Identification of risk loci for postpartum depression in a genome-wide association study.

AIM: Genome-wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD-associated loci. METHODS: The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders. RESULTS: A meta-analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10-8) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over-represented in categories including long-term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling. CONCLUSION: The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis.

Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population.

AIM: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. METHODS: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. RESULTS: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). CONCLUSION: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

The genetic architecture of schizophrenia: review of large-scale genetic studies.

Schizophrenia is a complex and often chronic psychiatric disorder with high heritability. Diagnosis of schizophrenia is still made clinically based on psychiatric symptoms; no diagnostic tests or biomarkers are available. Pathophysiology-based diagnostic scheme and treatments are also not available. Elucidation of the pathogenesis is needed for development of pathology-based diagnostics and treatments. In the past few decades, genetic research has made substantial advances in our understanding of the genetic architecture of schizophrenia. Rare copy number variations (CNVs) and rare single-nucleotide variants (SNVs) detected by whole-genome CNV analysis and whole-genome/-exome sequencing analysis have provided the great advances. Common single-nucleotide polymorphisms (SNPs) detected by large-scale genome-wide association studies have also provided important information. Large-scale genetic studies have been revealed that both rare and common genetic variants play crucial roles in this disorder. In this review, we focused on CNVs, SNVs, and SNPs, and discuss the latest research findings on the pathogenesis of schizophrenia based on these genetic variants. Rare variants with large effect sizes can provide mechanistic hypotheses. CRISPR-based genetics approaches and induced pluripotent stem cell technology can facilitate the functional analysis of these variants detected in patients with schizophrenia. Recent advances in long-read sequence technology are expected to detect variants that cannot be detected by short-read sequence technology. Various studies that bring together data from common variant and transcriptomic datasets provide biological insight. These new approaches will provide additional insight into the pathophysiology of schizophrenia and facilitate the development of pathology-based therapeutics.

Sex differences in neurodevelopmental trajectories in children with different levels of autistic traits.

AIM: Little is known about early manifestations of autism spectrum disorders (ASD) in females, including those who may be overlooked by the current diagnostic criteria. We longitudinally explored sex differences in the trajectories of cognitive and motor functions and adaptive behaviors in children with different levels of autistic traits. METHODS: The participants were 824 children from the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), Japan, who were classified into three autistic trait groups-low, moderate, and high-based on the Social Responsiveness Scale-Second Edition. Cognitive and motor functions were measured at seven time-points from 0.5 to 3.5 years of age using the Mullen Scales of Early Learning. Adaptive behaviors were measured at five time-points from 2.7 to 9 years of age using the Vineland Adaptive Behavior Scales-Second Edition. Trajectories were depicted using latent growth curve modeling. RESULTS: Sex-specific trajectories were observed in the high-autistic-trait group, with only males showing a temporary decline in expressive language around the age of 2 years and a slight improvement thereafter. They also showed a slight improvement around 3 years in the adaptive behavior communication domain but a gradual downward trend later. Females in the high-autistic-trait group showed no distinct manifestation before the age of 3 years but showed a downward trend after 3.5 years in the adaptive behavior communication domain. CONCLUSION: Females and males with higher autistic traits than their same-sex peers, independent of clinical diagnosis, may have different phenotypes in certain neurodevelopmental domains during infancy and early childhood.

Early temperament as a predictor of language skills at 40 months.

BACKGROUND: Mastering language involves the development of expressive and receptive skills among children. While it has been speculated that early temperament plays a role in the acquisition of language, the actual mechanism has not yet been explored. We investigated whether temperament at 18 months predicted expressive or receptive language skills at 40 months. METHODS: A representative sample of 901 children and their mothers who were enrolled and followed-up longitudinally in the Hamamatsu Birth Cohort for Mothers and Children study was included in the analysis. Child temperament was measured at 18 months using the Japanese version of the Early Childhood Behavior Questionnaire. Expressive and receptive language skills were measured at 40 months using the Mullen Scales of Early Learning. RESULTS: The multiple regression analysis, adjusting for potential confounders, suggested that higher motor activation (fidgeting) at 18 months was associated with lower expressive and receptive language skills at 40 months. Higher perceptual sensitivity was associated with higher expressive and receptive language skills at 40 months. CONCLUSIONS: Specific temperament at 18 months of age predicted the development of the child's expressive and receptive language skills at 40 months.

Elevated risk of attention deficit hyperactivity disorder (ADHD) in Japanese children with higher genetic susceptibility to ADHD with a birth weight under 2000 g.

BACKGROUND: Both genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children. METHODS: We conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children, we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as <2000 g, 2000-2499 g, and ≥2500 g. Polygenic risk score for ADHD was generated using the summary data of a large-scale genome-wide association study. The Rating Scale IV (ADHD-RS) assessed ADHD traits (inattention and hyperactivity/impulsivity) based on parental reports. Following previous studies, sex, birth order of the child, gestational age at birth, mother's age at delivery, educational attainment, pre-pregnancy body mass index, pre-pregnancy or during pregnancy smoking status, alcohol consumption during pregnancy, father's age, education, and annual family income were considered as covariates. Multivariable negative binomial regression was applied to evaluate the association between birth weight and ADHD traits, while adjusting for potential covariates. The interaction term between birth weight categories and binary polygenic risk was added to the model. RESULTS: Birth weight of 2000-2499 g was not associated with ADHD traits. Birth weight under 2000 g was significantly associated with both inattention and hyperactivity. When accounting for higher and lower genetic risk for ADHD, only those with higher genetic risk and birth weight < 2000 g were associated with inattention (rate ratio [RR] 1.56, 95% CI 1.07-2.27) and hyperactivity (RR 1.87, 95% CI 1.14-3.06). CONCLUSIONS: Birth weight under 2000 g, together with the genetic risk of ADHD, contributes to higher levels of ADHD traits among Japanese children aged 8 to 9 years. The suggested association between low birth weight and ADHD is confined to children with a genetic susceptibility to ADHD, indicating the relevance of genetic-environmental interactions in the etiology.

Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study.

BACKGROUND: Esketamine nasal spray (Spravato) in conjunction with oral antidepressants (ADs) is approved in the European Union, United States, and other markets for treatment-resistant depression (TRD). Efficacy, safety, and tolerability of esketamine nasal spray in Japanese patients with TRD needs to be assessed. METHODS: This Phase 2b, randomized, double-blind (DB), placebo-controlled study was conducted in adult Japanese patients with TRD meeting the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) criteria of major depressive disorder with nonresponse to ≥ 1 but < 5 different ADs in the current episode at screening. Patients were treated with a new oral AD for 6 weeks (prospective lead-in phase); nonresponders were randomized (2:1:1:1) to placebo or esketamine (28-, 56-, or 84-mg) nasal spray along with the continued use of AD for 4 weeks (DB induction phase). Responders (≥50% reduction from baseline in the Montgomery-Asberg Depression Rating Scale [MADRS] total score) from the DB induction phase continued into the 24-week posttreatment phase and patients who relapsed could participate in a 4-week open-label (OL) second induction (flexibly-dosed esketamine). The primary efficacy endpoint, change from baseline in the MADRS total score at Day 28 in the DB induction phase, was based on mixed-effects model using repeated measures pairwise comparisons using a Dunnett adjustment. RESULTS: Of the 202 patients randomized in the DB induction phase (esketamine [n = 122] or placebo [n = 80]), the MADRS total scores decreased from baseline to Day 28 of the DB induction phase (- 15.2, - 14.5, - 15.1, and - 15.3 for esketamine 28 mg, 56 mg, 84 mg, and placebo groups, respectively), indicating an improvement in depressive symptoms; however, the difference between the esketamine and placebo groups was not statistically significant. The most common treatment-emergent adverse events during the DB induction phase in the combined esketamine group (incidences ranging from 12.3 to 41.0%) were blood pressure increased, dissociation, dizziness, somnolence, nausea, hypoaesthesia, vertigo, and headache; the incidence of each of these events was > 2-fold higher than the corresponding incidence in the placebo group. CONCLUSIONS: Efficacy of esketamine plus oral AD in Japanese TRD patients was not established; further investigation is warranted. All esketamine doses were safe and tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02918318 . Registered: 28 September 2016.

Common genetic variants on 5p14.1 associate with autism spectrum disorders.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Assessment of executive functions using a 3D-video game in children and adolescents with ADHD.

Objective: Executive functions are important factors that affect the well-being of children with ADHD. Therefore, inclusion of a convenient assessment of executive dysfunction in diagnosis and treatment of ADHD patients is warranted. However, executive dysfunction assessment presently relies on lab-based neuropsychological tests and symptom rating scales. The present study examined the potential of a 3-D action puzzle video game to reflect ecologically valid executive functioning in pediatric ADHD patients. Methods: Participant gameplay metrics were compared to both their Cambridge Neuropsychological Test Automated Battery (CANTAB) and Conners 3 Parent Form's executive functioning subscale scores. Participants consisted of 33 ADHD and non-ADHD patients aged 8-21. Results: Metrics from gameplay were associated with distinct CANTAB test scores, and a composite score from gameplay was significantly correlated with executive dysfunction from Conners 3. Conclusion: For children with ADHD, cognitive domains related to executive function and overall real-life executive functioning appear to both be measurable via video games. It may be possible to develop individualized behavioral therapy based on the quantitative data obtained from the video game used in this study.

Interleukin-23 levels in umbilical cord blood are associated with neurodevelopmental trajectories in infancy.

Our previous study, which aimed to understand the early neurodevelopmental trajectories of children with and without neurodevelopmental disorders, identified five classes of early neurodevelopmental trajectories, categorized as high normal, normal, low normal, delayed, and markedly delayed. This investigation involved measurement using the Mullen Scale of Early Learning in a representative sample of Japanese infants followed up from the age of 0 to 2 years (Nishimura et al., 2016). In the present study, we investigated the potential association between cytokine concentrations in umbilical cord serum with any of the five classes of neurodevelopmental trajectories previously assigned, as follows: high normal (N = 85, 13.0%), normal (N = 322, 49.1%), low normal (N = 137, 20.9%), delayed (N = 87, 13.3%), and markedly delayed (N = 25, 3.8%) in infancy. Decreased interleukin (IL)-23 levels in the cord blood were associated with the markedly delayed class, independent of potential confounders (odds ratio, 0.44; 95%confidence interval: 0.26-0.73). Furthermore, IL-23 levels decreased as the developmental trajectory became more delayed, demonstrating that IL-23 plays an important role in development, and is useful for predicting the developmental trajectory at birth.

Roles of glial cells in schizophrenia: possible targets for therapeutic approaches.

Glial cells consisting of oligodendrocytes, astrocytes, microglia, and NG2 positive cells are major cell populations in the central nervous system, number-wise. They function as effectors and modulators of neurodevelopment through a wide variety of neuron-glial cell interactions in brain development and functions. Glial cells can be affected by both genetic and environmental factors, leading to their dysfunctions in supporting neuronal development and functions. These in turn can affect neuronal cells, causing alterations at the circuitry level that manifest as behavioral characteristics associated with schizophrenia in late teens-early twenties. Glial cells are also involved in neuroinflammatory processes, which sometimes have deleterious effects on the normal brain development. If the glial involvement plays significant roles in schizophrenia, the processes involving glial cells can become possible therapeutic targets for schizophrenia. A number of known antipsychotics are shown to have beneficial effects on glial cells, but other drugs targeting glial cell functions may also have therapeutic effects on schizophrenia. The latter can be taken into consideration for future drug development for schizophrenia.

A genome-wide study reveals copy number variants exclusive to childhood obesity cases.

The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Genomic copy number variations (CNVs) have been strongly implicated in subjects with extreme obesity and coexisting developmental delay. To complement these previous studies, we addressed CNVs in common childhood obesity by examining children with a BMI in the upper 5(th) percentile but excluding any subject greater than three standard deviations from the mean in order to reduce severe cases in the cohort. We performed a whole-genome CNV survey of our cohort of 1080 defined European American (EA) childhood obesity cases and 2500 lean controls (< 50(th) percentile BMI) who were genotyped with 550,000 SNP markers. Positive findings were evaluated in an independent African American (AA) cohort of 1479 childhood obesity cases and 1575 lean controls. We identified 17 CNV loci that were unique to at least three EA cases and were both previously unreported in the public domain and validated via quantitative PCR. Eight of these loci (47.1%) also replicated exclusively in AA cases (six deletions and two duplications). Replicated deletion loci consisted of EDIL3, S1PR5, FOXP2, TBCA, ABCB5, and ZPLD1, whereas replicated duplication loci consisted of KIF2B and ARL15. We also observed evidence for a deletion at the EPHA6-UNQ6114 locus when the AA cohort was investigated as a discovery set. Although these variants may be individually rare, our results indicate that CNVs contribute to the genetic susceptibility of common childhood obesity in subjects of both European and African ancestry.

Strong synaptic transmission impact by copy number variations in schizophrenia.

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 x 10(-7)). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.

The association between screen time and genetic risks for neurodevelopmental disorders in children.

Whether longer screen time in infancy increases risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and ADHD has long been debated, but no causal relationship between the two remains has been established. Using ongoing longitudinal cohort data, we found that in children 24 to 40 months of age, the genetic risk of ASD was associated with longer screen time and that of ADHD with an increase in screen time over time. These data suggest that prolonged screen time may not be a cause of the genetic risk for NDD, but an early sign of NDDs.

Outdoor Play as a Mitigating Factor in the Association Between Screen Time for Young Children and Neurodevelopmental Outcomes.

Importance: Whether the association between higher screen time in infancy and later suboptimal neurodevelopment can be mitigated by frequency of outdoor play is unknown. Objective: To investigate whether higher screen time at age 2 years is associated with neurodevelopmental outcomes at age 4 years and whether this association is mediated by frequency of outdoor play at age 2 years 8 months. Design, Setting, and Participants: Participants were a subsample of the Hamamatsu Birth Cohort Study for Mothers and Children (HBC Study, N = 1258). Children were born between December 2007 and March 2012 and followed up from 1 year 6 months to 4 years. The analysis was conducted from April 2021 to June 2022. Exposures: Screen time longer than 1 hour a day at age 2 years was coded as higher screen time. Main Outcomes and Measures: Standardized scores for communication, daily living skills, and socialization domains of the Vineland Adaptive Behavior Scale, second edition, at age 4 years were used (mean [SD], 100 [15]). The mediating factor was frequency of outdoor play at age 2 years 8 months, with 6 or 7 days per week coded as frequent outdoor play. Results: Of 885 participants, 445 children (50%) were female; mean (SD) screen time per day was 2.6 (2.0) hours. Causal mediation analyses revealed that higher screen time at age 2 years was associated with lower scores in communication at age 4 years (nonstandardized coefficient b = -2.32; 95% CI, -4.03 to -0.60), but the association was not mediated by frequency of outdoor play. Higher screen time was also associated with lower scores in daily living skills (b = -1.76; 95% CI, -3.21 to -0.31); 18% of this association was mediated by frequency of outdoor play. Frequency of outdoor play was associated with socialization (b = 2.73; 95% CI, 1.06 to 4.39), whereas higher screen time was not (b = -1.34; 95% CI, -3.05 to 0.36). Conclusions and Relevance: Higher screen time at age 2 years was directly associated with poorer communication at age 4 years. It was also associated with daily living skills, but frequency of outdoor play at age 2 years 8 months alleviated it, suggesting outdoor play mitigated the association between higher screen time and suboptimal neurodevelopment. Future research should specify the nature of the associations and intervention measures, enabling targeted interventions that reduce the potential risk in screen time.

Interaction of genetic liability for attention deficit hyperactivity disorder (ADHD) and perinatal inflammation contributes to ADHD symptoms in children.

Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8-9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. Results: Perinatal inflammation (ß [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (ß [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (ß [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (ß [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; ß [SE], 0.664[0.152]; P < 0.001 for the high-risk group). Conclusion: Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8-9 with genetically higher risk for ADHD.

Perfluorooctanoate and perfluorooctane sulfonate in umbilical cord blood and child cognitive development: Hamamatsu Birth Cohort for Mothers and Children (HBC Study).

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been shown to affect offspring behaviors in laboratory animals. Several epidemiological studies investigated associations between prenatal PFAS exposure and child neurodevelopment, but results were inconclusive. We examined associations between cord blood concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) and cognitive development in children from 4 to 40 months of age. METHODS: This study included 598 mother-child pairs who participated in the Hamamatsu Birth Cohort Study for Mothers and Children (HBC Study), a prospective birth cohort study in Japan. PFOA and PFOS were quantified in cord blood. The Mullen Scales of Early Learning (MSEL) was used to assess child cognitive function at 4, 6, 10, 14, 18, 24, 32, and 40 months of age. For each of log 2-transformed PFOA and PFOS concentrations, we examined: 1) associations with the scores of MSEL Early Learning Composite (Composite) and four subscales (Fine Motor, Visual Reception, Receptive Language, Expressive Language) at each assessment time point; and 2) associations with longitudinal changes in the Composite and subscale scores. RESULTS: MSEL Composite scores were inversely associated with PFOA at 18 months of age (per 2-fold increase in concentration: ß = -2.23, 95% CI: -3.91, -0.56), but not at other ages. When accounting for changes in scores from 4 to 40 months of age, PFOA and PFOS were positively associated with Composite as well as Receptive and Expressive Language scores. Child's sex modified associations between PFOA and Composite scores at 14, 18, and 40 months and those between PFOS and Composite scores at 14 months, showing negative associations among females. CONCLUSIONS: In this study, cord blood PFOA and PFOS concentrations showed mixed associations with child cognitive functions at specific age but had positive associations with longitudinal changes in cognitive development from 4 to 40 months of age.

Long-term effect of persistent postpartum depression on children's psychological problems in childhood.

BACKGROUND: Maternal postpartum depression (PPD) is a well-established risk factor for psychological problems in children; however, little is known about the sustained impact of persistent PPD patterns and severity on these problems in children. METHODS: Data were obtained from mothers (N = 714) and children (N = 768) from the Hamamatsu Birth Cohort for Mothers and Children. Maternal depression was measured using the Edinburgh Postpartum Depression Scale at 2, 4, 10 weeks and 10 months postpartum. Children's internalizing and externalizing problems were assessed using the Strengths and Difficulties Questionnaire at 6 years and 8-9 years old. Mothers were divided into 4 groups based on the trajectory of their PPD persistence: "No PPD," "Transient PPD," "Worsening PPD" and "Persistent PPD." Linear regression analysis was used to examine the association of PPD persistence and severity with children's internalizing and externalizing problems. RESULTS: "Persistent PPD" was significantly associated with children's internalizing problems at 6 years old (Coefficient [95%CI] = 2.74 [1.30-4.19], P < .001), but no association was found at 8-9 years old. No associations were found between PPD severity and children's internalizing and externalizing problems in either age category. LIMITATIONS: "Persistent PPD" and "Worsening PPD" groups had a relatively small sample size. The mothers' depression statuses were not ascertained simultaneously with the children's behavioral assessments. There was no information regarding the mothers' treatment for PPD. CONCLUSION: PPD persistence negatively affected children's internalizing problems but was not long-lasting. Future studies are needed to identify protective factors against PPD persistence in children's psychological problems.