The role of the hypothalamic-pituitary-adrenal axis in depression across the female reproductive lifecycle: current knowledge and future directions.

The aim of this narrative review is to consolidate knowledge on the role of the hypothalamic-pituitary-adrenal (HPA) axis in depression pathophysiology at different reproductive stages across the female lifespan. Despite growing evidence about the impact of gonadal hormones on mood disorders, no previous review has examined the interaction between such hormonal changes and the HPA axis within the context of depressive disorders in women. We will focus on HPA axis function in depressive disorders at different reproductive stages including the menstrual cycle (e.g., premenstrual dysphoric disorder [PMDD]), perinatally (e.g., postpartum depression), and in perimenopausal depression. Each of these reproductive stages is characterized by vast physiological changes and presents major neuroendocrine reorganization. The HPA axis is one of the main targets of such functional alterations, and with its key role in stress response, it is an etiological factor in vulnerable windows for depression across the female lifespan. We begin with an overview of the HPA axis and a brief summary of techniques for measuring HPA axis parameters. We then describe the hormonal milieu of each of these key reproductive stages, and integrate information about HPA axis function in depression across these reproductive stages, describing similarities and differences. The role of a history of stress and trauma exposure as a contributor to female depression in the context of HPA axis involvement across the reproductive stages is also presented. This review advances the pursuit of understanding common biological mechanisms across depressive disorders among women. Our overarching goal is to identify unmet needs in characterizing stress-related markers of depression in women in the context of hormonal changes across the lifespan, and to support future research in women's mental health as it pertains to pathophysiology, early diagnosis, and treatment targets.

Unique Characteristics of Women and Infants Moderate the Association between Depression and Mother-Infant Interaction.

Research has shown mixed results regarding the association between women's postpartum depression and mother-infant interactions, suggesting that a woman's unique experience and context may moderate how depression shapes these interactions. We examined the extent to which a woman's comorbid anxiety, her exposure to adversity, and infant characteristics moderate the relationship between depressive symptoms of women and interactions with their infants at 6 (n = 647) and 12 months (n = 346) postpartum. The methods included standardized coding of mother-infant interactions and structural regression modeling. The results at 6 months of infant age indicated that infant male sex and infant negative affectivity were risk factors for mothers' depression being associated with less optimal interactions. At 12 months of infant age, two moderators appeared to buffer the influence of depression: a woman's history of trauma and infant preterm birth (≤37 weeks gestation). The results reinforce the salience of infant characteristics in the relationship between maternal depression and mother-infant interactions. The findings also suggest that experiences of trauma may offer opportunities for psychological growth that foster constructive management of depression's potential effect on mother-infant interactions. Further research is needed to clarify the underlying processes and mechanisms that explain the influence of these moderators. The ultimate goals are to reduce the risk of suboptimal interactions and reinforce healthy dyadic relations.

Potential paths to suicidal ideation and suicide attempts among high-risk women.

Although men are more likely to die by suicide, women experience a greater and more rapidly increasing rate of suicidal ideation (SI) and are 3 times more likely to attempt suicide than men. Despite this increased risk, little is known about factors that contribute to SI or suicide attempts (SA) among women. We examined factors associated with SI and SA among women and identified mood-related symptoms that differentiate women who reported attempting suicide from those who did not. Women at elevated risk for depression from across the U.S. (N = 3372; age 18 to 90) completed a survey regarding depression, anxiety, sociodemographic and reproductive status, behavioral/mental health history, and exposure to adversity. Structural equation modeling and logistic regression were used to analyze the data. Variables with the most significant relationships to SI were severity of depression (OR = 5.2, p = 0.000) and perceived stress (OR = 1.18, p = 0.000) while frequency of suicidal thoughts (OR = 3.3, p = 0.000), family history of a depression diagnosis (OR = 1.6, p = 0.000) and exposure to violence (OR = 1.9, p = 0.000) had the strongest association with SA. Childhood abuse/trauma was associated with SA (OR = 1.13, p = 0.000) but not SI. 'Feeling bad about themselves, a failure, or having let themselves or their family down' was the symptom that most clearly differentiated women who attempted suicide from women who reported suicidal ideation but no SA. The salience of childhood abuse and domestic/community violence to women's risk for a suicide attempt reinforces previous findings that these adversities may differentiate suicide risk for women versus men. Continued research is essential to understand varied paths that may lead to suicidal behavior among women, some which appear unrelated to the frequency or intensity of their suicidal thoughts.

Maternal Interaction With Infants Among Women at Elevated Risk for Postpartum Depression.

Ample research links mothers' postpartum depression (PPD) to adverse interactions with their infants. However, most studies relied on general population samples, whereas a substantial number of women are at elevated depression risk. The purpose of this study was to describe mothers' interactions with their 6- and 12-month-old infants among women at elevated risk, although with a range of symptom severity. We also identified higher-order factors that best characterized the interactions and tested longitudinal consistency of these factors from 6 to 12 months of infant age. We leveraged data from eight projects across the United States (n = 647), using standardized depression measures and an adaptation of the NICHD Mother-Infant Interaction Scales. Overall, these depression-vulnerable mothers showed high levels of sensitivity and positive regard and low levels of intrusiveness, detachment, and negative regard with their infants. Factor analyses of maternal behaviors identified two overarching factors-"positive engagement" and "negative intrusiveness" that were comparable at 6 and 12 months of infant age. Mothers' ability to regulate depressed mood was a key behavior that defined "positive engagement" in factor loadings. An exceptionally strong loading of intrusiveness on the second factor suggested its central importance for women at elevated depression risk. Mothers with severe depressive symptoms had significantly more "negative intrusiveness" and less "positive engagement" with their 6-month-old infants than women with moderate or fewer depressive symptoms, suggesting a potential tipping point at which symptoms may interfere with the quality of care. Results provide the foundation for further research into predictors and moderators of women's interactions with their infant among women at elevated risk for PPD. They also indicate a need for evidence-based interventions that can support more severely depressed women in providing optimal care.

Symptom profiles of women at risk of mood disorders: A latent class analysis.

BACKGROUND: Depression is the leading cause of disease burden among women worldwide. However, an understanding of symptom profiles among women at risk of mood disorders is limited. We determined distinct profiles of affective symptoms among high risk women, along with their distinguishing characteristics. METHODS: Women were recruited from 17 clinical sites affiliated with the National Network of Depression Centers. They completed measures of depression (Patient Health Questionnaire - 9) and anxiety (Generalized Anxiety Disorder - 7) as well as questions regarding demographics, reproductive status, behavioral/mental health history, and life stress/adversity. Latent class analysis and multinomial logistic regression were used to identify and characterize symptom profiles. RESULTS: 5792 women participated, ages 18 to 90 (M = 38). Three latent classes were identified: generally asymptomatic (48%), elevated symptoms of comorbid anxiety and depression (16%), and somatic symptoms (36%). Financial security and greater social support were protective factors that distinguished asymptomatic women. The profile of the class with elevated anxiety/depressive symptoms constituted a complex mix of adverse social determinants and potentially heritable clinical features, including a diagnosis of Bipolar Disorder. Women in the 3rd latent class were characterized by menstrual irregularity and a stronger expression of neurovegetative symptoms, especially sleep disturbance and fatigue. LIMITATIONS: Limitations included less than optimal racial diversity of our sample and reliance on self-report. CONCLUSIONS: Different symptom profiles may reflect distinct subtypes of women at risk of mood disorders. Understanding the etiology and mechanisms underlying clinical and psychosocial features of these profiles can inform more precisely targeted interventions to address women's diverse needs.

Anxiety and physical health problems increase the odds of women having more severe symptoms of depression.

Severely depressed women incur substantial disability and suicide risk, necessitating an understanding of factors that may contribute to severe depression. The purpose of this research was to determine the degree to which age, physical morbidity, anxiety, and hormonal status predict the likelihood of severe depression among women with mood disorders (n = 298). Data arose from a standardized battery of measures in a multi-center clinical registry of patients with mood disorders. The women were being treated at 17 participating sites of the National Network of Depression Centers. Results of logistic regression analyses indicate that a woman's level of anxiety was the strongest predictor of her likelihood of having severe depression (Exp(B) = 1.33, p = .000), including thoughts of death or suicide. The number of physical health problems that a woman reported was also a significant predictor (Exp(B) = 1.09, p = .04). Neither age nor hormonal status was significant in the final model, although a trend was observed for women with surgically induced menopause to have more severe depression. Findings support the need to work closely with medical practitioners to address physical health problems as part of the treatment plan for depression and to give comorbid anxiety and depression equal priority in symptom management.

Longitudinal investigation of the relationship between family history of psychosis and affective disorders and Child Behavior Checklist ratings in clinical high-risk adolescents.

This is the first study to investigate whether positive family history (FH) of psychosis and affective disorders moderates the relationship between child diagnostic status and parent-reported social and behavioral problems on the Child Behavior Checklist (CBCL) in clinical high-risk adolescents. This longitudinal investigation assessed 122 participants (mean age=14.25±1.8years) from three groups (at-risk, other personality disorders, non-psychiatric controls) at baseline and one year follow-up. As predicted, there was a main effect of FH for a number of CBCL scales indicating higher scores for adolescents with positive FH. The findings also demonstrate a significant Diagnostic Status×Family History interaction for several behavioral scales providing support for FH as a concurrent and longitudinal moderator of the relationship between diagnostic status and CBCL scales. The moderating effect is present for areas of functioning associated with depression, anxiety, social adjustment, thought problems, attention problems, and aggressive behavior. The findings also indicate that both positive and negative symptoms are related to the genetic vulnerability for developing psychosis in clinical high-risk individuals, particularly those symptoms reflective of emotional, attentional, and interpersonal functioning. The present findings are novel and have significant clinical and research implications. This investigation provides a platform for future studies to clarify further the role of FH in clinical high-risk individuals and contributes to integration of this knowledge in the development of early intervention and prevention approaches in at-risk populations for the emergence of severe mental illness.

Temperament and behavior in toddlers of mothers with bipolar disorder: a preliminary investigation of a population at high familial risk for psychopathology.

OBJECTIVE: There are no published studies examining concurrent associations between temperament and behavior during toddlerhood in offspring of parents with bipolar disorder (OBD), a population at high familial risk for psychopathology. Better understanding of early determinants contributing to well-being or mental illness in this high-risk population has the potential to aid in the identification of problem domains to be targeted clinically, and facilitate the development of early intervention and prevention initiatives for an appropriate subgroup of children at the youngest possible age. METHODS: A total of 30 offspring of mothers with BD (mean age=25.4±4.9 months) participated in this study at Emory University. The mothers completed the Early Childhood Behavior Questionnaire (ECBQ) and the Child Behavior Checklist (CBCL). RESULTS: The results of the correlational analyses indicated that the broad temperament dimension Negative Affectivity and the individual ECBQ scales Sadness and Shyness were positively associated with the broad CBCL dimension Internalizing Problems, whereas Sociability was negatively associated with Internalizing Problems. In addition, the temperament scales Soothability and Frustration were negatively and positively associated with Internalizing Problems, respectively. All ECBQ scales included in the broad temperament dimension Effortful Control, except for Cuddliness, were significantly negatively associated with the broad CBCL dimension Externalizing Problems. A significant sex difference was found for the ECBQ scale Positive Anticipation and the CBCL scale Sleep Problems, with a higher mean rank score for girls than for boys. CONCLUSIONS: This is the first systematic investigation of temperament and behavior and concurrent associations between these two domains in toddlers of mothers with BD. The present findings provide a platform for future investigations of the contribution of temperament and early behavior to potential well-being or mental illness in OBD.

Psychosis risk screening in clinical high-risk adolescents: a longitudinal investigation using the Child Behavior Checklist.

This is the first study to investigate whether parent-reported social and behavioral problems on the Child Behavior Checklist (CBCL) can be used for psychosis risk screening and the identification of at-risk youth in the general population. This longitudinal investigation assessed 122 adolescent participants from three groups (at-risk, other personality disorders, non-psychiatric controls) at baseline and one year follow-up. The findings indicate that two individual CBCL rating scales, Withdrawn/Depressed and Thought Problems, have clinical and diagnostic utility as an adjunctive risk screening measure to aid in early detection of at-risk youth likely to develop psychosis. Furthermore, the findings shows that a cost-effective, general screening tool with a widespread use in community and pediatric healthcare settings has a promise to serve as a first step in a multi-stage risk screening process. This can potentially facilitate increased screening precision and reduction of high rate of false-positives in clinical high-risk individuals who present with elevated scores on psychosis-risk measures, but ultimately do not go on to develop psychosis. The findings of the present study also have significant clinical and research implications for the development of a broad-based psychosis risk screening strategy, and novel prevention and early intervention approaches in at-risk populations for the emergence of severe mental illness.

Amygdalar, hippocampal, and thalamic volumes in youth at high risk for development of bipolar disorder.

Children of parents with bipolar disorder (BD), especially those with attention deficit hyperactivity disorder (ADHD) and symptoms of depression or mania, are at significantly high risk for developing BD. As we have previously shown amygdalar reductions in pediatric BD, the current study examined amygdalar volumes in offspring of parents (BD offspring) who have not yet developed a full manic episode. Youth participating in the study included 22 BD offspring and 22 healthy controls of comparable age, gender, handedness, and IQ. Subjects had no history of a manic episode, but met criteria for ADHD and moderate mood symptoms. MRI was performed on a 3T GE scanner, using a 3D volumetric spoiled gradient echo series. Amygdalae were manually traced using BrainImage Java software on positionally normalized brain stacks. Bipolar offspring had similar amygdalar volumes compared to the control group. Exploratory analyses yielded no differences in hippocampal or thalamic volumes. Bipolar offspring do not show decreased amygdalar volume, possibly because these abnormalities occur after more prolonged illness rather than as a preexisting risk factor. Longitudinal studies are needed to determine whether amygdalar volumes change during and after the development of BD.

Does a parent-report measure of behavioral problems enhance prediction of conversion to psychosis in clinical high-risk adolescents?

Recent research on risk for psychosis has focused on youth who manifest subclinical signs that are often associated with the prodrome to psychosis. Standardized measures of prodromal symptoms have been shown to significantly enhance prediction of risk for conversion to an Axis I psychotic disorder. In the present study, a widely used parent-report measure of behavioral problems, the Child Behavior Checklist (CBCL) was administered to examine the clinical and diagnostic utility of the measure as an adjunctive screening instrument in the identification of at-risk youth. The CBCL, the Structured Interview for Prodromal Syndromes (SIPS), and other diagnostic measures were administered at baseline and at one year follow-up assessments to adolescents (n=41) at clinical high-risk for the development of a psychotic disorder. Analyses were conducted to compare the 14 at-risk adolescents who subsequently converted to psychosis to the 27 who did not. Conversion to psychosis was defined as conversion to an Axis I psychotic disorder or affective disorder with psychotic features. Consistent with expectations, at one year follow-up, compared to the Non-Converted participants, the Converted participants manifested significantly higher scores on the prodromal symptom scales of the SIPS. There were, however, no differences in CBCL social and behavioral ratings as a function of conversion status. It is concluded that the CBCL does not show promise as an alternative or adjunctive predictor of conversion to psychosis in at-risk adolescents.

Subcortical volumetric correlates of anxiety in familial pediatric bipolar disorder: a preliminary investigation.

Anxiety is a common comorbid condition in pediatric bipolar disorder (BD). However, there is little known about the effects of comorbidity on brain morphometry in this population. The aim of the present study was to examine subcortical correlates of anxiety in familial pediatric BD. The subject group comprised 120 children (mean age=12+/-3.3 years) with at least one parent diagnosed with BD. Bipolar offspring with BD were compared with bipolar offspring without BD on a measure of overall lifetime anxiety. A sub-sample of 20 bipolar offspring with BD (mean age=14.6+/-2.8 years) underwent magnetic resonance imaging (MRI) with a 3-T scanner. Correlational analyses were conducted between hippocampal and amygdalar volumes, and anxiety scores. The results showed significantly higher anxiety in bipolar offspring with BD compared to bipolar offspring without BD. There was a significant negative association between total hippocampal volume and anxiety scores. No significant association was found between total amygdalar volume and anxiety scores. Clinically, these findings suggest that anxiety comorbidity needs to be properly assessed and treated in the management of pediatric BD. This is the first study to show a negative association between hippocampal volume and anxiety in this population. The overlap between anxiety and familial pediatric BD suggests that anxiety may be one important area of future research in parsing out the heterogeneous nature and complex etiology of early-onset BD.

Movement abnormalities and the progression of prodromal symptomatology in adolescents at risk for psychotic disorders.

The link between movement abnormalities and psychotic disorders is presumed to reflect common neural mechanisms that influence both motor functions and vulnerability to psychosis. The prodromal period leading to psychotic disorders represents both a viable point for intervention and a developmental period that, if studied, could shed light on etiology; however, no published studies have examined the temporal progression of this link. A group with high levels of prodromal symptomatology (i.e., adolescents with schizotypal personality disorder [SPD]; n = 42) and both psychiatric controls (with other personality disorders or conduct disorder [OD]; n = 30) and nonpsychiatric controls ([NC]; n = 49) were recruited. Videotapes of structured psychiatric interviews were coded for movement abnormalities by raters blind to participants' diagnostic status, and follow-up assessments were conducted 1 year later. Controlling for psychotropic medications, the authors found that adolescents with SPD exhibited significantly more motor abnormalities in the face and upper body than did OD and NC controls. At baseline, movement abnormalities were positively correlated with the severity of positive, negative, and total prodromal symptoms. Within the SPD group, baseline movement abnormalities predicted symptom severity 1 year later. Movement abnormalities represent an early risk indicator that may be predictive of later symptom severity and potentially of psychosis onset.

Creativity in familial bipolar disorder.

Studies have demonstrated relationships between creativity and bipolar disorder (BD) in individuals, and suggested familial transmission of both creativity and BD. However, to date, there have been no studies specifically examining creativity in offspring of bipolar parents and clarifying mechanisms of intergenerational transmission of creativity. We compared creativity in bipolar parents and their offspring with BD and bipolar offspring with attention-deficit/hyperactivity disorder (ADHD) with healthy control adults and their children. 40 adults with BD, 20 bipolar offspring with BD, 20 bipolar offspring with ADHD, and 18 healthy control parents and their healthy control children completed the Barron-Welsh Art Scale (BWAS), an objective measure of creativity. Adults with BD compared to controls scored significantly (120%) higher on the BWAS Dislike subscale, and non-significantly (32%) higher on the BWAS Total scale. Mean BWAS Dislike subscale scores were also significantly higher in offspring with BD (107% higher) and offspring with ADHD (91% higher) than in healthy control children. Compared to healthy control children, offspring with BD had 67% higher and offspring with ADHD had 40% higher BWAS Total scores, but these differences failed to reach statistical significance when adjusted for age. In the bipolar offspring with BD, BWAS Total scores were negatively correlated with duration of illness. The results of this study support an association between BD and creativity and contribute to a better understanding of possible mechanisms of transmission of creativity in families with genetic susceptibility for BD. This is the first study to show that children with and at high risk for BD have higher creativity than healthy control children. The finding in children and in adults was related to an enhanced ability to experience and express dislike of simple and symmetric images. This could reflect increased access to negative affect, which could yield both benefits with respect to providing affective energy for creative achievement, but also yield liabilities with respect to quality of interpersonal relationships or susceptibility to depression.

Somatic and social: Chinese Americans talk about emotion.

Empirical findings suggest that Chinese and Americans differ in the ways that they describe emotional experience, with Chinese using more somatic and social words than Americans. No one, however, has investigated whether this variation is related to differences between Chinese and American conceptions of emotion or to linguistic differences between the English and Chinese languages. Therefore, in two studies, the authors compared the word use of individuals who varied in their orientation to Chinese and American cultures (European Americans [EA], more acculturated Chinese Americans [CA], and less acculturated CA) when they were speaking English during emotional events. Across both studies, less acculturated CA used more somatic (e.g., dizzy) and more social (e.g., friend) words than EA. These findings suggest that even when controlling for language spoken, cultural conceptions of emotion may shape how people talk about emotion.

Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: a functional magnetic resonance imaging investigation.

BACKGROUND: The neurobiological features of pediatric bipolar disorder (BD) are largely unknown. Children and adolescents with BD may be important to study with functional neuroimaging techniques because of their unique status of early-onset BD and high familial loading for the disorder. Neuroimaging studies of adults with BD have implicated the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in the development of this disorder. OBJECTIVES: To study children and adolescents with BD via functional magnetic resonance imaging using cognitive and affective tasks and to examine possible abnormalities in the DLPFC and ACC, as well as selected subcortical areas, in pediatric familial BD. DESIGN: We evaluated 12 male subjects aged 9 to 18 years with BD who had at least 1 parent with BD as well as 10 age- and IQ-matched healthy male controls. Stimulants were discontinued for at least 24 hours; other medications were continued. Subjects underwent functional magnetic resonance imaging at 3 T while performing a 2-back visuospatial working memory task and an affective task involving the visualization of positively, neutrally, or negatively valenced pictures. SETTING: An academic referral setting, drawing from the Bay Area of San Francisco, Calif. RESULTS: Compared with controls, for the visuospatial working memory task, subjects with BD had greater activation in several areas including the bilateral ACC, left putamen, left thalamus, left DLPFC, and right inferior frontal gyrus. Controls had greater activation in the cerebellar vermis. In viewing negatively valenced pictures, subjects with BD had greater activation in the bilateral DLPFC, inferior frontal gyrus, and right insula. Controls had greater activation in the right posterior cingulate gyrus. For positively valenced pictures, subjects with BD had greater activation in the bilateral caudate and thalamus, left middle/superior frontal gyrus, and left ACC, whereas controls had no areas of greater activation. CONCLUSIONS: Children and adolescents with BD may have underlying abnormalities in the regulation of prefrontal-subcortical circuits. Further functional magnetic resonance imaging studies of attention and mood with greater sample sizes are needed.