Practitioner Review: Neurobiological consequences of childhood maltreatment - clinical and therapeutic implications for practitioners.

BACKGROUND: Childhood maltreatment is one of the most important preventable risk factors for a wide variety of psychiatric disorders. Further, when psychiatric disorders emerge in maltreated individuals they typically do so at younger ages, with greater severity, more psychiatric comorbid conditions, and poorer response to established treatments, resulting in a more pernicious course with an increased risk for suicide. Practitioners treating children, adolescents, and young adults with psychiatric disorders will likely encounter the highest prevalence of clients with early-onset maltreatment-associated psychiatric disorders. These may be some of their most challenging cases. METHOD: In this report, we explore key validated alterations in brain structure, function, and connectivity associated with exposure to childhood maltreatment as potential mechanisms behind their patients' clinical presentations. RESULTS: We then summarize key behavioral presentations likely associated with neurobiological alterations and propose a toolkit of established trauma and skills-based strategies that may help diminish symptoms and foster recovery. We also discuss how some of these alterations may serve as latent vulnerability factors for the possible development of future psychopathology. CONCLUSIONS: Research on the neurobiological consequences of childhood adversity provides a vastly enriched biopsychosocial understanding of the developmental origins of health and pathology that will hopefully lead to fundamental advances in clinical psychology and psychiatry.

The effects of childhood maltreatment on brain structure, function and connectivity.

Maltreatment-related childhood adversity is the leading preventable risk factor for mental illness and substance abuse. Although the association between maltreatment and psychopathology is compelling, there is a pressing need to understand how maltreatment increases the risk of psychiatric disorders. Emerging evidence suggests that maltreatment alters trajectories of brain development to affect sensory systems, network architecture and circuits involved in threat detection, emotional regulation and reward anticipation. This Review explores whether these alterations reflect toxic effects of early-life stress or potentially adaptive modifications, the relationship between psychopathology and brain changes, and the distinction between resilience, susceptibility and compensation.

Annual Research Review: Enduring neurobiological effects of childhood abuse and neglect.

BACKGROUND: Childhood maltreatment is the most important preventable cause of psychopathology accounting for about 45% of the population attributable risk for childhood onset psychiatric disorders. A key breakthrough has been the discovery that maltreatment alters trajectories of brain development. METHODS: This review aims to synthesize neuroimaging findings in children who experienced caregiver neglect as well as from studies in children, adolescents and adults who experienced physical, sexual and emotional abuse. In doing so, we provide preliminary answers to questions regarding the importance of type and timing of exposure, gender differences, reversibility and the relationship between brain changes and psychopathology. We also discuss whether these changes represent adaptive modifications or stress-induced damage. RESULTS: Parental verbal abuse, witnessing domestic violence and sexual abuse appear to specifically target brain regions (auditory, visual and somatosensory cortex) and pathways that process and convey the aversive experience. Maltreatment is associated with reliable morphological alterations in anterior cingulate, dorsal lateral prefrontal and orbitofrontal cortex, corpus callosum and adult hippocampus, and with enhanced amygdala response to emotional faces and diminished striatal response to anticipated rewards. Evidence is emerging that these regions and interconnecting pathways have sensitive exposure periods when they are most vulnerable. CONCLUSIONS: Early deprivation and later abuse may have opposite effects on amygdala volume. Structural and functional abnormalities initially attributed to psychiatric illness may be a more direct consequence of abuse. Childhood maltreatment exerts a prepotent influence on brain development and has been an unrecognized confound in almost all psychiatric neuroimaging studies. These brain changes may be best understood as adaptive responses to facilitate survival and reproduction in the face of adversity. Their relationship to psychopathology is complex as they are discernible in both susceptible and resilient individuals with maltreatment histories. Mechanisms fostering resilience will need to be a primary focus of future studies.

Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes.

OBJECTIVE: Childhood maltreatment increases risk for psychopathology. For some highly prevalent disorders (major depression, substance abuse, anxiety disorders, and posttraumatic stress disorder) a substantial subset of individuals have a history of maltreatment and a substantial subset do not. The authors examined the evidence to assess whether those with a history of maltreatment represent a clinically and biologically distinct subtype. METHOD: The authors reviewed the literature on maltreatment as a risk factor for these disorders and on the clinical differences between individuals with and without a history of maltreatment who share the same diagnoses. Neurobiological findings in maltreated individuals were reviewed and compared with findings reported for these disorders. RESULTS: Maltreated individuals with depressive, anxiety, and substance use disorders have an earlier age at onset, greater symptom severity, more comorbidity, a greater risk for suicide, and poorer treatment response than nonmaltreated individuals with the same diagnoses. Imaging findings associated with these disorders, such as reduced hippocampal volume and amygdala hyperreactivity, are more consistently observed in maltreated individuals and may represent a maltreatment-related risk factor. Maltreated individuals also differ from others as a result of epigenetic modifications and genetic polymorphisms that interact with experience to increase risk for psychopathology. CONCLUSIONS: Phenotypic expression of psychopathology may be strongly influenced by exposure to maltreatment, leading to a constellation of ecophenotypes. While these ecophenotypes fit within conventional diagnostic boundaries, they likely represent distinct subtypes. Recognition of this distinction may be essential in determining the biological bases of these disorders. Treatment guidelines and algorithms may be enhanced if maltreated and nonmaltreated individuals with the same diagnostic labels are differentiated.

Increased Gsα within blood cell membrane lipid microdomains in some depressive disorders: an exploratory study.

The stimulatory guanine nucleotide binding protein Gs couples many cellular receptors to adenylate cyclase, and the Gsα subunit activates all 9 isoforms of the adenylate cyclase catalytic unit to produce the enzyme product cyclicAMP or cAMP. In prefrontal cortex and cerebellum of unipolar depressive suicides, Rasenick and colleagues have found increased concentrations of Gsα in membrane lipid microdomains (Donati et al., 2008), where the ensconced Gsα is less likely to activate adenylate cyclase by receptor and postreceptor pathways (Allen et al., 2005, 2009). We report that a group of 7 depressed patients (DP-1) had (1) reduced activation of platelet receptor-stimulated adenylate cyclase by both prostaglandins E2 and D2 compared to controls, and (2) reduced postreceptor stimulation of adenylate cyclase by aluminum fluoride ion in both platelets and mononuclear leukocytes when compared to both another group of depressed patients (DP-2, n = 17) and to controls (n = 21). Our observations in the blood cells of the group DP-1 support the findings of Donati et al. (2008), and they reflect the importance of this interaction between the activated Gsα subunit and membrane lipid microdomains in the pathophysiology and treatment of some major depressive disorders.

Psychiatric treatment of the VIP: some paradoxical risks.

One might expect that VIPs-individuals with wealth, fame, or power-would typically receive excellent care when treated for psychiatric disorders. Often, this is the case, but paradoxically, VIP status may compromise the quality of psychiatric treatment. In this article, we present four case examples, representing disguised amalgamations of actual cases from our experience, demonstrating how VIP patients may sometimes receive suboptimal psychiatric care. These cases show certain similarities; typically, there was no serious doubt about the general nature of the treatment that should be undertaken, but the treatment team was unable to deliver that treatment in the usual manner because of various outside pressures created by the VIP status of the patient and by the patient's entourage. One possible solution to this problem, when feasible, is to assign treatment to a team specifically experienced with VIP patients. A strong and united treatment team, accustomed to the unusual difficulties and pressures often encountered with VIP patients, can be prepared to act promptly, firmly, and unanimously to devise an appropriate treatment plan and then maintain this plan true to its course despite these pressures.

Hurtful words: association of exposure to peer verbal abuse with elevated psychiatric symptom scores and corpus callosum abnormalities.

OBJECTIVE: Previous studies have shown that exposure to parental verbal abuse in childhood is associated with higher rates of adult psychopathology and alterations in brain structure. In this study the authors sought to examine the symptomatic and neuroanatomic effects, in young adulthood, of exposure to peer verbal abuse during childhood. METHOD: A total of 848 young adults (ages 18-25 years) with no history of exposure to domestic violence, sexual abuse, or parental physical abuse rated their childhood exposure to parental and peer verbal abuse and completed a self-report packet that included the Kellner Symptom Questionnaire, the Limbic Symptom Checklist-33, and the Dissociative Experiences Scale. Diffusion tensor images were collected for a subset of 63 young adults with no history of abuse or exposure to parental verbal abuse selected for varying degrees of exposure to peer verbal abuse. Images were analyzed using tract-based spatial statistics. RESULTS: Analysis of covariance revealed dose-dependent effects of peer verbal abuse on anxiety, depression, anger-hostility, dissociation, "limbic irritability," and drug use. Peer and parental verbal abuse were essentially equivalent in effect size on these ratings. Path analysis indicated that peer verbal abuse during the middle school years had the most significant effect on symptom scores. Degree of exposure to peer verbal abuse correlated with increased mean and radial diffusivity and decreased fractional anisotropy in the corpus callosum and the corona radiata. CONCLUSIONS: These findings parallel results of previous reports of psychopathology associated with childhood exposure to parental verbal abuse and support the hypothesis that exposure to peer verbal abuse is an aversive stimulus associated with greater symptom ratings and meaningful alterations in brain structure.

Length of time between onset of childhood sexual abuse and emergence of depression in a young adult sample: a retrospective clinical report.

OBJECTIVE: Depression is the most common adult outcome of exposure to childhood sexual abuse (CSA). In this study, we retrospectively assessed the length of time from initial abuse exposure to onset of a major depressive episode. METHOD: A community-based survey of childhood experiences in 564 young adults aged 18 to 22 years, conducted between 1997 and 2001, identified 29 right-handed female subjects with CSA but no other exposure to trauma. Subjects were interviewed for lifetime history and age at onset of Axis I disorders using the Structured Clinical Interview for DSM-IV Axis I Disorders. RESULTS: Sixty-two percent (N = 18) of the sexual abuse sample met full lifetime criteria for major depressive disorder. Episodes of depression emerged a mean +/- SD of 9.2 +/- 3.6 years after onset of exposure to sexual abuse. Mean survival time from onset of abuse to onset of depression for the entire sample was 11.47 years (95% CI = 9.80 to 13.13 years). There was a surge in new cases between 12 and 15 years of age. Mean +/- SD time to onset of posttraumatic stress disorder was 8.0 +/- 3.9 years. CONCLUSIONS: Exposure to CSA appears to sensitize women to the development of depression and to shift age at onset to early adolescence. Findings from this formative study suggest that clinicians should not interpret the absence of symptoms at the time of CSA as a sign of resilience. Continued monitoring of victims of CSA as they pass through puberty is recommended. Reasons for the time lag between CSA and depression are proposed along with potential strategies for early intervention.

Enhanced norepinephrine output during long-term desipramine treatment: a possible role for the extraneuronal monoamine transporter (SLC22A3).

To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we examined the effects of desipramine treatment on urinary and plasma catecholamines and their metabolites during the initial 6 weeks of treatment in depressed patients. Catecholamines and metabolites in 24-h urine collections and 8:00 a.m. plasma samples were measured at baseline and after 1, 4, and 6 weeks of desipramine treatment. Desipramine treatment produced significant increases in urinary norepinephrine (NE) and normetanephrine (NMN) and plasma NE at Weeks 4 and 6, but not at Week 1. The ratio of urinary NE/NMN was increased at Weeks 4 and 6, suggesting a reduction in the metabolism of NE to NMN at extraneuronal sites by Weeks 4 and 6. The increases in urinary NE and NMN and plasma NE at Weeks 4 and 6 of desipramine treatment were associated with a reduction in the conversion of NE to NMN. This would be compatible with a blockade of the extraneuronal monoamine transporter (organic cation transporter 3; SLC22A3) by NMN. Inhibition of the extraneuronal monoamine transporter may be an important component in the clinical pharmacology of the norepinephrine reuptake inhibitor antidepressant drugs, such as desipramine.

The price of a gift: an approach to receiving gifts from patients in psychiatric practice.

When a patient or patient's family presents a psychiatrist with a gift, the clinician is challenged to maintain appropriate professional boundaries but have the flexibility to respond with warmth and appreciation. The psychiatrist must consider such factors as the intention of the gift, its value to the patient, and the anticipated effect of accepting or refusing it on the patient and the treatment. Psychiatric practitioners are ethically obligated to consider patients' best interests when deciding about how to handle the offer of a gift. Ethical deliberations about such situations occur on a case-by-case basis and require careful analysis of how to promote the patient's best interest while adhering to professional ethics. In this article, members of the McLean Hospital Ethics Committee present a pragmatic model for managing the presentation of a gift from a patient or a patient's family member. The pragmatic model, which focuses on the practical results of accepting or declining the gift, minimizes the risk of exploiting the patient by accepting a gift or hurting the patient by declining it. We present five clinical cases that raise ethical dilemmas concerning patient gift giving in psychiatry and discuss each case from the standpoint of the pragmatic model.

The physiological roles of extracellular metallothionein.

Metallothionein (MT) is a low-molecular-weight protein with a number of roles to play in cellular homeostasis. MT is synthesized as a consequence of a variety of cellular stressors, and has been found in both intracellular compartments and in extracellular spaces. The intracellular pool of this cysteine-rich protein can act as a reservoir of essential heavy metals, as a scavenger of reactive oxygen and nitrogen species, as an antagonist of toxic metals and organic molecules, and as a regulator of transcription factor activity. The presence of MT outside of cells due to the influence of stressors suggests that this protein may make important contributions as a "danger signal" that influences the management of responses to cellular damage. While conventional wisdom has held that extracellular MT is the result of cell death or leakage from stressed cells, there are numerous examples of selective release of proteins by nontraditional mechanisms, including stress response proteins. This suggests that MT may similarly be selectively released, and that the pool of extracellular MT represents an important regulator of various cellular functions. For example, extracellular MT has effects both on the severity of autoimmune disease, and on the development of adaptive immune functions. Extracellular MT may operate as a chemotactic factor that governs the trafficking of inflammatory cells that move to resolve damaged tissues, as a counter to extracellular oxidant-mediated damage, and as a signal that influences the functional behavior of wounded cells. A thorough understanding of the mechanisms of MT release from cells, the conditions under which MT is released to the extracellular environment, and the ways in which MT interacts with sensitive cells may both illuminate our understanding of an important control mechanism that operates in stressful conditions, and should indicate new opportunities for therapeutic management via the manipulation of this pool of extracellular MT.

Sticks, stones, and hurtful words: relative effects of various forms of childhood maltreatment.

OBJECTIVE: Childhood maltreatment is an important psychiatric risk factor. Research has focused primarily on the effects of physical abuse, sexual abuse, or witnessing domestic violence. Parental verbal aggression has received little attention as a specific form of abuse. This study was designed to delineate the impact of parental verbal aggression, witnessing domestic violence, physical abuse, and sexual abuse, by themselves and in combination, on psychiatric symptoms. METHOD: Symptoms and exposure ratings were collected from 554 subjects 18-22 years of age (68% female) who responded to advertisements. The Verbal Abuse Questionnaire was used to assess exposure to parental verbal aggression. Outcome measures included dissociation and symptoms of "limbic irritability," depression, anxiety, and anger-hostility. Comparisons were made by using effect sizes. RESULTS: Verbal aggression was associated with moderate to large effects, comparable to those associated with witnessing domestic violence or nonfamilial sexual abuse and larger than those associated with familial physical abuse. Exposure to multiple forms of maltreatment had an effect size that was often greater than the component sum. Combined exposure to verbal abuse and witnessing domestic violence had a greater negative effect on some measures than exposure to familial sexual abuse. CONCLUSIONS: Parental verbal aggression was a potent form of maltreatment. Exposure to multiple forms of abuse was associated with very large effect sizes. Most maltreated children had been exposed to multiple types of abuse, and the number of different types is a critically important factor.

Diabetes, the brain, and behavior: is there a biological mechanism underlying the association between diabetes and depression?

In summary, our review of the literature suggests that diabetes, especially type 1 diabetes, may place patients at risk for a depressive disorder through a biological mechanism linking the metabolic changes of diabetes to changes in brain structure and function. Further studies are warranted examining these relationships in order to better understand the impact of diabetes on brain functioning and structure as well as one potential manifestation of such changes--affective disorder. Moreover, such studies could play a useful role in better understanding mechanisms that commonly underlie the development of depression in individuals without diabetes but with other medical problems or conditions.