There is an enormous interest in identifying the causes of psychiatric disorders but there are considerable challenges in identifying which risks are genuinely causal. Traditionally risk factors have been inferred from observational designs. However, association with psychiatric outcome does not equate to causation. There are a number of threats that clinicians and researchers face in making causal inferences from traditional observational designs because adversities or exposures are not randomly allocated to individuals. Natural experiments provide an alternative strategy to randomized controlled trials as they take advantage of situations whereby links between exposure and other variables are separated by naturally occurring events or situations. In this review, we describe a growing range of different types of natural experiment and highlight that there is a greater confidence about findings where there is a convergence of findings across different designs. For example, exposure to hostile parenting is consistently found to be associated with conduct problems using different natural experiment designs providing support for this being a causal risk factor. Different genetically informative designs have repeatedly found that exposure to negative life events and being bullied are linked to later depression. However, for exposure to prenatal cigarette smoking, while findings from natural experiment designs are consistent with a causal effect on offspring lower birth weight, they do not support the hypothesis that intra-uterine cigarette smoking has a causal effect on attention-deficit/hyperactivity disorder and conduct problems and emerging findings highlight caution about inferring causal effects on bipolar disorder and schizophrenia.

Translational research focuses on innovation in healthcare settings, but this is a two-way process that may have implications for either treatment or prevention. Smoking and lung cancer and the fetal alcohol syndrome are used as examples. Experimental medicine that budges basic and clinical science often constitutes a key way forward. Areas of scientific progress and challenge are discussed in relation to drug action, social cognition, cognitive neuroscience, molecular genetics, gene–environment interaction, and epigenetics. Key concepts and challenges in relation to stress include toxicity, allostatic load, the hypothalamus–pituitary–adrenal axis, and objectives versus subjective stress. The reasons for the need to test causal inferences are discussed. Various kinds of “natural experiments” are discussed in illustration using the assisted conception design, the discordant monozygotic twin design, and the study of universal exposure. Animal models are discussed in relation to enrichment and deprivation effects and the effects of infant separation experiences, epigenetic effects, and the biological embedding of experiences. Translational issues are discussed in relation to the hypothalamic–pituitary–adrenal axis, epigenetics, and inflammation. In conclusion, it is suggested that there are immediate possibilities for experimental medicine but caution is needed with respect to moving into translation too quickly.

The aim of the study was to examine possible influences on individual differences in adolescence in response to early institutional care in infancy not involving either generalized privation or subnutrition. Fifty-two adopted adolescents aged 13 years who received institutional care in infancy at the Metera Babies Centre and 36 adolescents of the same age who were raised in their biological families participated in the study. Adolescents' attachment relationships, cognition, behavioral adjustment and use of psychological services were assessed. Marked heterogeneity in outcomes was found. No predictive effects were found for preinstitutional features or for adoptive circumstances. By contrast a large effect was found for institutional care extending beyond the age of 2 years and for quality of institutional care as experienced at an individual level. There was a close association between prolonged institutional care and disorganized attachment while in the institution, but the main institutional effect derived from the length of time in the institution.

Developmental psychopathology is described as a conceptual approach that involves a set of research methods that capitalize on developmental and psychopathological variations to ask questions about mechanisms and processes. Achievements are described in relation to attachment and attachment disorders, autism, schizophrenia, childhood antecedents of adult psychopathology, testing for environmental mediation of risk effects, gene–environment interplay, intellectual and language functioning, effects of mentally ill parents on the children, stress and vulnerability to depression, ethnicity and schizophrenia, and drug response. Continuities and discontinuities over the course of development are discussed in relation to attention-deficit/hyperactivity disorder, antisocial behavior, eating disorders, substance abuse and dependency, pharmacological and behavioral addictions, and a range of other disorders. Research challenges are considered in relation to spectrum concepts, the adolescent development of a female preponderance for depression, the mechanisms involved in age differences in response to drugs and to lateralized brain injury, the processing of experiences, the biological embedding of experiences, individual differences in response to environmental hazards, nature–nurture integration, and brain plasticity.

The concept of resilience has as its starting point the recognition that there is huge heterogeneity in people's responses to all manner of environmental adversities. Resilience is an inference based on evidence that some individuals have a better outcome than others who have experienced a comparable level of adversity; moreover, the negative experience may have either a sensitizing effect or a strengthening “steeling” effect in relation to the response to later stress or adversity. After noting the crucial importance of first testing for the environmental mediation of risk through “natural experiments,” findings are reviewed on “steeling effects” in animal models and humans. Gene–environment interaction findings are considered, and it is noted that there is some evidence that the genetic influences concerns responsivity to all environments and not just bad ones. Life course effects are reviewed in relation to evidence on turning point effects associated with experiences that increase opportunities and enhance coping. Attention is drawn to both research implications and substantive findings as features that foster resilience.

Psychopathy is not included in either of the main classification systems (ICD-10 or DSM-IV). Research has now extended the concept of psychopathy to childhood and has produced evidence that it is meaningfully distinct from antisocial behaviour. It is proposed that psychopathy should be accepted as a meaningful diagnosis in childhood.

Many prenatal risk factors are known to have adverse consequences on fetal development and there is increasing interest in effects on the mental health of offspring. However, associations with prenatal risk factors may arise because of postnatal risk or through confounders, including inherited ones. As a result, caution is required in assuming causation.

The study assessed conduct and emotional difficulties in a group of Romanian adoptees at age 11, and serves as a follow-up to assessments made when the children were 6 years old. It was found that there was a significant increase in emotional difficulties, but not conduct problems, for the Romanian sample since age 6. It was also found that emotional difficulty was significantly more prevalent at age 11 in the Romanian group than in a within-UK adoptee group. Emotional difficulties in the Romanian adoptee group were found to be significantly and strongly related to previous deprivation-specific problems (disinhibited attachment, cognitive impairment, inattention/overactivity and quasi-autism); however, the presence of such early problems did not account fully for the onset of later emotional problems. Five contrasting hypotheses concerning possible mediators for later onset of emotional difficulties for the Romanian group were examined. No links were found to duration of deprivation or other deprivation-related indices, stresses/difficulties in the postadoption family environment, or educational attainment and self-esteem. There was some evidence that emotion recognition might play a role in the emergence of these problems, but other measures of social competence and theory of mind showed no associations with the onset of emotional problems.

William Yule's many contributions to the field of reading disabilities over the last 40 years are reviewed and set in the context of recent research evidence. The value of regression methods in the measurement of reading performance remains valid, but spelling, as well as reading, difficulties need to be assessed in relation to the diagnosis of dyslexia. Although categorical approaches to diagnosis are needed for some purposes, it is likely that the genetic liability to dyslexia is dimensional. Overall, Yule's identification of the key features of specific reading retardation have been confirmed by subsequent research, but the concept of general reading backwardness as a diagnosis has proved less meaningful. The identification of the high rate of comorbidity between reading disability and emotional/behavioural disturbance, highlighted by Yule 35 years ago, has been amply confirmed but the causal mechanisms remain ill-understood.