Using randomized controlled trials to ask questions regarding developmental psychopathology: A tribute to Dante Cicchetti.

Dante Cicchetti, the architect of developmental psychopathology, has influenced so many of us in profound ways. One of his many contributions was in demonstrating the power of randomized controlled trials (RCTs) to study the effects of Child-Parent Psychotherapy (CPP). These RCTs have shed light on causal mechanisms in development. Following Cicchetti and colleagues' work, we designed a brief home visiting program, Attachment and Biobehavioral Catch-up (ABC), to help parents respond in sensitive, nurturing ways, so as to enhance children's attachment and self-regulatory capabilities. In the current study, we assessed adolescents' reports of the closeness of their relationships with their mothers 12 years after their mothers completed the intervention. A total of 142 adolescents participated (47 randomized to ABC, 45 randomized to a control intervention, and 50 from a low-risk comparison group). Adolescents whose mothers had been randomized to ABC reported closer relationships with their mothers than adolescents randomized to the control condition, with significant differences seen on approval, support, companionship, and emotional support subscales. Consistent with Cicchetti et al.'s work, these results provide powerful evidence of the long-term effects of an early parenting intervention.

GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder.

RATIONALE: Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD. AIMS: The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms. METHODS: Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5ß-THP; pregnenolone; 3α,5α-androsterone; 3α,5ß-androsterone; 3α,5α-A-diol; 3α5ß-A-diol; 3α,5α-THDOC; 3α5ß-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment. RESULTS: Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone. CONCLUSIONS: This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.

Reduction of anxiety symptoms among women within a collaborative care model and women's health settings.

AIM: The purpose of this study is to focus on changes in anxiety symptoms among women treated in women's health practices and under a collaborative care model. BACKGROUND: Research on collaborative care has largely focused on improving depressive and anxiety symptoms among adults in primary care settings. The applicability of collaborative care in other healthcare settings is underreported with limited research investigating if collaborative care has advantages in subpopulations treated in both traditional primary care settings and other healthcare settings, such as women's health practices. METHODS: This study, completed through secondary data analysis of the electronic record of N = 219 women across three women's healthcare centers, evaluated if instituting a collaborative care model is associated with reduced anxiety symptoms and which factors (eg, primary diagnosis, duration of care, and use of psychotropic medications) are associated with anxiety outcomes. Anxiety symptoms were assessed using the Generalized Anxiety Disorder 7-item scale (GAD-7) at entry into and at termination from collaborative care services. RESULTS: Overall, there was a significant reduction in average anxiety scores from baseline to termination of collaborative care (t(218) = 12.41, P < 0.001). There was a main effect for the duration of time receiving collaborative care services on anxiety score reduction (ß = -0.28, SE = 0.06, P < 0.001) with a significant reduction in anxiety symptoms at the 90-day mark (t(218) = 10.58, P < 0.001). Therefore, collaborative care can be useful in women's health practices in reducing anxiety symptoms over a 90-day time period.

Metabolites of progesterone in pregnancy: Associations with perinatal anxiety.

BACKGROUND: Anxiety disorders are the most common psychiatric disorder during the perinatal period and one of the major risk factors for postpartum depression, yet we know little about biological factors in the etiology of perinatal anxiety. A growing literature points to neuroactive steroid (NAS) dysregulation in perinatal mental illness, but directionality has not been clearly demonstrated, results are not consistent, and no studies have investigated NAS in a population with pure anxiety without comorbid depression. We aimed to add to the limited literature by examining the association between anxiety without comorbid depression and metabolic pathways of NAS longitudinally across the peripartum. METHODS: We measured anxiety symptoms by psychological scales and NAS levels using Gas Chromatography-Mass Spectrometry (GC-MS) at the second and third trimester (T2 and T3) and week 6 postpartum (W6) in n = 36 women with anxiety and n = 38 healthy controls. The anxiety group was determined by a data-driven approach, and cross-sectional and longitudinal statistical methods were used to examine the relationship between the study population and NAS. RESULTS: We found that anxiety had a significant moderating effect on the relationship between progesterone and allopregnanolone, with no such effect for the relationships between progesterone and the intermediate (5α-DHP) or isomeric (isoallopregnanolone) compounds in this pathway, and no effects on the corresponding pathway converting progesterone to pregnanolone and epipregnanolone. We also found a less precipitous decline in the ratio of allopregnanolone to progesterone between T3 and W6 in the anxiety group compared to the non-anxiety group. A genotype analysis of a single-nucleotide polymorphism in the AKR1C2 gene demonstrated that the relationship of allopregnanolone to the intermediate metabolite, 5α-DHP, differed by genotype. CONCLUSION: Our exploratory findings indicate that, for pregnant people with anxiety, metabolism is shunted more aggressively toward the endpoint of the progesterone to allopregnanolone metabolic pathway than it is for those without anxiety.

The Differential Impact of Parenting on Adolescent Externalizing Behaviors in the Context of Maternal Stress.

The effectiveness of parenting on child outcomes may be dependent on other contextual factors. To date, few studies have focused on the potential moderating effect of maternal stress on the relationship between parenting and youth externalizing behaviors. This study extends prior work by assessing how the relationship between parenting and youth outcomes varies by the presence of maternal stress, while focusing on the developmental period of adolescence and two dimensions of parenting, parental knowledge and maternal warmth. Data were collected from 278 Mother-adolescent dyads (Madolescent age = 14.05; 53.2% females; 61.9% minority) on maternal stress, maternal warmth and parental knowledge, and youth aggression and delinquency. Multi-level regression models found significant two-way interactions between parental knowledge and maternal stress on aggression and between maternal warmth and maternal stress on both outcomes. Parental knowledge was associated with lower aggression in the context of high maternal stress, but warmth only attenuated the risk of youth outcomes among low maternal stress. This study highlights the importance of considering how contextual factors impact the relationship between parenting and youth externalizing behaviors.

The immune phenotype of perinatal anxiety.

BACKGROUND: Immune dysregulation has been linked to both psychiatric illness and pregnancy morbidity, including perinatal depression, but little is known about the immune phenotype of perinatal anxiety. Here, we sought to identify the unique immune profile of antenatal anxiety. MATERIALS AND METHODS: Pregnant women (n = 107) were followed prospectively at 2nd and 3rd trimesters (T2, T3) and 6 weeks postpartum (PP6). Each visit included a blood draw and psychological evaluation, with clinical anxiety assessed using the Spielberg State-Trait Anxiety Scale. We enrolled both healthy controls and participants with anxiety alone; those with comorbid depression were excluded. Multiplex cytokine assays and flow cytometry were used to examine the association of anxiety symptoms with secreted immune markers and PBMC-derived immune cells. RESULTS: K cluster means revealed three clusters of anxiety symptomatology; due to low numbers in the highest severity anxiety group, these were collapsed into two groups: Non-Anxiety and Anxiety. Principal components analysis revealed two distinct clusters of cytokine secretion including one cluster that consisted of many innate immune cytokines and differed between groups. Compared to women in the Non-Anxiety group, women in the Anxiety group had lower levels of cytokine expression during pregnancy and an increase in levels into the postpartum, whereas Non-Anxiety women experienced a time-dependent decline. Immune cell populations also differed between our two groups, with the Anxiety group showing a decrease in the ratio of B cells to T cells from pregnancy to postpartum, whereas the Non-Anxiety women showed an increase in this ratio over time. Women in the Anxiety group also demonstrated an increased ratio of cytotoxic to helper T cells throughout pregnancy, a modest increase in the Th1:Th2 ratio across pregnancy, and a lower ratio of Th17:TREG cells in the postpartum as compared with Non-Anxiety women. CONCLUSION: These data suggest that the immune response throughout the antenatal period differs for women with anxiety symptoms compared to those without, suggestive of a unique immune phenotype of perinatal anxiety.