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Early life stress, HPA axis, and depression

Early life stress, HPA axis, and depression Considerable evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology, especially depression. The most recent studies reviewed herein suggest that early life stressors are associated with an increased risk for mood disorders in adulthood. This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and depression and the role of early life stress as an important risk factor for HPA axis dysregulation. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. Moreover, HPA axis changes appear to be state- dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during antidepressant treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in major depression, but few studies have assessed the activity of mineralocorticoid receptors in depression. Thus, more studies are needed to elucidate this issue. Keywords: early life stress, childhood trauma, depression, treatment-resistant depression, hypothalamic-pituitary-adrenal axis. Received 21 March 2011; received in revised form 11 June 2011; accepted 18 June 2011. Available on line 10 October 2011 Introduction states that the causes, development, and outcomes of disorders are determined by the relationships Psychological stress may change the internal between psychological, social, and cultural factors homeostatic state of an individual. During acute and biochemistry and physiology. Biochemistry and stress, adaptive physiological responses occur, physiology are not disconnected or different from including increased adrenocortical hormone secretion, the rest of our experiences and life events (Juruena, primarily cortisol. Whenever an acute interruption of Marques, Mello, & Mello, 2007). this balance occurs, illness may result. Particularly interesting are psychological stress (i.e., stress in Early life stress the mind) and the interactions with the nervous, endocrine, and immune systems. The concept of early life stress is quite broad and A key problem in diagnosis is the fact that elaborate includes the different traumatic experiences that occur classification systems that exist today are solely during childhood and adolescence, which may have based on subjective descriptions of symptoms. Such repercussions in adulthood. Among these are parental loss, detailed phenomenology includes the description of separation from parents, childhood illness, family violence, multiple clinical subtypes, but no biological feature can and deprivation of food, clothing, shelter, and love. distinguish one subtype from another. This approach In agreement with Bernstein et al. (1994), childhood maltreatment may be subdivided into the Sandra Marcia de Carvalho Tofoli, Cristiane Von Werne Baes, following domains: and Camila Maria Severi Martins, Department of Neuroscience and Behaviour, Faculty of Medicine Ribeirao Preto, University 1. Physical abuse: physical aggression by someone of Sao Paulo. Mario Juruena, Stress and Affective Disorders older, with the risk of or result of injury. Programme, Department of Neurosciences and Behaviour, Faculty of Medicine Ribeirao Preto, University of Sao Paulo. 2. Emotional abuse: verbal aggression that affects Correspondence regarding this article should be directed to: the welfare or morale of the child or any conduct that Mario Juruena, Saúde Mental-USP, Av. Tenente Catão Roxo, humiliates, embarrasses, or threatens the child. 2650, Monte Alegre - Campus Universitário, Ribeirão Preto, SP CEP 14051-140, Brazil. E-mail: juruena@fmrp.usp.br 230 Tofoli et al. 3. Sexual abuse: any type of sexual contact or conduct Psychoneuroendocrinology between a child and someone older. The maintenance of the internal homeostatic state 4. Emotional neglect: failure of caretakers to provide for of an individual is proposed to be based on the ability of basic emotional and psychological needs such as love, circulating glucocorticoids to exert negative feedback on motivation, and support. the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid receptors 5. Physical neglect: failure of caretakers to provide for (MRs) and glucocorticoid receptors (GRs), limiting the basic physical needs such as feeding, a home, security, vulnerability to diseases related to psychological stress supervision, and health (Bernstein et al., 1994, 2003). in genetically predisposed individuals. The HPA axis response to stress can be thought Childhood maltreatment is a major social problem. of as a mirror of the organism’s response to stress: It is a complex global phenomenon that does not respect acute responses are generally adaptive, but excessive boundaries of class, race, religion, age, or educational or prolonged responses can lead to deleterious effects. level and can occur both publicly and privately, resulting These deleterious effects, which may not be clinically in serious physical injury or even death. Moreover, its apparent, have the potential to serve as endophenotypic psychological consequences can acutely affect a child’s markers of disease susceptibility (Juruena, Cleare, mental health well into adulthood (Friedrich, 1998; Bauer, & Pariante, 2003; Mello et al., 2007). Because Cruz, Silva, & Alves, 2007). the HPA axis is activated in response to stressors, Early life stress is associated with a diverse stressful events in early life may also have an range of psychiatric consequences. In children etiologically significant role in the HPA abnormalities and adolescents, it increases the risk of behavioral found in psychiatric disorders including Depression, problems, including internalizing and externalizing Bipolar disorder, Anxiety disorders, Eating disorders, b e h a v i o r. I n t e r n a l i z i n g r e f e r s t o b e h a v i o r a l Schizophrenia, Substance abuse, Dissociative disorder, s y m p t o m s r e f l e c t e d b y a n x i e t y, d e p r e s s i o n , and PTSD, among other medical illnesses (Juruena, somatic complaints, and inhibition. Externalizing Cleare, & Pariante, 2004; Mello et al., 2007). refers to behavioral symptoms reflected by According to Favarelli et al. (2010), the aggression, delinquency, and increased activity effect of childhood trauma on the development level. Sexual behavior problems most likely fall into of psychopathology in adulthood is attributable this domain (Friedrich, 1998). to the HPA axis, which when activated during the Considerable evidence from various studies developmental process would be permanently suggests a preeminent role for early adverse experiences unstable, hyperstimulated, vulnerable, or dysfunctional in the development of mood and anxiety disorders. (Favarelli et al., 2010). Similar findings were found in Child abuse and neglect can be perceived as agents a recent study by Heim, Mletzko, Purselle, Musselman, for neurodevelopmental disruption and, depending on and Nemeroff (2008) that assessed HPA axis function when it occurs, can cause serious neurological “scars” in men with and without major depression and in some structures, which could make some individuals childhood abuse. Abused men exhibited an increased vulnerable to certain types of psychopathology, cortisol response compared with non-abused men, especially depression, posttraumatic stress disorder regardless of the presence of major depression. (PTSD), and substance abuse (Cohen, Brown, & Smaile, Increased responses were associated with exposure to 2001; Heim et al., 2000; Juruena, 2007). both sexual and physical abuse and were correlated with abuse severity. Their results suggested that childhood maltreatment is associated with impaired glucocorticoid-mediated feedback control of the HPA axis under stimulated conditions (Heim et al., 2008). Depression Approximately eight out of 10 people who experience a major depressive episode will have one or more further episodes during their lifetime (i.e., a recurrent major depressive disorder); therefore, early diagnosis and effective treatment are vital for reducing the effect of depression on the life of the individual, family, and community (Fava, Park, & Sonino, 2006; Figure 1. Model of vulnerability and stress. Adapted from Juruena, 2007. Juruena et al., 2003). Studies estimate that the currently HPA axis and depression 231 available antidepressant treatments are ineffective in 30- 50% of treatment-resistant depression (TRD), i.e., are considered resistant those patients who do not respond to antidepressant treatment performed with a sufficient of time at an adequate dose. Approximately 60% of cases of depressive episodes are preceded by exposure to stressors, especially psychosocial stressors (Joca, Padovan, & Guimarães, 2003). Among the factors associated with depression in adulthood are exposure to childhood stressors such as the death of a parent or substitute, maternal deprivation, paternal abandonment, parental separation, and divorce (Zavaschi et al., 2002). Maltreated children have a moderately increased risk of depression in adolescence and adulthood, which will partially mirror the family context in which Figure 2. Micro and macro stress in individuals with the maltreatment occurred. Depression is common. genetic vulnerability and its relationship to neuropsychiatric Approximately one-quarter to one-third of maltreated symptoms. Adapted from Juruena et al., 2003. children will meet the criteria for major depression by their late 20s, thus representing a substantial public Hyperactivity of the HPA axis in major depression health burden. For many of the affected individuals, the is one of the most consistent findings in psychiatry. A onset of depression begins in childhood, underscoring significant percentage of patients with major depression the importance of focusing on early intervention before have been shown to exhibit increased concentrations the symptoms of depression appear in the abused and of cortisol (i.e., the endogenous glucocorticoid in neglected children (Mello et al., 2009). humans) in plasma, urine, and cerebrospinal fluid, an Hormones play a critical role in the development exaggerated cortisol response to adrenocorticotropic and expression of a wide range of behaviors. One hormone, and an enlargement of both the pituitary and aspect of the influence of hormones on behavior is adrenal glands (Nemeroff, 1996). In the past several their potential contribution to the pathophysiology of years, many studies of the HPA axis in depressed psychiatric disorders and the mechanism of action of patients have been published. A new perspective for psychotropic drugs, particularly in depression. Of the these old findings of hypercortisolemia appears to endocrine axes, the HPA axis has been the most widely have been generated. Hypercortisolemia is apparently studied. It plays a fundamental role in the response to linked to some specific cases of depression, depending external and internal stimuli, including psychological on the type and severity of the illness, genotype, history stressors. Abnormalities in the function of the HPA of stress during childhood, and possibly resilience, axis have been described in people who experience leading us to hypothesize that an endophenotype psychiatric disorders (Nemeroff, 1996). may exist that is prone to depression (Mello et al., Studies conducted in both animals and humans 2007). Previous studies have described impaired HPA suggest that stress experienced during the early phases negative feedback, leading to hypercortisolemia, of development can induce persistent changes in the such as in melancholic depression (Nemeroff, 1996; ability of the HPA axis to respond to stress in adulthood, Gold, Goodwin, & Chrousos, 1988). In addition to increasing the susceptibility to depression (Glover & melancholic depression, a spectrum of other conditions O’Connor, 2002). Evidence suggests that neurochemical may be associated with increased and prolonged and molecular changes induced by stressful situations activation of the HPA axis, including anorexia nervosa and depression trigger changes in the HPA axis. Findings with and without malnutrition, obsessive-compulsive derived from multiple lines of research have provided disorder, panic disorder, anxiety, chronic active evidence that during depression, dysfunction of limbic alcoholism, alcohol and narcotic withdrawal, poorly structures, including the hypothalamus and hippocampus, controlled diabetes mellitus, and hyperthyroidism results in hypersecretion of corticotropin-releasing (Tsigos & Chrousos, 2002). Another group of states is factor (CRF), dehydroepiandrosterone, and vasopressin, characterized by hypoactivation of the stress system, which in turn determines HPA activation. A a fl w in this rather than sustained activation, in which chronically system caused by factors such as excessive stress, high reduced secretion of CRF may result in pathological glucocorticoid levels, social isolation, and depressive hypoarousal and enhanced HPA negative feedback. symptoms results in difc fi ulty adapting to stress and can Patients with PTSD, atypical depression, seasonal predispose the individual to depression by impairing depression, and chronic fatigue syndrome fall into hippocampal serotonergic neurotransmission (Holsboer, this category (Kellner & Yehuda, 1999; Juruena et al., 2000; Joca et al., 2003; Juruena et al., 2004; Figure 2). 2004; Juruena & Cleare, 2007; Table 1). 232 Tofoli et al. Table 1 - States associated with hyperactivation or hypoactivation of the HPA axis Increased HPA axis activity Decreased HPA axis activity Disrupted HPA axis activity Severe chronic disease Atypical depression Cushing syndrome Melancholic depression Seasonal depression Glucocorticoid deficiency Anorexia nervosa Chronic fatigue syndrome Glucocorticoid resistance Obsessive-compulsive disorder Fibromyalgia Panic disorder Hypothyroidism Chronic excessive exercise Adrenal suppression Malnutrition Post glucocorticoid therapy Diabetes mellitus Posttraumatic stress disorder Hyperthyroidism Nicotine withdrawal Central obesity Postpartum Childhood maltreatment Menopause Pregnancy Rheumatoid arthritis HPA, hypophysis-pituitary-adrenal. Adapted from Juruena et al., 2004. One of the mechanisms thought to be involved in suppressive test that uses another synthetic glucocorticoid, HPA axis hyperactivity in depression is impaired feedback prednisolone, was developed by Pariante et al. (2002). This inhibition of the HPA axis by circulating glucocorticoids test has a higher afn fi ity for MRs and, therefore, should (Pariante & Miller 2001). This impaired feedback inhibition probe both receptors (Juruena et al., 2006; Juruena et al., has been demonstrated in depressed patients in various 2009, 2010; Pariante et al., 2002). studies, many conducted in the 1970s and 1980s (Juruena et al., 2009; Juruena, Pariante, Papadopoulos, & Cleare, 2010; Ribeiro, Tandon, Grunhaus, & Greden, 1993). These abnormalities appear to be related to changes in the ability of circulating glucocorticoids to exert negative feedback on the secretion of HPA hormones through binding to MRs and GRs in HPA tissue (de Kloet, Vreugdenhil, Oitzl, & Joels, 1998; Gold et al., 1988; Juruena et al., 2003; Nemeroff, 1996; Figure 3). The r fi st study of hypercortisolemia in depressed patients was published in the 1970s and found that severely depressed patients exhibited non-suppression in the dexamethasone suppression test (DST). In the DST, a high proportion of patients with various affective disorders had elevated cortisol levels, thus negating the suppressive effect of dexamethasone. Unfortunately, dexamethasone has pharmacodynamic and pharmacokinetic features that are very distinct from those of the human endogenous Figure 3. Schematic diagram of the hypothalamic-pituitary- glucocorticoid cortisol. These features, together with adrenal (HPA) axis that describes the regulation and negative the low sensitivity of the DST in detecting patients with feedback (-) of cortisol via glucocorticoid receptors (GRs) major depression, have signic fi antly limited the use of this and mineralocorticoid receptors (MRs). Adapted from test in routine clinical and research practice. Recently, a Juruena et al., 2004. HPA axis and depression 233 Prediction of response early stage can reduce the likelihood of developing health problems in the long term and re-victimization Generally, HPA axis changes appear in chronic in adulthood. Furthermore, early interventions may depressive and more severe episodes. Moreover, HPA reduce the burden of public spending on healthcare axis changes appear to be state-dependent, tending to for abused individuals. improve upon resolution of the depressive syndrome The more recent studies reviewed in the present (Holsboer, 2000). Interestingly, persistent HPA paper suggest that early life stressors are associated with hyperactivity has been associated with higher rates an increased risk for mood disorders in adulthood. This of relapse (Juruena et al., 2009; Ribeiro et al., 1993; review examined the emerging literature concerning Zobel, Yassouridis, Frieboes, & Holsboer, 1999). the relationship between stress, HPA axis function, Studies conducted in patients who received a range and depression and early life stress as an important of antidepressants have shown that those who fail to risk factor for HPA axis dysregulation. The most show a normalization of post-dexamethasone cortisol consistent findings in the literature show increased levels tend to have a worse outcome with regard to activity of the HPA axis in depression associated with re-hospitalization, suicide, and the recurrence of hypercortisolemia and reduced inhibitory feedback. depression (Ribeiro et al., 1993). Recent reports have These findings suggest that this dysregulation of the described a prospective study of the relationship HPA axis is partially attributable to an imbalance between the results of the dexamethasone/CRF test between GRs and MRs. Evidence has consistently and clinical outcome. Specifically, Zobel et al. (1999; demonstrated that GR function is impaired in major Zobel et al., 2001) described a cohort of patients who depression, resulting in reduced GR-mediated negative were subjected to the dexamethasone/CRF test on two feedback on the HPA axis, but few studies have assessed separate occasions: within 1 week after admission (or the activity of MRs in depression. Thus, although a after the start of the first antidepressant treatment) and few studies suggested that MR activity remains intact a few days before discharge. The patients were then or is possibly oversensitive to compensate for reduced followed up for 6 months after discharge. The study GR function in depressed patients, more studies are found that the patients who exhibited increased cortisol needed to elucidate this issue (Young, Lopez, Murphy- levels after the dexamethasone/CRF test between Weinberg, Watson, & Akil, 2003; Juruena et al., 2009, admission and discharge tended to relapse during 2010; Pariante et al., 2001; Pariante, 2006). the follow-up period, whereas those who showed a decrease in post-dexamethasone/CRF cortisol levels Conclusion tended to remain clinically stable during the follow- up period (Zobel et al., 1999, 2001). Therefore, these Social and physical environments have an studies suggest that the evaluation of the HPA axis enormous impact on our physiology and behavior, and during antidepressant treatment may help identify they influence the process of adaptation or allostasis. patients who have a higher risk of relapse (Juruena et At the same time that our experiences change our brain al., 2009; Zobel et al., 1999). and thoughts (i.e., changing our mind), we change our neurobiology. Although disturbances in the HPA axis Synthesis are an important factor in the etiology of depression and severe treatment resistance, very little is known Studies of the association between early life about the neurobiology of these disorders. Therefore, stress and psychiatric disorders should be evaluated psychometric assessment that quantifies the level carefully. No consensus has been reached in the of early life stress, recent stress, the evolution of literature regarding the concept of early life stress, and affective symptoms and diagnosis, and neuroendocrine the respondents in these studies likely underestimated activity is essential. Childhood stressful events and or overestimated the frequency/intensity of events. HPA axis overactivity in adulthood are not specific Much descriptive work has been published on the to depressive states, but several studies have linked relationship between adult psychopathology and these conditions. As demonstrated in this review, early early adversities such as parental loss in childhood, life stress leads to permanent changes in the HPA inadequate parental care, divorce, “affectionless” or axis and may lead to the development of depression dysfunctional parenting, childhood physical and sexual in adulthood. Considering the importance of early abuse, and other childhood traumas. Importantly, detection of violence in childhood and adolescence, mood disorders such as depression are most associated to prevent the development of severe and disabling with the occurrence of early life stress subtypes. The psychiatric disorders in adulthood, further research is results of existing studies suggest the importance needed to elucidate the mechanisms involved in the of preventing early life stress and its consequences association between early stress and the development in both the short and long terms. Intervention at an of psychopathology in adulthood. 234 Tofoli et al. References to depression. Revista Brasileira de Psiquiatria, 26, 189-201. Juruena, M.F., Marques, A.H., Mello, A.F., & Mello, M.F. (2007). A paradigm for understanding and treating psychiatric illness. Revista Bernstein, D.P., Fink, L., Handelsman, L., Foote, J., Lovejoy, M., Brasileira de Psiquiatria, 29(Suppl. 1), S1-S2. Wenzel, K., Sapareto, E., & Ruggiero, J. (1994). 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(1999). dexamethasone and prednisolone in the same depressed patients. Prediction of medium-term outcome by cortisol response to the Psychopharmacology, 189, 225-235. combined dexamethasone-CRH test in patients with remitted Juruena, M.F., Cleare, A.J., & Pariante, C.M. (2004). The hypothalamic depression. American Journal of Psychiatry, 156, 949-951. pituitary adrenal axis, glucocorticoid receptor function and relevance http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Psychology & Neuroscience American Psychological Association

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American Psychological Association
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Copyright © 2011 The Authors
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1984-3054
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1983-3288
DOI
10.3922/j.psns.2011.2.008
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Abstract

Considerable evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology, especially depression. The most recent studies reviewed herein suggest that early life stressors are associated with an increased risk for mood disorders in adulthood. This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and depression and the role of early life stress as an important risk factor for HPA axis dysregulation. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. Moreover, HPA axis changes appear to be state- dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during antidepressant treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in major depression, but few studies have assessed the activity of mineralocorticoid receptors in depression. Thus, more studies are needed to elucidate this issue. Keywords: early life stress, childhood trauma, depression, treatment-resistant depression, hypothalamic-pituitary-adrenal axis. Received 21 March 2011; received in revised form 11 June 2011; accepted 18 June 2011. Available on line 10 October 2011 Introduction states that the causes, development, and outcomes of disorders are determined by the relationships Psychological stress may change the internal between psychological, social, and cultural factors homeostatic state of an individual. During acute and biochemistry and physiology. Biochemistry and stress, adaptive physiological responses occur, physiology are not disconnected or different from including increased adrenocortical hormone secretion, the rest of our experiences and life events (Juruena, primarily cortisol. Whenever an acute interruption of Marques, Mello, & Mello, 2007). this balance occurs, illness may result. Particularly interesting are psychological stress (i.e., stress in Early life stress the mind) and the interactions with the nervous, endocrine, and immune systems. The concept of early life stress is quite broad and A key problem in diagnosis is the fact that elaborate includes the different traumatic experiences that occur classification systems that exist today are solely during childhood and adolescence, which may have based on subjective descriptions of symptoms. Such repercussions in adulthood. Among these are parental loss, detailed phenomenology includes the description of separation from parents, childhood illness, family violence, multiple clinical subtypes, but no biological feature can and deprivation of food, clothing, shelter, and love. distinguish one subtype from another. This approach In agreement with Bernstein et al. (1994), childhood maltreatment may be subdivided into the Sandra Marcia de Carvalho Tofoli, Cristiane Von Werne Baes, following domains: and Camila Maria Severi Martins, Department of Neuroscience and Behaviour, Faculty of Medicine Ribeirao Preto, University 1. Physical abuse: physical aggression by someone of Sao Paulo. Mario Juruena, Stress and Affective Disorders older, with the risk of or result of injury. Programme, Department of Neurosciences and Behaviour, Faculty of Medicine Ribeirao Preto, University of Sao Paulo. 2. Emotional abuse: verbal aggression that affects Correspondence regarding this article should be directed to: the welfare or morale of the child or any conduct that Mario Juruena, Saúde Mental-USP, Av. Tenente Catão Roxo, humiliates, embarrasses, or threatens the child. 2650, Monte Alegre - Campus Universitário, Ribeirão Preto, SP CEP 14051-140, Brazil. E-mail: juruena@fmrp.usp.br 230 Tofoli et al. 3. Sexual abuse: any type of sexual contact or conduct Psychoneuroendocrinology between a child and someone older. The maintenance of the internal homeostatic state 4. Emotional neglect: failure of caretakers to provide for of an individual is proposed to be based on the ability of basic emotional and psychological needs such as love, circulating glucocorticoids to exert negative feedback on motivation, and support. the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid receptors 5. Physical neglect: failure of caretakers to provide for (MRs) and glucocorticoid receptors (GRs), limiting the basic physical needs such as feeding, a home, security, vulnerability to diseases related to psychological stress supervision, and health (Bernstein et al., 1994, 2003). in genetically predisposed individuals. The HPA axis response to stress can be thought Childhood maltreatment is a major social problem. of as a mirror of the organism’s response to stress: It is a complex global phenomenon that does not respect acute responses are generally adaptive, but excessive boundaries of class, race, religion, age, or educational or prolonged responses can lead to deleterious effects. level and can occur both publicly and privately, resulting These deleterious effects, which may not be clinically in serious physical injury or even death. Moreover, its apparent, have the potential to serve as endophenotypic psychological consequences can acutely affect a child’s markers of disease susceptibility (Juruena, Cleare, mental health well into adulthood (Friedrich, 1998; Bauer, & Pariante, 2003; Mello et al., 2007). Because Cruz, Silva, & Alves, 2007). the HPA axis is activated in response to stressors, Early life stress is associated with a diverse stressful events in early life may also have an range of psychiatric consequences. In children etiologically significant role in the HPA abnormalities and adolescents, it increases the risk of behavioral found in psychiatric disorders including Depression, problems, including internalizing and externalizing Bipolar disorder, Anxiety disorders, Eating disorders, b e h a v i o r. I n t e r n a l i z i n g r e f e r s t o b e h a v i o r a l Schizophrenia, Substance abuse, Dissociative disorder, s y m p t o m s r e f l e c t e d b y a n x i e t y, d e p r e s s i o n , and PTSD, among other medical illnesses (Juruena, somatic complaints, and inhibition. Externalizing Cleare, & Pariante, 2004; Mello et al., 2007). refers to behavioral symptoms reflected by According to Favarelli et al. (2010), the aggression, delinquency, and increased activity effect of childhood trauma on the development level. Sexual behavior problems most likely fall into of psychopathology in adulthood is attributable this domain (Friedrich, 1998). to the HPA axis, which when activated during the Considerable evidence from various studies developmental process would be permanently suggests a preeminent role for early adverse experiences unstable, hyperstimulated, vulnerable, or dysfunctional in the development of mood and anxiety disorders. (Favarelli et al., 2010). Similar findings were found in Child abuse and neglect can be perceived as agents a recent study by Heim, Mletzko, Purselle, Musselman, for neurodevelopmental disruption and, depending on and Nemeroff (2008) that assessed HPA axis function when it occurs, can cause serious neurological “scars” in men with and without major depression and in some structures, which could make some individuals childhood abuse. Abused men exhibited an increased vulnerable to certain types of psychopathology, cortisol response compared with non-abused men, especially depression, posttraumatic stress disorder regardless of the presence of major depression. (PTSD), and substance abuse (Cohen, Brown, & Smaile, Increased responses were associated with exposure to 2001; Heim et al., 2000; Juruena, 2007). both sexual and physical abuse and were correlated with abuse severity. Their results suggested that childhood maltreatment is associated with impaired glucocorticoid-mediated feedback control of the HPA axis under stimulated conditions (Heim et al., 2008). Depression Approximately eight out of 10 people who experience a major depressive episode will have one or more further episodes during their lifetime (i.e., a recurrent major depressive disorder); therefore, early diagnosis and effective treatment are vital for reducing the effect of depression on the life of the individual, family, and community (Fava, Park, & Sonino, 2006; Figure 1. Model of vulnerability and stress. Adapted from Juruena, 2007. Juruena et al., 2003). Studies estimate that the currently HPA axis and depression 231 available antidepressant treatments are ineffective in 30- 50% of treatment-resistant depression (TRD), i.e., are considered resistant those patients who do not respond to antidepressant treatment performed with a sufficient of time at an adequate dose. Approximately 60% of cases of depressive episodes are preceded by exposure to stressors, especially psychosocial stressors (Joca, Padovan, & Guimarães, 2003). Among the factors associated with depression in adulthood are exposure to childhood stressors such as the death of a parent or substitute, maternal deprivation, paternal abandonment, parental separation, and divorce (Zavaschi et al., 2002). Maltreated children have a moderately increased risk of depression in adolescence and adulthood, which will partially mirror the family context in which Figure 2. Micro and macro stress in individuals with the maltreatment occurred. Depression is common. genetic vulnerability and its relationship to neuropsychiatric Approximately one-quarter to one-third of maltreated symptoms. Adapted from Juruena et al., 2003. children will meet the criteria for major depression by their late 20s, thus representing a substantial public Hyperactivity of the HPA axis in major depression health burden. For many of the affected individuals, the is one of the most consistent findings in psychiatry. A onset of depression begins in childhood, underscoring significant percentage of patients with major depression the importance of focusing on early intervention before have been shown to exhibit increased concentrations the symptoms of depression appear in the abused and of cortisol (i.e., the endogenous glucocorticoid in neglected children (Mello et al., 2009). humans) in plasma, urine, and cerebrospinal fluid, an Hormones play a critical role in the development exaggerated cortisol response to adrenocorticotropic and expression of a wide range of behaviors. One hormone, and an enlargement of both the pituitary and aspect of the influence of hormones on behavior is adrenal glands (Nemeroff, 1996). In the past several their potential contribution to the pathophysiology of years, many studies of the HPA axis in depressed psychiatric disorders and the mechanism of action of patients have been published. A new perspective for psychotropic drugs, particularly in depression. Of the these old findings of hypercortisolemia appears to endocrine axes, the HPA axis has been the most widely have been generated. Hypercortisolemia is apparently studied. It plays a fundamental role in the response to linked to some specific cases of depression, depending external and internal stimuli, including psychological on the type and severity of the illness, genotype, history stressors. Abnormalities in the function of the HPA of stress during childhood, and possibly resilience, axis have been described in people who experience leading us to hypothesize that an endophenotype psychiatric disorders (Nemeroff, 1996). may exist that is prone to depression (Mello et al., Studies conducted in both animals and humans 2007). Previous studies have described impaired HPA suggest that stress experienced during the early phases negative feedback, leading to hypercortisolemia, of development can induce persistent changes in the such as in melancholic depression (Nemeroff, 1996; ability of the HPA axis to respond to stress in adulthood, Gold, Goodwin, & Chrousos, 1988). In addition to increasing the susceptibility to depression (Glover & melancholic depression, a spectrum of other conditions O’Connor, 2002). Evidence suggests that neurochemical may be associated with increased and prolonged and molecular changes induced by stressful situations activation of the HPA axis, including anorexia nervosa and depression trigger changes in the HPA axis. Findings with and without malnutrition, obsessive-compulsive derived from multiple lines of research have provided disorder, panic disorder, anxiety, chronic active evidence that during depression, dysfunction of limbic alcoholism, alcohol and narcotic withdrawal, poorly structures, including the hypothalamus and hippocampus, controlled diabetes mellitus, and hyperthyroidism results in hypersecretion of corticotropin-releasing (Tsigos & Chrousos, 2002). Another group of states is factor (CRF), dehydroepiandrosterone, and vasopressin, characterized by hypoactivation of the stress system, which in turn determines HPA activation. A a fl w in this rather than sustained activation, in which chronically system caused by factors such as excessive stress, high reduced secretion of CRF may result in pathological glucocorticoid levels, social isolation, and depressive hypoarousal and enhanced HPA negative feedback. symptoms results in difc fi ulty adapting to stress and can Patients with PTSD, atypical depression, seasonal predispose the individual to depression by impairing depression, and chronic fatigue syndrome fall into hippocampal serotonergic neurotransmission (Holsboer, this category (Kellner & Yehuda, 1999; Juruena et al., 2000; Joca et al., 2003; Juruena et al., 2004; Figure 2). 2004; Juruena & Cleare, 2007; Table 1). 232 Tofoli et al. Table 1 - States associated with hyperactivation or hypoactivation of the HPA axis Increased HPA axis activity Decreased HPA axis activity Disrupted HPA axis activity Severe chronic disease Atypical depression Cushing syndrome Melancholic depression Seasonal depression Glucocorticoid deficiency Anorexia nervosa Chronic fatigue syndrome Glucocorticoid resistance Obsessive-compulsive disorder Fibromyalgia Panic disorder Hypothyroidism Chronic excessive exercise Adrenal suppression Malnutrition Post glucocorticoid therapy Diabetes mellitus Posttraumatic stress disorder Hyperthyroidism Nicotine withdrawal Central obesity Postpartum Childhood maltreatment Menopause Pregnancy Rheumatoid arthritis HPA, hypophysis-pituitary-adrenal. Adapted from Juruena et al., 2004. One of the mechanisms thought to be involved in suppressive test that uses another synthetic glucocorticoid, HPA axis hyperactivity in depression is impaired feedback prednisolone, was developed by Pariante et al. (2002). This inhibition of the HPA axis by circulating glucocorticoids test has a higher afn fi ity for MRs and, therefore, should (Pariante & Miller 2001). This impaired feedback inhibition probe both receptors (Juruena et al., 2006; Juruena et al., has been demonstrated in depressed patients in various 2009, 2010; Pariante et al., 2002). studies, many conducted in the 1970s and 1980s (Juruena et al., 2009; Juruena, Pariante, Papadopoulos, & Cleare, 2010; Ribeiro, Tandon, Grunhaus, & Greden, 1993). These abnormalities appear to be related to changes in the ability of circulating glucocorticoids to exert negative feedback on the secretion of HPA hormones through binding to MRs and GRs in HPA tissue (de Kloet, Vreugdenhil, Oitzl, & Joels, 1998; Gold et al., 1988; Juruena et al., 2003; Nemeroff, 1996; Figure 3). The r fi st study of hypercortisolemia in depressed patients was published in the 1970s and found that severely depressed patients exhibited non-suppression in the dexamethasone suppression test (DST). In the DST, a high proportion of patients with various affective disorders had elevated cortisol levels, thus negating the suppressive effect of dexamethasone. Unfortunately, dexamethasone has pharmacodynamic and pharmacokinetic features that are very distinct from those of the human endogenous Figure 3. Schematic diagram of the hypothalamic-pituitary- glucocorticoid cortisol. These features, together with adrenal (HPA) axis that describes the regulation and negative the low sensitivity of the DST in detecting patients with feedback (-) of cortisol via glucocorticoid receptors (GRs) major depression, have signic fi antly limited the use of this and mineralocorticoid receptors (MRs). Adapted from test in routine clinical and research practice. Recently, a Juruena et al., 2004. HPA axis and depression 233 Prediction of response early stage can reduce the likelihood of developing health problems in the long term and re-victimization Generally, HPA axis changes appear in chronic in adulthood. Furthermore, early interventions may depressive and more severe episodes. Moreover, HPA reduce the burden of public spending on healthcare axis changes appear to be state-dependent, tending to for abused individuals. improve upon resolution of the depressive syndrome The more recent studies reviewed in the present (Holsboer, 2000). Interestingly, persistent HPA paper suggest that early life stressors are associated with hyperactivity has been associated with higher rates an increased risk for mood disorders in adulthood. This of relapse (Juruena et al., 2009; Ribeiro et al., 1993; review examined the emerging literature concerning Zobel, Yassouridis, Frieboes, & Holsboer, 1999). the relationship between stress, HPA axis function, Studies conducted in patients who received a range and depression and early life stress as an important of antidepressants have shown that those who fail to risk factor for HPA axis dysregulation. The most show a normalization of post-dexamethasone cortisol consistent findings in the literature show increased levels tend to have a worse outcome with regard to activity of the HPA axis in depression associated with re-hospitalization, suicide, and the recurrence of hypercortisolemia and reduced inhibitory feedback. depression (Ribeiro et al., 1993). Recent reports have These findings suggest that this dysregulation of the described a prospective study of the relationship HPA axis is partially attributable to an imbalance between the results of the dexamethasone/CRF test between GRs and MRs. Evidence has consistently and clinical outcome. Specifically, Zobel et al. (1999; demonstrated that GR function is impaired in major Zobel et al., 2001) described a cohort of patients who depression, resulting in reduced GR-mediated negative were subjected to the dexamethasone/CRF test on two feedback on the HPA axis, but few studies have assessed separate occasions: within 1 week after admission (or the activity of MRs in depression. Thus, although a after the start of the first antidepressant treatment) and few studies suggested that MR activity remains intact a few days before discharge. The patients were then or is possibly oversensitive to compensate for reduced followed up for 6 months after discharge. The study GR function in depressed patients, more studies are found that the patients who exhibited increased cortisol needed to elucidate this issue (Young, Lopez, Murphy- levels after the dexamethasone/CRF test between Weinberg, Watson, & Akil, 2003; Juruena et al., 2009, admission and discharge tended to relapse during 2010; Pariante et al., 2001; Pariante, 2006). the follow-up period, whereas those who showed a decrease in post-dexamethasone/CRF cortisol levels Conclusion tended to remain clinically stable during the follow- up period (Zobel et al., 1999, 2001). Therefore, these Social and physical environments have an studies suggest that the evaluation of the HPA axis enormous impact on our physiology and behavior, and during antidepressant treatment may help identify they influence the process of adaptation or allostasis. patients who have a higher risk of relapse (Juruena et At the same time that our experiences change our brain al., 2009; Zobel et al., 1999). and thoughts (i.e., changing our mind), we change our neurobiology. Although disturbances in the HPA axis Synthesis are an important factor in the etiology of depression and severe treatment resistance, very little is known Studies of the association between early life about the neurobiology of these disorders. Therefore, stress and psychiatric disorders should be evaluated psychometric assessment that quantifies the level carefully. No consensus has been reached in the of early life stress, recent stress, the evolution of literature regarding the concept of early life stress, and affective symptoms and diagnosis, and neuroendocrine the respondents in these studies likely underestimated activity is essential. Childhood stressful events and or overestimated the frequency/intensity of events. HPA axis overactivity in adulthood are not specific Much descriptive work has been published on the to depressive states, but several studies have linked relationship between adult psychopathology and these conditions. As demonstrated in this review, early early adversities such as parental loss in childhood, life stress leads to permanent changes in the HPA inadequate parental care, divorce, “affectionless” or axis and may lead to the development of depression dysfunctional parenting, childhood physical and sexual in adulthood. Considering the importance of early abuse, and other childhood traumas. 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