Searching for the developmental origins of mental disorders

Abstracts

INTRODUÇÃO: A psicopatologia desenvolvimental é uma disciplina que integra perspectivas epidemiológicas, sociais, genéticas, desenvolvimentais e de psicopatologia para entender as origens e o curso dos transtornos mentais. Neste artigo, são discutidos abordagens e conceitos utilizados para compreender as origens desenvolvimentais dos transtornos mentais. RESULTADOS: A psicopatologia desenvolvimental entende que os transtornos mentais são possíveis desfechos do processo de desenvolvimento e são dependentes de influências sociais, genéticas e ambientais. Esses diversos fatores estão inter-relacionados de diferentes formas e em diferentes níveis, exercendo um efeito dimensional. São discutidos: a) abordagens para determinar causalidade entre eventos ambientais e transtornos mentais; b) a importância de entendimento dos mecanismos biológicos através dos quais fatores ambientais e genéticos atuam; c) fatores genéticos predizendo a exposição a estressores ambientais; e d) fatores genéticos moderando o efeito de estressores ambientais. CONCLUSÕES: As origens dos transtornos mentais podem ser iluminadas por dados de estudos que utilizam enfoques e conceitos complementares e que integrem influências sociais, genéticas, ambientais e desenvolvimentais.

Psicopatologia desenvolvimental; transtornos mentais; origens; interação gene-ambiente; correlação gene-ambiente

SPECIAL ARTICLE

Searching for the developmental origins of mental disorders*

Guilherme V. Polanczyk

Child and Adolescent Psychiatrist, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil. MSc and PhD in Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Post-doctorate student, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, UK & Department of Psychology and Neuroscience, Duke University, USA.

Correspondence

ABSTRACT

INTRODUCTION: Developmental psychopathology is a discipline that integrates epidemiological, social, genetic, developmental, and psychopathological perspectives to understand the origins and courses of mental disorders. In the present paper, theoretical concepts and approaches applied with the purpose of understanding the developmental origins of mental disorders are discussed.

RESULTS: According to developmental psychopathology, mental disorders are possible outcomes of the developmental process that depend upon social, genetic, and environmental influences. These factors are linked in different ways and levels, exerting a dimensional effect. The following factors are addressed: a) approaches to determine a causal effect between environmental factors and mental disorders; b) the importance of understanding biological mechanisms by which environmental and genetic factors exert their effect; c) genetic factors predicting the exposure to environmental stressors; d) genetic factors moderating the effect of environmental stressors.

CONCLUSIONS: The origins of mental disorders can be clarified by data from studies that use complementary approaches and concepts, integrating social, genetic, environmental and developmental influences.

Keywords: Developmental psychopathology, mental disorders, origins, gene-environment interaction, gene-environment correlation.

Introduction

Developmental psychopathology is a dynamic field of knowledge that is continuously evolving. The term first appeared in the book by Thomas Achenbach, Developmental Psychopathology,¹ published in 1974, and the discipline developed mainly after the studies by Sroufe,² Cicchetti³ and Rutter,⁴ among others. Developmental psychopathology integrates social, genetic and developmental perspectives and tests its hypothesis using specific epidemiological and statistical methods, trying to understand the origin and course of mental disorder.⁴

At first, the emphasis on the developmental process was used mainly to understand child mental disorders.⁵ As a consequence of the field's evolution, studies have demonstrated that there is an important continuity of disorders from childhood, to adolescence and to adulthood, and that a large proportion of adults with mental disorders have been suffering from them since their adolescence.⁶ Therefore, adult psychiatrists have also adopted a developmental approach to understand the origins of their patients' current disorders.^7,8 In fact, results of studies using a developmental approach integrating epidemiology, genetics, neuropsychology and neuroimaging techniques have shown great potential to help us understand the origins of mental disorders.⁹

Developmental psychopathology can be understood as a conceptual model that enables the design of research strategies, the interpretation of observations and the generation of subsequent theories. Therefore, developmental psychopathology is one of the possible lenses through which psychopathology can be seen. In the present study, concepts and approaches used by this conceptual model to understand how and why certain individuals develop mental disorders are discussed. A number of reviews have been published on different aspects of this discipline,^2-4,10-13 as well as a textbook containing more than 3,000 pages.¹⁴ Thus, the aim of the present article is to stimulate that readers consider this approach on their individual search for tools to understand the development of mental disorders.

Which are the developmental concepts and approaches that help us to understand the origin of mental disorders?

Investigators on this field focus on different approaches and concepts, but they all agree that mental disorders are possible outcomes of the developmental process.¹² They also agree that mental disorders occur because of complex dimensional interrelationships at multiple levels between specific characteristics of individuals (biological, genetic and psychological factors), environmental characteristics (parental care, interpersonal relationships, exposure to stressful events) and social characteristics (social support network, neighbors, socioeconomic status).^4,14 Four concepts that guide developmental approaches should be highlighted.

First, developmental psychopathology assumes that there is continuity in the developmental process of mental disorders, that is, the effect of previous experiences is carried forward throughout development. Hence, the identification of lack of continuity in this process is an important opportunity to better understand it.² Second, there is an innate tendency for individuals to adapt to their environment; if the environment is pathological, adaptation is likely to be pathological as well.¹¹ Third, age and developmental stage are crucial factors based on which all other factors must be understood.¹¹ Fourth, maladaptive behaviors or mental disorders should be interpreted taking into consideration the context surrounding the individual. The last two concepts focus on the idea that the developmental process of mental disorders is specific, that is, the causal mechanisms produce different results depending on the individual's age, developmental phase, and familial and social context.⁴

As possible outcomes of the developmental process,¹² the mental disorders would not necessarily be different categories, but dimensional developmental pathways.¹⁰ Just like a complex highway network, where different highways can lead to the same place, different developmental pathways can lead to the same psychopathological process. On the other hand, in the same way as a highway can lead to different places, the same psychopathological pathways can result in different outcomes. Individuals who take a certain developmental pathway can then take a different one, and the earlier the detour is taken, the higher the difficulty to go back to the original path.³

Looking for environmental factors with causal effect

Environmental risk factors for mental disorders act by means of multiple mechanisms and levels and they are usually correlated with a chain of risk factors that, on its turn, can act using different mechanisms. The focus is not only on the effects of risk factors, but also on their origins, and therefore it is possible to understand in a more specific manner the actual mechanism they use to act.¹⁵

It is important to implement several strategies in order to demonstrate the presence of a causal effect between environmental risk factors and mental disorders. First, it is very important that the relationship exists based on a solid conceptual foundation, with evidence of possible mechanisms through which the events occur. For instance, there is consistent neurobiological evidence indicating the mechanism through which child abuse and maltreatment change the functioning of the hypothalamic-pituitary-adrenal axis, which may lead to depression in adulthood.¹⁶ Evidence regarding a possible mechanism is not always available, and often the conceptual basis is revealed based on epidemiological findings. However, at the current state of knowledge, new environmental risk factors for mental disorders have been rarely revealed. Second, it is crucial to demonstrate a consistent temporal connection between the stressful event and the onset of the disorder.¹⁷ Longitudinal studies are essential so that this objective can be achieved, and the challenge lays in the study of chronic events, of events that act through different mechanisms, or that change their intensity as time goes by. In order to clarify the temporal relation between both factors, it is important to distinguish if the environmental stressor led to the psychopathological process, or if the latter had its onset before the stressor and was the cause of it, which, on its turn, might have exacerbated the psychopathological process. For instance, mild depressive symptoms can lead to a job dismissal, which, as a consequence, can exacerbate the psychopathological process leading to a depressive episode. In that case, the job dismissal is correlated with the depressive episode, but it is not its cause. In a longitudinal study, if previous mild depressive symptoms are not identified, even when there is a temporal connection between the dismissal and the depressive episode, the interpretation that there is a causal relation between both events would be erroneous. The interpretations of results generated by cross-sectional studies are further limited. Third, it is necessary to apply strict methods of measurement to evaluate risk factors and outcomes using specific and dimensional measures.¹⁵ In the previous example, it would be necessary to use sensitive measures that would be able to identify mild depressive symptoms previous to dismissal. Fourth, it is important to contextualize environmental events. For instance, a job dismissal can have completely different meanings for two different persons. Such event can trigger a chain of stressful events, such as income reduction, depression, violence, criminal deeds, or can be the beginning of a new developmental pathway characterized by the search for new objectives and achievements.

The epidemiological approaches used to demonstrate that a specific environmental event has a causal effect are limited in face of the complexity of the processes and, mainly, due to the great range of confounding variables that are not taken into consideration. Randomization is the most appropriate methodological strategy to demonstrate a cause-effect relationship because individuals are randomly allocated to a specific type of intervention. However, obvious ethical issues do not allow the manipulation of individuals in order to expose them to stressful events. Therefore, natural experiments are unique opportunities to understand the origins of mental disorders. These studies use differences that occur naturally after the exposure to a certain stressor among different individuals, such as Romanian children reared in profoundly depriving institutions,¹⁸ the terrorist attacks of September 11 in the USA¹⁹ or the Hurricane Katrina.²⁰

A particular natural experiment tried to understand the relation between psychopathology and poverty by testing if poverty is the cause of psychopathology (social causation) or if psychopathology leads to poverty (social selection).²¹ A representative sample of children was being evaluated for mental disorders once a year. One quarter of the sample was comprised of American Indians, and the remaining were predominantly white. During the study period, a casino was opened in the indigenous reserve, and each family that lived in the area started to receive a monthly income. During the 4 years after the casino opening, some families did not change their socioeconomic status ("persistently poor"), even after receiving the additional income; others changed their socioeconomic status after the casino was opened ("ex-poor"); and a third group of families never belonged to the lowest socioeconomic class ("never poor").. Children continued to be evaluated once a year, and the investigators found that, at the end of this period (4 years), the levels of behavior and oppositional symptoms among the children who belonged to families that changed their socioeconomic status were reduced to the same levels as those who had never been poor. However, the levels of such symptoms among the children who belonged to families that did not change their socioeconomic status remained high. Thus, the authors demonstrated the effect of poverty as a cause of symptoms of behavior and oppositional disorder. Nevertheless, the mechanisms through which poverty leads to psychopathology were not revealed in that study. Specifically, it would be quite informative if we could understand which are the intermediate factors that respond to the increase in income and lead to a reduction in psychopathology. Therefore, the study of proximal risk factors for the development of psychopathology, such as quality of parental care, better nutritional status and housing conditions, can be more informative in order to understand the mechanisms and, as a consequence, to elaborate prevention strategies than distal risk factors, such as poverty.²²

Understanding the mechanism of action of causal agents

Developmental psychopathology is interested in understanding the specific mechanisms or processes through which causal agents act.¹⁵ First, it is crucial to understand if a certain factor acts by means of environmental or genetic aspects. Next, it is necessary to understand how the environmental effect "gets inside the skin," promoting the development of mental disorders, and how these genes also "get outside the skin,"¹⁵ leading to behaviors that can be observed.

A recently published study shows the necessity of understanding the mechanism through which an environmental factor acts.²³ There is a long and still unsettled discussion in the literature regarding the mechanism through which the intrauterine exposure to tobacco would lead to child psychopathology. There is evidence suggesting that such mechanism would occur by acting on the intrauterine environment, whereas other studies indicate that smoking during pregnancy is a marker of maternal psychopathology associated with genetic factors that, on their turn, are inherited by children, thus leading to the psychopathology.²⁴ Rice et al.²³ used a creative method to try to understand the mechanism through which intrauterine exposure to tobacco would affect children generated by in vitro fertilization. The contribution of in vitro fertilization to developmental psychopathology lays in the fact that children conceived by this method can be genetically related to their parents or not (if there was sperm and/or ovule donation), thus enabling the dissociation of potentially genetic effects from effects on the intrauterine environment. Hence, the authors compared the effect of maternal smoking with regard to birth weight and antisocial behavior among children who were or not genetically related to their mothers.²³ Birth weight was lower in the group of children exposed to intrauterine tobacco, regardless of being or not genetically related to their mothers. On the other hand, the levels of antisocial behavior were higher for those children exposed to intrauterine tobacco only when they were genetically related to their mothers (smokers), then suggesting that the intrauterine environmental effect caused by tobacco was not associated with antisocial behavior in these children. This study shows that intrauterine exposure to tobacco acts by means of different mechanisms on different outcomes and that, in terms of antisocial behavior, it does not act through the intrauterine environment. However, we cannot be sure that smoking during pregnancy is a marker of purely genetic risk or if it is associated with maternal behaviors throughout the child's development, which, on their turn, may exert causal effect on the development of antisocial behavior.

To understand the mechanisms through which environmental events "get inside the skin," promoting the development of mental disorders, is a challenge. Among the several possible approaches to this issue, there are three approaches that have been more successful to date. The first one is focused on the neuroendocrine effects of environmental stressors. There is a large number of studies in the literature showing the neuroendocrine effects of stressful events on the hypothalamic-pituitary-adrenal axis.¹⁶ The second one is focused on the study of the activity of environmental factors that act during the perinatal period. These factors seem to have persistent influences throughout the development (biological programming), leading individuals to take one or another developmental path (developmental plasticity).²⁵ How much the environment will agree or not with the initial programming throughout time could be related to the development of several physical diseases, such as obesity and diabetes, and also hormonal alterations related to mental disorders.²⁵ The third approach is focused on the change of the genetic expression caused by environmental stressors through the so-called epigenetic effects.²⁶ Environmental factors cannot change the DNA sequence, but it has been shown that throughout development they can change the way genes are expressed, changing the way they function and, in this way, contributing to the development of mental disorders.²⁷

The comprehension of the epigenetic activity of environmental factors is based on the fact that approximately 98% of the human genome is comprised of non-coding DNA, located in distant regions of the genes, that is, in regions that are not translated. Non-coding DNA is poorly preserved among the species in comparison with the coding DNA, which is highly preserved. Therefore, it is possible that non-coding DNA has great influence on the differences among the species. Once transcribed to RNA, such influence would occur through the regulation of the expression of genic products by means of the so-called epigenetic mechanisms (such as transcription-promoting and transcription-silencing factors, alternative splicing processes, protein unpacking during translation, genomic imprinting).²⁶ Also, gene expression is performed in a selective manner in different tissues, which is determined by mechanisms such as histone methylation and acetylation.²⁶

A recent study showed important data on the epigenetic effects of child abuse.²⁸ There is consistent evidence showing that the reduced expression of glucocorticoid receptors in the hippocampus is associated with several psychopathologies such as depression, schizophrenia and suicide.²⁶ At the same time, better maternal care in rodents is associated with a higher expression of this receptor.²⁹ Thus, McGowan et al.²⁸ studied the expression of hippocampal glucocorticoid receptors in brains of suicide victims who had been abused during childhood, suicide victims who had not been abused and controls. The expression of receptors was reduced in the suicide victims who had been abused during childhood in comparison with controls, and the authors did not find difference in the levels of expression between the group of victims with no history of abuse and controls. In spite of the inherent limitations of the study design, such fascinating data corroborate previous evidence in animal models and suggest that alteration in the expression of these receptors is related to child abuse. Such data, despite the limitations of interpretation, suggest a quite promising path so that we can understand the mechanisms through which adverse environmental events contribute to the development of mental disorders.

Genetic factors predisposing to the exposure to environmental stressors

The genes involved in the susceptibility to psychiatric disorders are comprised of several common allele variants that do not affect vital functions.³⁰ These genes also have a small susceptibility effect on the causal process, which, most of the time, is dimensional and interacts with complex processes. Also, genes often present an indirect effect, determining sensitivity to environmental risks that, on their turn, are correlated with the psychopathological process.^11,30,31

The correlation between genes and environment is one of the possible interrelations between these factors, with regard to the genetic influence on the variability of individuals exposed to different types of risk environments. That is, certain behaviors that become environmental stressors are determined by the individual's genotype. Such correlation can be passive, active or evocative. The passive correlation is the one that does not depend on the individual's action and is basically related his/her parents' genes, which have an influence on the environment where the individual is raised and the experiences he/she has to go through, mainly during the first years of life. The active correlation is related to the effect of genes on the individual's behavior, which determines the selection or pattern of environmental experiences to which the individual is exposed. The evocative correlation is related to the effect of genes on the individual's behavior that will trigger responses from other people, defining his/her environmental experiences.³¹

Genetic factors moderating the effect of environmental stressors

There are situations in which the individual's genotype changes the effect of an environmental stressor regarding the development of mental disorders, that is, genetic factors act as moderators of the effect produced by adverse events. Under such conditions, there is gene-environment interaction (GxE), opposing to the traditional notion that genes and environment would act in an additive, non-interactive mode.²² Some situations suggest the existence of an actual GxE. Evidence might indicate substantial risks of developing a disorder mediated by environmental factors; however, there must be a clear heterogeneity in the individual's response to such risks regarding differences in the probability of developing the specific disorder.³¹ Therefore, the same stressor can reach devastating proportions in one individual, while, in another person, it may promote growing and personal strengthening, originating the concept of resilience. Evidence has shown that the individual's characteristics that existed before the stressful event took place, such as temperament and cognitive functioning, which are under genetic influence, are associated with resilience, in addition to other factors that act at different moments with regard to the event.¹¹ Another sign of possible GxE is the existence of evidence of a substantial genetic risk; however, this genetic contribution must operate by means of indirect pathways and not through the direct connection to a specific condition.³¹ Gene-environment interactions probably occur when there is substantial disagreement in pairs of monozygotic twins in terms of the disorder being studied.^22,31 The first studies that showed the existence of GxE were focused on the origin of depression and behavior disorder.

In relation to depression, it is quite clear that adverse events involving life threat, losses, mortifications and deprivations are related to its development.^32,33 There is, however, an evident variation in the response of different individuals to such events. For certain individuals, stressful events trigger a depressive episode, while other individuals who undergo equally or more stressing events do not develop a mental disorder.^34,35 Furthermore, the weight of genetic and environmental factors in triggering depression seems to be influenced by the individual's developmental phase, with early stressful events having an effect of sensitization to the disorder throughout personal development.³⁶ In adolescence, genetic factors play a central role in triggering depression, a role that is played by environmental stressors during childhood.³⁷ Such findings are strong signs of the presence of interaction between environmental and genetic factors in the etiological process of depression.

Genes of the serotoninergic system are logical candidates to the study on the genetic components of depression, considering that drugs that are efficacious to treat depression act on such system.³⁸ The serotonin transporter (5-HTT) gene has been the focus of a number of studies, and its role as the candidate gene for depression has been demonstrated by association studies.³⁸ Taking into consideration the strong signs of the existence of GxE in the etiology of this disorder, Caspi et al.³⁹ studied the moderating role of a functional polymorphism in the promoter region of 5-HTT on the effects of stressful life events for the development of depression. Those individuals with a short allele of the 5-HTTLPR polymorphism received a significantly higher impact from stressful events than the homozygotic individuals for the long allele.

With regard to conduct disorder, its heritability coefficient (proportion of total variance of a characteristic explained by genetic factors) is of approximately 50%, with substantial disagreement between monozygotic twins. Environmental risk factors have important influence on the development of conduct disorder, with a strong heterogeneity regarding the response to stressors among individuals. In addition, the effects of stressors seem to be stronger in children and adolescents at genetic risk.

Based on such evidence, Caspi et al.⁴⁰ evaluated the effect of the interaction between a functional polymorphism in the promoter region of the monoamine oxidase A (MAO-A) gene and situations involving child maltreatment on the development of antisocial behaviors in adulthood. Consistent data suggest a relation between MAO-A and aggressiveness, both in animal and human models. This enzyme metabolizes neurotransmitters such as noradrenaline, serotonin and dopamine, and when its activity is reduced, the organism would be exposed to neural hyperactivity in response to threats. Child maltreatment is a well-known and studied risk factor for antisocial behavior in adulthood. However, a significant proportion of children who were maltreated during childhood do not present antisocial behavior throughout their development, which raises the hypothesis that genetic influences may have a moderator effect on such stressor. The results of the study showed that the MAO-A activity did not have main effect on the development of antisocial behavior.⁴⁰ On the other hand, child maltreatment had a significant effect on the outcome, and such effect was moderated by the MAO-A gene.⁴⁰ That is, individuals with low enzymatic activity and who were maltreated during childhood had higher chances of developing conduct disorder, being convicted for severe crimes and having higher scores on the violent and antisocial behavior scales than those who were maltreated but did not have low enzymatic activity.⁴⁰

The findings of these studies suggested a new investigation route, and several studies that approached different risk factors, genes and outcomes have been subsequently published.⁴¹ The reason for that is mainly the preventive potential presented by the identification of which genetic factors would make people more sensitive or resistant to the development of a mental disorder when exposed to adverse factors. However, in order to meet this goal, it is important to identify the actual interactions, with a plausible biological meaning, and not only statistical interactions. To reach that purpose, in addition to the study of the specific mental disorder, it seems crucial to understand the effect of the stressful event of interest on individuals without a psychopathology (from the phenotypical and neurobiological point-of-view), to study animal models, and to understand the functional relevance of the polymorphisms of interest.⁴²

Future perspectives

The complexity and specificity of processes that lead to the development of mental disorders challenge our ability to understand them in detail. Conducting longitudinal studies that follow-up individuals throughout their lives is the most promising way.⁴³ Indeed, in 2010, the National Children's Study, a longitudinal study that will follow-up more than 100,000 children in the USA, from pre-conception until they turn 20 years old, will be implemented.⁴⁴ Considering the statistical power and the complexity of the assessments that will be carried out in this study,¹³ there is great expectation regarding the data that will be generated in the next decades.

The development of new genetic analysis techniques, mainly the microarrays, will provide a global overview of the patterns of genic expression. Hundreds of genes will be evaluated at the same time, and the genetic risk of a given individual will be predicted. It will be possible to explore developmental issues after knowing the risk magnitude.²⁷ It is not clear, however, if this fantastic amount of information will produce sufficiently robust knowledge that will be transformed into clinical interventions.⁴⁵ At the same time, the development of new statistical tools, such as the analysis of developmental trajectories through the modeling of latent variables^46,47 or multi-level analysis,⁴⁸ will also enable us to understand more complex issues. However, all these techniques will only be successful if the assessment of environmental factors is performed in a refined manner, employing methodological accurate approach. It is clear that the way environmental variables are conceptualized and measured has a significant influence on the results.⁴⁹ Therefore, the assessment of environmental stressors must be supported by solid conceptual bases.

Conclusions

Developmental psychopathology, like a lens to observe and understand the mental disorders, minimizes certain aspects and focuses on others. It is the task of each investigator to critically consider the use of this conceptual model. Developmental psychopathology refuses the idea that risk factors act in an isolated manner and is not satisfied with the mere identification of associations or correlations. In order to be capable of translating the acquired knowledge into benefits to the population, we need to understand the mechanisms through which such risk factors lead to the development of mental disorders. With that purpose, studies including complementary approaches, which integrate different concepts and use designs provided by natural events, have a great potential to elucidate the developmental origins of mental disorders.

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Financiamento: Este trabalho é parcialmente financiado pela National Alliance for Research on Schizophrenia and Depression (NARSAD), The World's Leading Charity Dedicated to Mental Health Research, através do mecanismo 2008 Young Investigator Award.

Publication Dates

• Publication in this collection
  24 Aug 2009
• Date of issue
  2009

History

• Accepted
  16 Apr 2009
• Received
  31 Mar 2009