A two-stage estimation procedure for non-linear structural equation models.

Applications of structural equation models (SEMs) are often restricted to linear associations between variables. Maximum likelihood (ML) estimation in non-linear models may be complex and require numerical integration. Furthermore, ML inference is sensitive to distributional assumptions. In this article, we introduce a simple two-stage estimation technique for estimation of non-linear associations between latent variables. Here both steps are based on fitting linear SEMs: first a linear model is fitted to data on the latent predictor and terms describing the non-linear effect are predicted by their conditional means. In the second step, the predictions are included in a linear model for the latent outcome variable. We show that this procedure is consistent and identifies its asymptotic distribution. We also illustrate how this framework easily allows the association between latent variables to be modeled using restricted cubic splines, and we develop a modified estimator which is robust to non-normality of the latent predictor. In a simulation study, we compare the proposed method to MLE and alternative two-stage estimation techniques.

Pharmacologically Induced Sex Hormone Fluctuation Effects on Resting-State Functional Connectivity in a Risk Model for Depression: A Randomized Trial.

Women are at relatively greater lifetime risk for depression than men. This elevated risk in women is partly due to heightened risk during time periods characterized by marked fluctuations in sex hormones, including postpartum and perimenopausal periods. How sex hormone fluctuations contribute to heightened risk is not fully understood but may involve intrinsic functional connectivity. We induced a biphasic ovarian sex hormone fluctuation using the gonadotropin-releasing hormone agonist (GnRHa) goserelin to determine, with a randomized placebo-controlled design, intervention effects on or GnRHa-provoked depressive symptoms associations with change in resting-state functional connectivity (rs-FC) in 58 healthy women for six seeds (amygdala, hippocampus, anterior cingulate cortex, dorsal raphe, median raphe, and posterior cingulate cortex). GnRHa intervention did not significantly affect rs-FC in any seeds. Considering the GnRHa group only, the emergence of depressive symptoms following intervention was positively associated with amygdala-right temporal cortex and negatively associated with hippocampus-cingulate rs-FC. A test for mediation suggested that rs-FC changes in these networks marginally mediated the association between decrease in estradiol and increase in depressive symptoms in the GnRHa group (p=0.07). Our findings provide novel evidence-linking changes in rs-FC networks, the emergence of depressive symptoms and sex hormone fluctuations. Notably, we observed evidence that changes in rs-FC may represent a key neurobiological intermediary between molecular changes induced by hormone fluctuations and the emergence of depressive symptoms. Taken together, our findings indicate that sex hormone fluctuations may contribute to heightened risk for developing depressive symptoms by affecting intrinsic functional connectivity of key limbic brain structures.

Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study.

BACKGROUND: An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. METHODS: A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 ± 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start). RESULTS: Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003). CONCLUSIONS: Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups.

In abstinent MDMA users the cortisol awakening response is off-set but associated with prefrontal serotonin transporter binding as in non-users.

Serotonergic signaling is considered critical for an appropriate adaptation to stress. We have previously observed that in healthy volunteers, prefrontal serotonin transporter (SERT) binding is positively associated with hypothalamic-pituitary-adrenal (HPA)-axis output in terms of the cortisol awakening response (CAR). Here, we tested (1) if such a correlation persists in a human model of chronic serotonin depletion, namely in 3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') users, and (2) if CAR differed between MDMA users (N = 18) and non-using healthy volunteers (N = 32). Participants underwent SERT brain imaging with [11C]DASB-PET, and performed home-sampling of CAR, defined as the area under curve with respect to cortisol increase from awakening level. When adjusting for age and group, CAR was positively coupled to prefrontal SERT binding (p = 0.006) and MDMA users showed significantly higher CAR than the control group (p = 0.0003). In conclusion, our data confirm the recently described positive association between prefrontal SERT binding and CAR, this time in a human model of serotonin deficiency. Also, we find that CAR was higher in MDMA users relative to non-users. We suggest that the inhibitory control on HPA-axis output is less efficient in the off-balance state established by recent MDMA use, most likely through mechanisms other than those that can be compensated by lowering SERT levels.

Prefrontal serotonin transporter availability is positively associated with the cortisol awakening response.

UNLABELLED: Stress sensitivity and serotonergic neurotransmission interact, e.g. individuals carrying the low-expressing variants (S and LG) of the 5-HTTLPR promoter polymorphism of the serotonin transporter (SERT) gene are at higher risk for developing mood disorders when exposed to severe stress and display higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT binding in brain regions considered relevant to modify the cortisol awakening response. METHODS: thirty-two healthy volunteers underwent in vivo SERT imaging with [(11)C]DASB-Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. RESULTS: CAR, defined as the area under curve with respect to increase from baseline, was positively coupled to prefrontal SERT binding (p=0.02), independent of adjustment for 5-HTTLPR genotype. Although S- and LG-allele carriers tended to show a larger CAR (p=0.07) than LA homozygous, 5-HTTLPR genotype did not modify the coupling between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype×CAR). CONCLUSION: prefrontal SERT binding is positively associated with cortisol response to awakening. We speculate that in mentally healthy individuals prefrontal serotonergic neurotransmission may exert an inhibitory control on the cortisol awakening response.

Familial risk for mood disorder and the personality risk factor, neuroticism, interact in their association with frontolimbic serotonin 2A receptor binding.

Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability and is positively correlated to frontolimbic serotonin 2A (5-HT(2A)) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT(2A) receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent [(18)F]altanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT(2A) receptor binding (p=0.026) in an analysis adjusting for age and body mass index. Within the high-risk group only, neuroticism and frontolimbic 5-HT(2A) receptor binding was positively associated (p=0.0037). In conclusion, our data indicate that familial risk and neuroticism interact in their relation to frontolimbic 5-HT(2A) receptor binding. These findings point at a plausible neurobiological link between genetic and personality risk factors and vulnerability to developing mood disorders. It contributes to our understanding of why some people at high risk develop mood disorders while others do not. We speculate that an increased stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission.

Acute respiratory symptoms and general illness during the first year of life: a population-based birth cohort study.

Respiratory symptoms are common in infancy. Most illnesses occurring among children are dealt with by parents and do not require medical attention. Nevertheless, few studies have prospectively and on a community-basis assessed the amount of respiratory symptoms and general illness in normal infants. In this population-based birth cohort study, 228 healthy infants from Copenhagen, Denmark were followed from birth to 1 year of age during 2004-2006. Symptoms were registered using daily diaries and monthly home visits. Interviews were performed at inclusion and every second month. Risk factor analysis was carried out by multiple logistic regression analysis. On average, children had general symptoms for 3.5 months during their first year of life, nasal discharge being most frequent followed by cough. Frequency of all symptoms increased steeply after 6 months of age. Each child had on average 6.3 episodes (median: 5.1, inter-quartile range (IQR): 3.3-7.8) of acute respiratory tract illness (ARTI) (nasal discharge and > or = 1 of the following symptoms: cough, fever, wheezing, tachypnea, malaise, or lost appetite) and 5.6 episodes (median: 4.3, IQR: 2.1-7.3) of simple rhinitis per 365 days at risk. Determinants for respiratory symptoms were increasing age, winter season, household size, size of residence, day-care attendance, and having siblings aged 1-3 years attending a day nursery. In conclusion, the present study provides detailed data on the occurrence of disease symptoms during the first year of life in a general population cohort and emphasizes the impact of increasing age, seasonality, and living conditions on the occurrence of ARTI.