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The mental health of child and adolescent intensive care unit (ICU) survivors is increasingly being researched. However, the literature on how various types of critical illness influence specific psychiatric disorders remains limited. This study analyzed the data of 8704 child and adolescent ICU survivors and 87,040 age-, sex-, family income–, and residence-matched controls who were followed from enrollment to the end of 2013; the data covered the period from 1996 to 2013 and were extracted from a nationwide data set. The primary outcomes were the risks of five major psychiatric disorders (MPDs), namely schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), obsessive compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). Relative to the controls, the child and adolescent ICU survivors (mean age = 10.33 years) exhibited higher risks of developing five MPDs. The associated hazard ratios (HRs) and confidence intervals (CIs) are as follows: PTSD, HR = 4.67, 95 % CI = 2.42–9.01; schizophrenia, HR = 3.19, 95 % CI = 2.27–4.47; BD, HR = 2.02, 95 % CI = 1.33–3.05; OCD, HR = 1.96, 95 % CI = 1.21–3.16; and MDD, HR = 1.68, 95 % CI = 1.44–1.95. The risks of developing MPDs varied across multiple types of critical illness related to ICU admission. The risks of MPDs were significantly higher among the child and adolescent ICU survivors than among the controls. The development of appropriate MPD prevention strategies should be emphasized for this vulnerable population. • Child and adolescent ICU survivors had increased risks of schizophrenia, bipolar disorder, major depression and PTSD. • The ICU survivors with an ICU stay of ≥3 days was associated with a significantly higher risk (16-fold) of PTSD. • The development of mental health improvement strategies should be emphasized for child and adolescent ICU survivors. [ABSTRACT FROM AUTHOR]

Background: Migraine has been associated with mental disorders, however whether parental migraine is associated with an increased risk of major mental disorders (MMDs) in offspring has not been investigated. We aimed to examine the risk of the development of MMDs in the offspring of parents with migraine compared with those of parents without migraine. Methods: This study used data derived from the Taiwan National Health Insurance Research Database. Offspring of parents with migraine and a control group consisting of offspring of parents without migraine matched for demographic and parental mental disorders were included. Cox regression was used to estimate the risk of MMDs, including schizophrenia, depressive disorder, bipolar disorder, autistic spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Sub-analyses stratified by the fathers and mothers were further performed to separately clarify the risks of MMDs among the offspring. Results: We included 22,747 offspring of parents with migraine and 227,470 offspring of parents without migraine as the controls. Parental migraine was significantly associated with an increased risk of ADHD (reported as hazard ratios with 95% confidence intervals: 1.37, 1.25–1.50), bipolar disorder (1.35, 1.06–1.71), and depressive disorder (1.33, 1.21–1.47) compared to the offspring of parents without migraine. Importantly, sub-analyses showed that only maternal migraine was significantly associated with these risks. Conclusions: Due to the heavy burden of MMDs, healthcare workers should be aware of the risk of MMDs in the offspring of parents with migraine, particular in mothers. [ABSTRACT FROM AUTHOR]

Although a growing number of studies have investigated the relationship between psychosocial factors and periodontitis, studies investigating the association between bipolar disorder (BD) and periodontitis are lacking. Using the Taiwan National Health Insurance Research Database, 4251 adolescents with BD and 17,004 age- and sex-matched controls were included. They were followed up from enrollment to the end of 2011 or death. Periodontitis was diagnosed during the follow-up. Cox regression analysis indicated that adolescents with BD had a higher risk of periodontitis (hazard ratio [HR]: 2.96, 95% confidence interval [CI] 2.77–3.17) than did controls. Subanalyses stratified by sex revealed a higher risk of periodontitis in male (HR: 2.83, 95% CI 2.56–3.14) and female (HR: 3.01, 95% CI 2.74–3.30) adolescents with BD than their respective controls. The long-term use of mood stabilizers was associated with a higher risk of periodontitis (HR: 1.19, 95% CI 1.06–1.35) in the BD cohort. Our study highlighted an increased risk of periodontitis in adolescents with BD compared with controls during the follow-up. We recommend that more attention should be paid to the prevention of periodontitis in adolescents with BD, especially those who are female or receiving mood stabilizers. [ABSTRACT FROM AUTHOR]

Evidence suggests increased mortality rates among autistic individuals. However, risks of mortality, including natural-cause, suicide, and accident mortalities, among autistic individuals remain unclear. Among the entire Taiwanese population (N = 29,253,529), between 2003 and 2017, 45,398 autistic individuals were identified and 1:4 matched to 181,592 non-autistic individuals based on birth year and sex. All-cause mortality, including natural-cause, accident, and suicide mortalities, was assessed from 2003 to 2017 between the two cohorts. Cox regression models were used to investigate the mortality risk between autistic and non-autistic individuals. Autistic individuals had increased likelihoods (hazard ratio, 95% confidence interval) of all-cause mortality (3.43, 3.00–3.92), natural-cause mortality (4.73, 3.99–5.60), and suicide mortality (3.67, 2.37–5.68) compared with non-autistic individuals. In particular, autistic males were more likely to die by suicide (hazard ratio: 3.81, 95% confidence interval: 2.37–6.13), and autistic females were more likely to die of accident (hazard ratio: 5.07, 95% confidence interval: 2.54–10.13) compared with non-autistic individuals. Appropriate and effective medical and mental health care is recommended for autistic individuals. Our study was the first population-based study in an Asian country to investigate the mortality rates among autistic individuals. Among the entire Taiwanese population (N = 29,253,529), between 2003 and 2017, 45,398 autistic individuals were identified and 1:4 age-/sex-matched to 181,592 non-autistic individuals. We found that autistic individuals had increased risks of all-cause mortality, natural-cause mortality, and suicide mortality compared with non-autistic individuals. Furthermore, autistic males were more likely to die by suicide, and autistic females were more likely to die of accident compared with the non-autistic individuals. [ABSTRACT FROM AUTHOR]

The association between autism spectrum disorder (ASD) and subsequent sexually transmitted infections (STIs) and the potential effects of medications on STI risk remain unknown. In all, 5076 adolescents and young adults with ASD and 57,060 age-/sex-matched individuals without ASD were enrolled between 2001 and 2009 and followed-up to the end of 2011 for identification of subsequent STIs. The results revealed that patients with ASD were prone to acquiring an STI [hazard ratio (HR) 3.36] compared with the comparison group. Long-term use of atypical antipsychotics was associated with a lower risk of acquiring an STI later in life compared with nonuse (HR 0.34). We recommend that clinicians closely monitor risky sexual behaviors and STI risk in patients with ASD. [ABSTRACT FROM AUTHOR]

People with autism spectrum disorder (ASD) may have poor oral health status because they often experience challenges with daily oral hygiene and have inadequate access to oral health care services. This study explored periodontitis risk in adolescents with ASD compared with those who did not have a diagnosis of ASD. Data from 2001 through December 31, 2011 from the Taiwan National Health Insurance Research Database on 3,473 adolescents with ASD and 34,730 age- and sex-matched people who did not have a diagnosis of ASD were obtained, and subsequent periodontitis was identified from enrollment through December 31, 2011. Adolescents with ASD (hazard ratio, 2.01; 95% CI, 1.84 to 2.20) were more likely to develop periodontitis at follow-up than those who did not have a diagnosis of ASD. Findings remained consistent in subanalyses stratified by sex and intellectual disability. People with ASD had periodontitis onset at an earlier mean (SD) age than those who did not have a diagnosis of ASD (17.97 [3.12] vs 21.86 [2.28] years; P <.001). ASD is an independent risk factor for subsequent periodontitis development. Oral health should be closely monitored in adolescents with ASD. Future investigation of the common pathogenesis between periodontitis and ASD is warranted. [ABSTRACT FROM AUTHOR]

Evidence suggests a continuity between obsessive–compulsive disorder (OCD) and schizophrenia. However, the factors that may predict diagnostic progression from OCD to schizophrenia remain unclear. A total of 35,255 adolescents and adults with OCD (ICD-9-CM code: 300.3) were enrolled between 2001 and 2010 and followed up at the end of 2011 for the identification of de novo schizophrenia (ICD-9-CM code: 295). The Kaplan–Meier method was used to estimate incidence rates, and the Cox regression was used to determine the significance of candidate predictors. At the end of the 11-year follow-up period, the crude cumulative progression rate from OCD to schizophrenia was 6%, and the estimated progression rate totaled 7.80%. Male sex (hazard ratio: 1.23), obesity (1.77), autism spectrum disorder (1.69), bipolar disorder (1.69), posttraumatic stress disorder (1.65), cluster A personality disorder (2.50), and a family history of schizophrenia (2.57) also were related to an elevated likelihood of subsequent progression to schizophrenia in patients with OCD. Further study is necessary to elucidate the exact pathomechanisms underlying diagnostic progression to schizophrenia in patients with OCD. [ABSTRACT FROM AUTHOR]

Background and Objective: Ketamine may work as an anti-inflammatory agent, and it increases the levels of vascular endothelial growth factor (VEGF) in patients with treatment-resistant depression. However, whether genes related to pro-inflammatory and anti-inflammatory cytokines and VEGF may predict the treatment response to ketamine remains unknown.Therefore the aim of this study was to analyze whether specific genes related to inflammatory processes and VEGF were associated with treatment response to low-dose ketamine in patients with treatment-resistant depression. Methods: Based on the genome data from our clinical trial, this study was a secondary analysis of candidate genes correlated with different timepoints of depressive symptoms. In total, 65 patients with treatment-resistant depression (n = 21 for ketamine 0.5 mg/kg, 20 for ketamine 0.2 mg/kg, and 24 for normal saline) were genotyped for 684,616 single nucleotide polymorphisms. Genes associated with 80 cytokines (i.e., interleukin [IL]-1, IL-6, tumor necrosis factor-α, and adiponectin) and VEGF (i.e., VEGF and VEGF receptors) were selected for the gene-based genome-wide association study on the antidepressant effect of a ketamine infusion. Results: Specific single nucleotide polymorphisms, including rs2540315 and rs75746675 in IL1R1 and rs79568085 in VEGFC, were related to the rapid (within 240 min) antidepressant effect of a ketamine infusion; specific single nucleotide polymorphisms, such as Affx-20131665 in PIGF and rs8179353, rs8179353, and rs8179353 in TNFRSF8, were associated with the sustained (up to 2 weeks) antidepressant effect of low-dose (combined 0.5 mg/kg and 0.2 mg/kg) ketamine. Conclusions: Our findings further revealed that genes related to both anti-inflammatory and pro-inflammatory cytokines (i.e., IL-1, IL-2, IL-6, tumor necrosis factor-α, C-reactive protein, and adiponectin) and VEGF-FLK signaling predicted the treatment response to a ketamine infusion in patients with treatment-resistant depression. The synergic modulation of inflammatory and VEGF systems may contribute to the antidepressant effect of ketamine. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number: UMIN000016985. [ABSTRACT FROM AUTHOR]

All severe mental disorders, namely schizophrenia, bipolar disorder, and major depression, are associated with dementia. However, a head-to-head comparison study of severe mental disorders and dementia risk is lacking. This study was a retrospective analysis from Taiwan National Health Insurance Database. In the current study, we included 14,137, 14,138, and 14,137 patients aged 45–69 years diagnosed with schizophrenia, bipolar disorder, and major depressive disorder, respectively, between 2001 and 2009 and 42,412 matched controls. Four groups were age-matched based by age of identification. Any dementia, including Alzheimer disease and vascular dementia, was diagnosed from the identification date to the end of 2011. Alzheimer disease was more likely in patients with bipolar disorder (hazard ratio [HR]: 10.37, 95% confidence interval [CI]: 6.93–15.52) and major depression (HR: 8.92, 95% CI: 5.93–13.41) than in those with schizophrenia (HR: 4.50, 95% CI: 2.84–7.13) and in controls. The likelihood of developing vascular dementia during the follow-up period was greater in patients with schizophrenia (HR: 4.55, 95% CI: 3.14–6.59) and bipolar disorder (HR: 4.45, 95% CI: 3.13–6.31) than in those with major depression (HR: 3.18, 95% CI: 2.21–4.58) and in controls. However, the overlapped CIs indicated the non-significant between-category differences. There was an increased risk of Alzheimer disease and vascular dementia in all groups compared with controls. For Alzheimer disease risk was greater bipolar and depression compared with schizophrenia while for vascular dementia risk was greater for bipolar and schizophrenia compared with depression. Our findings may encourage clinicians to closely monitor the trajectory of cognitive function in middle-aged and elderly patients with schizophrenia, bipolar disorder, and major depressive disorder. [ABSTRACT FROM AUTHOR]

Previous studies have shown an association between early parental death and the risk of subsequent major mental disorders (MMDs) among the bereaved children and adolescents; however, it is unclear whether this risk exists in young adults and in individuals with premorbid mental comorbidities. We aimed to explore differences between children, adolescents, and young adults in the risk of MMDs after parental death. We analyzed data from the Taiwan National Health Research Database. The index cohort was offspring (divided into four groups: aged < 6, 6–11, 12–17, and 18–29 years) whose parents had died. The control cohort was demographically matched offspring whose parents were still alive. Cox regression with adjustments for demographics was used to estimate the risk of subsequent MMDs between the index and control cohorts, including schizophrenia, bipolar disorder, and depressive disorder. We included 202,837 cases and 2,028,370 matched controls. As with the bereaved children and adolescents, the bereaved young adults had a significantly higher risk of schizophrenia (hazard ratio with 95% confidence interval: 5.63; 5.01–6.33), bipolar disorder (3.37; 2.96–3.84), and depressive disorder (2.78; 2.68–2.90) than the control cohort. The risk of MMDs was similar for maternal death and paternal death. Among premorbid mental comorbidities, bereaved individuals with premorbid substance use disorder were associated with the highest risk of schizophrenia (10.43; 8.57–12.71), bipolar disorder (12.93; 10.59–15.79), and depressive disorder (10.97; 10.22–11.78). Healthcare workers should be aware that young adults and individuals with premorbid mental comorbidities are at a higher risk of subsequent MMDs than those without premorbid mental comorbidities after parental death. [ABSTRACT FROM AUTHOR]

Objective: This study explored the bidirectional relationship between fibromyalgia and migraine among probands with either of the two disorders and their unaffected siblings. Background: Evidence suggests a bidirectional association between fibromyalgia and migraine in individuals and in twins. However, whether a bidirectional association between fibromyalgia and migraine also occurs among siblings remains unknown. Methods: Using the Taiwan National Health Insurance Research Database, we examined the data of 2677 probands with fibromyalgia, 2780 unaffected siblings, and 11,120 matched controls to assess the risk of migraine. In contrast, 1830 probands with migraine, 1936 unaffected siblings, and 7744 matched controls to assess the risk of fibromyalgia. Results: Logistic regression analyses demonstrated that patients with fibromyalgia (odds ratio [OR]: 3.69; 95% confidence interval [CI]: 2.87–4.74) and unaffected siblings (OR: 1.51; 95% CI: 1.08–2.10) were more likely to develop migraine than the controls during the follow‐up period. Moreover, patients with migraine and unaffected siblings had a 4.86‐fold (95% CI: 3.86–6.09) and 1.59‐fold (95% CI: 1.18–2.12) increased risk of fibromyalgia than the controls. Conclusion: The bidirectional association between fibromyalgia and migraine among probands and unaffected siblings suggests a familial coaggregation of these two conditions. Additional studies are required to investigate the genetic and environmental etiologies for this coaggregation. [ABSTRACT FROM AUTHOR]

Studies have reported inconsistent results regarding associations between parental depression and offspring neurodevelopmental disorders, such as developmental delay and autism spectrum disorder (ASD). In all, 7,593 children who were born between 1996 and 2010 in Taiwan and had at least one parent with major depressive disorder and 75,930 birth-year- and sex-matched children of parents without major depressive disorder were followed from 1996 or time of birth to the end of 2011. Intergroup differences in neurodevelopmental conditions—including ASD, attention-deficit hyperactivity disorder (ADHD), tic disorder, developmental delay, and intellectual disability (ID)—were assessed. Compared with the children in the control group, the children of parents with major depression were more likely [hazard ratio (HR), 95% confidence interval (CI)] to develop ADHD (1.98, 1.80–2.18), ASD (1.52, 1.16–1.94), tic disorder (1.40, 1.08–1.81), developmental delay (1.32, 1.20–1.45), and ID (1.26, 1.02–1.55). Parental depression was associated with offspring neurodevelopmental disorders, specifically ASD, ADHD, developmental delay, ID, and tic disorder. Therefore, clinicians should closely monitor the neurodevelopmental conditions of children of parents with depression. [ABSTRACT FROM AUTHOR]

Objective: We investigated the diagnostic progression to bipolar disorder (BD) among adolescents and young adults with attention-deficit/hyperactivity disorder (ADHD).Methods: Using the Taiwan National Health Insurance Research Database, we enrolled adolescents and young adults aged 10-29 years with ADHD between January 1, 2001, and December 31, 2010, who were followed up until December 31, 2011, to determine progression to BD. Cox regression analysis was used to examine candidate risk and protective factors.Results: At the 11-year follow-up, the progression rate from ADHD to BD was 5.12%. Of the participants who progressed, 62.16% (322/518) progressed within the first 3 years. Risk factors for progression were as follows: older age (hazard ratio [HR], 1.058; 95% confidence interval [CI], 1.033-1.084), comorbidity with autistic spectrum disorder (HR, 1.839; 95% CI, 1.415-2.391), disruptive behavior disorder (HR, 1.434; 95% CI, 1.132-1.816), intelligence disability (HR, 1.744; 95% CI, 1.399-2.176), depressive disorder (HR, 1.978; 95% CI, 1.577-2.482), alcohol use disorder (HR, 1.705; 95% CI, 1.057-2.751), cluster A (HR, 2.508; 95% CI, 1.167-5.391) or B (HR, 2.718; 95% CI, 1.974-3.741) personality disorder, and a family history of BD (HR, 2.618; 95% CI, 1.823-3.758) Identified protective factors were male sex (HR, 0.771; 95% CI, 0.630-0.943) and cluster C personality disorder (HR, 0.278; 95% CI, 0.086-0.898).Conclusion: The study demonstrated the specific risk and protective factors for BD progression among adolescents and young adults with ADHD. It is important for clinician and mental health care providers to recognize identified factors to focus on early detection and prompt intervention. [ABSTRACT FROM AUTHOR]

Background: Gamma-aminobutyric acid type A (GABAA) receptors mainly mediate the effects of gamma-aminobutyric acid, which is the primary inhibitory neurotransmitter in the central nervous system. Abundant evidence suggests that GABAA receptors play a key role in sleep-regulating processes. No genetic association study has explored the relationships between GABAA receptor genes and sleep duration, sleep quality, and sleep timing in humans. Methods: We determined the association between single-nucleotide polymorphisms (SNPs) in the GABAA receptor genes GABRA1, GABRA2, GABRB3, GABRA5, and GABRG3 and sleep duration, sleep quality, and sleep timing in the Taiwan Biobank with a sample of 10,127 Taiwanese subjects. There were 10,142 subjects in the original study cohort. We excluded 15 subjects with a medication history of sedative-hypnotics. Results: Our data revealed an association of the GABRB3-GABRA5-GABRG3 gene cluster with sleep duration, which has not been previously identified: rs79333046 (beta = − 0.07; P = 1.21 × 10–3) in GABRB3, rs189790076 (beta = 0.92; P = 1.04 × 10–3) in GABRA5, and rs147619342 (beta = − 0.72; P = 3.97 × 10–3) in GABRG3. The association between rs189790076 in GABRA5 and sleep duration remained significant after Bonferroni correction. A variant (rs12438141) in GABRB3 was also found to act as a potential expression quantitative trait locus. Additionally, we discovered interactions between variants in the GABRB3-GABRA5-GABRG3 gene cluster and lifestyle factors, such as tea and coffee consumption, smoking, and physical activity, that influenced sleep duration, although some interactions became nonsignificant after Bonferroni correction. We also found interactions among GABRB3, GABRA5, and GABRG3 that affected sleep duration. Furthermore, we identified an association of rs7165524 (beta = − 0.06; P = 2.20 × 10–3) in GABRA5 with sleep quality and an association of rs79465949 (beta = − 0.12; P = 3.95 × 10–3) in GABRB3 with sleep timing, although these associations became nonsignificant after Bonferroni correction. However, we detected no evidence of an association of individual SNPs in GABRA1 and GABRA2. Conclusions: Our results indicate that rs189790076 in GABRA5 and gene–gene interactions among GABRB3, GABRA5, and GABRG3 may contribute to sleep duration in the Taiwanese population. [ABSTRACT FROM AUTHOR]

Aim: Evidence suggests an association between maternal hypothyroidism and risk of attention‐deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) in offspring. We examined the risk of ASD and ADHD in individuals with congenital hypothyroidism (CHT). Methods: A nationwide population‐based cohort study enrolled a total of 1260 children younger than 12 years with a confirmed diagnosis of CHT and no prior diagnosis of any neurodevelopmental disorders, selected from the National Health Insurance Research Database of Taiwan between 1998 to 2013. In addition, 12,600 controls matched for sex, age, and residence were selected. Cox proportional hazards analysis was used to investigate the association among CHT, ASD, and ADHD. Results: Children with CHT were associated with a higher incidence of ASD (7.1‰ vs 1.3‰, P < 0.001) and ADHD (39.7‰ vs 18.7‰, P < 0.001) than the control group. Cox regression analyses demonstrated that children with CHT were associated with elevated risks of ASD (hazard ratio [HR], 4.72 [95% confidence interval (CI), 2.08–10.70]) and ADHD (HR, 2.03 [95% CI, 1.49–2.77]), after adjusting for demographic data and family history of major psychiatric disorders, compared with the control group. Conclusion: Children with CHT were associated with approximately a two‐fold increased risk of ADHD and a four‐fold increased risk of ASD than the control group. Our study highlights the need for future research to elucidate the potential pathophysiology among CHD, ASD, and ADHD. [ABSTRACT FROM AUTHOR]

Schizophrenia is highly comorbid with obsessive–compulsive disorder (OCD); both conditions share numerous pathophysiological etiologies. We, thus, examined the risk of mental disorders in the parents of probands with schizophrenia, OCD, or both conditions. Between 2001 and 2011, we enrolled a nationwide cohort of 69,813 patients with schizophrenia, OCD, or both. The control cohort included 698,130 individuals matched for demographics. Poisson regression models were employed to examine the risk of six mental disorders in their parents, including schizophrenia, bipolar disorder, depressive disorder, OCD, alcohol use disorder, and substance use disorder. We stratified patients into schizophrenia-only, OCD-only, and dual-diagnosis groups, and the dual-diagnosis group was further divided into schizophrenia-first, OCD-first, and simultaneously diagnosed groups. Compared with controls, the schizophrenia, OCD, and dual-diagnosis groups had higher risks for the six mental disorders in their parents (range of odds ratio [OR] 1.50–7.83). The sub-analysis of the dual-diagnosis group showed that the schizophrenia-first, OCD-first, and simultaneously diagnosed groups had higher odds for schizophrenia, bipolar disorder, depressive disorder, and OCD (range of OR 1.64–6.45) in their parents than the control group; the simultaneously diagnosed and OCD-first diagnosed groups had a higher odds of parental substance use disorder, while the schizophrenia-first diagnosed group had a higher odds of parental alcohol use disorder. The interrelationship between OCD and schizophrenia is linked to bipolar disorder, depressive disorder, alcohol use disorder, and substance use disorder. The results have implications for mental health policy and future research. [ABSTRACT FROM AUTHOR]

• The noise-assisted EMD method, EEMD, was utilized to decompose the BOLD signals and further establish the timescale-specific functional brain networks (FBNs). • There were differences between intrinsic and traditional FBNs regarding global and regional network properties. • The intrinsic FBNs reveal more precise physiological information than traditional FBN. • The method that examined intrinsic FBNs could shed light on the critical components of the BOLD signals. Functional brain networks (FBNs) coordinate brain functions and are studied in fMRI using blood-oxygen-level-dependent (BOLD) signal correlations. Previous research links FBN changes to aging and cognitive decline, but various physiological factors influnce BOLD signals. Few studies have investigated the intrinsic components of the BOLD signal in different timescales using signal decomposition. This study aimed to explore differences between intrinsic FBNs and traditional BOLD-FBN, examining their associations with age and cognitive performance in a healthy cohort without dementia. A total of 396 healthy participants without dementia (men = 157; women = 239; age range = 20–85 years) were enrolled in this study. The BOLD signal was decomposed into several intrinsic signals with different timescales using ensemble empirical mode decomposition, and FBNs were constructed based on both the BOLD and intrinsic signals. Subsequently, network features—global efficiency and local efficiency values—were estimated to determine their relationship with age and cognitive performance. The findings revealed that the global efficiency of traditional BOLD-FBN correlated significantly with age, with specific intrinsic FBNs contributing to these correlations. Moreover, local efficiency analysis demonstrated that intrinsic FBNs were more meaningful than traditional BOLD-FBN in identifying brain regions related to age and cognitive performance. These results underscore the importance of exploring timescales of BOLD signals when constructing FBN and highlight the relevance of specific intrinsic FBNs to aging and cognitive performance. Consequently, this decomposition-based FBN-building approach may offer valuable insights for future fMRI studies. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most prevalent and serious types of cancer globally. Previous literature has shown that women with mental illness may have an increased risk of breast cancer, however whether this risk is associated with the use of psychotropic drugs has yet to be elucidated. This study aimed to assess such risk among women with major depressive disorder (MDD) and bipolar disorder (BD). A nested case–control study design was used with data obtained from the Taiwan National Health Insurance Research Database. Logistic regression analysis with adjustments for demographic characteristics, medical and mental comorbidities, and all-cause clinical visits was performed to estimate the risk of breast cancer according to the cumulative defined daily dose (cDDD) of psychotropic drugs. The study included 1564 women with MDD or BD who had breast cancer, and 15,540 women with MDD or BD who did not have breast cancer. After adjusting for important confounders, the long-term use of valproic acid (odds ratio, 95% confidence interval: 0.58, 0.39–0.56, cDDD ≥ 365), citalopram (0.58, 0.37–0.91, cDDD 180–365), and sertraline (0.77, 0.61–0.91, cDDD ≥ 365) was associated with a lower risk of breast cancer compared to a cDDD < 30. The short-term use of fluvoxamine (0.82, 0.69–0.96, cDDD 30–180), olanzapine (0.54, 0.33–0.89, cDDD 30–179), risperidone (0.7, 0.51–0.98, cDDD 30–179), and chlorpromazine (0.48, 0.25–0.90, cDDD 30–179) was associated with a lower risk of breast cancer. We found no evidence of an increased risk of breast cancer in patients with MDD or BD receiving psychotropic drugs. [ABSTRACT FROM AUTHOR]

Background: Sleep is a key factor for health-related quality of life since sleep disturbances are a significant and common problem for patients with various human diseases such as psychiatric disorders. While single nucleotide polymorphisms (SNPs) in circadian clock genes have been indicated to be associated with sleep duration, most of the association studies have been investigated in populations with European ancestry. It is believed that no studies have been conducted to investigate a link between sleep duration and the circadian clock genes RORA and RORB, which play a key role, with NR1D1, in an additional feedback loop for the circadian rhythm machinery.Methods: In this study, we assessed the relationships between sleep duration and SNPs in the circadian clock genes NR1D1, RORA, and RORB in the Taiwan Biobank with a sample of 10,112 Taiwanese subjects.Results: From our data, we revealed a novel significant association in sleep duration with the rs75981965 SNP (P = 9.93 × 10-5) in the RORA gene that has not been previously identified. The association of sleep duration with this SNP remained significant after performing Bonferroni correction. RORA is a potential candidate for sleep duration as RORA has been suggested to play a key role in the regulation of sleep disorders. Additionally, we pinpointed the effects of interactions between RORA rs75981965 and environmental factors such as tea consumption (P = 0.0015), coffee consumption (P = 0.0029), physical activity (P = 0.011), alcohol consumption (P = 0.0146), and smoking (P = 0.0223) in influencing sleep duration. We also found interactions between RORA and NR1D1 (P = 0.0023) as well as between RORA and RORB (P = 0.0061) in affecting sleep duration.Conclusions: Our results indicate that the circadian clock gene RORA may contribute to sleep duration independently as well as through gene-gene and gene-environment interactions in the Taiwanese population. [ABSTRACT FROM AUTHOR]

Objectives: We compared serum levels of chemokines between male elders with major depressive disorder (MDD) and healthy controls, verifying whether any difference exists in the levels of these mediators between those with and without current suicidal ideation (SI). Methods: We enrolled 145 male elders aged 65 or older and analyzed 40 chemokines in patients with MDD with SI (n = 24) and without SI (n = 23), as well as healthy controls (n = 98). Results: The patients with MDD with SI presented higher levels of MCP-2/CCL8 (p < 0.001) compared with the patients with MDD without SI and the healthy controls. Conclusions: Current findings suggest a potential role of MCP-2/CCL8 in suicidality among elderly males with depression. [ABSTRACT FROM AUTHOR]

Aim: Large language models (LLMs) have been suggested to play a role in medical education and medical practice. However, the potential of their application in the psychiatric domain has not been well‐studied. Method: In the first step, we compared the performance of ChatGPT GPT‐4, Bard, and Llama‐2 in the 2022 Taiwan Psychiatric Licensing Examination conducted in traditional Mandarin. In the second step, we compared the scores of these three LLMs with those of 24 experienced psychiatrists in 10 advanced clinical scenario questions designed for psychiatric differential diagnosis. Result: Only GPT‐4 passed the 2022 Taiwan Psychiatric Licensing Examination (scoring 69 and ≥ 60 being considered a passing grade), while Bard scored 36 and Llama‐2 scored 25. GPT‐4 outperformed Bard and Llama‐2, especially in the areas of 'Pathophysiology & Epidemiology' (χ2 = 22.4, P < 0.001) and 'Psychopharmacology & Other therapies' (χ2 = 15.8, P < 0.001). In the differential diagnosis, the mean score of the 24 experienced psychiatrists (mean 6.1, standard deviation 1.9) was higher than that of GPT‐4 (5), Bard (3), and Llama‐2 (1). Conclusion: Compared to Bard and Llama‐2, GPT‐4 demonstrated superior abilities in identifying psychiatric symptoms and making clinical judgments. Besides, GPT‐4's ability for differential diagnosis closely approached that of the experienced psychiatrists. GPT‐4 revealed a promising potential as a valuable tool in psychiatric practice among the three LLMs. [ABSTRACT FROM AUTHOR]

This longitudinal study aimed to investigate the risk of subsequent autoimmune disease in patients with post-traumatic stress disorder (PTSD) in Asian population. Between 2002 and 2009, we enrolled 5273 patients with PTSD and 1:4 matched controls from the National Health Insurance Database of Taiwan, and followed up the patients until December 31, 2011, or death. The investigated autoimmune diseases included thyroiditis, lupus, rheumatic arthritis, inflammatory bowel disease, Sjogren's syndrome, dermatomyositis, and polymyositis. The Cox regression model was used to estimate the risk of developing autoimmune diseases, with adjustment for demographics and psychiatric and medical comorbidities. Furthermore, we examined the psychiatric clinics utility of patients with PTSD indicating the severity of PTSD in association with autoimmune diseases. After adjusting for confounders, patients with PTSD had a 2.26-fold higher risk of developing any autoimmune diseases (reported as hazard ratios with 95% confidence intervals: 1.82–2.80) than the controls. For specific autoimmune diseases, patients with PTSD had a 2.70-fold higher risk (1.98–3.68) of thyroiditis, a 2.95-fold higher risk (1.20–7.30) of lupus, and a 6.32-fold higher risk (3.44–11.60) of Sjogren's syndrome. Moreover, the PTSD severity was associated with the risk of autoimmune diseases in a dose-dependent manner. The patient with the highest psychiatric clinics utility was associated with an 8.23-fold higher risk (6.21–10.90) of any autoimmune diseases than the controls. Patients with PTSD had an increased risk of autoimmune diseases, and such risk was associated with the severity of PTSD in a dose-dependent manner. However, the present study did not provide a direct effect between PTSD and autoimmune diseases, but rather an association. Further studies are warranted to examine the underlying pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is common, with claims that it is associated with an increased risk for suicide. A nationwide cohort study conducted in Taiwan assessed suicide risk in patients with PCOS after adjustment for multiple variables, including age, demographic characteristics, comorbid conditions, income, and frequency of medical visits. Visual Abstract. Suicide Attempts After a Diagnosis of Polycystic Ovary Syndrome: Polycystic ovary syndrome (PCOS) is common, with claims that it is associated with an increased risk for suicide. A nationwide cohort study conducted in Taiwan assessed suicide risk in patients with PCOS after adjustment for multiple variables, including age, demographic characteristics, comorbid conditions, income, and frequency of medical visits. Background: Limited evidence exists about suicide risk in persons with polycystic ovary syndrome (PCOS). Objective: To assess suicide risk in persons with PCOS, accounting for psychiatric comorbid conditions and age group. Design: Cohort study. Setting: Data from the Taiwanese nationwide database from 1997 to 2012. Patients: A cohort of 18 960 patients diagnosed with PCOS, each matched with control participants in a 1:10 ratio on the basis of age, psychiatric comorbid conditions, urbanization level, and income. Suicide attempts were evaluated using Cox regression models. Measurements: Suicide risk with hazard ratios (HRs). Results: Participants with PCOS had a notable 8.47-fold increase in risk for suicide attempt compared with the control group (HR, 8.47 [95% CI, 7.54 to 9.51]), after adjustment for demographic characteristics, psychiatric comorbid conditions, Charlson Comorbidity Index scores, and frequency of all-cause clinical visits. The elevated risk was evident across the adolescent (HR, 5.38 [CI, 3.93 to 7.37]), young adult (<40 years; HR, 9.15 [CI, 8.03 to 10.42]), and older adult (HR, 3.75 [CI, 2.23 to 6.28]) groups. Sensitivity analyses involving the exclusion of data from the first year or the first 3 years of observation yielded consistent results. Limitation: Potential underestimation of PCOS and mental disorder prevalence due to use of administrative claims data; lack of clinical data, such as body mass index and depressive symptoms; and no assessment of a confounding effect of valproic acid exposure. Conclusion: This study underscores the heightened risk for suicide attempt that persons with PCOS face, even after adjustment for demographics, psychiatric comorbid conditions, physical conditions, and all-cause clinical visits. This suggests the importance of routine monitoring of mental health and suicide risk in persons diagnosed with PCOS. Primary Funding Source: Taipei Veterans General Hospital, Yen Tjing Ling Medical Foundation, and Ministry of Science and Technology of Taiwan. [ABSTRACT FROM AUTHOR]

A high level of Interleukin-1beta (IL1B), a key mediator of inflammation, is expressed in the brain, particularly in the hippocampus, which plays a pivotal role in memory and mood regulation. In the brain, IL1B exerts a myriad of effects such as neuronal proliferation, differentiation, apoptosis, and long-term potentiation. Considering its pleiotropic effects in the brain, IL1B has been implicated in the pathogenesis of various psychiatric disorders as well as cognitive function in normal individuals. Thus, IL1B has been considered a candidate gene for the study of psychiatric diseases as well as brain function in normal individuals. The polymorphisms of IL1B have been described in relation to various expression levels in response to stimulation. This review describes previous studies on the genetic effects of IL1B, which relate it to psychiatric diseases such as major depressive disorder, bipolar disorder, schizophrenia, and Alzheimer’s disease, as well as cognitive function in normal individuals. Although many reports have indicated a possible role of the genetic effects of IL1B or its phenotypes in psychiatric diseases, some reports were unable to confirm these findings. IL1B release is mediated by an inflammatory response or psychological stress, leading to a cascade of immune reactions involving numerous immune components. To further explore the genetic effects of IL1B on mental diseases and brain function, gene–gene and gene–environment interactions should also be considered. [ABSTRACT FROM AUTHOR]

Neurotrophins (NTs), a family of proteins including nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4, are essential for neural growth, survival, and differentiation, and are therefore crucial for brain development. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by problems of inattention and/or hyperactivity-impulsivity. ADHD is one of the most common childhood onset psychiatric disorders. Studies have suggested that both genetic and environmental factors influence the development of the disorder, although the precise causes of ADHD have not yet been identified. In this review, we assess the role of NTs in the pathophysiology of ADHD. Preclinical evidence indicates that BDNF knockout mice are hyperactive, and an ADHD rodent model exhibited decreased cerebral BDNF levels. Several lines of evidence from clinical studies, including blood level and genetic studies, have suggested that NTs are involved in the pathogenesis of ADHD and in the mechanism of biological treatments for ADHD. Future directions for research are proposed, such as using blood NTs as ADHD biomarkers, optimizing NT genetic studies in ADHD, considering NTs as a link between ADHD and other comorbid mental disorders, and investigating methods for optimally modulating NT signaling to discover novel therapeutics for treating ADHD. [ABSTRACT FROM AUTHOR]

Background/Aims: There is growing evidence that the RE1-silencing transcription factor (REST) gene may contribute to cognitive aging and Alzheimer diseases. In this replication study, we reassessed whether single nucleotide polymorphisms (SNPs) within the REST gene are linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. Methods: A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) scores were performed for all subjects to weigh cognitive functions. Results: Our data showed that the REST rs1277306 SNP was significantly associated with cognitive aging among all subjects (p = 0.0052). Furthermore, the association remained significant for individuals without APOE ε4 allele (p = 0.0092), but not for individuals with at least 1 APOE ε4 allele. This association remained significant after Bonferroni correction. Additionally, we found the interactions between the rs1713985 and rs1277306 SNPs on cognitive aging (p = 0.016). However, the 3-marker haplotype derived from the rs1713985, rs3796529, and rs7680734 SNPs in the REST gene demonstrated no association with cognitive aging. Conclusion: Our study indicates that the REST gene may contribute to susceptibility to cognitive aging independently as well as through SNP-SNP and APOE - REST interactions. [ABSTRACT FROM AUTHOR]

Evidence indicates that the pathophysiologic mechanisms associated with insulin resistance may contribute to cognitive aging and Alzheimer’s diseases. In this study, we hypothesize that single nucleotide polymorphisms (SNPs) within insulin resistance-associated genes, such as the ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9), glucokinase regulator (GCKR), and peroxisome proliferator activated receptor gamma (PPARG) genes, may be linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. A total of 547 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examinations (MMSE) were administered to all subjects, and MMSE scores were used to measure cognitive functions. Our data showed that four SNPs (rs73832338, rs9985304, rs4317088, and rs9831846) in the ADAMTS9 gene were significantly associated with cognitive aging among the subjects (P = 1.5 x 10−6 ~ 0.0002). This association remained significant after performing Bonferroni correction. Additionally, we found that interactions between the ADAMTS9 rs9985304 and ADAMTS9 rs76346246 SNPs influenced cognitive aging (P < 0.001). However, variants in the GCKR and PPARG genes had no association with cognitive aging in our study. Our study indicates that the ADAMTS9 gene may contribute to susceptibility to cognitive aging independently as well as through SNP-SNP interactions. [ABSTRACT FROM AUTHOR]

Panic disorder is commonly prevalent in the population, but the treatment response for panic disorder in clinical practice is much less effective than that in our imagination. Increasing evidence suggested existence of a chronic or remitting–relapsing clinical course in panic disorder. In this systematic review, we re-examine the definition of treatment-resistant panic disorder, and present the potential risk factors related to the treatment resistance, including the characteristics of panic disorder, other psychiatric and physical comorbidities, and psychosocial stresses. Furthermore, we summarize the potential pathophysiologies, such as genetic susceptibility, altered brain functioning, brain-derived neurotrophic factor, and long-term inflammation, to explain the treatment resistance. Finally, we conclude the current therapeutic strategies for treating treatment-resistant panic disorder from pharmacological and non-pharmacological views. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a serious health concern worldwide. Currently there are no predictive tests for the effectiveness of any particular antidepressant in an individual patient. Thus, doctors must prescribe antidepressants based on educated guesses. With the recent advent of scientific research, genome-wide gene expression microarray studies are widely utilized to analyze hundreds of thousands of biomarkers by high-throughput technologies. In addition to the candidate-gene approach, the genome-wide approach has recently been employed to investigate the determinants of MDD as well as antidepressant response to therapy. In this review, we mainly focused on gene expression studies with genome-wide approaches using RNA derived from peripheral blood cells. Furthermore, we reviewed their limitations and future directions with respect to the genome-wide gene expression profiling in MDD pathogenesis as well as in antidepressant therapy. [ABSTRACT FROM AUTHOR]

• Youth with antidepressant-resistant depression had a higher risk of bipolar disorder than those with antidepressant-responsive depression. • Youth who responded poorly to both SSRIs and SNRIs exhibited the highest likelihood of developing bipolar disorder. • Treatment responses to different classes of antidepressants may affect the diagnostic progression to bipolar disorder among depressed youth. Studies have demonstrated a positive relationship between antidepressant resistance and the progression of bipolar disorder. However, the influence of antidepressant classes such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) in this context has yet to be investigated. A total of 5,285 adolescents and young adults with antidepressant-resistant depression and 21,140 with antidepressant-responsive depression were recruited in the present study. The antidepressant-resistant depression group was divided into two subgroups: only resistant to SSRIs (n = 2,242, 42.4%) and additionally resistant to non-SSRIs (n = 3,043, 57.6%) groups. The status of bipolar disorder progression was monitored from the date of depression diagnosis to the end of 2011. Patients with antidepressant-resistant depression were more likely to develop bipolar disorder during the follow-up (hazard ratio [HR]: 2.88, 95% confidence interval [CI]: 2.67–3.09) than those with antidepressant-responsive depression. Furthermore, the group that was additionally resistant to non-SSRIs were at the highest risk of bipolar disorder (HR: 3.02, 95% CI: 2.76–3.29), followed by the group that was only resistant to SSRIs (2.70, 2.44–2.98). Adolescents and young adults with antidepressant-resistant depression, especially those who responded poorly to both SSRIs and SNRIs, were at increased risk of subsequent bipolar disorder compared with those with antidepressant-responsive depression. Further studies are warranted to elucidate the molecular pathomechanisms underlying the resistance to SSRIs and SNRIs and subsequent bipolar disorder. [ABSTRACT FROM AUTHOR]

Abstract: A defining but elusive feature of the human brain is its astonishing complexity. This complexity arises from the interaction of numerous neuronal circuits that operate over a wide range of temporal and spatial scales, enabling the brain to adapt to the constantly changing environment and to perform various amazing mental functions. In mentally ill patients, such adaptability is often impaired, leading to either ordered or random patterns of behavior. Quantification and classification of these abnormal human behaviors exhibited during mental illness is one of the major challenges of contemporary psychiatric medicine. In the past few decades, attempts have been made to apply concepts adopted from complexity science to better understand complex human behavior. Although considerable effort has been devoted to studying the abnormal dynamic processes involved in mental illness, unfortunately, the primary features of complexity science are typically presented in a form suitable for mathematicians, physicists, and engineers; thus, they are difficult for practicing psychiatrists or neuroscientists to comprehend. Therefore, this paper introduces recent applications of methods derived from complexity science for examining mental illness. We propose that mental illness is loss of brain complexity and the complexity of mental illness can be studied under a general framework by quantifying the order and randomness of dynamic macroscopic human behavior and microscopic neuronal activity. Additionally, substantial effort is required to identify the link between macroscopic behaviors and microscopic changes in the neuronal dynamics within the brain. [Copyright &y& Elsevier]

Background: This study estimates the risk of stroke within 5 years of newly diagnosed dementia among elderly persons aged 65 and above. We examined the relationship between antipsychotic usage and development of stroke in patients with dementia. Methods: We conducted a nationwide 5-year population-based study using data retrieved from the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan. The study cohort comprised 2243 patients with dementia aged ≥65 years who had at least one inpatient service claim or at least 2 ambulatory care claims, whereas the comparison cohort consisted of 6714 randomly selected subjects (3 for every dementia patient) and were matched with the study group according to sex, age, and index year. We further classified dementia patients into 2 groups based on their history of antipsychotic usage. A total of 1450 patients were classified into the antipsychotic usage group and the remaining 793 patients were classified into the non-antipsychotic usage group. Cox proportional-hazards regressions were performed to compute the 5-year stroke-free survival rates after adjusting for potentially confounding factors. Results: The dementia patients have a 2-fold greater risk of developing stroke within 5 years of diagnosis compared to non-dementia age- and sex-matched subjects, after adjusting for other risk factors (95% confidence interval (CI) = 2.58–3.08; P<.001). Antipsychotic usage among patients with dementia increases risk of stroke 1.17-fold compared to patients without antipsychotic treatment (95% CI = 1.01–1.40; P<.05). Conclusions: Dementia may be an independent risk factor for stroke, and the use of antipsychotics may further increase the risk of stroke in dementia patients. [ABSTRACT FROM AUTHOR]

Purpose: The impact of media reporting on copycat suicides has been well established in various cases of celebrity suicide. However, knowledge is limited about the spatial and temporal relationship between suicide death and media reporting over a long period of time. This study investigated the association of suicide deaths with suicide news in longitudinal and spatial dimensions. Methods: All suicides during 2003-2010 ( n = 31,364) were included. Suicide news in the study period was retrieved from Google News, and included all available news media in Taiwan. Empirical mode decomposition was used to identify the main intrinsic oscillation, reflecting both major and minor suicide events, and time-dependent intrinsic correlation was used to quantify the temporal correlation between suicide deaths and suicide news. Results: The media reporting of suicide was synchronized with increased suicide deaths during major suicide events such as celebrity death, and slightly lagged behind the suicide deaths for 1 month in other periods without notable celebrity deaths. The means of suicide reported in the media diversely affected the suicide models. Reports of charcoal burning suicide exhibited an exclusive copycat effect on actual charcoal burning deaths, whereas media reports of jumping had a wide association with various suicide models. Media reports of suicide had a higher association with suicide deaths in urban than in rural areas. Conclusions: This report suggested that a delayed effect of copycat suicide may exist in media reports of minor suicide events. The competitive reporting of minor suicide events must be avoided and addressed by media professionals. [ABSTRACT FROM AUTHOR]

Major depressive disorder places a great burden on healthcare resources worldwide. Antidepressants are the first-line treatment for major depressive disorder, but if patients don't respond adequately, brain stimulation therapy may be needed as second-line treatment. Digital phenotyping in patients with major depressive disorder will aid in the timely prediction of treatment effectiveness. This study explored electroencephalographic (EEG) signatures that diversify depression treatment responsivity, including antidepressant administration or brain stimulation therapy. Resting-state, pre-treatment EEG sequences from depressive patients who received fluoxetine treatment (n = 55; 26 remitters and 29 poor responders) or electroconvulsive therapy (ECT, n = 58; 36 remitters and 22 nonremitters) were recorded on 19 channels. Twenty-nine EEG segments were obtained from each patient per recording electrode. Power spectral analysis was conducted for feature extraction and showed the highest predictive accuracy for fluoxetine or ECT outcomes. Both occurred with beta-band oscillations within right-side frontal-central (F1-score = 0.9437) or prefrontal areas of the brain (F1-score = 0.9416), respectively. Significantly higher beta-band power was observed among patients who lacked adequate treatment response than the remitters, specifically at 19.2 Hz or 24.5 Hz for fluoxetine administration or ECT outcome, respectively. Our findings indicated that pre-treatment, right-side cortical hyperactivation is associated with poor outcomes of antidepressant-based or ECT-based treatment in major depression. Whether depression treatment response rates can be improved by reducing the high-frequency EEG power in corresponding areas of the brain to provide a protective effect against depression recurrence warrants further study. [ABSTRACT FROM AUTHOR]

Objective: Few studies have investigated the parental risk of major psychiatric disorders among patients with comorbid autism spectrum disorder and attention deficit hyperactivity disorder. This study examined the differences in such risk among patients with autism spectrum disorder–only, with attention deficit hyperactivity disorder–only and both conditions. Methods: Between 2001 and 2011, we enrolled 132,624 patients with autism spectrum disorder or attention deficit hyperactivity disorder and 1:10 matched controls for age, sex and demographics from the National Health Insurance Database of Taiwan. Poisson regression models were used to examine the risk of five major psychiatric disorders in the patients' parents compared with those of the controls, including schizophrenia, bipolar disorder, major depressive disorder, alcohol use disorder, and substance use disorder. Patients were classified into the autism spectrum disorder–only, attention deficit hyperactivity disorder–only and dual-diagnosis groups. Results: The parents of attention deficit hyperactivity disorder–only and dual-diagnosis groups had a higher likelihood to be diagnosed with (odds ratios [95% confidence intervals]) schizophrenia (attention deficit hyperactivity disorder: 1.48 [1.39, 1.57]; dual: 1.79 [1.45, 1.20]), bipolar disorder (attention deficit hyperactivity disorder: 1.91 [1.82, 2.01]; dual: 1.81 [1.51, 2.17]), major depressive disorder (attention deficit hyperactivity disorder: 1.94 [1.89, 2.00]; dual: 1.99 [1.81, 2.20]), alcohol use disorder (attention deficit hyperactivity disorder: 1.39 [1.33, 1.45]; dual: 1.20 [1.01, 1.42]) and substance use disorder (attention deficit hyperactivity disorder: 1.66 [1.59, 1.73]; dual: 1.34 [1.13, 1.58]) than the controls. In contrast, the parents of autism spectrum disorder–only group had a higher likelihood to be diagnosed with schizophrenia (1.77 [1.46, 2.15]) and major depressive disorder (1.45 [1.32, 1.61]) and a lower likelihood to be diagnosed with alcohol use disorder (0.68 [0.55, 0.84]) than the controls. Conclusion: The autism spectrum disorder–only group had a different parental incidence of major psychiatric disorders than the attention deficit hyperactivity disorder–only and dual-diagnosis groups. Our findings have implications for clinical practice and future genetic research. [ABSTRACT FROM AUTHOR]

Aims: Aging is associated with cognitive deterioration, and genetic factors are implicated in individual cognitive differences in the aged. The C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) yields a common thermolabile variant (T) with reduced enzyme activity and consequent elevation of serum homocysteine concentrations. We designed the present study to investigate whether this functional polymorphism may affect global and specific cognitive functions in older Chinese males without dementia. Methods: The subjects included 356 elderly males without major psychiatric disorders or dementia, who were assessed by the Cognitive Abilities Screening Instruments (CASI) and the Wechsler Digit Span Task tests. Results: A significant association was found between the MTHFR C677T polymorphism and total CASI scores (p = 0.012), particularly in short-term memory (p = 0.002) and concentration/mental manipulation (p = 0.007). Post hoc tests indicated that the C/T heterozygotes achieved better cognitive function test results than C/C or T/T carriers. No association was found between the MTHFR genotype and the Wechsler Digit Span Task tests. Conclusion: These results suggest that a heterozygote advantage exists for the MTHFR C677T polymorphism in specific cognitive functions in elderly Chinese males without dementia. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: To explore the effects of varenicline on the psychopathology and cognition of chronic inpatients with schizophrenia, we conducted a non-randomized control group time series investigation between March 2009 and April 2010. In a mandatory smoking cessation intervention, 41 male inpatient smokers were scheduled to undergo either a 5-week varenicline treatment (varenicline group) or the use of no drugs (non-treatment group). Depression (HAM-D), anxiety (HAM-A), and psychosis (PANSS) were evaluated at baseline, and at the 2nd, 4th, 8th and 12th week after abstinence; four neuropsychological tests, including Digit Span Forward and Backward (DSF and DSB), and Trail Making Test-A and -B, were evaluated at baseline and at the 4th, 8th and 12th week. .Thirty patients completed the study. Among 15 patients in the non-treatment group, the HAM-D, HAM-A, DSF, and DSB scores were exacerbated during the 2–8weeks of abstinence, but there were no changes in psychotic symptoms and the other two neuropsychological tests. Compared with the non-treatment group, varenicline users experienced less impairment in HAM-D and HAM-A scores at the 2nd and 4th weeks, and in DSF tasks at the 4th week after abstinence. In conclusions, varenicline can attenuate abstinence-induced adverse outcomes and appears to be well-tolerated in smokers with schizophrenia. [Copyright &y& Elsevier]

Abstract: Suicide behavior (SB) spans a spectrum ranging from suicidal ideation to suicide attempts and completed suicide. Strong evidence suggests a genetic susceptibility to SB, including familial heritability and common occurrence in twins. This review addresses recent molecular genetic studies in SB that include case–control association, genome gene-expression microarray, and genome-wide association (GWA). This work also reviews epigenetics in SB and pharmacogenetic studies of antidepressant-induced suicide. SB fulfills criteria for a complex genetic phenotype in which environmental factors interact with multiple genes to influence susceptibility. So far, case–control association approaches are still the mainstream in SB genetic studies, although whole genome gene-expression microarray and GWA studies have begun to emerge in recent years. Genetic association studies have suggested several genes (e.g., serotonin transporter, tryptophan hydroxylase 2, and brain-derived neurotrophic factor) related to SB, but not all reports support these findings. The case–control approach while useful is limited by present knowledge of disease pathophysiology. Genome-wide studies of gene expression and genetic variation are not constrained by our limited knowledge. However, the explanatory power and path to clinical translation of risk estimates for common variants reported in genome-wide association studies remain unclear because of the presence of rare and structural genetic variation. As whole genome sequencing becomes increasingly widespread, available genomic information will no longer be the limiting factor in applying genetics to clinical medicine. These approaches provide exciting new avenues to identify new candidate genes for SB genetic studies. The other limitation of genetic association is the lack of a consistent definition of the SB phenotype among studies, an inconsistency that hampers the comparability of the studies and data pooling. In summary, SB involves multiple genes interacting with non-genetic factors. A better understanding of the SB genes by combining whole genome approaches with case–control association studies, may potentially lead to developing effective screening, prevention, and management of SB. [Copyright &y& Elsevier]

Abstract: Background: Depression is known to be associated with altered cardiovascular variability and increased cardiovascular comorbidity, yet it is unknown whether altered cardiac autonomic function in depression is associated with insomnia, a common symptom comorbid with depression. This study aimed to investigate the long-term diurnal profile of autonomic function as measured by heart rate variability (HRV) in both major depression and primary insomnia patients. Method: A total of 52 non-medicated patients with major depression, 47 non-medicated patients with primary insomnia, and 88 matched controls without insomnia were recruited. Each subject was assessed by means of sleep and mood questionnaires and underwent twenty-four-hour ambulatory electrocardiogram monitoring. Standard HRV analysis and a well-validated complexity measure, multiscale entropy, were applied to comprehensively assess the diurnal profiles of autonomic function and physiologic complexity in our study sample. Results: Compared with the controls, the patients with major depression and those with primary insomnia exhibited significant reductions in parasympathetic-related HRV indices, and this association was mainly driven by the presence of poor sleep. Both groups of patients also exhibited significant reductions in physiologic complexity during the sleep period as compared with the healthy controls. Alterations in HRV indices were correlated with perceived sleep questionnaire scores but not with depression scales. Conclusions: Our findings suggest a pivotal role of sleep disturbance in regulating cardiovascular variability in major depression and primary insomnia patients. These findings could highlight the importance of treating insomnia as an independent disease rather than a symptom. [Copyright &y& Elsevier]

Abstract: Interleukin-1 beta (IL-1 beta), a proinflammatory cytokine, plays a significant role in age-related changes in long-term potentiation (a biological substrate for learning and/or memory) in the hippocampus of experimental animals. This study tests the hypothesis that a biallelic functional polymorphism in the promoter region (position-511) (rs16944) of the IL-1 beta gene is associated with cognitive performance in elderly males without dementia. A total of 161 elderly male subjects without major psychiatric disorders or dementia participated in this research. Cognitive functions were assessed by the Cognitive Abilities Screening Instruments (CASI) test as well as The Wechsler Digit Span Task test. A significant association was found between the IL-1 beta C-511T polymorphism and CASI score (p =0.008), particularly in the abstraction and judgment subtest (p =0.010), and the backward digit span test (p =0.004). Post hoc tests indicated that the C/C genotype gained better cognitive function test results than T/T carriers, mainly in the non-apolipoprotein E allele epsilon 4 carriers. These results suggest that genetic variants of the IL-1 beta C-511T polymorphism may play a role in specific cognitive functions in normal aged males. Considering that cognitive decline in the elderly is associated with local inflammation processes, genetic variants of cytokines and their receptors should be tested to improve gene-based prediction of general cognitive function in the elderly. [ABSTRACT FROM AUTHOR]

Abstract: Vascular endothelial growth factor (VEGF) has been implicated in neurotrophy and neurogenesis, which play a pivotal role in brain development and may be involved in antidepressant therapeutic mechanisms. Recent animal studies demonstrate that VEGF levels are increased by several antidepressants, including selective serotonin reuptake inhibitors, and that VEGF signalling is required for antidepressant-induced behavioural response. We hypothesized that common genetic variants in the VEGF gene (official gene name: VEGFA) may be associated with the therapeutic response to antidepressants in major depressive disorders (MDD). Seven VEGFA polymorphisms were genotyped in 351 patients with MDD who were treated with selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressants and who were were studied in a therapeutic evaluation for at least 4 weeks. Of the 351 patients, 158 completed an 8-week therapeutic evaluation. No significant association with either 4-week or 8-week antidepressant therapeutic effect was shown in the alleles and genotypes of single loci, or haplotypes from two blocks constructed from these polymorphisms. Our findings suggested that VEGFA genetic variants do not play a major role in the response to selective serotonin reuptake inhibitors. [Copyright &y& Elsevier]

Abstract: Tryptophan hydroxylase-2 (TPH2) is the rate-limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and has been implicated in the pathogenesis of major depressive disorder (MDD) and in the mechanism of antidepressant action. This study aimed to investigate whether common genetic variation in the TPH2 gene is associated with MDD and therapeutic response to antidepressants in a Chinese population. A total of 508 MDD patients and 463 unrelated controls were recruited. Among the MDD patients, 187 accepted selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressant treatment for 8 weeks with therapeutic evaluation before and after treatment. Five TPH2 polymorphisms were genotyped and their association with MDD or treatment response was assessed by haplotype and single-marker analysis. In single-marker-based analysis, the rs17110747-G homozygote polymorphism was found to be more frequent in the MDD patients than in the controls (P =0.002). Genotype analysis in responders (defined as those with a 50% reduction in baseline Hamilton score) and non-responders after 8 weeks of antidepressant treatment showed that the proportion of rs2171363 heterozygote carriers was higher in the responders than the non-responders (P =0.009). No significant association with MDD or antidepressant therapeutic response was discovered in haplotype analyses. Our findings show that TPH2 genetic variants may play a role in MDD susceptibility and in acute therapeutic response to selective serotonin reuptake inhibitors. [Copyright &y& Elsevier]

Abstract: Background: Essential in dopamine degradation, it was suggested that catechol-O-methyltransferase (COMT) might be involved in the action of antidepressants and may therefore be a promising candidate for antidepressant pharmacogenetic studies. Methods: COMT Val158met polymorphism was genotyped in 334 Chinese major depressive disorder (MDD) patients who were treated with fluoxetine for at least 4 weeks. Clinical response was evaluated using the 21-item Hamilton Rating Scale for Depression (HAM-D21). In the analysis of association, response was defined as ≥50% decrease in HAM-D21 score after treatment and then further clarified by intra-individual changes in HAM-D21 score. Results: We found that the COMT val158met polymorphism was not associated with 4-week fluoxetine therapeutic response; however, association analysis showed that patients with the COMT Val/Val genotype had poorer responses in the eighth week (CLUMP T1 P =0.020) and consistently showed significantly smaller reductions in HAM-D21 scores in the eighth week (P =0.027). Further stratification based on gender revealed an isolated effect of the COMT genotype in males (P =0.035) but not in females (P =0.650) in percent reduction in HAM-D21 scores in the eighth week. Limitations: There was a lack of placebo control and the serum fluoxetine concentration was not taken into account. Conclusions: This identified association between the COMT genetic variation and antidepressant response may be useful either as a clinical predictor in the future. [Copyright &y& Elsevier]

Evidence suggests that plasminogen activator inhibitor type 1 gene (SERPINE1) is a stress-related gene and serum plasminogen activator inhibitor type 1 levels are increased in patients with major depressive disorders (MDD).To investigate whether common genetic variation in the SERPINE1 gene is associated with MDD and the therapeutic response to antidepressants, six polymorphisms (rs2227631, rs1799889, rs6092, rs6090, rs2227684 and rs7242) of the SERPINE1 gene were genotyped in 188 Chinese MDD patients and 346 controls. Among the MDD patients, 140 accepted selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressant treatment for 4 weeks with therapeutic evaluation before and after.In single-marker-based analysis, the rs2227684-G and rs7242-T alleles were more frequent in MDD patients than in controls (P=0.010 and 0.010, respectively). The haplotype derived from the rs6090-G, rs2227684-G and rs7242-T polymorphisms was 1.19-fold higher in patients with MDD than in controls (P=0.0038). Haplotype analysis in responders (defined as a 50% reduction of the initial Hamilton score) and nonresponders after 4 weeks of antidepressant treatment showed that the haplotype derived from the rs2227631-G and rs1799889-4G polymorphisms was lower in responders than nonresponders (11.4 vs. 22.4%, P=0.014).Our findings show, for the first time, that SERPINE1 genetic variants may play a role in MDD susceptibility and in the acute therapeutic response to selective serotonin reuptake inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Genetic factors for inter-individual variation in cognition have been arousing great interest among researchers. Among the many associated genes, brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE), as two of the most frequently studied, might be good prospects for cognitive genetics. Thus, the aim of this study was to investigate both the isolated and cooperative effect of BDNF and APOE on normal cognitive ageing. A homogeneous population of Chinese aged males (N =161) were genotyped for functional genetic variants of BDNF (BDNF-G196A) and APOE (APOE-ɛ4) and assessed by a comprehensive neuropsychological measurement (Cognitive Abilities Screening Instrument Chinese version; CASI C-2.0). Thereafter genotypic group differences of BDNF and APOE in CASI cognitive profiles were tested. Results from the present study suggest the possible influence of APOE on specific cognitive domains (CASI orientation and language domains; p =0.010 and 0.028, respectively), whereas there was no significant role of BDNF, either solely or with APOE, in cognition in the elderly. Our findings suggest a possible association between APOE-ɛ4 and specific cognitive domains in the aged male, whereas the functional genetic variant of BDNF (BDNF-G196A) played no significant role in normal cognitive ageing. [Copyright &y& Elsevier]

Abstract: Disturbance in glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. Since glutamate receptor interacting protein 1 (GRIP1), a modular protein that enables anchoring of AMPA receptors via its PDZ (postsynaptic density-95/discs large/zona occludens-1) domain and modulates d-serine release, plays an important role in glutamatergic function, this study tests the hypothesis that GRIP1 genetic variants confer susceptibility to schizophrenia. This study investigated whether GRIP1 genetic polymorphisms (rs1038923 and rs4913301) cause a predisposal to schizophrenia. Two GRIP1 polymorphisms were studied in a sample population of 252 people with schizophrenia and 207 normal controls. Significant linkage disequilibrium was obtained between the two polymorphisms. Results demonstrated that neither single marker nor haplotype analysis revealed an association between variants at the GRIP1 locus and schizophrenia, suggesting that it is unlikely that the GRIP1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia. However, association between schizophrenia and other polymorphisms in the GRIP1 gene cannot be totally ruled out as the whole gene was not covered by the two polymorphisms studied. [Copyright &y& Elsevier]

Abstract: Brain-derived neurotrophic-factor (BDNF), the most abundant of the neurotrophins in the brain, has been implicated in both major depression and cognitive function. This study examines the association between the BDNF-gene Val66Met polymorphism and depression susceptibility and severity, age-of-onset, cognitive function and suicidal attempt history in an elderly Chinese sample population. We genotyped the BDNF-gene Val66Met polymorphism in 110 elderly inpatients diagnosed with major depression and 171 age- and sex-similar control subjects. All patients were assessed with the Hamilton Rating Scale for Depression (HAM-D) for depression severity and the Mini-Mental Status Examination (MMSE) for cognitive function after admission. Suicide attempt history and age-of-onset of depression were evaluated by interview and medical record. The BDNF Val66Met genotype distribution was significantly different between depressed patients and control subjects (P =0.003) and there was a significant excess of Met allele in the depressed patients compared to the control group (P =0.001). The BDNF polymorphism did not affect age-of-onset, depression severity, cognitive function or suicidal attempt history. The results suggest that the BDNF Val66Met polymorphism is a relevant risk factor for geriatric depression. [Copyright &y& Elsevier]

Abstract: The firing rate of dorsal raphe serotonergic neurons is modulated by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors. Evidence from animal and clinical studies has suggested that desensitization of HTR1A is implicated in the antidepressant therapeutic mechanism of selective serotonin reuptake inhibitors (SSRIs). Recent studies, including our recent findings, have reported that a functional HTR1A C-1019G polymorphism in the promoter region, as well as a nonsynonymous polymorphism, Gly272Asp, may be associated with SSRI pharmacogenetics. In this study, we tested whether Gly272Asp genetic variants are related to a 4-week fluoxetine antidepressant effect in 222 Chinese major depressive patients. We also tested the linkage disequilibrium (LD) measurement between HTR1A Gly272Asp and C-1019G polymorphisms, and haplotype analysis was conducted to assess the association between the two markers within the HTR1A gene and fluoxetine antidepressant response. The results show that the HTR1A Gly272Asp polymorphism was not associated with fluoxetine therapeutic response. The two markers are in strong LD and the HTR1A haplotype of the two polymorphisms is associated with fluoxetine therapeutic response. This association is gender-specific and mostly arises from the effect of HTR1A C-1019G polymorphism: female patients with -1019C/C genotype showed a better response than -1019G carriers. These findings need to be confirmed in other ethnic populations. [Copyright &y& Elsevier]

Summary: The action of androgens is mediated by the androgen receptors (ARs), which are located throughout the brain. The AR gene is implicated in the pathogenesis of schizophrenia because male siblings with schizophrenia share alleles at this gene at a rate higher than chance predicts, and differences in sex hormone function may explain the gender difference in schizophrenic manifestations. Since the shorter alleles of the AR CAG repeat polymorphism are associated with increased gene expression, we tested the hypothesis that the AR CAG repeat variant confers susceptibility to schizophrenia using a sample of 225 people with schizophrenia and 247 normal controls. Using the median AR repeat length in the normal group as the arbitrary cut-off point (<24 and >25 CAG repeats), the results show no association between the AR repeat length and schizophrenia in either sex. Furthermore. AR CAG repeat length did not affect the age of symptom onset in the schizophrenic population. Our findings suggest that it is unlikely that the AR CAG repeat polymorphism plays a major role in the pathogenesis of schizophrenia. Nevertheless, given that androgens affect cognitive function, violent behavior and mood, the effect of the AR CAG polymorphism on the clinical manifestations of schizophrenia may warrant further exploration. [Copyright &y& Elsevier]

Abstract: From studies of genetic-knockout animals, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth-factor family, has been implicated in both alcohol preference and aggressive behaviour. To test whether a BDNF genetic variant may be associated with alcohol-dependent and violent behaviours, we studied Val66Met polymorphism of the BDNF-gene in 110 cases of alcohol-dependence, in 134 extremely violent convicts, and in 149 individuals without psychosis or mood disorders. We also examined the association of this polymorphism with antisocial personality disorder comorbidity in the extremely violent convicts. The results showed that the genotype and allele frequencies for Val66Met polymorphism at the BDNF-gene site did not differ among the three groups. Furthermore, it was not demonstrated that this polymorphism is associated with antisocial personality disorder comorbidity in the extremely violent convicts. Based on these findings, it seems reasonable to suggest that this BDNF-gene Val66Met polymorphism is unlikely to play a major role in the genetic susceptibility to the traits of alcohol-dependence or violence proneness. [Copyright &y& Elsevier]