Lymphocyte-related ratios in methamphetamine-induced psychotic disorder in Taiwan, comparing with patients with schizophrenia.

The lymphocyte-related ratios, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR) are new measures of inflammation within the body. Few studies have investigated the inflammatory response of patients with methamphetamine-induced psychotic disorder. Clinically, the psychotic symptoms and behavioural manifestation of methamphetamine-induced psychotic disorder are often indistinguishable from paranoid schizophrenia. We aimed to determine the differences in these inflammatory markers between patients with methamphetamine-induced psychotic disorder, patients with schizophrenia and healthy individuals. A total of 905 individuals were recruited. The NLR and MLR were found to be higher in both patients with methamphetamine-induced psychotic disorders and patients with schizophrenia compared with healthy controls. There was no significant difference between the three groups in PLR. When compared with the control group, the methamphetamine-induced psychotic disorder group was significantly higher in NLR 27% (95%CI = 11 to 46%, p = 0.001), MLR 16% (95%CI = 3% to 31%, p = 0.013) and PLR 16% (95%CI = 5% to 28%, p = 0.005). NLR of the group with methamphetamine-induced psychotic disorder was 17% (95%CI = 73% to 94%, p = 0.004) less than the group with schizophrenia, while MLR and PLR did not differ significantly between the two groups. This is the first study that investigated the lymphocyte-related ratios in methamphetamine-induced psychotic disorder when compared with patients with schizophrenia and healthy individuals. The results showed that both patients with methamphetamine-induced psychotic disorder and patients with schizophrenia had stronger inflammatory responses than the healthy control. Our finding also indicated that the inflammatory response of methamphetamine-induced psychotic disorder was between those of patients with schizophrenia and healthy individuals.

Assessing the impact of public funding in alleviating participant reduction and improving the retention rate in methadone maintenance treatment clinics in Taiwan: an interrupted time series analysis.

BACKGROUND: Given the steady decline in patient numbers at methadone maintenance treatment (MMT) clinics in Taiwan since 2013, the government initiated Patients' Medical Expenditure Supplements (PMES) in January 2019 and the MMT Clinics Accessibility Maintenance Program (MCAM) in September 2019. This study aims to evaluate the impact of the PMES and MCAM on the enrollment and retention of patients attending MMT clinics and whether there are differential impacts on MMT clinics with different capacities. METHODS: The monthly average number of daily participants and 3-month retention rate from 2013 to 2019 were extracted from MMT databases and subjected to single interrupted time series analysis. Pre-PMES (from February 2013 to December 2018) was contrasted with post-PMES, either from January 2019 to December 2019 for clinics funded solely by the PMES or from January 2019 to August 2019 for clinics with additional MCAM. Pre-MCAM (from January 2019 to August 2019) was contrasted with post-MCAM (from September 2019 to December 2019). Based on the monthly average number of daily patients in 2018, each MMT clinic was categorized as tiny (1-50), small (51-100), medium (101-150), or large (151-700) for subsequent stratification analysis. RESULTS: In terms of participant numbers after the PMES intervention, a level elevation and slope increase were detected in the clinics at every scale except medium in MMT clinics funded solely by PMES. In MMT clinics with subsequent MCAM, a level elevation was only detected in small-scale clinics, and a slope increase in the participant numbers was detected in tiny- and small-scale clinics. The slope decrease was also detected in medium-scale clinics. In terms of the 3-month retention rate, a post-PMES level elevation was detected at almost every scale of the clinics, and a slope decrease was detected in the overall and tiny-scale clinics for both types of clinics. CONCLUSIONS: Supplementing the cost of a broad treatment repertoire enhances the enrollment of people with heroin use in MMTs. Further funding of human resources is vital for MMT clinics to keep up with the increasing numbers of participants and their retention.

Reduced mortality in patients with extended duration of methadone maintenance treatment: a five-year retrospective nationwide study.

BACKGROUND: The retention of patients under methadone maintenance treatment (MMT) is an indication for the effectiveness of the therapy. We aimed to explore the relation between mortality and the cumulative MMT duration. METHODS: A retrospective cohort analysis was performed using Taiwan Illicit Drug Issue Database (TIDID) and National Health Insurance Research Database (NHIRD) during 2012-2016. We included 9149 and 11 112 MMT patients as the short and long groups according to the length of their cumulative MMT duration, 1-364 and ⩾365 days, respectively. The risk of mortality was calculated by Cox proportional hazards regression model with time-dependent exposure to MMT, and the survival probability was plotted with the Kaplan-Meier curve. RESULTS: The mortality rates were 2.51 and 1.51 per 100 person-years in the short and long cumulative MMT duration groups, respectively. After adjusting for on or off MMT, age, sex, marital status, education level, maximum methadone dose, and comorbidities (human immunodeficiency virus, depression, hepatitis C virus, hepatitis B virus, alcoholic liver disease, and cardiovascular disease), the long group had a lower risk of death (hazard ratio = 0.67; 95% confidence interval 0.60-0.75) than the short group. Increased risk was observed in patients with advanced age, being male, unmarried, infected by HIV, HCV, and HBV, and diagnosed with depression, ALD, and CVD. Causes of death were frequently related to drug and injury. CONCLUSIONS: Longer cumulative MMT duration is associated with lower all-cause and drug-related mortality rate.

Association of a Common NOS1AP Variant with Attenuation of QTc Prolongation in Men with Heroin Dependence Undergoing Methadone Treatment.

Background: The effects of methadone-induced severe prolongation of the corrected QT interval (QTc) and sudden cardiac death appear unpredictable and sex-dependent. Genetic polymorphisms in the nitric oxide synthase 1 adaptor protein (NOS1AP) have been implicated in QTc prolongation in general populations. We investigated whether common NOS1AP variants interact with methadone in relation to QTc prolongation in patients with heroin dependence. Methods: We genotyped 17 NOS1AP variants spanning the entire gene in heroin-dependent patients who received a 12-lead electrocardiography (ECG) examination both at baseline and during maintenance methadone treatment in Cohort 1 and only during maintenance methadone treatment in Cohort 2. The QT interval was measured automatically by the Marquette 12SL program, and was corrected for heart rate using Bazett's formula. Results: Cohort 1 consisted of 122 patients (age: 37.65 ± 8.05 years, 84% male, methadone dosage: 42.54 ± 22.17 mg/day), and Cohort 2 comprised of 319 patients (age: 36.9 ± 7.86 years, 82% male, methadone dosage: 26.08 ± 15.84 mg/day), with complete genotyping data for analyses. Before methadone, the QTc intervals increased with increasing age (r = 0.3541, p < 0.001); the age-adjusted QTc showed dose-dependent prolongation in men (r = 0.6320, p < 0.001), but abbreviation in women (r = −0.5348, p = 0.018) in Cohort 1. The pooled genotype-specific analysis of the two cohorts revealed that the QTc interval was significantly shorter in male carriers of the rs164148 AA variant than in male carriers of the reference GG genotype (GG: n = 262, QTc = 423 ± 1.4 ms; AA: n = 10, QTc = 404.1 ± 7 ms, p = 0.009), according to univariate analysis. The QTc remained shorter in male carriers of the rs164148 AA variant compared to GG genotype (423 ± 1.4 ms vs. 405.9 ± 6.9 ms, p = 0.016) in multivariate analysis after adjusting for age and methadone dosage. A cut-off QTc interval of <410 ms identifies 100% of AA carriers compared to none of GG carriers when receiving a daily methadone dosage of 30.6 ± 19.3 mg. There was no significant gene-drug interaction in contributing to the adjusted QTc (p = 0.2164) in male carriers of the rs164148 variants. Conclusions: Carriers of a common NOS1AP rs164148 AA genotype variant were associated with a shorter QTc interval in men receiving maintenance methadone treatment. This genetic polymorphism attenuates the QTc-prolonging effect by methadone, and thus may explain at least in part the unpredictable and heterogeneous risks for severe QTc prolongation and sudden cardiac death in patients on methadone.

Efficacy and safety of lemborexant over 12 months in Asian adults with insomnia disorder.

Study objectives: Lemborexant (LEM) is a dual orexin receptor antagonist approved for treating adults with insomnia. We analyzed the efficacy (subjective sleep outcomes) and safety of LEM over 12 months in the subgroup of Asian subjects from Study E2006-G000-303 (Study 303). Methods: Study 303 was a 12-month, randomized, placebo-controlled (first 6 months), double-blind, parallel-group, phase 3 study of adults with insomnia disorder. During the 6-month Period 1, subjects were randomized (1:1:1) to placebo, LEM 5 mg (LEM5), or LEM 10 mg (LEM10); LEM subjects continued treatment in the following 6-month Period 2. Outcome measures included subject-reported (subjective) sleep onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), total sleep time (sTST), Insomnia Severity Index (ISI), and Patient Global Impression-Insomnia version (PGI-I). Treatment-emergent adverse events (TEAEs) were assessed. Results: Overall, 178 Asian subjects (Japanese, n = 161; Chinese, n = 4; other Asian, n = 13) were included. Greater decreases in sSOL and sWASO and increases in sSE and sTST from baseline were observed with LEM vs placebo at 6 months; LEM benefits were sustained through 12 months. Greater decreases in ISI total score were seen with LEM vs placebo at 6 months; improvements from baseline with LEM continued through 12 months. For each PGI-I item, LEM-treated subjects had more positive medication effects than placebo-treated subjects at 6 months; these effects were maintained with LEM in Period 2. TEAEs were generally mild to moderate. Conclusions: LEM improved subjective sleep parameters and was well-tolerated in Asian subjects with insomnia disorder over 12 months. Clinical trial registration: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

Risk of psychosis in illicit amphetamine users: a 10 year retrospective cohort study.

QUESTION: Amphetamine use is a risk factor for psychosis, which imposes a substantial burden on society. We aimed to investigate the incidence of psychosis associated with illicit amphetamine use and whether rehabilitation treatments could influence the psychosis risk. STUDY SELECTION AND ANALYSIS: A retrospective cohort study was conducted using the population based Taiwan Illicit Drug Issue Database (TIDID) and the National Health Insurance Research Database (NHIRD), from 2007 to 2016. We identified 74 601 illicit amphetamine users as the amphetamine cohort and 2 98 404 subjects as the non-amphetamine cohort. The incidence rate of newly diagnosed psychosis was the main outcome. Cox proportional hazards models were applied to assess the effects of amphetamine, and the Kaplan-Meier method was used to estimate the cumulative psychosis incidence curves. FINDINGS: Illicit amphetamine users were 5.28 times more likely to experience psychosis than those without illicit drug use records. The risk was higher for subjects with multiple arrests for amphetamine use. A greater hazard ratio (HR) magnitude was observed in female patients. We also observed a significant decrease in the risk of psychosis in patients receiving rehabilitation treatments during deferred prosecution (adjusted HR 0.74, 95% CI 0.61 to 0.89). CONCLUSIONS: Illicit amphetamine use was associated with an increased incidence of psychosis. The risk was identified across all age groups, particularly in women and in those arrested multiple times, and was inversely correlated with rehabilitation treatments for amphetamine misuse.

Add-On Selective Estrogen Receptor Modulators for Methadone Maintenance Treatment.

Methadone maintenance treatment (MMT) remains the cornerstone for the management of opiate abuse. However, MMT can be associated with complex factors, including complications during the tolerance phase, the inability of some patients to maintain treatment effects during the tapering or abstinence phases, and the development of methadone dependence. Previous studies have revealed a sex disparity in MMT efficacy, showing that women undergoing MMT experiencing an increase in psychological symptoms compared with men and suggesting a link between disparate responses and the effects of estrogen signaling on methadone metabolism. More specifically, estradiol levels are positively associated with MMT dosing, and the expression of a single-nucleotide polymorphism (SNP) associated with estrogen receptor (ER) regulation is also associated with MMT dosing. In addition to performing mechanistic dissections of estrogen signaling in the presence of methadone, past studies have also proposed the targeting of estrogen signaling during MMT. The present report provides an overview of the relevant literature regarding sex effects, including differences in sex hormones and their potential impacts on MMT regimens. Moreover, this article provides a pharmacological perspective on the targeting of estrogen signals through the use of selective ER modulators (SERMs) during MMT. Preliminary preclinical experiments were also performed to evaluate the potential effects of targeting estrogen signaling with tamoxifen on methadone metabolism.

Appetitive Motivation and Regulatory Processes in Adolescent Ketamine Users.

BACKGROUND: Ketamine has remained the most commonly used illicit drug among adolescents in Taiwan. A dual process model proposes that addictive behaviors develop in adolescents as a result of an imbalance between an appetitive, approach-oriented system (implicit and explicit attitudes) and a regulatory executive system (cool and hot executive functions). We aimed to examine the appetitive and regulatory processes in adolescent ketamine users in comparison to matched healthy adolescents. Method: The participants were 30 adolescent ketamine users and 32 nondrug controls, matched with gender, age, education years, and education systems. Both groups completed the affective priming task (APT), the stop-signal task (SST), an Iowa Gambling Task (IGT), and finally a Drug Use Disorders Identification Test: Extended (DUDIT-E). Results: The controls had higher positive and negative outcome expectancy with respect to using ketamine compared to the adolescent ketamine users. There was no significant between-group performance difference in APT. The adolescent ketamine users may have shown marginally poorer performance compared to the controls in hot executive functions (IGT), but their cold executive functions (SST) remained intact. Conclusion: The current study reported that the adolescent ketamine users may not have imbalanced dual processes (biased appetitive motivation and impaired regulatory executive process). A different therapeutic focus on adolescent ketamine users may be developed accordingly. More advocacies on ketamine's aversive outcomes are needed, particularly on campus in order to reduce substance misuse.

An Investigation into Smartphone Addiction with Personality and Sleep Quality among University Students.

Over the past two decades, smartphones have become common, and the accompanying devices have also become much more popular and easily accessible worldwide. With the development of smartphones, accompanied by internet facilities, excessive smartphone use or smartphone addiction may cause sleep disturbance and daily dysfunction. This study proposed examining the association between personality traits and smartphone addiction and its effects on sleep disturbance. Four hundred and twenty-two university participants (80 male and 342 female participants) with a mean age of 20.22 years old were recruited in this study. All participants were asked to complete the following questionnaires: Smartphone Addiction Inventory (SPAI), Tri-dimensional personality questionnaire (TPQ), and Chinese Pittsburgh Sleep Questionnaire Index (CPSQI). The results showed that people with a high tendency toward novelty seeking (NS) as a personality trait, compared to those with lower tendency toward NS, are more likely to become addicted to smartphone use. Moreover, those with a stronger trait of being NS and specific impulsivity factor were found to have higher total scores in the SPAI (p < 0.05). In addition, linear regression analysis showed that the individuals with higher scores for withdrawal symptoms on the SPAI and anticipatory worry factor on the TPQ tended to have higher CPSQI total scores (p < 0.05). This information may be useful for prevention in individuals with personality traits making them vulnerable to smartphone addiction and for designing intervention programs to reduce intensive smartphone use and programs to increase capability in managing smartphone use.

Risk Assessment for Heroin Use and Craving Score Using Polygenic Risk Score.

Addiction is characterized by drug-craving, compulsive drug-taking, and relapse, and results from the interaction between multiple genetic and environmental factors. Reward pathways play an important role in mediating drug-seeking and drug-taking behaviors, and relapse. The objective of this study was to identify heroin addicts who carry specific genetic variants in their dopaminergic reward systems. A total of 326 heroin-dependent patients undergoing methadone maintenance therapy (MMT) were recruited from the Addiction Center of the China Medical University Hospital. A heroin-use and craving questionnaire was used to evaluate the urge for heroin, the daily or weekly frequency of heroin usage, daily life disturbance, anxiety, and the ability to overcome heroin use. A general linear regression model was used to assess the associations of genetic polymorphisms in one's dopaminergic reward system with heroin-use and craving scores. Results: The most significant results were obtained for rs2240158 in GRIN3B (p = 0.021), rs3983721 in GRIN3A (p = 0.00326), rs2129575 in TPH2 (p = 0.033), rs6583954 in CYP2C19 (p = 0.033), and rs174699 in COMT (p = 0.036). These were all associated with heroin-using and craving scores with and without adjustments for age, sex, and body mass index. We combined five variants, and the ensuing dose-response effect indicated that heroin-craving scores increased with the numbers of risk alleles (p for trend = 0.0008). These findings will likely help us to understand the genetic mechanism of craving, which will help in predicting the risk of relapse in clinical practice and the potential for therapies to target craving in heroin addiction.

Augmentation in Healthcare Utilization of Patients with Opioid Use Disorder After Methadone Maintenance Treatment: A Retrospective Nationwide Study.

INTRODUCTION: The health benefits of entering methadone maintenance treatment (MMT) for opioid-dependent persons may not be merely limited to therapy of opioid use disorder. We aimed to compare the healthcare utilization of MMT patients before and after MMT. METHODS: A retrospective analysis was performed using the Taiwan Illicit Drug Issue Database and the National Health Insurance Research Database (NHIRD) between 2014 and 2016. We included 1255 newly enrolled MMT patients in 2015 and randomly selected 5020 patients from NHIRD matched by age and gender as the comparison group. Changes in healthcare utilization 1 year before and 1 year after the date of the index date (MMT initiation) were compared within and between MMT and comparison groups. RESULTS: During the 1-year period following MMT, the hospitalization length was considerably decreased, while the number of outpatient visits, emergency department (ED) visits, and ED expenditure significantly increased in MMT patients. Multivariable linear regression with the difference-in-difference approach revealed that all the categories of healthcare utilization increased, except for a minor increase of outpatient expenditure and a slight decrease of hospitalization length for the MMT group relative to the comparison group. Increases in utilization of the departments of psychiatry and infectious diseases of the MMT patients were considerable. CONCLUSION: MMT is associated with increased healthcare utilization, and departments of psychiatry and infectious diseases play substantial roles. Policy-makers should warrant access for all who need healthcare by ensuring the availability of the treatment for drug dependence.

Precision therapeutic opioid dosing implications from genetic biomarkers and craving score.

Determining the clinically optimal dose in methadone maintenance therapy (MMT) is a time-consuming procedure, which considers clinical signs and symptoms.To perform a quantitative trait locus association for identifying genetic variants for MMT dosage that underlie heroin addiction and methadone metabolism and then integrate several genotypic and phenotypic factors are potential predictors for clinically optimal MMT dose for personalized prescription.In total, 316 heroin-dependent patients undergoing MMT were recruited at the Addiction Center of the China Medical University Hospital. A multinomial logistic regression model was used to assess associations between genetic polymorphisms and MMT dosing. The data were randomly separated into training and testing sets. In order to enhance the prediction accuracy and the reliability of the prediction model, we used areas under the receiver operating characteristic curves to evaluate optimal MMT dose in both training and testing sets.Four single nucleotide polymorphisms, namely rs806368 in CNR1, s1386493 in TPH2, s16974799 in CYP2B6, and rs2229205 in OPRL1, were significantly associated with the maximum MMT dose (P < .05). The genetic risk score (GRS) was associated with maximum MMT dose, and after adjustments for age, sex, and body mass index, the GRS remained independently associated with the maximum MMT dose. The area under the receiver operating characteristic curve of the combined GRS and craving score was 0.77 for maximum MMT dose, with 75% sensitivity and 60% specificity.Integrating the GRS and craving scores may be useful in the evaluation of individual MMT dose requirements at treatment initiation. Optimal dose prediction allows clinicians to tailor MMT to each patient's needs.

Correction: Artocarpin, an isoprenyl flavonoid, induces p53-dependent or independent apoptosis via ROS-mediated MAPKs and Akt activation in non-small cell lung cancer cells.

[This corrects the article DOI: 10.18632/oncotarget.16058.].

Impacts of GRIN3A, GRM6 and TPH2 genetic polymorphisms on quality of life in methadone maintenance therapy population.

Opioid addiction is a major public health issue worldwide. Methadone maintenance treatment (MMT) is used to detoxify users of illicit opiates, but drug relapse is common and associated with poor quality of life (QoL). This study investigated the associations between the GRIN3A, GRM6, and TPH2 genetic variants and QoL in the MMT population. A total of 319 participants were included in the study, and genotyping of GRIN3A, GRM6, and TPH2 genes was performed using the Sequenom iPLEX. Associations between genotypes and the domains of QoL were examined through posthoc analysis with LSMEANS syntax using SAS 9.1.3. The single nucleotide polymorphisms rs9325202 and rs1487275 in the TPH2 gene were significantly associated with the QoL domain of physical functioning. The least absolute shrinkage and selection operator regression model revealed that the risk allele rs1487275-G was significantly correlated with the domain of physical functioning when clinical characteristics were considered as covariates. The results of the present study illuminate the importance of the genetic basis of QoL in the MMT population, and suggest that genotypes should be considered as a potential QoL indicator.

Genetic polymorphisms of FADS1, FADS2, and FADS3 and fatty acid profiles in subjects received methadone maintenance therapy.

Abnormal fatty acid metabolism and the related enzymes had been observed to be associated with psychiatric disorders. We investigated FADS gene family genetic polymorphisms and variations of lipid profiles in patients with heroin dependence receiving 6-month methadone maintenance therapy (MMT). We recruited 89 MMT drug abusers and analyzed 3 tag single nucleotide polymorphisms (SNPs) from Fatty acid desaturases (FADS), FADS1, FADS2 and FADS3. The fatty acid profiles of erythrocyte membranes were analyzed based on genetic variations. Six-month MMT therapy were significantly associated with decreased C20: 5n3 and C22:4n6 levels in the whole group of drug abusers. The decreases of C22: 6n3 after MMT therapy were associated with specific genetic variations, including FADS1 C/C, FADS2 T/T and FADS3 C/C genotypes. The variations on n3 and n6 PUFA composition were significantly shown in different alleles of FADS in MMT drug abusers. Further studies are needed to elucidate the role of fatty acid metabolism on rehabilitation by MMT.

Corrigendum to "Effects of Electroacupuncture on Methamphetamine-Induced Behavioral Changes in Mice".

[This corrects the article DOI: 10.1155/2017/5642708.].

Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction.

Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen-response element single nucleotide polymorphism (ERE-SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R- or S-) of 2-ethylidene-1,5-dimethyl-3,3-dipheny-pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug-seeking behaviour, implicating oestradiol-CYP-EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up-regulates methadone-associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration-induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6-ERE-SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add-on therapy clinical trial introducing SERM in MMT regimen is suggested.