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1.  Perinatal maternal life events and psychotic experiences in children at twelve years in a birth cohort study☆ 
Schizophrenia Research  2014;152(1):158-163.
International studies indicate that the median prevalence of psychotic experiences in children is 7%. It has been proposed that environmental stress during pregnancy may affect the neurodevelopment of the foetus and lead to a vulnerability in the child to later stressors and psychopathology.
In this study we explore the relationship between environmental stress during pregnancy and psychotic experiences in children in the general population at 12 years.
We analysed a birth cohort of 5038 children from the Avon Longitudinal Study of Parents and Children. Environmental stress was measured as life event exposure. Data on life events were collected on women during their pregnancy, whilst psychotic experiences in the offspring were assessed at age 12.
There was a weak association between maternal exposure to life events and psychotic experiences at twelve years (crude OR 1.10 95% CI 1.02–1.18) per quartile of life event score. This association was not reduced after adjustment for socio-economic status, family history of schizophrenia, maternal education or birth weight but after adjustment for maternal anxiety and depression and smoking in early pregnancy there was no longer any evidence for an association (OR 1.01 95% CI 0.93–1.10).
This study provides some evidence to suggest that stressful life events may affect child psychotic experiences through effects on maternal psychopathology, and possibly physiology, during pregnancy.
PMCID: PMC3906533  PMID: 24275580
HPA, hypothalamic–pituitary–adrenal axis; Psychosis; Schizophrenia; Life events; HPA axis; Perinatal psychiatry; Child psychiatry; ALSPAC
2.  A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence☆ 
Schizophrenia Research  2014;152(1):139-145.
Schizophrenia is associated with atopy and increased inflammatory markers. We report a population-based longitudinal study of the associations between childhood atopic disorders, subsequent serum inflammatory markers, interleukin 6 (IL-6) and C-reactive protein (CRP), and the risk of psychotic experiences (PEs).
PEs were assessed at age 13 years (n = 6785). Presence of clinician-diagnosed atopic disorders (asthma and eczema) was determined from parent-completed questionnaires at age 10 years (n = 7814). Serum IL-6 and CRP were measured at age 9 years (n = 5076). Logistic regression examined the association between (1) atopy and PEs, (2) inflammatory markers and PEs, and (3) mediating effects of inflammatory markers on the atopy–PEs association. Linear regression examined the association between atopy and inflammatory markers. Age, gender, social class, ethnicity and body mass index were included as potential confounders.
At age 10 years, about 14% of the sample was reported to have asthma, 12% eczema, and 7% both asthma and eczema. Compared with children with no atopy, risk of PEs at age 13 years was increased for all of these groups; adjusted odds ratios (95% CI) were, respectively, 1.39 (1.10–1.77), 1.33 (1.04–1.69), and 1.44 (1.06–1.94). Atopy was associated with increased serum IL-6 and CRP; however, this did not mediate association between atopy and PEs. Inflammatory markers were not associated with later PEs.
Childhood atopic disorders increase the risk of psychotic experiences in adolescence. Follow-up of these individuals will be useful to determine the effect of atopy and inflammation on different trajectories of early-life PEs.
PMCID: PMC3906534  PMID: 24268471
PEs, psychotic experiences; IL-6, interleukin 6; CRP, C-reactive protein; OR, odds ratio, 95%; CI, 95% confidence interval; Atopic disorders; Asthma; Eczema; Childhood; Adolescence; Psychotic experiences; Psychotic symptoms; Schizophrenia; Inflammatory markers; IL-6; CRP; Cytokine; Immunity; Birth cohort; Prospective study; ALSPAC
3.  Systematic review and meta-analysis of serotonin transporter genotype and discontinuation from antidepressant treatment 
European Neuropsychopharmacology  2013;23(10):1143-1150.
There is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced serotonin transporter expression, compared to the long (L) allele, and has been reported to be associated with poorer response in Europeans, with the effect in other populations unclear. However the published literature is inconsistent. A systematic review and meta-analysis was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data were obtained from 17 studies including 4309 participants. The principal outcome measure was the allelic odds ratio (OR) for the 5-HTTLPR S allele and discontinuation status. A random effects meta-analysis provided no evidence that the S allele was associated with increased odds of discontinuation from SSRIs in Europeans (OR 1.09, 95% CI 0.83–1.42, p=0.53; 10 studies, n=2504) but in East Asians there was evidence of a reduced odds of discontinuation (OR 0.28, 95% CI 0.12–0.64, p=0.002; 2 studies, n=136). There was a suggestion of small study bias (p=0.05). This meta-analysis provides no evidence of an association between 5-HTTLPR and discontinuation from antidepressant treatment in Europeans. The low number of studies in East Asian samples using SSRIs reduces confidence in our evidence that the S allele decreases the odds of discontinuation in this population. At present, there is no evidence of an association between 5-HTTLPR and discontinuation from SSRI treatment in a European population with further studies required to investigate its effects in different populations.
PMCID: PMC3791403  PMID: 23265954
5-HTTLPR; Antidepressant; SSRI; Meta-analysis; Discontinuation
4.  Lack of Association Between COMT and Working Memory in a Population-Based Cohort of Healthy Young Adults 
Neuropsychopharmacology  2013;38(7):1253-1263.
The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is an important regulator of dopamine in the prefrontal cortex, an area critical to working memory. Working memory deficits are present in several psychiatric disorders, and there is wide variation in working memory capacity in the normal population. Association studies of COMT and working memory in healthy volunteers have yielded inconsistent results, possibly because of small sample sizes. Here we examine COMT in relation to N-Back working memory task performance in a large population-based cohort of young adults. We predicted individuals with one or two copies of the Met allele would perform better, and that this relationship would be more evident in males than females. Participants (N=1857–2659) tested at 18 years of age, were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). We used multiple regression to examine effects of sex and COMT genotype on N-Back hits, false positives, discriminability (d'), and reaction time while controlling for important covariates. COMT genotype did not predict hits or d'. There was a nominally significant interaction between COMT and sex on false positives, but this was not in the predicted direction, and was not significant after controlling for covariates. COMT genotype was not related to working memory in this large population-based cohort. It is possible COMT is not meaningfully associated with working memory in healthy young adults, or that COMT effects are detectable only in assessments reflecting neural processes underlying cognition, such as fMRI, rather than in behavioral performance.
PMCID: PMC3656369  PMID: 23337869
dopamine; cognition; learning & memory; neurogenetics; COMT genotype; executive functioning; ALSPAC; COMT genotype; executive functioning; working memory; genetics; ALSPAC
5.  Exploring patients' reasons for declining contact in a cognitive behavioural therapy randomised controlled trial in primary care 
The British Journal of General Practice  2012;62(598):e371-e377.
The difficulties of recruiting individuals into mental health trials are well documented. Few studies have collected information from those declining to take part in research, in order to understand the reasons behind this decision.
To explore patients' reasons for declining to be contacted about a study of the effectiveness of cognitive behavioural therapy as a treatment for depression.
Design and setting
Questionnaire and telephone interview in general practices in England and Scotland.
Patients completed a short questionnaire about their reasons for not taking part in research. Semi-structured telephone interviews were conducted with a purposive sample to further explore reasons for declining.
Of 4552 patients responding to an initial invitation to participate in research involving a talking therapy, 1642 (36%) declined contact. The most commonly selected reasons for declining were that patients did not want to take part in a research study (n = 951) and/or did not want to have a talking therapy (n = 688) (more than one response was possible). Of the decliners, 451 patients agreed to an interview about why they declined. Telephone interviews were completed with 25 patients. Qualitative analysis of the interview data indicated four main themes regarding reasons for non-participation: previous counselling experiences, negative feelings about the therapeutic encounter, perceived ineligibility, and misunderstandings about the research.
Collecting information about those who decline to take part in research provides information on the acceptability of the treatment being studied. It can also highlight concerns and misconceptions about the intervention and research, which can be addressed by researchers or recruiting GPs. This may improve recruitment to studies and thus ultimately increase the evidence base.
PMCID: PMC3338059  PMID: 22546597
cognitive behaviour therapy; depression; non-participation; qualitative research/mixed methods; randomised controlled trials
6.  Detection of patient psychological distress and longitudinal patient–doctor relationships: a cross-sectional study 
The British Journal of General Practice  2012;62(596):e167-e173.
Psychological distress in patients who attend their GP is thought to be under-recognised. However, it is likely that both disclosure and detection are influenced by how well the patient and doctor know each another.
To examine whether patient–doctor depth of relationship is associated with identification of psychological distress.
Design and setting
Cross-sectional study in general practices in and around Bristol, England.
Patients (aged ≥16 years) were asked to complete a questionnaire and consent to their electronic medical records being reviewed. Study GPs independently assessed patient psychological distress. Multivariable logistic regression was used to look for associations between patient–doctor depth of relationship and GP detection of patient psychological distress (defined according to the 12-item General Health Questionnaire, GHQ-12).
There were 643 eligible appointments with 31 GPs. In total, 541 (84.1%) patients returned questionnaires and 490 (76.2%) consented to their records being reviewed. Patient–doctor depth of relationship was not associated with GP detection of mild to severe patient psychological distress (adjusted odds ratio [OR] 0.94, 95% CI = 0.87 to 1.02) but, in secondary analyses, it was associated with the identification of moderate to severe distress (adjusted OR 1.13, 95% CI = 1.02 to 1.26). GPs reported more patient psychological distress in patients who reported a greater depth of relationship but this did not relate to patients' GHQ-12 scores.
Evidence to support an association between patient–doctor depth of relationship and improved GP detection of patients with psychological distress was weak, except in those patients who GPs thought were more distressed. GPs may overestimate emotional distress in patients who report deeper patient–doctor relationships.
PMCID: PMC3289822  PMID: 22429433
continuity of patient care; diagnosis; family practice; mental disorders; patient–doctor relationships; psychological stress
7.  Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A Genome-Wide Analysis of Individual-Level Data and a Meta-Analysis 
PLoS Medicine  2012;9(10):e1001326.
Testing whether genetic information could inform the selection of the best drug for patients with depression, Rudolf Uher and colleagues searched for genetic variants that could predict clinically meaningful responses to two major groups of antidepressants.
It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.
Methods and Findings
The NEWMEDS consortium, an academia–industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10−8). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10−8) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.
No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study.
Please see later in the article for the Editors' Summary
Editors' Summary
Genetic and environmental factors can influence a person's response to medications. Taking advantage of the recent advancements in genetics, scientists are working to match specific gene variations with responses to particular medications. Knowing whether a patient is likely to respond to a drug or have serious side effects would allow doctors to select the best treatment up front. Right now, there are only a handful of examples where a patient's version of a particular gene predicts their response to a particular drug. Some scientists believe that there will be many more such matches between genetic variants and treatment responses. Others think that because the action of most drugs is influenced by many different genes, a variant in one of those genes is unlikely to have measurable effect in most cases.
Why Was This Study Done?
One of the areas where patients' responses to available drugs vary widely is severe depression (or major depressive disorder). Prescription of an antidepressant is often the first step in treating the disease. However, less than half of patients get well taking the first antidepressant prescribed. Those who don't respond to the first drug need to, together with their doctors, try multiple courses of treatment to find the right drug and the right dose for them. For some patients none of the existing drugs work well.
To see whether genetic information could help improve the choice of antidepressant, researchers from universities and the pharmaceutical industry joined forces in this large study. They examined two ways to use genetic information to improve the treatment of depression. First, they searched all genes for common genetic variants that could predict which patients would not respond to the two major groups of antidepressants (serotonin reuptake inhibitors, or SRIs, and noradrenaline reuptake inhibitors, or NRIs). They hoped that this would help with the development of new drugs that could help these patients. Second, they looked for common genetic variants in all genes that could identify patients who responded to one of the two major groups of antidepressants. Such predictors would make it possible to know which drug to prescribe for which patient.
What Did the Researchers Do and Find?
The researchers selected 1,790 patients with severe depression who had participated in one of several research studies; 1,222 of the patients had been treated with an SRI, the remaining 568 with an NRI, and it was recorded how well the drugs worked for each patient. The researchers also had a detailed picture of the genetic make-up of each patient, with information for over half a million genetic variants. They then looked for an association between genetic variants and responses to drugs.
They found not a single genetic variant that could predict clearly whether a person would respond to antidepressants in general, to one of the two main groups (SRIs and NRIs), or much better to one than the other. They also didn't find any combination of variants in groups of genes that work together that could predict responses. Combining their data with those from another large study did not yield any robust predictors either.
What Do These Findings Mean?
This study was large enough that it should have been possible to find common genetic variants that by themselves could predict a clinically meaningful response to SRIs and/or NRIs, had such variants existed. The fact that the study failed to find such variants suggests that such variants do not exist. It is still possible, however, that variants that are less common could predict response, or that combinations of variants could. To find those, if they do exist, even larger studies will need to be done.
Additional Information
Please access these websites via the online version of this summary at
The National Institute of General Medical Sciences at the US National Institutes of Health has a fact sheet on personalized medicine
PubMed Health at the US National Library of Medicine has a page on major depressive disorder
Wikipedia has pages on major depressive disorder and pharmacogenetics, the study of how genetic variation affects response to certain drugs (note that Wikipedia is a free online encyclopedia that anyone can edit)
The UK National Health Service has comprehensive information pages on depression
PMCID: PMC3472989  PMID: 23091423
The low level of response (LR) to alcohol is one of several genetically-influenced characteristics that increase the risk for heavy drinking and alcohol problems. Efforts to understand how LR operates through additional life influences have been carried out primarily in modest sized U.S.-based samples with limited statistical power, raising questions about generalizability and about the importance of components with smaller effects. This study evaluates a full LR-based model of risk in a large sample of adolescents from the U.K.
Cross-sectional structural equation models (SEM) were used for the approximate first half of the age 17 subjects assessed by the Avon Longitudinal Study of Parents and Children (ALSPAC), generating data on 1,905 adolescents (0 age 17.8 years, 44.2% males). LR was measured with the Self-Rating of the Effects of Alcohol (SRE) Questionnaire, outcomes were based on drinking quantities and problems, and standardized questionnaires were used to evaluate peer substance use, alcohol expectancies, and using alcohol to cope with stress.
In this young and large U.K. sample, a low LR related to more adverse alcohol outcomes both directly and through partial mediation by all three additional key variables (peer substance use, expectancies, and coping). The models were similar in males and females.
These results confirm key elements of the hypothesized LR-based model in a large U.K. sample, supporting some generalizability beyond U.S. groups. They also indicate that with enough statistical power multiple elements contribute to how LR relates to alcohol outcomes, and reinforce the applicability of the model to both genders.
PMCID: PMC3183150  PMID: 21762180
ALSPAC; alcohol; level of response; structural equation models; adolescents
9.  Childhood diet and behavioural problems: results from the ALSPAC cohort 
To investigate whether a ‘junk food’ diet at 81 months of age is associated with the development of behavioural problems over the following 16 months.
The study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 12,942 children were included. The main outcome measure was behavioural problems, measured using the Strengths and Difficulties Questionnaire (SDQ). SDQ scores were available at 81 and 97 months of age. Child-based dietary data were collected at 81 months by food frequency questionnaire; from this a ‘junk food’ score was derived, and mean weekly non-milk extrinsic sugar (NMES) intake estimated. Statistical analyses examined the associations between dietary exposures at 81 months and SDQ outcomes at 97 months. Children with SDQ scores suggesting behavioural problems at baseline were excluded in order to identify new cases. Adjustments were made for potential confounders such as socioeconomic status.
Unadjusted analyses suggested associations between the ‘junk food’ score at 81 months and both total difficulties and pro-social behaviour at 97 months. However, adjustment for baseline SDQ scores attenuated these associations, with confidence intervals including the null for both total difficulties [OR(95% CI):1.05(0.92,1.21);P=0.45] and pro-social behaviour [1.13(1.00,1.26);P=0.04]. Adjustment for other potential confounders further attenuated the effects. Adjustment for confounders similarly attenuated modest associations between NMES intake and behavioural problems.
There was no evidence to support an association between a ‘junk food’ diet at 81 months of age and behavioural problems 16 months later.
PMCID: PMC3447259  PMID: 21427741
ALSPAC; child behaviour; diet
10.  Childhood infection and adult schizophrenia: A meta-analysis of population-based studies 
Schizophrenia Research  2012;139(1-3):161-168.
To determine whether exposures to infectious illness during childhood involving the CNS or elsewhere is associated with adult schizophrenia or other psychoses.
Systematic review and meta-analysis of published literature identified by electronic and manual search meeting three inclusion criteria: population-base, objective assessment of childhood infection at the individual level, standard definition of adult psychotic outcomes. We calculated risk ratio for all CNS infection, and separately for viral and bacterial infection in relation to non-affective psychosis and schizophrenia, which was combined in meta-analysis.
Seven studies were included. Meta-analysis involving 2424 cases and over 1.2 million controls showed CNS viral infection was associated with nearly two-fold increased risk of adult non-affective psychosis (risk ratio 1.70; 95% CI 1.13–2.55; p = 0.01). There was no significant heterogeneity between studies (p = 0.26; I2 = 20%). Separate meta-analysis involving 1035 cases and over 1.2 million controls suggested all childhood CNS infections, particularly viral infections, may be associated with nearly two-fold risk of adult schizophrenia. However, there was evidence of some heterogeneity between these studies (p = 0.07; I2 = 70%). CNS bacterial infections were not associated with risk of psychosis. Data on childhood infections with no obvious involvement of the CNS is insufficient.
These findings indicate childhood CNS viral infections increase the risk of adult psychotic illness. Possible mechanisms may include both direct effects of pathogens, and the effects of inflammatory response on the developing brain.
PMCID: PMC3485564  PMID: 22704639
CNS, Central Nervous System; ICD, International Classification of Diseases; DSM, Diagnostic and Statistical Manual of Mental Disorders; 95% CI, 95% Confidence Interval; Adult; Schizophrenia; Psychotic Disorders; Neurodevelopment; Childhood; Infection; Inflammation; Central Nervous System; Meningitis; Illness; Meta-analysis
11.  Serum 25-Hydroxyvitamin D3 and D2 and Non-Clinical Psychotic Experiences in Childhood 
PLoS ONE  2012;7(7):e41575.
Non-clinical psychotic experiences are common and distressing. It has been hypothesized that early life vitamin D deficiency may be a risk factor for psychosis-related outcomes, but it is not known if circulating concentrations of 25-hydroxyvitamin D (25(OH)D) during childhood are associated with psychosis-related outcomes or whether the two different forms of 25(OH)D, (25(OH)D3 and 25(OH)D2, have similar associations with psychosis-related outcomes.
We investigated the association between serum 25(OH)D3 and 25(OH)D2 concentrations and psychotic experiences in a prospective birth cohort study. Serum 25(OH)D3 and 25(OH)D2 concentrations were measured at mean age 9.8 years and psychotic experiences assessed at mean age 12.8 years by a psychologist (N = 3182).
Higher 25(OH)D3 concentrations were associated with lower risk of definite psychotic experiences (adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.75–0.95)). Higher concentrations of 25(OH)D2 were associated with higher risk of suspected and definite psychotic experiences (adjusted odds ratio: OR (95% confidence interval: CI) 1.26 (1.11, 1.43)). Higher 25(OD)D2 concentrations were also weakly associated with definite psychotic experiences (adjusted OR (95% CI) 1.17 (0.96, 1.43), though with wide confidence intervals including the null value.
Our findings of an inverse association of 25(OH)D3 with definite psychotic experiences is consistent with the hypothesis that vitamin D may protect against psychosis-related outcomes.
PMCID: PMC3405076  PMID: 22848531
12.  The Association of 25-Hydroxyvitamin D3 and D2 with Behavioural Problems in Childhood 
PLoS ONE  2012;7(7):e40097.
Higher serum concentrations of 25-hydroxyvitamin D (25(OH)D), an indicator of vitamin D synthesis and intake, have been associated with better mental health and cognitive function. Concentrations of 1,25-dihydroxyvitamin D3 (the active vitamin D3 metabolite) have been associated with openness and extrovert behaviour, but 25(OH)D concentrations have not been associated with behavioural problems in humans.
We investigated the prospective association between the different forms of 25(OH)D - 25(OH)D3 and 25(OH)D2– and childhood behavioural problems in Avon Longitudinal Study of Parents and Children (ALSPAC). Serum 25(OH)D3 and 25(OH)D2 concentrations were assessed at mean age 9.9 years. Incident behavioural problems were assessed with Strengths and Difficulties Questionnaire (SDQ; emotional symptoms, conduct problems, hyperactivity-inattention problems, peer relationship problems and pro-social behaviour subscales and total difficulties score) at mean age 11.7. Sample sizes varied between 2413-2666 depending on the outcome.
Higher 25(OH)D3 concentrations were weakly associated with lower risk of prosocial problems (fully adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.74, 0.98)). Serum 25(OH)D3 or 25(OH)D2 concentrations were not associated with other subscales of SDQ or total difficulties score after adjusting for concfounders and other measured analytes related to vitamin D.
Our findings do not support the hypothesis that 25-hydroxyvitamin D status in childhood has important influences on behavioural traits in humans.
PMCID: PMC3393748  PMID: 22808099
13.  Adolescent self-harm and suicidal thoughts in the ALSPAC cohort: a self-report survey in England 
BMC Psychiatry  2012;12:69.
Substantial numbers of adolescents self-harm, but the majority of cases do not reach the attention of medical services, making community studies essential. The prevalence of suicidal thoughts and plans at this age, and the inter-relationships between suicidal thoughts, plans and self-harm remain largely unexplored.
Cross-sectional analysis of self-reported questionnaire data collected from members of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England. Respondents (n = 4810) were aged 16–17 years old and have been followed up since birth.
Altogether 905 (18.8%) respondents had ever self-harmed. The prevalence of lifetime self-harm was higher in females (25.6%) than males (9.1%). The most commonly used method was self-cutting: this was used alone or in combination in 73.5% of episodes, compared to 10.0% who took overdoses alone or in combination with other methods. Of those who reported self-harm, 25.3% wanted to die during the most recent episode. Concurrent depression was associated with a greatly increased risk of self-harm (OR 5.43). Only 12.4% of participants sought medical help following their most recent episode of self-harm, although this figure was higher (30.1%) where self-harm was carried out with desire to die. Of the whole sample, 15.8% had ever thought of killing themselves, and 4.3% had ever made plans to kill themselves. Compared to those who had never self-harmed, those who had self-harmed but not wanted to die during the most recent episode were at increased risk of ever having had suicidal thoughts (37.6% compared to 7.8% χ2 =102.3, p < 0.001) and ever making suicidal plans (8.7% compared to 0.7%, χ2 =166.9, p < 0.001). As the frequency of self-harm increased, so did the risk of suicidal thoughts and plans.
Self-harm and suicidal thoughts are common among 16/17 year olds. Although the majority of self-harm behaviour is not accompanied by a desire to die, all self-harm regardless of motivation is associated with increased risk of suicidal thoughts and plans, particularly when it is carried out repeatedly.
PMCID: PMC3439325  PMID: 22737989
Self-harm; Suicidal thoughts; Suicidal plans; Adolescence
14.  40,000 memories in young teenagers: Psychometric properties of the Autobiographical Memory Test in a UK cohort study 
Memory (Hove, England)  2012;20(3):300-320.
Although the Autobiographical Memory Test (AMT) is widely used its psychometric properties have rarely been investigated. This paper utilises data gathered from a 10-item written version of the AMT, completed by 5792 adolescents participating in the Avon Longitudinal Study of Parents and Children, to examine the psychometric properties of the measure. The results show that the scale derived from responses to the AMT operates well over a wide range of scores, consistent with the aim of deriving a continuous measure of over-general memory. There was strong evidence of group differences in terms of gender, low negative mood, and IQ, and these were in agreement when comparing an item response theory (IRT) approach with that based on a sum score. One advantage of the IRT model is the ability to assess and consequently allow for differential item functioning. This additional analysis showed evidence of response bias for both gender and mood, resulting in attenuation in the mean differences in AMT across these groups. Implications of the findings for the use of the AMT measure in different samples are discussed.
PMCID: PMC3379787  PMID: 22348421
Avon Longitudinal Study of Parents and Children; ALSPAC; Autobiographical Memory Test; AMT; Graded response model; Differential item functioning; Mood congruence
15.  Prenatal and Early Life Exposure to Stressful Life Events and Risk of Autism Spectrum Disorders: Population-Based Studies in Sweden and England 
PLoS ONE  2012;7(6):e38893.
Background and Aim
Exposure to stressful life events during pregnancy has been suggested as a potential risk factor for offspring Autism Spectrum Disorders (ASD), but the literature is limited and inconsistent. We tested the hypothesis that maternal exposure to stressful life events would be associated with increased risks of offspring ASD, and that these risks would be highest for exposures during the prenatal period.
Methods and Results
We used prospectively collected data from two large population based studies in Sweden and England. In the Swedish study of 4429 ASD cases and 43277 controls, our exposure comprised the occurrence of any severe life event before and during pregnancy and the child's early life. In the English study (maximum n = 11554, ASD n = 72), we studied the risk of offspring ASD in relation to a combined maternal exposure to multiple (up to 42) common and rare life events, as well as their perceived impact upon the mother during pregnancy and early life. In crude and adjusted regression analyses in both studies, we found no evidence of an association between prenatal life events, or their number and perceived impact and the risk of offspring ASD. Sub-group analysis of ASD with and without intellectual disability in the Swedish study yielded similar results.
We found no evidence to support the hypotheses that exposure to stressful life events during the prenatal period is associated with an increased risk of offspring ASD.
PMCID: PMC3374800  PMID: 22719977
16.  Patients' views of physical activity as treatment for depression: a qualitative study 
The British Journal of General Practice  2011;61(585):e149-e156.
Clinical guidance recommends physical activity to manage patients with persistent subthreshold depressive symptoms or mild-to-moderate depression. However, little is known regarding the acceptability of physical activity as a treatment for depression from patients' perspective.
To explore patients' views of physical activity for the treatment of depression in the context of primary care.
Design of study
In-depth interviews were held with 33 participants taking part in a randomised controlled trial assessing the effectiveness of physical activity for the management of depression.
Primary care.
Most participants perceived physical activity to be an acceptable treatment for depression. The mechanisms by which physical activity could enhance mood were attributed to a number of subjective benefits including biochemical pathways, providing a source of distraction from negative thoughts, and a sense of purpose. Participants who expressed a belief that their depression was caused by biochemical mechanisms reported activity that ‘raised the heartbeat’ as most beneficial, while those who believed depression was situational in origin tended to state the benefits of less-aerobic activities, such as walking. Many participants reported low motivation and a lack of confidence as barriers to undertaking physical activity. These patients suggested that medication could be helpful for initiating and maintaining activity.
Patients view physical activity as an effective treatment for depression. However, they vary in their views about how physical activity might impact on depression, what intensity and form of activity is necessary to enhance mood, and the barriers to undertaking activity. This variation suggests the need for GPs to elicit patients' views on physical activity as a treatment, and offer interventions that are tailored to the needs and expectations of individual patients.
PMCID: PMC3063043  PMID: 21439172
antidepressants; depression; guidelines; physical activity; primary health care; qualitative research
17.  Involving patients with depression in research: survey of patients' attitudes to participation 
The British Journal of General Practice  2011;61(585):e134-e141.
Clinicians report barriers to involving their patients in mental health research and have concerns that participation may have negative effects.
To investigate patients' views on participating in a primary care randomised controlled trial (RCT) comparing two antidepressant drugs.
Design of study
Cross-sectional survey.
General practices, England.
Six hundred and one trial participants were surveyed about their reasons for, and experience of, participating.
The questionnaire was completed by 252/601 (42%) participants. The most influential factors determining participation were: wanting to help others with depression (94%, 95% confidence interval [CI] = 90 to 97%) of responders rated this as ‘important’ or ‘very important’); friendly researchers (94%, 95% CI = 90 to 96%); and interest in the research (88%, 95% CI = 83 to 91%). Most were glad they took part and would consider participating in future research. Ninety-six per cent (95% CI = 92 to 98%) reported that their confidence in their GP had increased or remained unchanged since referral. Qualitative analysis of free-text responses indicated that patients found participation beneficial and liked: being altruistic, doing something positive, feeling supported by the researchers, and having time to talk. Many gained understanding of their depression and valued feedback on their progress. A minority reported negative views, which commonly related to taking antidepressants, and answering questionnaires.
GPs have a vital role in facilitating patient involvement in research but report barriers to referring depressed patients to RCTs. However, this data suggests that patients are willing to participate and many find this beneficial. Understanding attitudes to participation in mental health research is a crucial step in designing trials that are more acceptable to patients and GPs. This will strengthen the evidence for therapeutic approaches in primary care.
PMCID: PMC3063041  PMID: 21439170
depression; general practice; patient participation; qualitative research; randomised controlled trials
18.  Assessing negative cognitive style: Development and validation of a Short-Form version of the Cognitive Style Questionnaire 
The Cognitive Style Questionnaire (CSQ) is a frequently employed measure of negative cognitive style, associated with vulnerability to anxiety and depression. However, the CSQ's length can limit its utility in research. We describe the development of a Short-Form version of the CSQ. After evaluation and modification of two pilot versions, the 8-item CSQ Short Form (CSQ-SF) was administered to a convenience sample of adults (N = 278). The CSQ-SF was found to have satisfactory internal reliability and test-retest reliability. It also exhibited construct validity by demonstrating predicted correlations with measures of depression and anxiety. Results suggest that the CSQ-SF is suitable for administration via the Internet.
PMCID: PMC3289144  PMID: 22389545
Cognitive style; Depression; Anxiety
19.  Assessing negative cognitive style: Development and validation of a Short-Form version of the Cognitive Style Questionnaire 
► We developed a Short-Form version of the Cognitive Style Questionnaire (CSQ). ► The CSQ Short Form (CSQ-SF) demonstrated satisfactory internal reliability. ► Test–retest reliability was also satisfactory. ► Scores demonstrated predicted correlations with measures of depression and anxiety. ► The CSQ-SF may be a useful research tool in assessing vulnerability to depression.
The Cognitive Style Questionnaire (CSQ) is a frequently employed measure of negative cognitive style, associated with vulnerability to anxiety and depression. However, the CSQ’s length can limit its utility in research. We describe the development of a Short-Form version of the CSQ. After evaluation and modification of two pilot versions, the 8-item CSQ Short Form (CSQ-SF) was administered to a convenience sample of adults (N = 278). The CSQ-SF was found to have satisfactory internal reliability and test–retest reliability. It also exhibited construct validity by demonstrating predicted correlations with measures of depression and anxiety. Results suggest that the CSQ-SF is suitable for administration via the Internet.
PMCID: PMC3289144  PMID: 22389545
Cognitive style; Depression; Anxiety
20.  Patterns of Alcohol Use in Early Adolescence Predict Problem Use at Age 16 
Aims: Teenagers in the UK report some of the highest rates of alcohol use in Europe. We identify patterns of alcohol use in early adolescence and relate these to hazardous and harmful alcohol use at age 16. Methods: In a UK birth cohort, we analysed repeated measures of alcohol use from age 13 to 15 in a sample of 7100 adolescents. Data on drinking frequency and typical consumption when drinking were modelled separately using a pair of latent class models. Classes of alcohol-use behaviour were contrasted across a range of risk factors and then to hazardous and harmful alcohol use as assessed using the Alcohol Use Disorders Identification Test scale at age 16. Results: Heterogeneity in drinking frequency and consumption could each be captured with three classes corresponding to low, medium and high levels. In total, 14.2% were classified as high-frequency and 8.9% as high consumption alcohol users. Socio-demographic factors, maternal substance use and the young persons' use of tobacco and cannabis were associated with class membership. At age 16, 29% were drinking hazardously and a further 5.6% were assessed as harmful drinkers. Young people in the high drinking frequency or consumption class had a 9-fold increased risk of reporting harmful drinking at age 16. Conclusions: By the age of 16, a substantial proportion of teenagers in this sample were drinking at levels that could be considered hazardous or harmful for an adult. Patterns of alcohol exposure in early adolescence were strongly associated with later alcohol use. Altering drinking patterns in middle adolescence has the potential to reduce harmful use in later adolescence.
PMCID: PMC3284685  PMID: 22215001
21.  Physical activity and depression in adolescents: cross-sectional findings from the ALSPAC cohort 
Few studies have examined the association between physical activity (PA), measured objectively, and adolescent depressive symptoms. The aim of this study was to determine whether there is an association between objective measures of PA (total PA and time spent in moderate and vigorous PA (MVPA)) and adolescent depressive symptoms.
Data on 2,951 adolescents participating in ALSPAC were used. Depressive symptoms were measured using the self-report Mood and Feelings Questionnaire (MFQ) (short version). Measures of PA were based on accelerometry. The association between PA and MFQ scores was modelled using ordinal regression.
Adolescents who were more physically active (total PA or minutes of MVPA) had a reduced odds of depressive symptoms [ORadj total PA (tertiles): medium 0.82 (95% CI: 0.69, 0.97); high 0.69 (95% CI: 0.57, 0.83)]; ORadj per 15 min MVPA: 0.92 (95% CI: 0.86, 0.98). In a multivariable model including both total PA and the percentage of time spent in MVPA, total PA was associated with depressive symptoms (ORadj total PA (tertiles): medium 0.82 (95% CI: 0.70, 0.98); high 0.70 (95% CI: 0.58, 0.85) but the percentage of time spent in MVPA was not independently associated with depressive symptoms [ORadj MVPA (tertiles) medium 1.05 (95% CI: 0.88, 1.24), high 0.91 (95% CI: 0.77, 1.09)].
The total amount of PA undertaken was associated with adolescent depressive symptoms, but the amount of time spent in MVPA, once total PA was accounted for, was not. If confirmed in longitudinal studies and randomised controlled trials, this would have important implications for public health messages.
Electronic supplementary material
The online version of this article (doi:10.1007/s00127-011-0422-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3382270  PMID: 21826444
Physical activity; Depressive symptoms; Adolescence; ALSPAC
22.  The association between bullying and early stages of suicidal ideation in late adolescents in Greece 
BMC Psychiatry  2011;11:22.
Bullying in schools has been associated with suicidal ideation but the confounding effect of psychiatric morbidity has not always been taken into account. Our main aim was to test the association between bullying behavior and early stages of suicidal ideation in a sample of Greek adolescents and to examine whether this is independent of the presence of psychiatric morbidity, including sub-threshold symptoms.
5614 pupils 16-18 years old and attending 25 senior high schools were screened in the first phase and a stratified random sample of 2431 were selected for a detailed interview at the second phase. Psychiatric morbidity and suicidal ideation were assessed with the revised Clinical Interview Schedule (CIS-R) while bullying was assessed with the revised Olweus bully/victim questionnaire.
Victims of bullying behavior were more likely to express suicidal ideation. This association was particularly strong for those who were bullied on a weekly basis and it was independent of the presence of psychiatric morbidity (Odds Ratio: 7.78; 95% Confidence Interval: 3.05 - 19.90). In contrast, being a perpetrator ("bullying others") was not associated with this type of ideation after adjustment. These findings were similar in both boys and girls, although the population impact of victimization in the prevalence of suicidal ideation was potentially higher for boys.
The strong cross-sectional association between frequent victimization and suicidal ideation in late adolescence offers an opportunity for identifying pupils in the school setting that are in a higher risk for exhibiting suicidal ideation.
PMCID: PMC3042930  PMID: 21303551
23.  Physical activity as a treatment for depression: the TREAD randomised trial protocol 
Trials  2010;11:105.
Depression is one of the most common reasons for consulting a General Practitioner (GP) within the UK. Whilst antidepressants have been shown to be clinically effective, many patients and healthcare professionals would like to access other forms of treatment as an alternative or adjunct to drug therapy for depression. A recent systematic review presented some evidence that physical activity could offer one such option, although further investigation is needed to test its effectiveness within the context of the National Health Service.
The aim of this paper is to describe the protocol for a randomised, controlled trial (RCT) designed to evaluate an intervention developed to increase physical activity as a treatment for depression within primary care.
The TREAD study is a pragmatic, multi-centre, two-arm RCT which targets patients presenting with a new episode of depression. Patients were approached if they were aged 18-69, had recently consulted their GP for depression and, where appropriate, had been taking antidepressants for less than one month. Only those patients with a confirmed diagnosis of a depressive episode as assessed by the Clinical Interview Schedule-Revised (CIS-R), a Beck Depression Inventory (BDI) score of at least 14 and informed written consent were included in the study. Eligible patients were individually randomised to one of two treatment groups; usual GP care or usual GP care plus facilitated physical activity. The primary outcome of the trial is clinical symptoms of depression assessed using the BDI four months after randomisation. A number of secondary outcomes are also measured at the 4-, 8- and 12-month follow-up points including quality of life, attitude to and involvement in physical activity and antidepressant use/adherence. Outcomes will be analysed on an intention-to-treat (ITT) basis and will use linear and logistic regression models to compare treatments.
The results of the trial will provide information about the effectiveness of physical activity as a treatment for depression. Given the current prevalence of depression and its associated economic burden, it is hoped that TREAD will provide a timely contribution to the evidence on treatment options for patients, clinicians and policy-makers.
Trial registration: ISRCTN 16900744
PMCID: PMC2993700  PMID: 21073712
24.  Study protocol for a randomized controlled trial comparing mindfulness-based cognitive therapy with maintenance anti-depressant treatment in the prevention of depressive relapse/recurrence: the PREVENT trial 
Trials  2010;11:99.
Depression is a common and distressing mental health problem that is responsible for significant individual disability and cost to society. Medication and psychological therapies are effective for treating depression and maintenance anti-depressants (m-ADM) can prevent relapse. However, individuals with depression often express a wish for psychological help that can help them recover from depression in the long-term. We need to develop psychological therapies that prevent depressive relapse/recurrence. A recently developed treatment, Mindfulness-based Cognitive Therapy (MBCT, see shows potential as a brief group programme for people with recurring depression. In two studies it has been shown to halve the rates of depression recurring compared to usual care.
This trial asks the policy research question, is MBCT superior to m-ADM in terms of: a primary outcome of preventing depressive relapse/recurrence over 24 months; and, secondary outcomes of (a) depression free days, (b) residual depressive symptoms, (c) antidepressant (ADM) usage, (d) psychiatric and medical co-morbidity, (e) quality of life, and (f) cost effectiveness? An explanatory research question asks is an increase in mindfulness skills the key mechanism of change?
The design is a single blind, parallel RCT examining MBCT vs. m-ADM with an embedded process study. To answer the main policy research question the proposed trial compares MBCT plus ADM-tapering with m-ADM for patients with recurrent depression. Four hundred and twenty patients with recurrent major depressive disorder in full or partial remission will be recruited through primary care. Depressive relapse/recurrence over two years is the primary outcome variable. The explanatory question will be addressed in two mutually informative ways: quantitative measurement of potential mediating variables pre/post-treatment and a qualitative study of service users' views and experiences.
If the results of our exploratory trial are extended to this definitive trial, MBCT will be established as an alternative approach to maintenance anti-depressants for people with a history of recurrent depression. The process studies will provide evidence about the effective components which can be used to improve MBCT and inform theory as well as other therapeutic approaches.
Trial registration number
PMCID: PMC2972263  PMID: 20961444
25.  The association between birth condition and neuropsychological functioning and educational attainment at school age: a cohort study 
Poor condition at birth may impact on IQ, although its effect on other measures of neurodevelopment is unclear. The authors' aim was to determine whether infants receiving resuscitation after birth have reduced scores in measures of attention, memory and language skills or the need for educational support at school even in the absence of clinical encephalopathy.
Three groups of term infants were identified from the Avon longitudinal study of parents and children: infants resuscitated at birth but asymptomatic for encephalopathy (n=612), infants resuscitated who developed symptoms of encephalopathy (n=40) and the reference infants who were not resuscitated and had no further neonatal care (n=8080). Measures of attention, language, memory and the need for educational support were obtained for children between 8 years and 11 years. Test results (standardised to a mean of 100 and SD of 15) were adjusted for clinical and social covariates. Missing covariate data were imputed using chained equations.
Infants asymptomatic after resuscitation had similar scores to those not requiring resuscitation for all measures while infants who developed encephalopathy had lower working memory (−6.65 (−12.34 to −0.96)), reading accuracy (−7.95 (−13.28 to −2.63)) and comprehension (−9.32 (−14.47 to −4.17) scores and increased risk of receiving educational support (OR 6.24 (1.52 to 26.43)) than infants thought to be well at birth, although there was little evidence for an association after excluding infants who developed cerebral palsy.
The authors found no evidence that infants who were resuscitated but remained well afterwards differed from those not requiring resuscitation in the aspects of neuropsychological functioning assessed in this study. Infants who developed neonatal encephalopathy had evidence of worse functioning, particularly in language skills and were more likely to receive educational support at school.
PMCID: PMC3015086  PMID: 20705720

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