biological changes that are detectable early on. Observed changes indicate effect on neural plasticity and inflammation. Changes observed in children ( in case of BDNF) are different from that in adults. Further research is needed to see  why some of those exposed to trauma show better outcomes than others, and to determine  vulnerability/ safety ‘windows’  in relation to age of trauma.

Summary of the article:

Brain-derived neurotrophic factor and inflammatory markers in school-aged children with early trauma.

Bücker J, Fries GR, Kapczinski F, Post RM, Yatham LN, Vianna P, Bogo Chies JA, Gama CS, Magalhães PV, Aguiar BW, Pfaffenseller B, Kauer-Sant’Anna M. Acta Psychiatr Scand. 2015 May;131(5):360-8.

School-based suicide prevention programmes: Are they effective? Lancet.April.2015.

24.04.2015

Suicide is the second  the leading cause of death in young people. Globally, suicide account for 7.3% of all deaths in the age group 15-19 yrs. (Road traffic accidents is the first leading cause  (11.6%)) . Suicide prevention among this group is a national priority in many countries. School based intervention programmes usually  adopt universal ( delivered to all), selective ( high risk groups only) or indicated ( for those presenting with suicidal ideas) approach.

 What kind of school intervention programme is  effective?

Empowering Young Lives in Europe (SEYLE) study is a large, multi country, randomised controlled trial of school-based prevention of suicidal behaviour in adolescents.Pupils were recruited from 168 schools in ten European Union countries.Pupils with incident (new) suicide attempt(s) or severe suicidal ideation at 3 months and 12 months follow-up were identified to investigate the preventive effects of the interventions. Pupils who reported suicide attempts ever, or severe suicidal ideation in the past 2 weeks before the baseline assessment were not included in the final analysis.

Intervention included one of the following: 1. Question, Persuade, and Refer (QPR): a manualised programme to train teachers and other school personnel to recognise the risk of suicidal behaviour in pupils and to enhance their com- munication skills to motivate and help pupils at risk of suicide to seek professional care  2.Youth Aware of Mental Health Programme (YAM): A manualised, universal intervention targeting all pupils, which includes  role-play sessions with interactive workshops ,  booklet that pupils could take home, educational posters displayed  classroom and interactive lectures about mental health at the beginning and end of the intervention.3.Screening by Professionals programme (ProfScreen): is a selective or indicated intervention based on responses to the  baseline questionnaire.

All interventions were undertaken during a 4 week period, after a baseline assessment. Pupils received one of the  three interventions or were in control group. Control group had  posters in their class rooms.Study recruited 11110 pupils.

Results:

At 3 months, of 9724 pupils who answered both outcome questions,( suicidal ideation, suicidal attempt)   3·4% reported either an attempt or ideation and  0·9% reported both. At 12 months, this was 2·9%  reported either and 0·6% reported both.

At the 3 month follow-up, there were no significant effects of QPR, YAM, or ProfScreen compared with the control group.

At the 12 month follow-up, YAM was associated with a significant reduction of incident suicide attempts (odds ratios [OR] 0·45, 95% CI 0·24–0·85; p=0·014) and severe suicidal ideation (0·50, 0·27–0·92; p=0·025), compared with the control group.

At 12 months in the YAM group absolute risk for suicide attempt fell by 0·60 % (ie, 6·0 of 1000 pupils) and relative risk (RR) was reduced by 54·6% (ie, of 1000 pupils, 11 attempted suicide in the control group vs five attempts in YAM).  In terms of severe suicidal ideation, in the YAM group absolute risk fell by 0·50% and RR fell by 49·6%. 

Conclusion: YAM, a universal, school-based intervention of short duration (5 h in 4 weeks), was significantly more effective in preventing new cases of suicide attempts and severe suicidal ideation, including planning, than no intervention

Decrease in suicidal attempt at 3 months is previously reported by Signs of Suicide (SOS) , a US  school intervention. Good Behaviour Game , another US  class room intervention study  has shown  reduced incidence of suicidal ideation and suicide attempts when followed up at ages 21–22 years.

The QPR and ProfScreen interventions did not have significant effects. The result show that  adolescents personal engagement in the intervention is crucial in bringing benefits. Adolescents might be reluctant to accept adult driven interventions.

Summary of the article:

School-based suicide prevention programmes: the SEYLE cluster-randomisedcontrolled trial.

Wasserman D, Hoven CW, Wasserman C, Wall M, Eisenberg R, Hadlaczky G, Kelleher I, Sarchiapone M, Apter A, Balazs J, Bobes J, Brunner R, Corcoran P, Cosman D, Guillemin F, Haring C, Iosue M, Kaess M, Kahn JP, Keeley H, Musa GJ, Nemes B, Postuvan V, Saiz P, Reiter-Theil S, Varnik A, Varnik P, Carli V.

Lancet. 2015, Vol 385 April 18, 2015

Is Extremely low birth weight linked to poor adult mental health? Pediatrics. March.2015.

20.04.2015

We know that roots of many mental health problems in adult age group can be traced to childhood events, relationships and difficulties.Many physical disorders in adult life also have their origins in early life (= ‘foetal origin of adult disorders’).

Is extreme low birth weight ( less than 1000g) a risk factor for mental disorders in adult life? 

Ryan J. Van Lieshout and team from McMaster University, Canada studied the oldest followed up cohort of Extremely Low Birth Weight (ELBW) infants in the world. Participants were followed up to their early 30s. Control participants had normal birth weight. Structured diagnostic interview (MINI) was administered by assessors blind to birthweight status. Assessment focused on 9 diagnostic groups. Low Birth Weight survivors who had birth weights less than 10th percentile for gestational age were classified as SGA ( Small for Gestational age) and the remainder were born at an appropriate weight for gestational age as AGA ( appropriate for gestational age).

Of the 397 ELBW infants recruited at birth 45% survived to leave hospital and were followed up.  60% of this group participated in the psychiatric assessment.

Results

In unadjusted models , ELBW groups had higher odds for any current non–substance use disorder (OR = 2.47; 95% CI, 1.19–5.14) but lower odds of any current alcohol or substance use disorder (OR = 0.38; 95% CI, 0.17–0.86). Adjusted models also support this relationship. ELBW with SGA showed same relationship i.e. higher odds of any non substance use disorder, with a larger OR of 3.82.
What about the risk among those who received antenatal steroids? (ACS group): The ELBW and ACS group had higher odds of a current psychiatric disorder and 3 times the odds of a current diagnosis of GAD, were 6 times more likely to have social phobia, and had 11 times the odds of having ADHD. Data is also suggestive of the possibility of a dose response relationship here. The protection from substance use see in others disappeared if they have had antenatal steroids. Steroids that cross the placenta might be influencing the glucocorticoid receptors in limbic region, amplifying/generating the psychiatric effects.

The study show that the odds of people born at ELBW having a clinically significant psychiatric problem were twice as high as those of NBW control participants.Thye have lower odds of having a current or lifetime alcohol or substance use disorder.

Why a less chance of having sub use disorder in this group? It is possible that shy/risk avoidant personality style and higher parental monitoring in childhood could explain some of this. Prenatal factors associated with preterm birth and stressful earlylife experiences may explain the increased prevalence of non substance related disorders. As in these situations, complex and multifactorial factors are likely to be in action.
Limitations: Sample attrition over years is significant. Sample size may limit the power to detect differences in multiple comparisons.
Comments: extremely low birthweight is associated with different profile of mental health.  Antenatal steroid use is a life saving intervention, but this might be associated with an increase of psychopathology in adult life.

Summary of the article:
Mental health of extremely low birth weight survivors in their 30s.Van Lieshout RJ, Boyle MH, Saigal S, Morrison K, Schmidt LA.Pediatrics. 2015 Mar;135(3):452-9

Can divorce increase risk of acute myocardial infarction? Circulation. ahead of print.

15.04.2015
Smoking, hypertension and diabetes are the major risk factors for myocardial infarction.Psychological/Social stress can affect cardiac functioning and contribute to myocardial infarctions.Divorce is linked to poorer physical health outcomes. Can divorce  significantly increase the chances of having acute myocardial infarction?
Matthew E. Dupre, Linda K. George, Guangya Liu and Eric D. Peterson from Duke University used a nationally representative sample ( from the Health and Retirement Study) of married people (~15,000) to answer this question.These participants were followed up during 1992 to 2010.

Results:

35% of the cohort had one or more divorces during the observation period.During the 200524 person-years of follow-up, 8% (n=1211) of the cohort had an Acute MI. Age-specific rates of AMI were consistently higher in those who were divorced compared with those who were continuously married. Associations were not accounted for by socioeconomic, psychosocial, behavioral, or physiological factors.

Women with multiple divorces were at especially high risk of AMI; and remarried women had risks that were similar in magnitude to divorced women.
Hazard ratio for women differed according to number of divorces. Those  who had 1 divorce = hazard ratio, 1.24; (95% confidence interval, 1.01–1.55), those with  ≥2 divorces =hazard ratio, 1.77; ( 95% confidence interval, 1.30–2.41). Remarriage didn’t help women. Among the remarried women= hazard ratio, 1.35 (95% confidence interval, 1.07–1.70) All the above ratio is in comparison with continuously married women after adjusting for multiple risk factors.

Men who remarried had no significant increase in risk.

This is the first prospective study on the cumulative association between divorce and MI.This study show that life time exposure to divorce is a serious risk factor for acute MI. Women with multiple divorce are at significant risk. Remarriage protects men but not women.

Factors like loss of income, changes in health insurance, depressive symptoms, smoking , alcohol use etc did not account for the excess risk observed. Authors suggest that direct biological mechanisms of stress ( inflammatory activation) may explain the observed association.

Limitations: Patient reported data was used to find out acute MI event.

Comment: It would be interesting to see the association ( with MI) in subgroups of divorced people. For example among those who consider divorce as an escape from stressful relationships.It will help us explore the cognitive and emotional mediators of divorce and how they may bring about physical effects.  Previous research have shown that cardiac health is affected by emotional status/stress/traumatic events. Higher risk among women needs special attention.Men possibly get along easily with relationship changes where as  women may be continuing to struggle emotionally.

Summary of the article:
Association Between Divorce and Risks for Acute Myocardial Infarction.Matthew E. Dupre, PhD; Linda K. George, PhD; Guangya Liu, PhD; Eric D. Peterson, MD, MPH.Circ Cardiovasc Qual Outcomes. 2015;8:00-00. DOI: 10.1161/CIRCOUTCOMES.114.001291.) Ahead of print.

Do children who were breastfed have sharper minds and better income? Lancet.April 2015.

24.03.2015

Breastfeeding has short-term and longterm beneficial effects on child.It is already known that breastfeeding increase the average IQ by 3.5 points at childhood and adolescence. RCT evidence also support this meta analytic measure from observational studies. In developed countries, longer duration of breastfeeding is associated with higher socio-economic status and thus this might confound the observed associations.The real life effect of small differences in IQ is not known.It is not known whether breastfeeding will influence the income in adults.

This study reported by Cesar G Victora et al from Brasil offers a rare opportunity to unravel such long-term effects. They studied the associations between infant feeding and IQ, educational attainment, and income in participants aged 30 years in a large population-based birth cohort, in Brazil ( a setting where no strong social patterning of breastfeeding exists). The neonatal cohort was recruited in 1982 with 5914 participants.IQ (Wechsler Adult Intelligence Scale) was assessed at mean age of 30. A range of confounders were measured (income, maternal education, smoking,maternal age,gestational age, birth weight etc). Genomic ancestry analysis was also done.

Results

At the age of 30 years, the mean IQ of offspring was 98·0 (SD 12·6) points and the average number of years of education was 11·4. Distribution of monthly income had a median of  R$1000 and a mean of R$1501.

Durations (total/predominant) breastfeeding  were positively associated with IQ, educational attainment, and income.The adjusted differences  between the extreme groups ( on breast feeding) were 3·76 (95% CI 2·20–5·33) IQ points, 0·91 (0·42–1·40) years of education, and R$341 (93·8–588·3) in adult income. Dose-response associations with breastfeeding duration for IQ and educational attainment and income were clear. Income difference was on average of 341·0 Brazilian reals compared to  those who were breastfed for less than 1 month.

This is the first study to show a positive association of breastfeeding  with adult earnings. The analysis also show that this effect was  largely mediated through intelligence levels.

Comments: Breastfeeding’s effect on IQ , education and income need to be brought in to antenatal discussions/public health campaign . The positive effects  shown here are very much likely to contribute to better mental health as well.

Summary of the article:

Association between breastfeeding and intelligenceeducational attainment, and income at 30years of age: a prospective birth cohort study from Brazil.

Victora CG, Horta BL, Loret de Mola C, Quevedo L, Pinheiro RT, Gigante DP, Gonçalves H, Barros FC.

Lancet Glob Health. 2015 Apr;3(4):e199-205.

First episode psychosis : Are we prescribing well?

17.03.2015

There are suggestions that we should adopt different pharmacological strategies for first episode schizophrenia and multi episode illness.The state of present practice in treating first episode is important to see how we stick to guidances and what factors  are associated with choices we make.

Delbert G. Robinson et al report  prescription practices in USA, using data from NIMH funded RAISE-ETP (Recovery After an Initial Schizophrenia Episode (RAISE) Project :Early Treatment Program (ETP)) study.Patients included were those between ages 15 yrs-40yrs with diagnosis of non affective psychosis with no previous discrete psychotic episode. Site randomisation was used to compare a  specialty care treatment program for first-episode psychosis that includes medical management guided by a decision support system and community care where treatment is by physician choice.Thirty-four  community treatment sites in 21 US states participated.

Results

There were 404 patients in the sample.12.6% did not have prescriptions for any psychotropic medications at study entry. of the 337 patients who were on antipsychotics at entry, 12% received First Generation Antipsychotic (FGA)including those who had both FGA and Second Generation Antispychotic (SGA).10% were on LA depot injections: half of this were  paliperidone depot and one third were haloperidol depot.Nearly 90% received only one antipsychotic agent.10% had two antipsychotics. Risperidone accounted for one-third of antipsychotic monotherapy. 17% were for olanzapine. Aripiprazole, Paliperidone, and Quetiapine, each accounting for around 10% of prescriptions.Few patients received higher than recommended doses. This was particularly more if they were on olanzapine. 21% of those who received antipsychotics also had perception for anticholinergic agents.11% of those pn antipsychotics also received anti anxiety medications.One third of those on antipsychotics also received antidepressants i.e. 115/337, though only half them had any documented life time depression/anxiety disorders.Negative symptoms possibly explained only 10% of the remaining 58 patients ( after accounting for depression).

Women were more likely to get lower doses. They were more likely to be on depot and receive antidepressants. African Americans were  more likely to get FGA.Young patients were more likely to get risperidone. Specific diagnosis had no effect on choice of medications.

Prescriptions were initiated mostly by inpatients units, after which patients were referred to community centres. Information on decision making reasons/indications /patient choices is not available to offer further interpretations.

A large number of first episode patients received antidepressants without clear indications.Preference for SGA is clear. Choice of agents with in SGA,  esp with regard to metabolic side effects need to be considered.

Potentially problematic prescribing was identified in 40% of the sample.This include 1. use of antidepressants where there was no clear indication 2. use of olanzapine (PORT recommends against using olanzapine as first choice due to metabolic side effects) 3. use of more than one antipsychotic.

It is important to audit and reflect on local prescribing patterns. It is essential that  patients and their families are engaged in a comprehensive discussion of the risks and benefits of different medication choices. This is the only way to ensure well-informed decisions are made.

Prescription Practices in the Treatment of First-Episode Schizophrenia Spectrum DisordersData From the National RAISE-ETPStudy.

Robinson DG, Schooler NR, John M, Correll CU, Marcy P, Addington J, Brunette MF, Estroff SE, Mueser KT, Penn D, Robinson J, Rosenheck RA, Severe J, Goldstein A, Azrin S, Heinssen R, Kane JM.

Am J Psychiatry. 2015 Mar 1;172(3):237-48.

How do maternal thinking during pregnancy affect offsprings at age 13 ? Translational psych.Feb 2015

Stress have long-lasting effect on human body. Prenatal maternal stress is shown to have many negative effects in the offspring, some lasting in to adulthood. Stress can bring about epigenetic changes , like DNA methylation.It is unclear which aspect of stress is the active ingredient in these changes. Is it the objective  severity of stress that matters? Or is it  the  cognitive appraisal of the stressor, or the subjective degree of distress?

How can you study this question?  You need a major independent stressor affecting a large population  to control for genetic bias and to differentiate the objective degree of exposure to an event from the cognitive appraisal and subjective degree of distress.

January 1998 ice storm in Quebec offered such an opportunity and was used to examine this issue. This project ( project Ice storm) have already shown that higher levels of maternal stress is associated with poorer physical, behavioral, motor and cognitive measures among the offspring from those pregnancies. DNA methylation levels among offsprings at  age 13 higher and correlated with maternal objective stress.

The team now try to address whether cognitive appraisal ( as reported by participants in 1998: about the overall consequences of the ice storm on them and their families, and to provide a rating on a five-point scale from very negative to neutral to very positive) is correlated with DNA methylation at age 13.

Results

Among 218 women who completed the assessments in 1998, nearly 35% rated the effect of storm as negative and 65% rated the effect as neutral or positive.  The three aspects of the stress experience (the objective hardship, the cognitive appraisal of the storm’s consequences and the enduring subjective distress) were  relatively independent of each other. At age, 13, offsprings blood study showed that 2872 candidate genes were significantly differentially methylated between these two appraisal groups. These are mostly those  involved in immune function. Some changes were uniquely associated with maternal cognitive appraisal of the ice storm, and not with their objective exposure.

So,  mothers cognitive appraisal of the situation is transmitted to the unborn child and this is perhaps NOT through the subjective stress and its physiological effects. Cognitive appraisal may have direct effect on stress hormone release.

Limitations:

Study has a small sample size.It is possible that the studied aspect of stress might have affected other areas of child development resulting in observed methylation changes.Peripheral DNA methylation is studied, this may not be truly reflective of brain levels.

This is the first human prenatal maternal stress study investigating the effect of maternal cognitive appraisal from an independent stressor that detects DNA methylation differences throughout the genome in the offspring during adolescence.

Summary of the article:

Pregnant women’s cognitive appraisal of a natural disaster affects DNA methylation in their children 13 years laterProject IceStorm. Cao-Lei L, Elgbeili G, Massart R, Laplante DP, Szyf M, King S. Transl Psychiatry. 2015 Feb 24;5:e515.