Antidepressant exposure in pregnancy and child sensorimotor and visuospatial development

Motor development underlies many aspects of education and learning. There has been uncertainty about the impact of exposure of antidepressant medication in pregnancy on child motor outcomes. This paper examines whether exposure to antidepressants in utero increases the risk of poorer motor development in two areas: sensorimotor and visuospatial processing. Data were obtained from 195 women and children across 3 groups: women with untreated depression in pregnancy, women treated with antidepressants and control women. Data were collected across pregnancy, postpartum and until 4 years for mother and child. Maternal depression was established at baseline with the Structured Clinical Interview for DSM-IV. Antidepressant exposure, including type, dose and timing, was measured through repeated self-report across pregnancy and the postpartum, medical records at delivery and in cord blood samples collected at delivery. Child sensorimotor and visuospatial outcomes were assessed at 4 years of age with four subtests from the NEPSY-II. Our study found for sensorimotor development, visuomotor precision completion time was associated with better performance for antidepressant exposed children compared to those with mothers with untreated depression. Yet another measure of sensorimotor development, motor manual sequences, was poorer in those exposed to antidepressants. One subtest for visuospatial processing, block construction, was associated with poorer performance in antidepressant-exposed children who had poor neonatal adaptation and those exposed to a higher dose of antidepressant. These findings suggest an inconsistent association between sensorimotor development and antidepressant use in pregnancy. However, the findings for visuospatial processing would support further exploration of antidepressant associated poor neonatal adaption and later motor development

Risk factors for hospitalizations associated with depression among women during the years around a birth: a retrospective cohort study

Introduction Socio-economic status (SES) is an important determinant of health and low SES is associated with higher rates of prenatal and post-partum depression while prenatal and post-partum depression are associated with sub-optimal maternal and infant health. Furthermore, increased negative effects of post-partum depression have been reported in children from low SES backgrounds. Objectives To assess whether socio-economic status (SES) was related to the risk of a medical or psychiatric hospitalization associated with depression (HAWD) and the risk of a HAWD by anti-depressant (AD) use during the years around a birth Methods This retrospective cohort study used linked birth, hospitalization, prescription and tax-file records of the study cohort. We linked registry data of 243,933 women delivering 348,273 live infants in British Columbia (1999-2009). The outcomes of interest were a HAWD and a HAWD and the associated patient anti-depressant (AD) use. Ranked area-based measures of equivalised, family disposable income were used to create income deciles (Decile-1 low), our proxy for SES. Mothers from Decile-6 were the comparator group. Anti-depressant use was defined as having a prenatal prescription for a serotonin reuptake inhibitor or other AD and the years around a birth were the period beginning 12 months before conception and ending 12 months after the birth. We analysed by pregnancy using mixed effects logistic regression whilst adjusting for maternal age and parity. Results                                                                                    Compared to middle-income mothers from Decile-6, (Decile-1, Decile-2) mothers from low income neighbourhoods had increased odds of HAWDs [aOR=1.77(CI: 1.43, 2.19); aOR=1.56(CI: 1.26, 1.94)]. Mothers from low income areas with depression and no AD use had even higher odds of HAWDs [aOR=1.83(CI: 1.33, 2.20); aOR=1.71(CI: 1.33, 2.20)]. Conclusions Results provide preliminary evidence that barriers to treating depression with ADs in mothers from low income areas during the years around a birth might contribute to their increased risk of a hospitalization associated with non-pharmacologically treated depression. Further research is implicated to further elucidate the origins of this increased risk

Prenatal antidepressant exposure associated with CYP2E1 DNA methylation change in neonates

Some but not all neonates are affected by prenatal exposure to serotonin reuptake inhibitor antidepressants (SRI) and maternal mood disturbances. Distinguishing the impact of these 2 exposures is challenging and raises critical questions about whether pharmacological, genetic, or epigenetic factors can explain the spectrum of reported outcomes. Using unbiased DNA methylation array measurements followed by a detailed candidate gene approach, we examined whether prenatal SRI exposure was associated with neonatal DNA methylation changes and whether such changes were associated with differences in birth outcomes. Prenatal SRI exposure was first associated with increased DNA methylation status primarily at CYP2E1(βNon-exposed = 0.06, βSRI-exposed = 0.30, FDR = 0); however, this finding could not be distinguished from the potential impact of prenatal maternal depressed mood. Then, using pyrosequencing of CYP2E1 regulatory regions in an expanded cohort, higher DNA methylation status both the mean across 16 CpG sites (P < 0.01) and at each specific CpG site (P < 0.05) was associated with exposure to lower 3rd trimester maternal depressed mood symptoms only in the SRI-exposed neonates, indicating a maternal mood x SRI exposure interaction. In addition, higher DNA methylation levels at CpG2 (P = 0.04), CpG9 (P = 0.04) and CpG10 (P = 0.02), in the interrogated CYP2E1 region, were associated with increased birth weight independently of prenatal maternal mood, SRI drug exposure, or gestational age at birth. Prenatal SRI antidepressant exposure and maternal depressed mood were associated with altered neonatal CYP2E1 DNA methylation status, which, in turn, appeared to be associated with birth weight

Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome

Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2,500 fewer steps compared to placebo (pinteraction=0.04). There were no differences between clonidine and placebo amongst patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (pint=0.003) and quality of life (pint=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions

Meta-analyses of genome-wide association studies for postpartum depression

Objective: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. Method: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)–based heritability (), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. Results: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. Conclusions: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone)

Placebo and nocebo effects in youth: subjective thermal discomfort can be modulated by a conditioning paradigm utilizing mental states of low and high self-efficacy

Introduction: Conditioning is a key mechanism of placebo and nocebo effects in adults, but little is known about these effects in youth. This study investigated whether personalized verbal cues evoking a sense of high or low self-efficacy can induce conditioned placebo and nocebo effects on subjective discomfort of noxious heat in youth. Methods: In a structured interview, 26 adolescents (13–18 years) described personal situations in which they experienced a sense of high, low or neutral self-efficacy. Participants were then asked to recall these memories during a conditioning paradigm, in which a high thermal stimulus applied to the forearm was repeatedly paired with a low self-efficacy cue and a low thermal stimulus with a high self-efficacy cue. In a testing phase, high, low and neutral self-efficacy cues were paired with the same moderate temperature. We hypothesized that conditioned high and low self-efficacy cues would induce conditioned placebo and nocebo responses to moderate temperatures. Results: Moderate temperatures were rated as more uncomfortable when paired with the conditioned low compared with the neutral self-efficacy cue (nocebo effect). While in the whole-group analysis, there was no significant difference between ratings of moderate thermal stimuli paired with high compared with neutral self-efficacy cues (placebo effect), a sub-group of participants with a greater range of emo- tional valence between high and neutral self-efficacy cues revealed a significant placebo effect. The strength of the nocebo effect was associated with higher anxiety and lower hope. Conclusion: Conditioned associations using internal self-efficacy states can change subjective discom- fort of thermal sensations. Keywords Adolescents, nocebo effect, placebo effect, thermal perception, self-efficacy, anxiety, hop

Conditioned Placebo- and Nocebo-Like Effects in Adolescents: The Role of Conscious Awareness, Sensory Discrimination, and Executive Function

Background: Conditioning is a key mechanism of placebo and nocebo effects in adults. Little is known about the underlying mechanisms of placebo and nocebo effects in youth and how they might be influenced by conscious awareness and cognitive abilities. In this study, the role of conditioning on thermal perception in youth was investigated. Methods: Differences in thermal ratings were assessed in response to consciously and non-consciously perceived cues that were conditioned to either low or high heat. Furthermore, we tested whether executive function mediates the effect of conditioning on thermal perception. Thirty-five high-school students (14–17 years) completed an executive function task and underwent a sensory perception paradigm. In a conditioning phase, two distinct neutral faces (conditioned cues) were coupled to either a low or a high temperature stimulus delivered to participants’ forearms. In a testing phase, the conditioned cues, and novel faces (non-conditioned control cues), were paired with identical moderate thermal stimuli. In this testing phase, for half of the participants cues were presented consciously (supraliminally) and for the other half non-consciously (subliminally). Results: We found a significant main effect of cue type on thermal ratings (p = 0.003) in spite of identical heat being administered following all cues. Post-hoc analyses indicated that the nocebo-like effect (conditioned high cue compared to control) was significant (p = 0.027); the placebo-like effect (conditioned low cue compared to control) was non-significant. No difference between cues presented supra- vs. subliminally and no significant interaction effects were found. The association between sensory discrimination and the magnitude of the nocebo-like effect was mediated by executive function. Conclusions: To our best knowledge, this is the first study establishing a relationship between thermal perception, nocebo effects, and executive function in youth. Our results may have important implications for understanding cognitive/ learning processes involved in nocebo effects