What's so funny? An evaluation of the relations among humour use, mirth, and depressive symptomatology

Humour production and showing mirth (i.e., smiling and laughing) confer prosocial advantages. However, there is a paucity of literature evaluating how humour manifests in psychopathology. Humour and mirth may be especially relevant in depression, wherein profound impairments are evident in emotional and social functioning. Chapters 2 and 3 present correlational and predictive relations of depressive, social anxiety, and social anhedonia symptoms with humour styles, and consider the role of motivational systems and expressivity of positive affect as they relate to humour. As expected, symptoms and avoidance-based motivation were positively related to maladaptive humour styles and negatively related to adaptive humour styles. Interestingly, the pattern of relations shifted when considered among individuals in a depressive episode; acutely depressed individuals generally shy away from any humour style rather than gravitating toward specific styles. In a mediation model, the inverse relation between depressive symptoms and affiliative humour was fully mediated by approach-based motivation and expressivity of positive emotions. Chapters 4 and 5 examined subjective and observed mirth responses (facial affect and laughter) demonstrated by depressed and healthy comparison groups. Relative to non-depressed individuals, depressed persons reported less enjoyment, lower ratings of funniness, and fewer instances and shorter durations of positive facial affect and laughter when viewing humourous videos. There was no significant change in retrospective ratings of enjoyment and funniness at a one-week follow-up. The pattern of responsivity by depressed persons shifted when they viewed humourous videos while hearing others laughing. Both groups demonstrated more mirth when hearing others laugh; there were no differences between groups on mirthful behaviours. The one exception was that the total duration of laugher produced by depressed individuals was shorter than that produced by individuals in the healthy comparison group. This research project demonstrates that facets of depressive symptomatology are differentially associated with humour use and depressed individuals show blunted emotional responsivity to humourous stimuli. However, the pattern of reduced affective responsivity is context specific in that it fluctuates in response to hearing others’ laughter. These findings have important implications for the conceptualization of depression and the subsequent avenues for the treatment of individuals with depression.

Exploring non-cancer pain conditions in a community sample : critiquing a current conceptual model of the acute to chronic pain transition and examining predictors of chronicity

This program of research examines the experience of chronic pain in a community sample. While, it is clear that like patient samples, chronic pain in non-patient samples is also associated with psychological distress and physical disability, the experience of pain across the total spectrum of pain conditions (including acute and episodic pain conditions) and during the early course of chronic pain is less clear. Information about these aspects of the pain experience is important because effective early intervention for chronic pain relies on identification of people who are likely to progress to chronicity post-injury. A conceptual model of the transition from acute to chronic pain was proposed by Gatchel (1991a). In brief, Gatchel’s model describes three stages that individuals who have a serious pain experience move through, each with worsening psychological dysfunction and physical disability. The aims of this program of research were to describe the experience of pain in a community sample in order to obtain pain-specific data on the problem of pain in Queensland, and to explore the usefulness of Gatchel’s Model in a non-clinical sample. Additionally, five risk factors and six protective factors were proposed as possible extensions to Gatchel’s Model. To address these aims, a prospective longitudinal mixed-method research design was used. Quantitative data was collected in Phase 1 via a comprehensive postal questionnaire. Phase 2 consisted of a follow-up questionnaire 3 months post-baseline. Phase 3 consisted of semi-structured interviews with a subset of the original sample 12 months post follow-up, which used qualitative data to provide a further in-depth examination of the experience and process of chronic pain from respondents’ point of view. The results indicate chronic pain is associated with high levels of anxiety and depressive symptoms. However, the levels of disability reported by this Queensland sample were generally lower than those reported by clinical samples and consistent with disability data reported in a New South Wales population-based study. With regard to the second aim of this program of research, while some elements of the pain experience of this sample were consistent with that described by Gatchel’s Model, overall the model was not a good fit with the experience of this non-clinical sample. The findings indicate that passive coping strategies (minimising activity), catastrophising, self efficacy, optimism, social support, active strategies (use of distraction) and the belief that emotions affect pain may be important to consider in understanding the processes that underlie the transition to and continuation of chronic pain.

Factors associated with the wish to hasten death : a study of patients with terminal illness

Background. There is considerable debate regarding the clinical issues surrounding the wish to hasten death (WTHD) in the terminally ill. The clinical factors contributing to the WTHD need further investigation among the terminally ill in order to enhance understanding of the clinical assessment and treatment needs that underlie this problem. A more detailed understanding may assist with the development of appropriate therapeutic interventions. Method. A sample of terminally ill cancer patients (N=256) recruited from an in-patient hospice unit, home palliative care service and a general hospital palliative care consulting service from Brisbane Australia between 1998–2001 completed a questionnaire assessing psychological (depression and anxiety), social (family relationship, social support, level of burden on others) and the impact of physical symptoms. The association between these factors and the WTHD was investigated. Results. A high WTHD was reported by 14% of patients. A discriminant function analysis revealed that the following variables were associated with a high WTHD (P<0·001): higher levels of depressive symptoms, being admitted to an in-patient hospice setting, a greater perception of being a burden on others, lower family cohesion, lower levels of social support, higher levels of anxiety and greater impact of physical symptoms. Conclusions. Psychological and social factors are related to a WTHD among terminally ill cancer patients. Greater attention needs to be paid to the assessment of psychological and social issues in order to provide appropriate therapeutic interventions for terminally ill patients.

Neurocognitive profiles of people with comorbid depression and alcohol use : implications for psychological interventions

Depression and alcohol use disorders frequently co-occur and are highly prevalent. Both conditions are known to impair cognitive functioning, yet research into the role of these impairments in response to Cognitive Behaviour Therapy (CBT) is limited. The purpose of the present study was to examine the relationship between baseline neuropsychological performance, severity of depressive symptoms and alcohol use disorders. Participants with current depression and hazardous alcohol use were functioning in the average range on all neuropsychological measures prior to treatment entry. Baseline measures of drinking severity and a range of cognitive functions were inversely correlated. After controlling for other baseline variables, superior baseline cognitive functioning predicted greater reductions in depression severity after 17 weeks. These predictive effects occurred across both brief and extended interventions. Findings suggest that improvement in depression following psychological treatment is enhanced by greater fluid reasoning ability and is predicted by executive functioning, regardless of the treatment length or problem focus.

Kava Anxiety Depression Spectrum Study (KADSS): a mixed methods RCT using an aqueous extract of Piper methysticum

Objectives: To report on the design, significance and potential impacts of the first documented human clinical trial assessing the anxiolytic and thymoleptic efficacy of an aqueous monoextract of Piper methysticum (kava). The significance of the qualitative element of our clinical trial is also explored. The Kava Anxiety Depression Spectrum Study (KADSS) is a 3-week placebocontrolled, double-blind, cross-over trial involving 60 adult participants (18—65) with elevated stable anxiety and varying levels of depressive symptoms. Aims: The aims of KADSS are: (1) to determine whether an aqueous standardised extract of kava is effective for the treatment of anxiety; (2) to assess the effects of kava on differing levels of depression; and (3) to explore participants’ experience of taking kava via qualitative research. The study also provides preliminary assessment of the safety of an aqueous extract of kava in humans. Conclusion: If results reveal that the aqueous kava preparation exerts significant anxiolytic effects and appears safe, potentially beneficial impacts may occur. Data supporting a safe and effective kava extract may encourage a re-introduction of kava to Europe, UK and Canada. This may provide a major socioeconomic benefit to Pacific Island nations, and to sufferers of anxiety disorders.

Randomized controlled trial of cognitive-behavioural therapy for coexisting depression and alcohol problems : short-term outcome

AIMS: Alcohol use disorders and depression co-occur frequently and are associated with poorer outcomes than when either condition occurs alone. The present study (Depression and Alcohol Integrated and Single-focused Interventions; DAISI) aimed to compare the effectiveness of brief intervention, single-focused and integrated psychological interventions for treatment of coexisting depression and alcohol use problems. METHODS: Participants (n = 284) with current depressive symptoms and hazardous alcohol use were assessed and randomly allocated to one of four individually delivered interventions: (i) a brief intervention only (single 90-minute session) with an integrated focus on depression and alcohol, or followed by a further nine 1-hour sessions with (ii) an alcohol focus; (iii) a depression focus; or (iv) an integrated focus. Follow-up assessments occurred 18 weeks after baseline. RESULTS: Compared with the brief intervention, 10 sessions were associated with greater reductions in average drinks per week, average drinking days per week and maximum consumption on 1 day. No difference in duration of treatment was found for depression outcomes. Compared with single-focused interventions, integrated treatment was associated with a greater reduction in drinking days and level of depression. For men, the alcohol-focused rather than depression-focused intervention was associated with a greater reduction in average drinks per day and drinks per week and an increased level of general functioning. Women showed greater improvements on each of these variables when they received depression-focused rather than alcohol-focused treatment. CONCLUSIONS: Integrated treatment may be superior to single-focused treatment for coexisting depression and alcohol problems, at least in the short term. Gender differences between single-focused depression and alcohol treatments warrant further study.

Building resilience to prevent mental health problems in young people : The resourceful adolescent programme (RAP)

This chapter describes an evidence-based programme called the Resourceful Adolescent Program (RAP), which has been successful in building resilience in young people to prevent depressive symptoms developing.The programme adopts a strengths-focused approach. It aims to build a range of coping resources that foster teenagers’ abilities to maintain a positive sense of self and regulate emotions in the face of the vicissitudes of everyday struggles and difficult life events.This groupbased programme can be implemented routinely in schools or by counselling professionals as an early intervention or prevention programme. While there is no universal definition, ‘resilience’ generally means the process of avoiding the negative trajectories associated with exposure to risk factors (Fergus and Zimmerman, 2005). Current models of resilience are also very clear that there ‘are many pathways to resilience’ (Bonanno, 2004) and there is no

Determinants of participation restriction among community dwelling stroke survivors : a path analysis

Background: Apart from promoting physical recovery and assisting in activities of daily living, a major challenge in stroke rehabilitation is to minimize psychosocial morbidity and to promote the reintegration of stroke survivors into their family and community. The identification of key factors influencing long-term outcome are essential in developing more effective rehabilitation measures for reducing stroke-related morbidity. The aim of this study was to test a theoretical model of predictors of participation restriction which included the direct and indirect effects between psychosocial outcomes, physical outcome, and socio-demographic variables at 12 months after stroke.--------- Methods: Data were collected from 188 stroke survivors at 12 months following their discharge from one of the two rehabilitation hospitals in Hong Kong. The settings included patients' homes and residential care facilities. Path analysis was used to test a hypothesized model of participation restriction at 12 months.---------- Results: The path coefficients show functional ability having the largest direct effect on participation restriction (β = 0.51). The results also show that more depressive symptoms (β = -0.27), low state self-esteem (β = 0.20), female gender (β = 0.13), older age (β = -0.11) and living in a residential care facility (β = -0.12) have a direct effect on participation restriction. The explanatory variables accounted for 71% of the variance in explaining participation restriction at 12 months.---------- Conclusion: Identification of stroke survivors at risk of high levels of participation restriction, depressive symptoms and low self-esteem will assist health professionals to devise appropriate rehabilitation interventions that target improving both physical and psychosocial functioning.

Social Participation of Community Dwelling Stroke Survivors [Published Abstract: From the Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke Conference 2009]

Disability following a stroke can impose various restrictions on patients’ attempts at participating in life roles. The measurement of social participation, for instance, is important in estimating recovery and assessing quality of care at the community level. Thus, the identification of factors influencing social participation is essential in developing effective measures for promoting the reintegration of stroke survivors into the community. Data were collected from 188 stroke survivors (mean age 71.7 years) 12 months after discharge from a stroke rehabilitation hospital. Of these survivors, 128 (61 %) had suffered a first ever stroke, and 81 (43 %) had a right hemisphere lesion. Most (n = 156, 83 %) were living in their own home, though 32 (17 %) were living in residential care facilities. Path analysis was used to test a hypothesized model of participation restriction which included the direct and indirect effects between social, psychological and physical outcomes and demographic variables. Participation restriction was the dependent variable. Exogenous independent variables were age, functional ability, living arrangement and gender. Endogenous independent variables were depressive symptoms, state self-esteem and social support satisfaction. The path coefficients showed functional ability having the largest direct effect on participation restriction. The results also showed that more depressive symptoms, low state self-esteem, female gender, older age and living in a residential care facility had a direct effect on participation restriction. The explanatory variables accounted for 71% of the variance in explaining participation restriction. Prediction models have empirical and practical applications such as suggesting important factors to be considered in promoting stroke recovery. The findings suggest that interventions offered over the course of rehabilitation should be aimed at improving functional ability and promoting psychological aspects of recovery. These are likely to enhance stroke survivors resume or maximize their social participation so that they may fulfill productive and positive life roles.

Comparison of U.S., Canadian, and Australian participants' performance on the Algase Wandering Scale-Version 2 (AWS-V2)

Background Wandering represents a major problem in the management of patients with Alzheimer’s disease (AD). In this study we examined the utility of the Algase Wandering Scale (AWS), a newly developed psychometric instrument that asks caregivers to assess the likelihood of wandering behavior. Methods The AWS was administered to the caregivers of 40 AD patients and total and subscale scores were examined in relation to measures of mental and functional status, depressive symptoms and medication usage. Results AWS scores were comparable, though slightly lower, than those normative values previously published. Higher scores were associated with more severe dementia. The Negative Outcome subscale showed a significant increase in reported falls or injuries in association with anti-depressant use. Conclusions These data provide some construct validation for the AWS as a potentially useful scale to assess wandering behaviors in AD.

Cigarette smoking in young adults : the influence of the HTR2A T102C polymorphism and punishment sensitivity

Background: The C allele of a common polymorphism of the serotonin 2A receptor (HTR2A) gene, T102C, results in reduced synthesis of 5-HT2A receptors and has been associated with current smoking status in adults. The -1438A/G polymorphism, located in the regulatory region of this gene, is in linkage disequilibrium with T102C, and the A allele is associated with increased promoter activity and with smoking in adult males. We investigated the contributions of the HTR2A gene, chronic psychological stress, and impulsivity to the prediction of cigarette smoking status and dependence in young adults. Methods: T102C and -1438A/G genotyping was conducted on 132 healthy Caucasian young adults (47 smokers) who completed self-report measures of chronic stress, depressive symptoms, impulsive personality and cigarette use. Results: A logistic regression analysis of current cigarette smoker user status, after adjusting for gender, depressive symptom severity and chronic stress, indicated that the T102C TT genotype relative to the CC genotype (OR = 7.53), and lower punishment sensitivity (OR = 0.91) were each significant predictive risk factors. However, for number of cigarettes smoked, only lower punishment sensitivity was a significant predictor (OR = 0.81). Conclusions: These data indicate the importance of the T102C polymorphism to tobacco use but not number of cigarettes smoked for Caucasian young adults. Future studies should examine whether this is explained by effects of nicotine on the serotonin system. Lower punishment sensitivity increased risk of both smoking and of greater consumption, perhaps via a reduced sensitivity to cigarette health warnings and negative physiological effects.

Physical activity, sitting and depression during pregnancy

Aims The aim of this cross sectional study is to explore levels of physical activity and sitting behaviour amongst a sample of pregnant Australian women (n = 81), and investigate whether reported levels of physical activity and/or time spent sitting were associated with depressive symptom scores after controlling for potential covariates. Methods Study participants were women who attended the antenatal clinic of a large Brisbane maternity hospital between October and November 2006. Data relating to participants. current levels of physical activity, sitting behaviour, depressive symptoms, demographic characteristics and exposure to known risk factors for depression during pregnancy were collected; via on-site survey, follow-up telephone interview (approximately one week later) and post delivery access to participant hospital records. Results Participants were aged 29.5 (¡¾ 5.6) years and mostly partnered (86.4%) with a gross household income above $26,000 per annum (88.9%). Levels of physical activity were generally low, with only 28.4 % of participants reporting sufficient total activity and 16% of participants reporting sufficient planned (leisure-time) activity. The sample mean for depressive symptom scores measured by the Hospital Anxiety and Depression Scale (HADS-D) was 6.38 (¡¾ 2.55). The mean depressive symptom scores for participants who reported total moderate-to-vigorous activity levels of sufficient, insufficient, and none, were 5.43 (¡¾ 1.56), 5.82 (¡¾ 1.77) and 7.63 (¡¾ 3.25), respectively. Hierarchical multivariable linear regression modelling indicated that after controlling for covariates, a statistically significant difference of 1.09 points was observed between mean depressive symptom scores of participants who reported sufficient total physical activity, compared with participants who reported they were engaging in no moderate-to-vigorous activity in a typical week (p = 0.05) but this did not reach the criteria for a clinically meaningful difference. Total physical activity was contributed 2.2% to the total 30.3% of explained variance within this model. The other main contributors to explained variance in multivariable regression models were anxiety symptom scores and the number of existing children. Further, a trend was observed between higher levels of planned sitting behaviour and higher depressive symptom scores (p = 0.06); this correlation was not clinically meaningful. Planned sitting contributed 3.2% to the total 31.3 % of explained variance. The number of regression covariates and limited sample size led to a less than ideal ratio of covariates to participants, probably attenuating this relationship. Specific information about the sitting-based activities in which participants engaged may have provided greater insight about the relationship between planned sitting and depressive symptoms, but these data were not captured by the present study. Conclusions The finding that higher levels of physical activity were associated with lower levels of depressive symptoms is consistent with the current body of existing literature in pregnant women, and with a larger body of evidence based in general population samples. Although this result was not considered clinically meaningful, the criterion for a clinically meaningful result was an a priori decision based on quality of life literature in non-pregnant populations and may not truly reflect a difference in symptoms that is meaningful to pregnant women. Further investigation to establish clinically meaningful criteria for continuous depressive symptom data in pregnant women is required. This result may have implications relating to prevention and management options for depression during pregnancy. The observed trend between planned sitting and depressive symptom scores is consistent with literature based on leisure-time sitting behaviour in general population samples, and suggests that further research in this area, with larger samples of pregnant women and more specific sitting data is required to explore potential associations between activities such as television viewing and depressive symptoms, as this may be an area of behaviour that is amenable to modification.

Antiretroviral therapy (ART) adherence among people living with HIV/AIDS (PLHIV) in the north of Vietnam : a multi-method approach

The antiretroviral therapy (ART) program for People Living with HIV/AIDS (PLHIV) in Vietnam has been scaled up rapidly in recent years (from 50 clients in 2003 to almost 38,000 in 2009). ART success is highly dependent on the ability of the patients to fully adhere to the prescribed treatment regimen. Despite the remarkable extension of ART programs in Vietnam, HIV/AIDS program managers still have little reliable data on levels of ART adherence and factors that might promote or reduce adherence. Several previous studies in Vietnam estimated extremely high levels of ART adherence among their samples, although there are reasons to question the veracity of the conclusion that adherence is nearly perfect. Further, no study has quantitatively assessed the factors influencing ART adherence. In order to reduce these gaps, this study was designed to include several phases and used a multi-method approach to examine levels of ART non-adherence and its relationship to a range of demographic, clinical, social and psychological factors. The study began with an exploratory qualitative phase employing four focus group discussions and 30 in-depth interviews with PLHIV, peer educators, carers and health care providers (HCPs). Survey interviews were completed with 615 PLHIV in five rural and urban out-patient clinics in northern Vietnam using an Audio Computer Assisted Self-Interview (ACASI) and clinical records extraction. The survey instrument was carefully developed through a systematic procedure to ensure its reliability and validity. Cultural appropriateness was considered in the design and implementation of both the qualitative study and the cross sectional survey. The qualitative study uncovered several contrary perceptions between health care providers and HIV/AIDS patients regarding the true levels of ART adherence. Health care providers often stated that most of their patients closely adhered to their regimens, while PLHIV and their peers reported that “it is not easy” to do so. The quantitative survey findings supported the PLHIV and their peers’ point of view in the qualitative study, because non-adherence to ART was relatively common among the study sample. Using the ACASI technique, the estimated prevalence of onemonth non-adherence measured by the Visual Analogue Scale (VAS) was 24.9% and the prevalence of four-day not-on-time-adherence using the modified Adult AIDS Clinical Trials Group (AACTG) instrument was 29%. Observed agreement between the two measures was 84% and kappa coefficient was 0.60 (SE=0.04 and p<0.0001). The good agreement between the two measures in the current study is consistent with those found in previous research and provides evidence of cross-validation of the estimated adherence levels. The qualitative study was also valuable in suggesting important variables for the survey conceptual framework and instrument development. The survey confirmed significant correlations between two measures of ART adherence (i.e. dose adherence and time adherence) and many factors identified in the qualitative study, but failed to find evidence of significant correlations of some other factors and ART adherence. Non-adherence to ART was significantly associated with untreated depression, heavy alcohol use, illicit drug use, experiences with medication side-effects, chance health locus of control, low quality of information from HCPs, low satisfaction with received support and poor social connectedness. No multivariate association was observed between ART adherence and age, gender, education, duration of ART, the use of adherence aids, disclosure of ART, patients’ ability to initiate communication with HCPs or distance between clinic and patients’ residence. This is the largest study yet reported in Asia to examine non-adherence to ART and its possible determinants. The evidence strongly supports recent calls from other developing nations for HIV/AIDS services to provide screening, counseling and treatment for patients with depressive symptoms, heavy use of alcohol and substance use. Counseling should also address fatalistic beliefs about chance or luck determining health outcomes. The data suggest that adherence could be enhanced by regularly providing information on ART and assisting patients to maintain social connectedness with their family and the community. This study highlights the benefits of using a multi-method approach in examining complex barriers and facilitators of medication adherence. It also demonstrated the utility of the ACASI interview method to enhance open disclosure by people living with HIV/AIDS and thus, increase the veracity of self-reported data.

The relationship of meta-worry and intolerance of uncertainty with pathological worry, anxiety, and depression

This study explored how meta-worry and intolerance of uncertainty relate to pathological worry, generalised anxiety, obsessive compulsive disorder, social phobia, and depression. University students (n = 253) completed a questionnaire battery. A series of regression analyses were conducted. The results indicated that meta-worry was associated with GAD, social phobia, obsessive compulsive, and depressive symptoms. Intolerance of uncertainty was related to GAD, social phobia, and obsessive compulsive symptoms, but not depressive symptoms. The importance of meta-worry and intolerance of uncertainty as predictors of pathological worry, GAD, social phobia, obsessive compulsive and depressive symptoms was also examined. Even though both factors significantly predicted the aforementioned symptoms, meta-worry emerged as a stronger predictor of GAD and obsessive compulsive symptoms than did intolerance of uncertainty. Intolerance of uncertainty, compared with meta-worry, appeared as a stronger predictor of social phobia symptoms. Findings emphasise the importance of addressing meta-worry and/or intolerance of uncertainty not only for the assessment and treatment of generalised anxiety disorder (GAD), but also obsessive compulsive disorder, social phobia, and depression.

Neuropsychological development in children with early and continuously treated phenylketonuria : association with biochemical markers

PKU is a genetically inherited inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. The failure of this enzyme causes incomplete metabolism of protein ingested in the diet, specifically the conversion of one amino acid, phenylalanine, to tyrosine, which is a precursor to the neurotransmitter dopamine. Rising levels of phenylalanine is toxic to the developing brain, disrupting the formation of white matter tracts. The impact of tyrosine deficiency is not as well understood, but is hypothesized to lead to a low dopamine environment for the developing brain. Detection in the newborn period and continuous treatment (a low protein phe-restricted diet supplemented with phenylalanine-free protein formulas) has resulted in children with early and continuously treated PKU now developing normal I.Q. However, deficits in executive function (EF) are common, leading to a rate of Attention Deficit Hyperactivity Disorder (ADHD) up to five times the norm. EF worsens with exposure to higher phenylalanine levels, however recent research has demonstrated that a high phenylalanine to tyrosine ratio (phenylalanine:tyrosine ratio), which is hypothesised to lead to poorer dopamine function, has a more negative impact on EF than phenylalanine levels alone. Research and treatment of PKU is currently phenylalanine-focused, with little investigation of the impact of tyrosine on neuropsychological development. There is no current consensus as to the veracity of tyrosine monitoring or treatment in this population. Further, the research agenda in this population has demonstrated a primary focus on EF impairment alone, even though there may be additional neuropsychological skills compromised (e.g., mood, visuospatial deficits). The aim of this PhD research was to identify residual neuropsychological deficits in a cohort of children with early and continuously treated phenylketonuria, at two time points in development (early childhood and early adolescence), separated by eight years. In addition, this research sought to determine which biochemical markers were associated with neuropsychological impairments. A clinical practice survey was also undertaken to ascertain the current level of monitoring/treatment of tyrosine in this population. Thirteen children with early and continuously treated PKU were tested at mean age 5.9 years and again at mean age 13.95 years on several neuropsychological measures. Four children with hyperphenylalaninemia (a milder version of PKU) were also tested at both time points and provide a comparison group in analyses. Associations between neuropsychological function and biochemical markers were analysed. A between groups analysis in adolescence was also conducted (children with PKU compared to their siblings) on parent report measures of EF and mood. Minor EF impairments were evident in the PKU group by age 6 years and these persisted into adolescence. Life-long exposure to high phenylalanine:tyrosine ratio and/or low tyrosine independent of phenylalanine were significantly associated with EF impairments at both time points. Over half the children with PKU showed severe impairment on a visuospatial task, and this was associated only with concurrent levels of tyrosine in adolescence. Children with PKU also showed a statistically significant decline in a language comprehension task from 6 years to adolescence (going from normal to subnormal), this deficit was associated with lifetime levels of phenylalanine. In comparison, the four children with hyperphenylalaninemia demonstrated normal function at both time points, across all measures. No statistically significant differences were detected between children with PKU and their siblings on the parent report of EF and mood. However, depressive symptoms were significantly correlated with: EF; long term high phe:tyr exposure; and low tyrosine levels independent of phenylalanine. The practice survey of metabolic clinics from 12 countries indicated a high level of variability in terms of monitoring/treatment of tyrosine in this population. Whilst over 80% of clinics surveyed routinely monitored tyrosine levels in their child patients, 25% reported treatment strategies to increase tyrosine (and thereby lower the phenylalanine:tyrosine ratio) under a variety of patient presentation conditions. Overall, these studies have shown that EF impairments associated with PKU provide support for the dopamine-deficiency model. A language comprehension task showed a different trajectory, serving a timely reminder that non-EF functions also remain vulnerable in this population; and that normal function in childhood does not guarantee normal function by adolescence. Mood impairments were associated with EF impairments as well as long term measures of phenylalanine:tyrosine and/or tyrosine. The implications of this research for enhanced clinical guidelines are discussed given varied current practice.