Kathryn J. Lester

Therapygenetics: the 5HTTLPR and response to psychological therapy

Whilst pharmacogenetic research thrives 1 , genetic determinants of response to purely psychotherapeutic treatments remain unexplored. In a sample of children undergoing Cognitive Behavior Therapy (CBT) for an anxiety disorder, we tested whether treatment response is associated with the serotonin transporter gene promoter region (5HTTLPR), previously shown to moderate environmental influences on depression. Children with the short-short genotype were significantly more likely to respond to CBT than those carrying a long allele.

Words matter: increasing the implementation of clinical guidelines

Objectives: To determine whether writing clinical guideline recommendations in behaviourally specified “plain English” language increases the likelihood of their implementation by service users (patients). Design: Randomised controlled trial in which participants received either the original text of the National Institute for Clinical Excellence (NICE) public guidelines for the management of schizophrenia or a behaviourally specified text with the same content. Setting: Mental health service user networks and voluntary sector organisations within two inner London boroughs. Participants: Eighty four mental health service users recruited by post or face to face contact at service user meetings. Intervention: The section of the NICE public guidelines for schizophrenia concerning psychological and pharmacological treatments was rewritten to improve style and behavioural specificity by applying evidence-based and psychologically informed principles of good written communication. Outcome measures: Cognitive predictors of behaviour, as specified by the evidence based theory of planned behaviour, constituted the primary outcome as it was not possible to measure the actual behaviour of guideline implementation. The predictors were behavioural intentions to implement the guidelines, attitudes towards implementation, and perceived behavioural control over implementation. Satisfaction with the guidelines and perceived comprehension were also measured. Results: Behaviourally specified “plain English” guidelines led to stronger intentions to implement the guidelines, more positive attitudes towards them, and greater perceived behavioural control over using them. There was no difference in satisfaction or perceived comprehension. Conclusions: Writing guidelines with high behavioural specificity in conjunction with the use of “plain English” may be a simple and effective method of increasing their implementation. Evaluation with a behavioural outcome is now needed.

Genome-wide Methylomic Analysis of Monozygotic Twins Discordant for Adolescent Depression

Background Adolescent depression is a common neuropsychiatric disorder that often continues into adulthood and is associated with a wide range of poor outcomes including suicide. Although numerous studies have looked at genetic markers associated with depression, the role of epigenetic variation remains relatively unexplored. Methods Monozygotic (MZ) twins were selected from an adolescent twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties. There were 18 pairs of MZ twins identified in which one member scored consistently higher (group mean within the clinically significant range) on self-rated depression than the other. We assessed genome-wide patterns of DNA methylation in twin buccal cell DNA using the Infinium HumanMethylation450 BeadChip from Illumina. Quality control and data preprocessing was undertaken using the wateRmelon package. Differentially methylated probes (DMPs) were identified using an analysis strategy taking into account both the significance and the magnitude of DNA methylation differences. The top differentially methylated DMP was successfully validated by bisulfite-pyrosequencing, and identified DMPs were tested in postmortem brain samples obtained from patients with major depressive disorder (n = 14) and matched control subjects (n = 15). Results Two reproducible depression-associated DMPs were identified, including the top-ranked DMP that was located within STK32C, which encodes a serine/threonine kinase, of unknown function. Conclusions Our data indicate that DNA methylation differences are apparent in MZ twins discordant for adolescent depression and that some of the disease-associated variation observed in buccal cell DNA is mirrored in adult brain tissue obtained from individuals with clinical depression.

Short-term serotonergic but not noradrenergic antidepressant administration reduces attentional vigilance to threat in healthy volunteers

Anxiety is associated with threat-related biases in information processing such as heightened attentional vigilance to potential threat. Such biases are an important focus of psychological treatments for anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of a range of anxiety disorders. The aim of this study was to assess the effect of an SSRI on the processing of threat in healthy volunteers. A selective noradrenergic reuptake inhibitor (SNRI), which is not generally used in the treatment of anxiety, was used as a contrast to assess the specificity of SSRI effects on threat processing. Forty-two healthy volunteers were randomly assigned to 7 d double-blind intervention with the SSRI citalopram (20 mg/d), the SNRI reboxetine (8 mg/d), or placebo. On the final day, attentional and interpretative bias to threat was assessed using the attentional probe and the homograph primed lexical decision tasks. Citalopram reduced attentional vigilance towards fearful faces but did not affect the interpretation of ambiguous homographs as threatening. Reboxetine had no significant effect on either of these measures. Citalopram reduces attentional orienting to threatening stimuli, which is potentially relevant to its clinical use in the treatment of anxiety disorders. This finding supports a growing literature suggesting that an important mechanism through which pharmacological agents may exert their effects on mood is by reversing the cognitive biases that characterize the disorders that they treat. Future studies are needed to clarify the neural mechanisms through which these effects on threat processing are mediated.

Psychometric properties of reaction time based experimental paradigms measuring anxiety-related information-processing biases in children

Theoretical frameworks highlight the importance of threat-related information-processing biases for understanding the emergence of anxiety in childhood. The psychometric properties of several tasks measuring these biases and their associations with anxiety were examined in an unselected sample of 9-year-old children (N=155). In each task, threat bias was assessed using bias scores reflecting task performance on threat versus non-threat conditions. Reliability was assessed using split-half and test-retest correlations of mean reaction times (RTs), accuracy and bias indices. Convergence between measures was also examined. Mean RTs showed substantial split-half and test-retest correlations. Bias score reliability coefficients were near zero and non-significant, suggesting poor reliability in children of this age. Additionally, associations between bias scores and anxiety were weak and inconsistent and performance between tasks showed little convergence. Bias scores from RT based paradigms in the current study lacked adequate psychometric properties for measuring individual differences in anxiety-related information-processing in children.

Therapygenetics: Using genetic markers to predict response to psychological treatment for mood and anxiety disorders

Considerable variation is evident in response to psychological therapies for mood and anxiety disorders. Genetic factors alongside environmental variables and gene-environment interactions are implicated in the etiology of these disorders and it is plausible that these same factors may also be important in predicting individual differences in response to psychological treatment. In this article, we review the evidence that genetic variation influences psychological treatment outcomes with a primary focus on mood and anxiety disorders. Unlike most past work, which has considered prediction of response to pharmacotherapy, this article reviews recent work in the field of therapygenetics, namely the role of genes in predicting psychological treatment response. As this is a field in its infancy, methodological recommendations are made and opportunities for future research are identified.

Is There Room for ‘Development’ in Developmental Models of Information Processing Biases to Threat in Children and Adolescents?

Clinical and experimental theories assume that processing biases in attention and interpretation are a causal mechanism through which anxiety develops. Despite growing evidence that these processing biases are present in children and, therefore, develop long before adulthood, these theories ignore the potential role of child development. This review attempts to place information processing biases within a theoretical developmental framework. We consider whether child development has no impact on information processing biases to threat (integral bias model), or whether child development influences information processing biases and if so whether it does so by moderating the expression of an existing bias (moderation model) or by affecting the acquisition of a bias (acquisition model). We examine the extent to which these models fit with existing theory and research evidence and outline some methodological issues that need to be considered when drawing conclusions about the potential role of child development in the information processing of threat stimuli. Finally, we speculate about the developmental processes that might be important to consider in future research.

Do anxious parents interpretive biases towards threat extend into their child's environment?

Anxiety disorders are known to run in families [Turner, S. M., Beidel, D. C., & Costello, A. (1987). Psychopathology in the offspring of anxiety disorder patients. Journal of Consulting and Clinical Psychology, 55(2), 229-235] and environmental factors may largely account for the concordance between parental and child anxieties. Cognitive psychology models emphasise the importance of interpretive biases towards threat in the maintenance of anxiety and it is well established that anxious adults and children display similar interpretive biases and that these biases in anxious parents and their children are correlated. This raises the question of whether anxious cognitions/cognitive style may be transmitted from parent to child. We propose that this is more likely if anxious parents demonstrate interpretive biases not only about potential threats in their own environment but also about potential threats in their childs environment. Forty parents completed a recognition memory measure of interpretation bias adapted from Eysenck, Mogg, May, Richards, and Mathews (1991) [Bias in interpretation of ambiguous sentences related to threat in anxiety. Journal of Abnormal Psychology, 100(2), 144-150] to measure biases in response to potentially threat provoking situations involving themselves and their child. The interpretive biases demonstrated by parents were similar across situations involving themselves and their children. As expected, parental interpretive biases were further modified by anxiety with higher levels of parental anxiety associated with more negative interpretive biases about situations in their own and their childs environment, although this association was significantly stronger for potentially threat provoking situations in their own environment. These results are consistent with parents interpretive biases extending beyond their own environment into their childs environment, although future research should continue to consider the mechanisms by which anxious parents may transmit fear cognitions to their children.

Clinical Predictors of Response to Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders: The Genes for Treatment (GxT) Study

Objective The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child’s gender, type of anxiety disorder, initial severity and comorbidity, and parents’ psychopathology would significantly predict outcome. Method A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. Results Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. Conclusion SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes.

Serotonin tranporter methylation and response to cognitive behaviour therapy in children with anxiety disorders

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35–45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.