Machine learning for prediction of schizophrenia based on identifying the primary and interaction effects of minor physical anomalies.

In the neurodevelopmental model of schizophrenia, minor physical anomalies (MPAs) are considered neurodevelopmental markers of schizophrenia. To date, there has been no research to evaluate the interaction between MPAs. Our study built and used a machine learning model to predict the risk of schizophrenia based on measurements of MPA items and to investigate the potential primary and interaction effects of MPAs. The study included 470 patients with schizophrenia and 354 healthy controls. The models used are classical statistical model, Logistic Regression (LR), and machine leaning models, Decision Tree (DT) and Random Forest (RF). We also plotted two-dimensional scatter diagrams and three-dimensional linear/quadratic discriminant analysis (LDA/QDA) graphs for comparison with the DT dendritic structure. We found that RF had the highest predictive power for schizophrenia (Full-training AUC = 0.97 and 5-fold cross-validation AUC = 0.75). We identified several primary MPAs, such as the mouth region, high palate, furrowed tongue, skull height and mouth width. Quantitative MPA analysis indicated that the higher skull height and the narrower mouth width, the higher the risk of schizophrenia. In the interaction, we further identified that skull height and mouth width, furrowed tongue and skull height, high palate and skull height, and high palate and furrowed tongue, showed significant two-item interactions with schizophrenia. A weak three-item interaction was found between high palate, skull height, and mouth width. In conclusion, we found that the two machine learning methods showed good predictive ability in assessing the risk of schizophrenia using the primary and interaction effects of MPAs.

DNA methylation signature aberration as potential biomarkers in treatment-resistant schizophrenia: Constructing a methylation risk score using a machine learning method.

Treatment-resistant schizophrenia (TRS) is defined as a non-response to at least two trials of antipsychotic medication with an adequate dose and duration. We aimed to evaluate the discriminant abilities of DNA methylation probes and methylation risk score between treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. This study recruited 96 schizophrenia patients (TRS and non-TRS) and 56 healthy controls (HC). Participants were divided into a discovery set and a validation set. In the discovery set, we conducted genome-wide methylation analysis (human MethylationEPIC 850K BeadChip) on the subject's blood DNA and discriminated significant methylation signatures, then verified these methylation signatures in the validation set. Based on genome-wide scans of TRS versus non-TRS, thirteen differentially methylated probes were identified at FDR <0.05 and >20% differences in DNA methylation ß-values. Next, we selected six probes within gene coding regions (LOC404266, LOXL2, CERK, CHMP7, and SLC17A9) to conduct verification in the validation set using quantitative methylation-specific PCR (qMSP). These six methylation probes showed satisfactory discrimination between TRS patients and non-TRS patients, with an AUC ranging from 0.83 to 0.92, accuracy ranging from 77.8% to 87.3%, sensitivity ranging from 80% to 90%, and specificity ranging from 65.6% to 85%. This methylation risk score model showed satisfactory discrimination between TRS patients and non-TRS patients, with an accuracy of 88.3%. These findings support that methylation signatures may be used as an indicator of TRS vulnerability and provide a model for the clinical use of methylation to identify TRS.

Profiling antibody signature of schizophrenia by Escherichia coli proteome microarrays.

Schizophrenia (SZ) is influenced by genetic and environmental factors, and associated with chronic neuroinflammation. If the symptoms express after adolescence, environmental impacts are more substantial, and the disease is defined as adult-onset schizophrenia (AOS). Effects of environmental factors on antibody responses such as Escherichia coli (E. coli) to immunoglobulin G (IgG) and immunoglobulin M (IgM) might increase the severity of symptoms in SZ via the gut-brain axis. The purpose of this study is to reveal antibody profiles of SZ against bacterial protein antigens. We analyzed the IgG and IgM antibodies using E. coli proteome microarrays from 80 SZ patients and 40 healthy controls (HC). Using support vector machine to select panels of proteins differentiating between groups and conducted enrichment analysis for those proteins. We identified that the groL, pldA, yjjU, livG, and ftsE can classify IgGs in AOS vs HC achieved accuracy of 0.7. The protein yjjU, livG and ftsE can form the best combination panel to classify IgG in AOS vs HC with accuracy of 0.8. The enrichment results are highly related to ABC (ATP binding cassette) transporter in the protein domain and cellular component. We further found that the human ATP binding cassette subfamily b member 1 (ABCB1) autoantibody level in AOS is significantly higher than in HC. The findings suggest that AOS had different immunoglobulin production compared to early-onset schizophrenia (EOS) and HC. We also identified potential antibody biomarkers of AOS and found their antigens are enriched in ABC transporter related domains, including human ABCB1 protein.

Development and validation of a web-based prediction tool on minor physical anomalies for schizophrenia.

In support of the neurodevelopmental model of schizophrenia, minor physical anomalies (MPAs) have been suggested as biomarkers and potential pathophysiological significance for schizophrenia. However, an integrated, clinically useful tool that used qualitative and quantitative MPAs to visualize and predict schizophrenia risk while characterizing the degree of importance of MPA items was lacking. We recruited a training set and a validation set, including 463 schizophrenia patients and 281 healthy controls to conduct logistic regression and the least absolute shrinkage and selection operator (Lasso) regression to select the best parameters of MPAs and constructed nomograms. Two nomograms were built to show the weights of these predictors. In the logistic regression model, 11 out of a total of 68 parameters were identified as the best MPA items for distinguishing between patients with schizophrenia and controls, including hair whorls, epicanthus, adherent ear lobes, high palate, furrowed tongue, hyperconvex fingernails, a large gap between first and second toes, skull height, nasal width, mouth width, and palate width. The Lasso regression model included the same variables of the logistic regression model, except for nasal width, and further included two items (interpupillary distance and soft ears) to assess the risk of schizophrenia. The results of the validation dataset verified the efficacy of the nomograms with the area under the curve 0.84 and 0.85 in the logistic regression model and lasso regression model, respectively. This study provides an easy-to-use tool based on validated risk models of schizophrenia and reflects a divergence in development between schizophrenia patients and healthy controls ( https://www.szprediction.net/ ).

Neurodevelopment regulators miR-137 and miR-34 family as biomarkers for early and adult onset schizophrenia.

Early-onset schizophrenia (EOS) may have stronger familial aggregation and a more severe outcome than adult-onset schizophrenia (AOS). MicroRNA (miRNA) takes on dual roles as a genetic and epigenetic modulator, which may mediate the influence of genetic risk. Neurological soft signs (NSS) are neurological abnormalities that may be intermediate phenotypes or endophenotypes for schizophrenia. Our previous study found poorer performance on NSS tests from patients with EOS and their unaffected first-degree relatives. Thus, we aimed to identify a set of aberrant neurodevelopmental-related miRNAs that could serve as potential biomarkers for EOS or schizophrenia with NSS. This study included 215 schizophrenia patients (104 EOS and 111 AOS), 72 unaffected first-degree relatives, 31 patients with bipolar disorder, and 100 healthy controls. Differential expression analysis revealed that miR-137, miR-34b, and miR-34c were significantly up-regulated in patients with schizophrenia and their unaffected first-degree relatives compared to healthy controls. Receiver operating characteristic (ROC) analysis showed that the miR-137 expression signature could be used to discriminate between patients with EOS and healthy controls (AUC = 0.911). Additionally, miR-34b had the highest ability to discriminate between EOS and AOS (AUC = 0.810), which may indicate different aetiological pathways to disease onset. Moreover, miR-137 dysregulation was correlated with almost all NSS subscales (i.e., sensory integration, motor sequencing, etc.) and, when EOS patients with NSS, miR-137 expression discriminated these patients from healthy controls to a greater extent (AUC = 0.957). These findings support the potential for neurodevelopmental-related miRNAs to be used as indicators of vulnerability to EOS.

Alterations of plasma cytokine biomarkers for identifying age at onset of schizophrenia with neurological soft signs.

Several studies have been suggested that immunity plays a part in neurodevelopment and schizophrenia pathogenesis. Early age of onset in schizophrenia is associated with genetic factors which affect neurodevelopment. This study aims to identify immune abnormalities associated with neurodevelopmental impairments in early-onset schizophrenia (EOS) and adult-onset schizophrenia (AOS) patients. We determined the plasma levels of six cytokines (IL-1ß, IL-4, IL-6, IL-10, IL-12 and TNF-α) in schizophrenia patients and healthy controls. Measurements included neurological soft signs (NSS) to distinguish and subgroup those with neurodevelopmental impairments. The study included 210 schizophrenia patients, which were divided into 84 EOS and 126 AOS patients, as well as 122 healthy controls. We observed significant differences in levels of IL-4, IL-6 and IL-10 between EOS and AOS patients. The results demonstrated the area under ROC curve (AUC) of the IL-4 in EOS and healthy controls was 0.81. Moreover, these results indicated that AUC of the IL-4 and the combination of IL-4, IL-6 and IL-12 in EOS with NSS and healthy controls were 0.91 and 0.95. These cytokines are altered in EOS and schizophrenia patients with neurodevelopmental impairments and demonstrated good classification abilities. These findings manifested that both pro- and anti-inflammatory cytokines are contributed to the clinical and pathophysiological features of schizophrenia. Future works are expected to explore potential genetic effectors and predictors as well as therapeutic directions in personalized medicine for early-onset schizophrenia.

Risk Model Assessment in Early-Onset and Adult-Onset Schizophrenia Using Neurological Soft Signs.

Age at onset is one of the most important clinical features of schizophrenia that could indicate greater genetic loadings. Neurological soft signs (NSS) are considered as a potential endophenotype for schizophrenia. However, the association between NSS and different age-onset schizophrenia still remains unclear. We aimed to compare risk model in patients with early-onset schizophrenia (EOS) and adult-onset schizophrenia (AOS) with NSS. This study included 262 schizophrenia patients, 177 unaffected first-degree relatives and 243 healthy controls. We estimated the discriminant abilities of NSS models for early-onset schizophrenia (onset age < 20) and adult-onset schizophrenia (onset age ≥ 20) using three data mining methods: artificial neural networks (ANN), decision trees (DT) and logistic regression (LR). We then assessed the magnitude of NSS performance in EOS and AOS families. For the four NSS subscales, the NSS performance were greater in EOS and AOS families compared with healthy individuals. More interestingly, there were significant differences found between patients' families and control group in the four subscales of NSS. These findings support the potential for neurodevelopmental markers to be used as schizophrenia vulnerability indicators. The NSS models had higher discriminant abilities for EOS than for AOS. NSS were more accurate in distinguishing EOS patients from healthy controls compared to AOS patients. Our results support the neurodevelopmental hypothesis that EOS has poorer performance of NSS than AOS. Hence, poorer NSS performance may be imply trait-related NSS feature in EOS.

Impact of preoperative anxiety and depression on quality of life before and after resection of hepatocellular carcinoma.

OBJECTIVE: The impact of anxiety and depression symptoms (ADS) is often estimated in terms of clinical endpoints such as the risk of complications and probabilities of readmission and survival. The purpose of this study was to provide a benchmark for capturing the negative effects of ADS on quality of life after hepatocellular carcinoma (HCC) surgery and to provide an evidence base for future research and clinical interventions aimed at understanding and remediating these effects. METHODS: This prospective study analyzed 410 HCC patients at three tertiary academic hospitals. The Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Functional Assessment of Cancer Therapy- Hepatobiliary (FACT-H) were administered before HCC surgery and at 6 months, 1 year, and 2 years after HCC surgery. Generalized estimating equations were used to estimate differences-in-differences models for examining the effects of ADS. RESULTS: At baseline, 9.0% of the participants had anxiety symptom (BAI > 10), 17.1% had depression symptom (BDI > 13), and 7.1% had ADS. Throughout the study period, anxiety and depression (differences-in-differences value) had significant (P < 0.001) negative net effects on mean scores for all FACT-H dimensions, and the differences gradually increased over time. From baseline through all follow-up years, the two groups significantly (P < 0.001) differed in scores for all FACT-H dimensions, and the differences increased over time. CONCLUSIONS: For healthcare providers, this study highlights the need for continued monitoring for ADS in patients who have undergone hepatic resection and the need for timely and appropriate psychological care for these patients.

Do preoperative depressive symptoms predict quality of life after laparoscopic cholecystectomy: A longitudinal prospective study.

OBJECTIVE: The impact of preoperative depressive symptoms on quality of life (QOL) after laparoscopic cholecystectomy (LC) remains unclear. The purpose of this study was to develop a benchmark for capturing the burden of depressive symptoms on QOL after LC and for supporting evidence-based clinical interventions for remediating these effects. METHODS: Patients diagnosed with depressive symptoms (Beck Depression Inventory score > 13) after LC (n = 336) were classified into a depressive symptoms group. Propensity score matching was then used to match them with 336 patients in a non-depressive symptoms group for all potential confounding factors. All patients completed the 36-item Short Form Health Survey (SF-36) and the Gastrointestinal Quality of Life Index (GIQLI) at baseline and at 2 years postoperatively. The 95% confidence intervals (CIs) for differences in responsiveness estimates were derived by bootstrap estimation. RESULTS: The GIQLI results revealed that the non-depressive symptoms group had relatively stronger responses for emotional impairment (4.10, 95% CI 2.81 to 5.39) and social impairment (4.06, 95% CI 2.65 to 5.46) in comparison with the depressive symptoms group. In the SF-36, the non-depressive symptoms group also had stronger responses for role emotional (12.63, 95% CI 10.73 to 14.54), social functioning (11.25, 95% CI 9.85 to 12.65), vitality (3.81, 95% CI 2.82 to 4.81), mental health (11.97, 95% CI 10.36 to 13.56) and general health (3.84, 95% CI 2.95 to 4.75). CONCLUSIONS: Depressive symptoms complicate the management of LC patients and are associated with poorer outcomes. Because depressive symptoms are very common, further studies are needed to evaluate integrated and comprehensive approaches for assessing and treating these symptoms.

Leading causes of death among decedents with mention of schizophrenia on the death certificates in the United States.

BACKGROUND: Little is known about the changes in the ranking of leading cause of death (COD) among people died with schizophrenia across years in the United States (U.S.). This study aims to determine the ranking of leading COD among U.S. decedents with mention of schizophrenia by age from 2000 to 2015. METHODS: The mortality multiple COD files maintained by the National Center for Health Statistics were used to identify decedents aged 15 years old and above with mention of schizophrenia anywhere on the death certificates to determine the number and proportion of deaths attributed to various underlying CODs. RESULTS: Of 13,289, 13,655, 14,135, and 15,033 people who died in 2000-2003, 2004-2007, 2008-2011and 2012-2015 with mention of schizophrenia, similar to all decedents, heart disease and cancer was the first and the second leading COD throughout the study years. Schizophrenia ranked the third in most years except in 2004-2007. The first leading COD for decedents with mention of schizophrenia aged 15-24, 25-44, 45-64, 65-74, and 75+ years old in 2012-2015 was suicide, accidents, heart disease, heart disease, and Alzheimer's disease and related dementia, respectively. Nevertheless, it was accidents, accidents, cancer, cancer, and heart disease, respectively for all decedents. CONCLUSION: The ranking of leading CODs among U.S. decedents with mention of schizophrenia changed across years and differed from all decedents by age, which suggest that different interventions should be designed accordingly.

Anxiety and depression are associated with long-term outcomes of hepatocellular carcinoma: A nationwide study of a cohort from Taiwan.

OBJECTIVES: A natural experimental design was coupled with propensity score matching to assess the risks of anxiety and depression and to assess the longitudinal effects of anxiety and depression on healthcare utilisation and mortality in hepatocellular carcinoma (HCC) patients. METHODS: This nationwide population-based cohort study retrospectively analysed 7304 patients treated for HCC during 1996-2010. Generalised estimating equations were used to estimate differences-in-differences models for examining the effects of anxiety and depression disorders. RESULTS: Independent risk factors for anxiety and depression in the HCC patients were female gender (hazard ratio (HR) 1.45; P < 0.001), Charlson co-morbidity index score (HR 1.12; P = 0.005), and liver cirrhosis (HR 1.35; P = 0.004). Anxiety and depression (differences-in-differences value) had a significant (P < 0.001) positive net effect on number of physician visits. Furthermore, the mean overall survival time was 83.4 months (SD 5.4 months) in the anxiety/depression group and 65.4 months (SD 4.8 months) in the non-disorder group. Additionally, the overall survival rate was significantly higher in the anxiety/depression group compared to the non-disorder group during the study period (P = 0.003). CONCLUSIONS: Anxiety disorders and depression disorders are associated with a significantly increased overall survival rate in HCC patients. However, further studies are needed to investigate this association.

Prevalence and clinical correlates of flunitrazepam-related complex sleep behaviors.

AIM: Complex sleep behaviors (CSB) are often associated with the use of hypnotic drugs. This study investigated the prevalence and correlates of CSB among psychiatric patients who were given flunitrazepam. METHODS: From June 2011 to May 2012, a total of 268 psychiatric outpatients who had received flunitrazepam for at least 3 months were enrolled. Data on occurrence of CSB, demographic characteristics, flunitrazepam dosage and duration of use, psychiatric diagnoses, physical illnesses, and alcohol use were collected. Logistic regression analysis was used to examine the clinical correlates of CSB. RESULTS: Sixty-six participants (24.6%) reported experiencing CSB. Logistic regression analysis showed that a high dosage (>2 mg/day) of flunitrazepam (odds ratio [OR] = 1.941, 95% confidence interval [CI] = 1.090-3.455, P = 0.024) and alcohol use (OR = 1.948, 95%CI = 1.023-3.709, P = 0.042) were significantly associated with the occurrence of CSB. Sex, age, duration of flunitrazepam use, psychiatric diagnoses, and physical illnesses were not significantly associated with the occurrence of CSB. CONCLUSION: CSB among flunitrazepam users should be monitored routinely, especially among those receiving a high dosage who also consume alcohol.

Improving risk assessment and familial aggregation of age at onset in schizophrenia using minor physical anomalies and craniofacial measures.

Age at onset is the most important feature of schizophrenia that could indicate its origin. Minor physical anomalies (MPAs) characterize potential marker indices of disturbances in early neurodevelopment. However, the association between MPAs and age at onset of schizophrenia is still unclear. We aimed to compare risk assessment and familial aggregation in patients with early-onset schizophrenia (EOS) and adult-onset schizophrenia (AOS) with MPAs and craniofacial measures.We estimated the risk assessment of MPAs among patients with EOS (n = 68), patients with AOS (n = 183), nonpsychotic relatives (n = 147), and healthy controls (n = 241) using 3 data-mining algorithms. In addition, we assessed the magnitude of familial aggregation of MPAs with respect to the age at onset of schizophrenia.The performance of EOS was superior to that of AOS, with discrimination accuracies of 89% and 76%, respectively. Combined MPA scores as the risk assessment were significantly higher in all schizophrenia subgroups and the nonpsychotic relatives of EOS patients than in the healthy controls. The recurrence risk ratio for familial aggregation of the MPA scores of EOS families (odds ratio 9.27) was substantially higher than that of AOS families (odds ratio 2.47).The results highlight that EOS improves risk assessment and has a severe magnitude of familial aggregation of MPAs. These findings indicate that EOS might result from a stronger genetic susceptibility to neurodevelopmental deficits.

Association of stress coping strategies with Internet addiction in college students: The moderating effect of depression.

BACKGROUND: This study examined the association between stress-related coping strategies and Internet addiction and the moderating effect of depression in a sample of Taiwanese college students. METHOD: A total of 500 college students (238 men and 262 women) participated in this study. Internet addiction was assessed using the Chen Internet Addiction Scale. Participants' stress coping strategies and depressive symptoms were measured using the Coping Orientation to Problems Experienced and the Beck Depression Inventory-II, respectively. We used t and chi-square tests to examine differences in demographic characteristics, depression, and stress coping strategies between participants with and without Internet addiction. Significant variables were used in a logistic regression model to examine the association between stress coping strategies and Internet addiction and the moderating effect of depression on the association. RESULTS: Results indicated that use of restraint coping was negatively associated with Internet addiction (odds ratio [OR]=0.886, 95% confidence interval [CI]: 0.802-0.977), whereas denial (OR=1.177, 95% CI: 1.029-1.346) and mental disengagement (OR=2.673, 95% CI: 1.499-4.767) were positively associated with Internet addiction. Depression had a moderating effect on the association between denial and Internet addiction (OR=0.701, 95% CI: 0.530-0.927). CONCLUSIONS: Stress coping strategies and depression are important factors to evaluate when developing intervention programs targeting college undergraduate students with Internet addiction.

Correlates of dependence and beliefs about the use of hypnotics among zolpidem and zopiclone users.

BACKGROUND: Zolpidem and zopiclone are the two most commonly prescribed Z-drugs approved to treat insomnia. OBJECTIVES: To examine the demographic and clinical correlates of dependence and beliefs about hypnotic use among long-term zolpidem and zopiclone users in psychiatric treatment for insomnia. METHODS: A total of 392 psychiatric outpatients who received zolpidem or zopiclone treatment for at least 3 months for insomnia were studied. Participants' severity of hypnotic dependence and beliefs about the use of hypnotics to treat sleep problems were assessed. The correlation of dependence and beliefs about zolpidem and zopiclone treatment with demographic characteristics, hypnotic-using behaviors, co-use of addictive substances, and depressive symptoms were analyzed using multiple regression analysis models. RESULTS: Zolpidem users reported more severe dependence and a lower level of necessity regarding the use of hypnotics than zopiclone users did. High equivalent doses of hypnotics and long duration of use were significantly associated with severe dependence and a low level of necessity. Severe depressive symptoms were signiciantly associated with severe dependence, a low level of necessity, and a low level of concern. Educational level was also associated with the levels of concern and necessity. Conclusions/Importance: There were differences in the level of dependence and belief about hypnotic use between zolpidem and zopiclone users. The correlates of dependence and belief identified in this study can serve as the basis for prevention and intervention programs.

Dependence, misuse, and beliefs regarding use of hypnotics by elderly psychiatric patients taking zolpidem, estazolam, or flunitrazepam.

INTRODUCTION: To examine the prevalence rates and correlates of dependence on, misuse of, and beliefs regarding use of hypnotics in elderly psychiatric patients with long-term use of zolpidem, estazolam, or flunitrazepam. METHODS: A total of 139 psychiatric outpatients 65 or more years of age who used zolpidem, estazolam, or flunitrazepam for at least 3 months were studied. The levels of hypnotic dependence and beliefs regarding hypnotic use (necessity and concern) were assessed. Three patterns of hypnotic misuse in the past 1 month were also explored. The correlates of high dependence, misuse, and unfavorable attitude and high concern toward hypnotic use were examined using logistic regression analyses. RESULTS: A total of 28.8%, 7.9%, 12.2%, and 22.3% of participants reported high dependence on, misuse of, unfavorable attitude toward, and high concern toward hypnotic use, respectively. Males were more likely to report unfavorable attitude toward hypnotic use than females. Elders with significant depression were more likely to report high concern toward hypnotic use than those without significant depression. Elders with high concern toward hypnotic use were more likely to report high dependence on hypnotics than those with low concern. Elders with significant depression and taking zolpidem were more likely to misuse hypnotics than those without significant depression and taking estazolam or flunitrazepam, respectively. DISCUSSION: Clinicians should monitor the possibility of dependence on and misuse of hypnotics among elderly psychiatric patients who had the correlates identified in this study.

Severity of alprazolam dependence and associated features among long-term alprazolam users from psychiatric outpatient clinics in Taiwan.

BACKGROUND/PURPOSE: The aim of this study was to examine the correlations between the severity of alprazolam dependence and socio-demographic characteristics, the characteristics of alprazolam use, psychiatric comorbidity, and beliefs toward alprazolam use among long-term alprazolam users in Taiwan. METHODS: A total of 148 long-term alprazolam users participated in this study. The Chinese version of the Severity of Dependence Scale was used to assess participants' severity of alprazolam dependence in the preceding month. Their socio-demographic characteristics, family function characteristics, dosage of prescribed alprazolam, duration of alprazolam use, alcohol use pattern, pain reliever and cigarette use pattern, severity of depressive symptoms, psychiatric diagnosis, and belief toward alprazolam use were investigated. RESULTS: The results of multiple regression analysis indicated that a longer duration of alprazolam use, severe depressive symptoms, a high level of belief in the necessity of alprazolam treatment, and a high level of concern about the potential adverse consequences of alprazolam use were significantly associated with more severe alprazolam dependence. CONCLUSION: Doctors should closely monitor the severity of alprazolam dependence among long-term users, especially patients' levels of depression, beliefs in the necessity of alprazolam treatment, and their concerns over the adverse consequences of continued treatment with alprazolam.

Clinical correlates of zolpidem-associated complex sleep-related behaviors: age effect.

OBJECTIVE: Complex sleep-related behaviors (CSBs) are often associated with hypnotic use, especially zolpidem. The age effect on the occurrence of CSBs has not been adequately investigated. This study aimed to investigate and compare the clinical correlates of CSBs between adult and elderly subjects who were taking zolpidem. METHOD: A total of 253 adults (aged 20-55 years) and 64 elderly subjects (aged ≥ 65 years) who were administered zolpidem for at least 3 months were enrolled from psychiatric outpatient clinics from June 2011 to May 2012. The sociodemographic characteristics of the participants, the dose of zolpidem, and the occurrence of CSBs were collected. Logistic regression analysis was used to examine the clinical correlates of CSBs. RESULTS: In total, there were 62 members of the adult group (24.5%) and 11 elderly subjects (17.2%) with CSBs; however, the difference did not reach statistical significance. Logistic regression analysis showed that there was a main effect of zolpidem dose (≥ 10 mg; OR = 2.82, P = .038) and alcohol use (OR = 2.05, P = .026), but not sex or age group. There were interactive effects between age group and zolpidem dose (P = .043), indicating that a higher dose of zolpidem was associated with CSBs only in the adult group and not in the elderly group. Adults with CSBs used a higher dose of zolpidem than adults without (mean ± SD: 15.4 ± 6.8 mg vs 11.3 ± 5.7 mg), whereas elderly patients with CSBs did not use a higher dose of zolpidem than those without (12.2 ± 5.4 mg vs 11.9 ± 7.0 mg). CONCLUSIONS: A higher dose of zolpidem was correlated with CSBs only in the adult group and not in the elderly group. Future studies investigating the factors, other than dose, related to CSBs in the elderly will be performed.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Factors associated with the decline in suicide by pesticide poisoning in Taiwan: a time trend analysis, 1987-2010.

OBJECTIVE: Pesticide self-poisoning accounts for one-third of suicides worldwide, but few studies have investigated the national epidemiology of pesticide suicide in countries where it is a commonly used method. We investigated trends in pesticide suicide, and factors associated with such trends, in Taiwan, a rapidly developing East Asian country. METHODS: We conducted an ecological study using graphical approaches and Spearman's correlation coefficients to examine trends in pesticide suicide (1987-2010) in Taiwan in relation to pesticide sales, bans on selected pesticides, the proportion of the workforce involved in agriculture and unemployment. We compared pesticide products banned by the Taiwanese government with products that remained on the market and pesticides that accounted for the most poisoning deaths in Taiwan. RESULTS: Age-standardised rates of pesticide suicide showed a 67% reduction from 7.7 per 100,000 (42% of all suicides) in 1987 to 2.5 per 100,000 (12% of all suicides) in 2010, in contrast to a 69% increase in suicide rates by other methods. Pesticide poisoning was the most commonly used method of suicide in 1987 but had become the third most common method by 2010. The reduction was paralleled by a 66% fall in the workforce involved in agriculture but there was no strong evidence for its association with trends in pesticide sales, bans on selected pesticide products or unemployment. The bans mostly post-dated the decline in pesticide suicides; furthermore, they did not include products (e.g. paraquat) that accounted for most deaths and were mainly restricted to selected high-strength formulated products whilst their equivalent low-strength products were not banned. CONCLUSIONS: Access to pesticides, indicated by the size of agricultural workforce, appears to influence trends in pesticide suicide in Taiwan. Targeted bans on pesticides should focus on those products that account for most deaths.