Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells.

A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1K74R/K74R or Klf1(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the Klf1(K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1(K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

A Positive Regulatory Feedback Loop between EKLF/KLF1 and TAL1/SCL Sustaining the Erythropoiesis.

The erythroid Krüppel-like factor EKLF/KLF1 is a hematopoietic transcription factor binding to the CACCC DNA motif and participating in the regulation of erythroid differentiation. With combined use of microarray-based gene expression profiling and the promoter-based ChIP-chip assay of E14.5 fetal liver cells from wild type (WT) and EKLF-knockout (Eklf-/-) mouse embryos, we identified the pathways and direct target genes activated or repressed by EKLF. This genome-wide study together with the molecular/cellular analysis of the mouse erythroleukemic cells (MEL) indicate that among the downstream direct target genes of EKLF is Tal1/Scl. Tal1/Scl encodes another DNA-binding hematopoietic transcription factor TAL1/SCL, known to be an Eklf activator and essential for definitive erythroid differentiation. Further identification of the authentic Tal gene promoter in combination with the in vivo genomic footprinting approach and DNA reporter assay demonstrate that EKLF activates the Tal gene through binding to a specific CACCC motif located in its promoter. These data establish the existence of a previously unknow positive regulatory feedback loop between two DNA-binding hematopoietic transcription factors, which sustains mammalian erythropoiesis.

Negative Regulation of the Differentiation of Flk2- CD34- LSK Hematopoietic Stem Cells by EKLF/KLF1.

Erythroid Krüppel-like factor (EKLF/KLF1) was identified initially as a critical erythroid-specific transcription factor and was later found to be also expressed in other types of hematopoietic cells, including megakaryocytes and several progenitors. In this study, we have examined the regulatory effects of EKLF on hematopoiesis by comparative analysis of E14.5 fetal livers from wild-type and Eklf gene knockout (KO) mouse embryos. Depletion of EKLF expression greatly changes the populations of different types of hematopoietic cells, including, unexpectedly, the long-term hematopoietic stem cells Flk2- CD34- Lin- Sca1+ c-Kit+ (LSK)-HSC. In an interesting correlation, Eklf is expressed at a relatively high level in multipotent progenitor (MPP). Furthermore, EKLF appears to repress the expression of the colony-stimulating factor 2 receptor ß subunit (CSF2RB). As a result, Flk2- CD34- LSK-HSC gains increased differentiation capability upon depletion of EKLF, as demonstrated by the methylcellulose colony formation assay and by serial transplantation experiments in vivo. Together, these data demonstrate the regulation of hematopoiesis in vertebrates by EKLF through its negative regulatory effects on the differentiation of the hematopoietic stem and progenitor cells, including Flk2- CD34- LSK-HSCs.

Comorbidity of Narcolepsy and Psychotic Disorders: A Nationwide Population-Based Study in Taiwan.

BACKGROUND: Narcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Psychotic disorders are characterized by delusion, hallucination, and reality impairments. This study investigates the relationship between narcolepsy and psychotic disorders. DESIGN AND METHODS: This study involves patients who were diagnosed with narcolepsy between January 2002 and December 2011 (n = 258) and age- and gender-matched controls (n = 2580) from Taiwan's National Health Insurance database. Both the patients and the controls were monitored from January 1, 2002 to December 31, 2011 to identify any occurrence of a psychotic disorder. Drugs that have been approved for treating narcolepsy: immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulations of methylphenidate (OROS-MPH), and modafinil, were analyzed. A multivariate logistic regression model was used to evaluate the potential comorbidity of narcolepsy with psychotic disorders. RESULTS: During the study period, 8.1% of the narcoleptic patients exhibited comorbidity with a psychotic disorder, whereas only 1.5% of the control subjects (1.5%) had psychotic disorders (aOR, 4.07; 95% CI, 2.21-7.47). Of the narcolepsy patients, 41.5, 5.4, and 13.2% were treated with MPH-IR, MPH-OROS, and modafinil, accordingly. Pharmacotherapy for narcolepsy did not significantly affect the risk of exhibiting a psychotic disorder. CONCLUSIONS: This nationwide study revealed that narcolepsy and psychotic disorders commonly co-occur. Pharmacotherapy for narcolepsy was not associated with the risk of psychotic disorders. Our findings serve as a reminder that clinicians must consider the comorbidity of narcolepsy and psychosis.

Testicular Function After Long-Term Methylphenidate Treatment in Boys with Attention-Deficit/Hyperactivity Disorder.

Objective: Treating attention-deficit/hyperactivity disorder (ADHD) with methylphenidate (MPH) has become increasingly common, while both animal studies and case reports have previously suggested that MPH may exert adverse effects on the reproductive system or gonadal hormones. This study aims to investigate whether long-term MPH treatment of boys with ADHD can induce testicular dysfunction (TD). Methods: A nationwide cohort that included 59,746 boys diagnosed with ADHD and 52,008 healthy subjects retrieved from the National Health Insurance database in Taiwan was also observed between 1999 and 2011. TD was defined by the International Classification of Diseases, 9th revision, Clinical Modifications codes (257.0, 257.1, 257.2, 257.8, or 257.9). Cumulative time of MPH use was categorized into nonuse, short-term use (1-365 days), and long-term use (>365 days). We compared the rate of TD diagnosis between ADHD patients and controls and analyzed the risk of developing a TD after MPH treatment. Results: Compared with the control group (0.06%), the ADHD group had a higher comorbidity rate of TD (0.14%) (adjusted odds ratio [aOR] = 1.95, 95% confidence interval [95% CI]: 1.26-3.04, p = 0.003). However, MPH did not significantly influence the risk of developing TD (adjusted hazard ratio = 1.40, 95% CI: 0.77-2.54, p = 0.272). Compared with ADHD boys without MPH treatment, patients who were prescribed short-term MPH (aOR = 0.96, 95% CI: 0.51-1.82, p = 0.900) and long-term MPH (aOR = 1.40, 95% CI: 0.69-2.83, p = 0.351) showed no significance associated with an increased risk of developing TD. Conclusions: Our nationwide cohort showed that long-term treatment with MPH has no harmful effect on the testosterone function of ADHD patients. However, due to the increased comorbidity rate of ADHD and TD, early recognition and detection of TD in ADHD children have the potential to change the trajectory of TD morbidity later in life.

Impact of Drug Adherence on Oppositional Defiant Disorder and Conduct Disorder Among Patients With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) may be a predecessor of oppositional defiant disorder (ODD) and conduct disorder (CD), and medication is an effective treatment option for ADHD. This study aims to examine whether adherence to medication treatment is associated with developing ODD and CD among youths with ADHD. METHODS: A total of 33,835 youths (4 years ≤ age of diagnosis ≤ 18 years) with ADHD (ICD-9-CM code 314.X) undergoing medication treatment for at least 90 days were selected from Taiwan's National Health Insurance Research Database during the period of January 2000 through December 2009. Patients' medical records were monitored through December 31, 2011, or until they had a diagnosis of ODD or CD. We categorized participants as compliant or noncompliant on the basis of a medication possession ratio (MPR) of 50%. RESULTS: The patients with better drug adherence (MPR ≥ 50%) exhibited a significantly decreased probability of developing ODD (53% reduction, P < .001) or CD (58% reduction, P < .001) when compared to the patients with poor drug adherence (MPR < 50%). The results in our sensitivity analyses showed that good drug adherence consistently exerted protective effects on ODD or CD, irrespective of patients' characteristics. Moreover, the patients with the best drug adherence (MPR ≥ 75%) had the lowest risks of developing ODD or CD. CONCLUSION: Among patients with ADHD undergoing drug therapy, a better drug adherence is associated with a lower likelihood of their developing ODD or CD in later life.

Correlation between attention-deficit/hyperactivity disorder, its pharmacotherapy and thyroid dysfunction: A nationwide population-based study in Taiwan.

OBJECTIVE: The aim of this study was to examine the comorbid rates of thyroid dysfunction among patients with attention-deficit/hyperactivity disorder (ADHD) and the general population. We further examined whether pharmacotherapy affects ADHD patients' risk of developing thyroid dysfunction. DESIGN AND MEASUREMENT: We recruited 75 247 newly diagnosed ADHD patient and 75 247 healthy controls between January 1999 and December 2011 from the National Health Insurance database in Taiwan. We compared hyperthyroidism, hypothyroidism and other common paediatric psychiatric diseases between ADHD patients and controls. We carried out logistic regression analysis to identify an independent factor for predicting thyroid dysfunction. Furthermore, we analysed the time sequence of the diagnosis and the risk of developing a thyroid disorder after receiving pharmacotherapy. RESULTS: Compared to the control group, the ADHD group had higher comorbidity rates of both hyperthyroidism (1.1% of ADHD vs 0.7% of controls, aOR: 1.72, P < 0.001) and hypothyroidism (0.6% of ADHD vs 0.2% of controls, aOR: 2.23, P < 0.001). Of the ADHD patients with comorbid thyroid dysfunction, about two-thirds and half of patients were diagnosed with ADHD prior to their diagnosis of hyperthyroidism and hypothyroidism, respectively. Furthermore, pharmacotherapy had no significant influence on the risk of developing hyperthyroidism (aHR: 1.09, P = 0.363) or hypothyroidism (aHR: 0.95, P = 0.719) among ADHD patients. CONCLUSION: Patients with ADHD had greater comorbid rates with thyroid dysfunction than the control subjects, but pharmacotherapy for treating ADHD did not affect thyroid dysfunction later in life. However, these findings should be further verified using a clinical cohort with comprehensive laboratory assessment in future.

Serum Glutamine Levels as a Potential Diagnostic Biomarker in Sepsis following Surgery for Peritonitis.

Few diagnostic biomarkers for sepsis after emergency peritonitis surgery are available to clinicians, and, thus, it is important to develop new biomarkers for patients undergoing this procedure. We investigated whether serum glutamine and selenium levels could be diagnostic biomarkers of sepsis in individuals recovering from emergency peritonitis surgery. From February 2012 to March 2013, patients who had peritonitis diagnosed at the emergency department and underwent emergency surgery were screened for eligibility. Serum glutamine and selenium levels were obtained at pre-operative, post-operative and recovery time points. The average level of pre-operation serum glutamine was significantly different from that on the recovery day (0.317 ± 0.168 vs. 0.532 ± 0.155 mM, P < 0.001); moreover, serum glutamine levels were unaffected by surgery. Selenium levels were significantly lower on the day of surgery than they were at recovery (106.6 ± 36.39 vs. 130.68 ± 56.98 ng/mL, P = 0.013); no significant difference was found between pre-operation and recovery selenium levels. Unlike selenium, glutamine could be a sepsis biomarker for individuals with peritonitis. We recommend including glutamine as a biomarker for sepsis severity assessment in addition to the commonly used clinical indicators.

Comorbidity of narcolepsy and depressive disorders: a nationwide population-based study in Taiwan.

OBJECTIVE: Narcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Depression is a serious mood disorder that affects individuals' daily activities and functions. The current study aimed to investigate the relationship between narcolepsy and depressive disorders. METHODS: The study consisted of patients diagnosed with narcolepsy between January 2002, and December 2011 (n = 258), and age-matched and gender-matched controls (n = 2580) from Taiwan's National Health Insurance database. Both the patients and the controls were monitored through December 31, 2011, to identify the occurrence of a depressive disorder. A multivariate logistic regression model was used to assess the narcolepsy's potential influence on the comorbidity of a depressive disorder. RESULTS: During the study period, 32.7%, 24.8%, and 10.9% of the narcoleptic patients were comorbid with any depressive disorder, dysthymic disorder, and major depressive disorder, respectively. When compared to the control subjects, the patients with narcolepsy were at greater risks of having any depressive disorder (aOR 6.77; 95% CI 4.90-9.37), dysthymic disorder (aOR 6.62; 95% CI 4.61-9.57), and major depressive disorder (aOR 6.83; 95% CI 4.06-11.48). Of the narcoleptic patients that were comorbid with depression, >50% had been diagnosed with depression prior to being diagnosed with narcolepsy. CONCLUSIONS: This nationwide data study revealed that narcolepsy and depression commonly co-occurred. Since some symptoms of narcolepsy overlapped with those of depressive disorders, the findings serve as a reminder that clinicians must pay attention to the comorbidity of narcolepsy and depression.

Trend, characteristics, and pharmacotherapy of adults diagnosed with attention-deficit/hyperactivity disorder: a nationwide survey in Taiwan.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) in adults may result in functional impairment warranting clinical interventions. However, few studies have investigated the diagnosis and treatment rates of adult ADHD in non-Caucasian ethnic groups. This study used nationwide population-based data to investigate the rate of diagnosis, associated characteristics, and pharmacological treatment for adult ADHD in Taiwan. METHODS: Adults (age ≥18 years) newly diagnosed with ADHD (n=5,397) between January 2000 and December 2011 were enrolled from the National Health Insurance database in Taiwan. All patients were monitored until December 31, 2011. Patients who received treatment with immediate-release methylphenidate (IR-MPH), osmotic release oral system-methylphenidate (OROS-MPH), and atomoxetine (ATX) were analyzed. RESULTS: The cumulative prevalence of adult ADHD was 0.028%, and the incidence increased 10.9-fold from 2000 to 2011. The male to female ratio was 1.16, and 74.9% of the patients had the inattentive type. Overall, 55% of the patients received drug therapy for ADHD, and the average treatment duration was 478.3 days. Of the total patients, 50.4%, 13.3%, and 1.7% were prescribed with IR-MPH, OROS-MPH, and ATX, for a mean duration of 453.9, 327.7, and 161.4 days, respectively. CONCLUSION: This population-based study showed an increasing trend in the diagnosis rate of adult ADHD; however, this rate is still low compared with Western countries. Approximately 45% of the adult patients with ADHD never received medication for their ADHD. Continuous efforts are needed to increase public awareness of adult ADHD.

Initiation and Persistence of Pharmacotherapy for Youths with Attention Deficit Hyperactivity Disorder in Taiwan.

BACKGROUND: Pharmacotherapy is an effective therapeutic option for attention deficit hyperactivity disorder (ADHD). Understanding the patterns of medication treatment is crucial for clinical practice. This study employed nationwide population-based data to elucidate the initiation and persistence of pharmacotherapy (immediate-release methylphenidate [IR-MPH], osmotic controlled-release formulations of methylphenidate [OROS-MPH] and atomoxetine [ATX]) for youths with ADHD in Taiwan. METHODS: Patients first receiving an ADHD diagnosis at age 18 or younger between January 2000 and December 2009 (n = 112,140; mean age at ADHD diagnosis: 7.7 years) were selected from Taiwan's National Health Insurance database. All patients were monitored through December 31, 2011, with an average follow-up time of 5.8 years. The initiation of ADHD drug therapy was defined as the first patient prescription, and discontinuation was defined as the cessation of ADHD medication for 180 days or longer. RESULTS: Within the first year after ADHD diagnosis, 47.3%, 14.4%, and 0.8% of the patients were prescribed IR-MPH, OROS-MPH, and ATX, respectively. Regarding the patients prescribed IR-MPH, OROS-MPH, and ATX, 17.8%, 12.6%, and 18.8%, respectively, received the prescription only once and never returned for a drug refill, and 51.0%, 38.9%, and 58.8%, respectively, discontinued drug therapy within 1 year after the first prescription. Male sex and neuropsychiatric comorbidities were associated with higher probabilities of being prescribed one of the medications. An older age at first prescription and a higher daily dose of prescription were significant predictors of early discontinuation of ADHD medication. CONCLUSIONS: The current findings suggest that IR-MPH is the most frequently prescribed drug for ADHD treatment in Taiwan. Patients treated with OROS-MPH possessed the highest persistence rate, whereas those treated with ATX had the lowest persistence rate. The results provide insight into the delivery of pediatric mental health services and have crucial implications for ADHD medication treatment in real clinical settings.

miR-122-mediated translational repression of PEG10 and its suppression in human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC), a primary liver malignancy, is the most common cancer in males and fourth common cancer in females in Taiwan. HCC patients usually have a poor prognosis due to late diagnosis. It has been classified as a complex disease because of the heterogeneous phenotypic and genetic traits of the patients and a wide range of risk factors. Micro (mi)RNAs regulate oncogenes and tumor suppressor genes that are known to be dysregulated in HCC. Several studies have found an association between downregulation of miR-122, a liver-specific miRNA, and upregulation of paternally expressed gene 10 (PEG10) in HCC; however, the correlation between low miR-122 and high PEG10 levels still remains to be defined and require more investigations to evaluate their performance as an effective prognostic biomarker for HCC. METHODS: An in silico approach was used to isolate PEG10, a potential miR-122 target implicated in HCC development. miR-122S binding sites in the PEG10 promoter were evaluated with a reporter assay. The regulation of PEG10 by miR-122S overexpression was examined by quantitative RT-PCR, western blotting, and immunohistochemistry in miR-122 knockout mice and liver tissue from HCC patients. The relationship between PEG10 expression and clinicopathologic features of HCC patients was also evaluated. RESULTS: miR-122 downregulated the expression of PEG10 protein through binding to 3'-untranslated region (UTR) of the PEG10 transcript. In miR-122 knockout mice and HCC patients, the deficiency of miR-122 was associated with HCC progression. The expression of PEG10 was increased in 57.3 % of HCC as compared to paired non-cancerous tissue samples. However, significant upregulation was detected in 56.5 % of patients and was correlated with Okuda stage (P = 0.05) and histological grade (P = 0.001). CONCLUSIONS: miR-122 suppresses PEG10 expression via direct binding to the 3'-UTR of the PEG10 transcript. Therefore, while PEG10 could not be an ideal diagnostic biomarker for HCC but its upregulation in HCC tissue still has predictive value for HCC prognosis.

Seasonal Patterns of Medications for Treating Attention-Deficit/Hyperactivity Disorder: Comparison of Methylphenidate and Atomoxetine.

PURPOSE: Medication is a first-line effective treatment for attention-deficit/hyperactivity disorder (ADHD). Currently, immediate-release methylphenidate (IR-MPH), the osmotic, controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) are the only 3 medications approved in Taiwan for the treatment of ADHD. Short-term discontinuation of ADHD treatment is often seen among patients undergoing drug therapy. The goal of this study was to evaluate potential seasonal patterns in ADHD prescriptions and compare the seasonal changes of IR-MPH, OROS-MPH, and ATX use. METHODS: Taiwan's National Health Insurance database was used to gather information on patients diagnosed with ADHD (N = 145,269) from January 2000 to December 2011. The monthly data regarding person-days and receipt of treatment with IR-MPH, OROS-MPH, and ATX were analyzed. Time series analyses and autoregressive integrated moving average models were used to examine the seasonal patterns in person-days receiving ADHD pharmacotherapy. A general linear model with a post hoc test was used to determine the differences in monthly consumption of ADHD medications. FINDINGS: This study comprised 145,269 patients (mean age: 7.7 years; 78.6% were boys) diagnosed with ADHD. The prescriptions of IR-MPH (seasonal autoregressive: estimate [SE], 0.92 [0.04], t = 22.87, P < 0.001) and OROS-MPH (estimate [SE], 0.84 [0.09], t = 9.41, P < 0.001) both showed significant seasonal patterns, but ATX prescriptions did not (estimate [SE], 0.50 [0.55]; t = 0.90; P = 0.373). IR-MPH and OROS-MPH prescriptions shared similar seasonal trends. The mean person-days of consumption in July were lower than in other months, with the exception of February and August. Meanwhile, for ATX, the person-days of consumption in February were the lowest. The mean person-days in February were significantly lower than in March and May but did not differ from those in other months. IMPLICATIONS: The seasonal patterns of IR-MPH and OROS-MPH use coincide with school holidays. These findings suggest that discontinuing a drug during the holiday period may be popular for people undergoing ADHD pharmacotherapy, especially with regard to methylphenidate prescriptions. However, additional research is necessary to determine whether temporary discontinuation of drug therapy is related to patient outcomes.

Impact of negative media publicity on attention-deficit/hyperactivity disorder medication in Taiwan.

PURPOSE: This study explores trends in attention-deficit/hyperactivity disorder (ADHD) medications in Taiwan from 2000 to 2011 and whether negative media coverage of Ritalin in January 2010 impacted ADHD prescriptions throughout the country. METHOD: Patients throughout Taiwan who had been newly diagnosed with ADHD (n = 145,269) between January 2000 and December 2011 were selected from Taiwan's National Health Insurance database as subjects for this study. We analyzed monthly and yearly data on person-days of treatment with immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) using linear models of curve estimation and the time series expert modeler. RESULTS: Of our sample, 57.8%, 28.9%, and 4.3% had been prescribed one or more doses of IR-MPH, OROS-MPH, or ATX, respectively. The annual person-days of IR-MPH use increased regularly from 2000 to 2009, dropped abruptly in 2010, and then increased again the next year. Furthermore, the person-days of OROS-MPH prescriptions did not reach their expected goal in 2010; however, the person-days of ATX prescriptions have increased constantly since entering the market in 2007. Compared with patients newly diagnosed with ADHD in 2009, those newly diagnosed in 2010 were less likely to be treated with medication. CONCLUSION: These findings suggest that negative publicity affected the writing of stimulant prescriptions for ADHD patients throughout Taiwan. Media reporting has a vital role in influencing children with ADHD, their parents, and their willingness to accept pharmacotherapy as treatment.

Attention-deficit hyperactivity disorder, its treatment with medication and the probability of developing a depressive disorder: A nationwide population-based study in Taiwan.

OBJECTIVE: The purpose of this study is to determine the risk of developing depressive disorders by evaluating children with attention-deficit/hyperactivity disorder (ADHD) in comparison to controls that do not have ADHD, as well as to analyze whether the medications used to treat ADHD, methylphenidate (MPH) and atomoxetine (ATX), influence the risk of depression. METHODS: A group of patients newly diagnosed with ADHD (n=71,080) and age- and gender-matching controls (n=71,080) were chosen from Taiwan's National Health Insurance database during the period of January 2000 to December 2011. Both the patients and controls were monitored through December 31, 2011. We also explore the potential influence of the length of MPH and ATX treatment on developing depressive disorders. RESULTS: The ADHD patients showed a significantly increased probability of developing a depressive disorder when compared to the control group (ADHD: 5.3% vs. CONTROLS: 0.7%; aHR, 7.16, 99% CI: 6.28-8.16). Regarding treatment with MPH, a longer MPH use demonstrates significant protective effects against developing a depressive disorder (aOR, 0.91, 99%CI: 0.88-0.94). However, the duration of ATX treatment could not be significantly correlated with the probability of developing a depressive disorder. LIMITATIONS: The database employed in this study lacks of comprehensive clinical information for the patients with ADHD. Potential moderating factors between ADHD and depression were not considered in-depth in this study. CONCLUSIONS: The results of this study reveal that youths diagnosed with ADHD have a greater risk of developing depressive disorders. Long-term treatment with MPH correlated to the reduced probability of developing a depressive disorder among youths with ADHD.

Attention-deficit hyperactivity disorder, its pharmacotherapy, and the risk of developing bipolar disorder: A nationwide population-based study in Taiwan.

UNLABELLED: In this study, we aimed to evaluate the relationship between attention-deficit/hyperactivity disorder (ADHD) during childhood and subsequent diagnoses of bipolar disorder (BD), as well as to determine whether the pharmacotherapy for ADHD (methylphenidate and atomoxetine) influence the risks of developing BD. A nationwide cohort of patients newly diagnosed with ADHD (n = 144,920) and age- and gender-matching controls (n = 144,920) were found in Taiwan's National Health Insurance database from January 2000 to December 2011. Both patients and controls were observed until December 31, 2011. To determine the effect that the duration of methylphenidate and atomoxetine exposure had on BD, the difference in the risk of developing BD was compared among non-users, short-term users (≤ 365 days), and long-term users (>365 days). In comparison to the control group, the ADHD group showed a significantly increased risk of developing BD (ADHD: 2.1% vs. CONTROLS: 0.4%; aHR: 7.85, 95% CI: 7.09-8.70), and had a younger mean age at the time of first diagnosis (ADHD: 12.0 years vs. CONTROLS: 18.8 years). Compared to ADHD patients that had never taken methylphenidate, patients with long-term use of methylphenidate were less likely to be diagnosed with BD (aOR: 0.72, 95% CI: 0.65-0.80). However, the duration of exposure to atomoxetine did not have a significant relationship to a BD diagnosis. The results suggested that a previous diagnosis of ADHD was a powerful indicator of BD, particularly juvenile-onset BD. Nevertheless, the exact mechanisms of the relationships among ADHD, its pharmacotherapy, and BD require further clarification in the future.

Risk of Mortality Among Patients Treated With Antipsychotic Medications: A Nationwide Population-Based Study in Taiwan.

In this nationwide population-based study, we examined whether haloperidol exposure is associated with a higher risk of mortality than are other antipsychotic medications. Patients who newly received monotherapy with chlorpromazine (n = 2133), haloperidol (n = 4454), quetiapine (n = 1513), and risperidone (n = 1046) between January 1, 2001, and December 31, 2011, were selected from a random sample of the 1 million enrollees of the Taiwan National Health Insurance Research Database. The association between antipsychotic prescription and mortality was estimated through Cox proportional hazard regression. To examine the mortality rates of antipsychotics at different exposure durations, we compared the differences among short-term (≤30 days), midterm (31-90 days), and long-term (>90 days) antipsychotic use. The mortality rates during the follow-up among the chlorpromazine, haloperidol, quetiapine, and risperidone groups were 17.4%, 45.5%, 26.8%, and 25.9%, respectively. The mortality risk among patients receiving haloperidol was the highest within 30 days of the prescription, after which the risk reduced rapidly. Compared with the patients receiving chlorpromazine, the mortality risk was higher in short-term (adjusted hazard ratio, 2.11; 95% confidence interval, 1.87-2.39) and midterm haloperidol users (1.86; 1.54-2.25) than in long-term users (0.99; 0.61-1.61). In conclusion, haloperidol use is associated with higher mortality risk than other antipsychotic medications. The mortality risk varies according to the duration of drug exposure. Underlying characteristics and medical conditions may influence the estimation of the mortality risk. Clinicians should pay attention to the mortality risk when prescribing antipsychotic medications, particularly for the elderly and critically ill patients.

Attention-deficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: A nationwide population-based study in Taiwan.

This study estimated the risk of developing psychotic disorders by comparing children with ADHD to non-ADHD controls, and to examine whether methylphenidate (MPH) treatment influences the risks of psychotic disorders. A nationwide cohort of patients who were newly diagnosed with ADHD (n=73,049) and age- and gender-matched controls (n=73,049) were selected from Taiwan's National Health Insurance database from January 2000 to December 2011. All participants were observed until December 31, 2011. Cox regression models were used to estimate the effects of ADHD diagnosis and MPH use on subsequent outcomes. Having a diagnosis of any psychotic disorder and of schizophrenia were set as two different outcomes and were analyzed separately. Compared to the control group, the ADHD group showed significantly increased risk of developing any psychotic disorder (adjusted hazard ratio [aHR], 5.20; 95% confidence interval [CI], 4.30-6.30) and schizophrenia (aHR, 4.65; 95% CI, 3.59-6.04). Compared to ADHD patients without psychosis, patients with ADHD who developed psychosis had significantly older age at first diagnosis of ADHD (9.4±3.3years vs. 10.6±4.0years). Among patients with ADHD, MPH use significantly increased the risk of developing any psychotic disorder (aHR, 1.20; 95% CI, 1.04-1.40), but did not increase the risk of developing schizophrenia (aHR, 1.16; 95% CI, 0.94-1.42). The results indicated that previous diagnoses of ADHD are a powerful indicator of developing psychotic disorders. Nevertheless, the specific mechanisms of the relationships between ADHD, MPH use and psychotic disorders need further elucidation in future clinical studies.