Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Cognitive enhancing effect of rTMS combined with tDCS in patients with major depressive disorder: a double-blind, randomized, sham-controlled study.

BACKGROUND: Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. METHODS: In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients' cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients' depressive symptoms at baseline and week 2. RESULTS: After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p < 0.05). Moreover, post hoc tests revealed a significant increase in the RBANS total score and Visuospatial/Constructional in the combined treatment group compared to the other three groups but in the immediate memory, the combined treatment group only showed a better improvement than the sham group. The results also showed the RBANS total score increased significantly higher in the active rTMS group compared with the sham group. However, rTMS or tDCS alone was not superior to the sham group in terms of other cognitive performance. In addition, the rTMS combined with the tDCS group showed a greater reduction in HDRS-24 total score and a better depression response rate than the other three groups. CONCLUSIONS: rTMS combined with tDCS treatment is more effective than any single intervention in treating cognitive dysfunction and depressive symptoms in MDD patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052122).

Epidemiology, clinical presentation, pathophysiology, and management of long COVID: an update.

The increasing number of coronavirus disease 2019 (COVID-19) infections have highlighted the long-term consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection called long COVID. Although the concept and definition of long COVID are described differently across countries and institutions, there is general agreement that it affects multiple systems, including the immune, respiratory, cardiovascular, gastrointestinal, neuropsychological, musculoskeletal, and other systems. This review aims to provide a synthesis of published epidemiology, symptoms, and risk factors of long COVID. We also summarize potential pathophysiological mechanisms and biomarkers for precise prevention, early diagnosis, and accurate treatment of long COVID. Furthermore, we suggest evidence-based guidelines for the comprehensive evaluation and management of long COVID, involving treatment, health systems, health finance, public attitudes, and international cooperation, which is proposed to improve the treatment strategies, preventive measures, and public health policy making of long COVID.

A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action.

The long-term physical and mental sequelae of COVID-19 are a growing public health concern, yet there is considerable uncertainty about their prevalence, persistence and predictors. We conducted a comprehensive, up-to-date meta-analysis of survivors' health consequences and sequelae for COVID-19. PubMed, Embase and the Cochrane Library were searched through Sep 30th, 2021. Observational studies that reported the prevalence of sequelae of COVID-19 were included. Two reviewers independently undertook the data extraction and quality assessment. Of the 36,625 records identified, a total of 151 studies were included involving 1,285,407 participants from thirty-two countries. At least one sequelae symptom occurred in 50.1% (95% CI 45.4-54.8) of COVID-19 survivors for up to 12 months after infection. The most common investigation findings included abnormalities on lung CT (56.9%, 95% CI 46.2-67.3) and abnormal pulmonary function tests (45.6%, 95% CI 36.3-55.0), followed by generalized symptoms, such as fatigue (28.7%, 95% CI 21.0-37.0), psychiatric symptoms (19.7%, 95% CI 16.1-23.6) mainly depression (18.3%, 95% CI 13.3-23.8) and PTSD (17.9%, 95% CI 11.6-25.3), and neurological symptoms (18.7%, 95% CI 16.2-21.4), such as cognitive deficits (19.7%, 95% CI 8.8-33.4) and memory impairment (17.5%, 95% CI 8.1-29.6). Subgroup analysis showed that participants with a higher risk of long-term sequelae were older, mostly male, living in a high-income country, with more severe status at acute infection. Individuals with severe infection suffered more from PTSD, sleep disturbance, cognitive deficits, concentration impairment, and gustatory dysfunction. Survivors with mild infection had high burden of anxiety and memory impairment after recovery. Our findings suggest that after recovery from acute COVID-19, half of survivors still have a high burden of either physical or mental sequelae up to at least 12 months. It is important to provide urgent and appropriate prevention and intervention management to preclude persistent or emerging long-term sequelae and to promote the physical and psychiatric wellbeing of COVID-19 survivors.

Enhancing post-traumatic stress disorder patient assessment: leveraging natural language processing for research of domain criteria identification using electronic medical records.

BACKGROUND: Extracting research of domain criteria (RDoC) from high-risk populations like those with post-traumatic stress disorder (PTSD) is crucial for positive mental health improvements and policy enhancements. The intricacies of collecting, integrating, and effectively leveraging clinical notes for this purpose introduce complexities. METHODS: In our study, we created a natural language processing (NLP) workflow to analyze electronic medical record (EMR) data and identify and extract research of domain criteria using a pre-trained transformer-based natural language model, all-mpnet-base-v2. We subsequently built dictionaries from 100,000 clinical notes and analyzed 5.67 million clinical notes from 38,807 PTSD patients from the University of Pittsburgh Medical Center. Subsequently, we showcased the significance of our approach by extracting and visualizing RDoC information in two use cases: (i) across multiple patient populations and (ii) throughout various disease trajectories. RESULTS: The sentence transformer model demonstrated high F1 macro scores across all RDoC domains, achieving the highest performance with a cosine similarity threshold value of 0.3. This ensured an F1 score of at least 80% across all RDoC domains. The study revealed consistent reductions in all six RDoC domains among PTSD patients after psychotherapy. We found that 60.6% of PTSD women have at least one abnormal instance of the six RDoC domains as compared to PTSD men (51.3%), with 45.1% of PTSD women with higher levels of sensorimotor disturbances compared to men (41.3%). We also found that 57.3% of PTSD patients have at least one abnormal instance of the six RDoC domains based on our records. Also, veterans had the higher abnormalities of negative and positive valence systems (60% and 51.9% of veterans respectively) compared to non-veterans (59.1% and 49.2% respectively). The domains following first diagnoses of PTSD were associated with heightened cue reactivity to trauma, suicide, alcohol, and substance consumption. CONCLUSIONS: The findings provide initial insights into RDoC functioning in different populations and disease trajectories. Natural language processing proves valuable for capturing real-time, context dependent RDoC instances from extensive clinical notes.

A systematic review and meta-analysis on prevalence of and risk factors associated with depression, anxiety and insomnia in infectious diseases, including COVID-19: a call to action.

Infectious disease epidemics have become more frequent and more complex during the 21st century, posing a health threat to the general public and leading to psychological symptoms. The current study was designed to investigate the prevalence of and risk factors associated with depression, anxiety and insomnia symptoms during epidemic outbreaks, including COVID-19. We systematically searched the PubMed, Embase, Web of Science, OVID, Medline, Cochrane databases, bioRxiv and medRxiv to identify studies that reported the prevalence of depression, anxiety or insomnia during infectious disease epidemics, up to August 14th, 2020. Prevalence of mental symptoms among different populations including the general public, health workers, university students, older adults, infected patients, survivors of infection, and pregnant women across all types of epidemics was pooled. In addition, prevalence of mental symptoms during COVID-19 was estimated by time using meta-regression analysis. A total of 17,506 papers were initially retrieved, and a final of 283 studies met the inclusion criteria, representing a total of 948,882 individuals. The pooled prevalence of depression ranged from 23.1%, 95% confidential intervals (95% CI: [13.9-32.2]) in survivors to 43.3% (95% CI: [27.1-59.6]) in university students, the pooled prevalence of anxiety ranged from 25.0% (95% CI: [12.0-38.0]) in older adults to 43.3% (95% CI: [23.3-63.3]) in pregnant women, and insomnia symptoms ranged from 29.7% (95% CI: [24.4-34.9]) in the general public to 58.4% (95% CI: [28.1-88.6]) in university students. Prevalence of moderate-to-severe mental symptoms was lower but had substantial variation across different populations. The prevalence of mental problems increased over time during the COVID-19 pandemic among the general public, health workers and university students, and decreased among infected patients. Factors associated with increased prevalence for all three mental health symptoms included female sex, and having physical disorders, psychiatric disorders, COVID infection, colleagues or family members infected, experience of frontline work, close contact with infected patients, high exposure risk, quarantine experience and high concern about epidemics. Frequent exercise and good social support were associated with lower risk for these three mental symptoms. In conclusion, mental symptoms are common during epidemics with substantial variation across populations. The population-specific psychological crisis management are needed to decrease the burden of psychological problem and improve the mental wellbeing during epidemic.

Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Cognitive Deficits and Clinical Symptoms with Hippocampal Subfields in First-Episode and Never-Treated Patients with Schizophrenia.

Memory dysfunction and associated hippocampal disturbances play crucial roles in cognitive impairment of schizophrenia. To examine the relationships between cognitive function and the hippocampal subfields (HSs) in first-episode never-treated (FENT) schizophrenia patients, the HSs were segmented in 39 FENT patients and 30 healthy controls using a state-of the-art automated algorithm. We found no significant differences in any HSs between the patients and controls. However, multivariate regression analysis showed that the left cornu ammonis 1 (CA1), left hippocampal tail, left presubiculum, and right molecular layer contributed 40% to the variance of the PANSS negative symptom score. After adjusting for sex, age, education, and intracranial volume, the partial correlation analysis showed that the volumes of left CA1, CA3, CA4, molecular layer, granule cell layer and both left and right subiculum were negatively correlated with the MATRICS consensus cognitive battery (MCCB) Hopkins Verbal Learning Test (HVLT). Multiple regression analysis showed that the left CA1 and CA3 hippocampal abnormalities contributed 66% to the variance of the HVLT. Our results suggest no detectable HS deficits were found in FENT schizophrenia patients. However, the HSs may be involved in the symptoms and cognitive deficits of schizophrenia patients in the early phase of their illness.

Exenatide Adjunct to Nicotine Patch Facilitates Smoking Cessation and May Reduce Post-Cessation Weight Gain: A Pilot Randomized Controlled Trial.

INTRODUCTION: Approved pharmacological treatments for smoking cessation are modestly effective, underscoring the need for improved pharmacotherapies. Glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the rewarding effects of nicotine in preclinical studies. We examined the efficacy of extended-release exenatide, a GLP-1R agonist, combined with nicotine replacement therapy (NRT, patch) for smoking cessation, craving, and withdrawal symptoms, with post-cessation body weight as a secondary outcome. METHODS: Eighty-four prediabetic and/or overweight smokers were randomized (1 : 1) to once-weekly placebo or exenatide, 2 mg, subcutaneously. All participants received NRT (21 mg) and brief smoking cessation counseling. Seven-day point prevalence abstinence (expired CO level ≤5 ppm), craving, withdrawal, and post-cessation body weight were assessed following 6 weeks of treatment. A Bayesian approach for analyzing generalized linear models yielded posterior probabilities (PP) to quantify the evidence favoring hypothesized effects of treatment on the study outcomes. RESULTS: Exenatide increased the risk for smoking abstinence compared to placebo (46.3% and 26.8%, respectively), (risk ratio [RR] = 1.70; 95% credible interval = [0.96, 3.27]; PP = 96.5%). Exenatide reduced end-of-treatment craving in the overall sample and withdrawal among abstainers. Post-cessation body weight was 5.6 pounds lower in the exenatide group compared to placebo (PP = 97.4%). Adverse events were reported in 9.5% and 2.3% of participants in the exenatide and placebo groups, respectively. CONCLUSIONS: Exenatide, in combination with the NRT improved smoking abstinence, reduced craving and withdrawal symptoms, and decreased weight gain among abstainers. Findings suggest that the GLP-1R agonist strategy is worthy of further research in larger, longer duration studies. IMPLICATIONS: Despite considerable progress in tobacco control, cigarette smoking remains the leading cause of preventable disease, disability, and death. In this pilot study, we showed that extended-release exenatide, a glucagon-like peptide-1 receptor agonist, added to the nicotine patch, improved abstinence and mitigated post-cessation body weight gain compared to patch alone. Further research is needed to confirm these initial positive results.

Nicotine Inhalation and Suicide: Clinical Correlates and Behavioral Mechanisms.

BACKGROUND AND OBJECTIVES: Extensive evidence links smoking and suicide independently of psychiatric diagnoses, but there are questions about the pathophysiology and specificity of this relationship. We examined characteristics of this linkage to identify potential transdiagnostic mechanisms in suicide and its prevention. METHODS: We reviewed literature that associated suicide with smoking and e-cigarettes, including the temporal sequence of smoking and suicide risk and their shared behavioral risk factors of sensitization and impulsivity. RESULTS: Smoking is associated with increased suicide across psychiatric diagnoses and in the general population, proportionately to the number of cigarettes smoked per day. Rapid nicotine uptake into the brain through inhalation of conventional cigarettes, electronic cigarettes (e-cigarette), or even second-hand smoke can facilitate long-term sensitization and short-term impulsivity. Both impair action regulation and predispose to negative affect, continued smoking, and suicidal behavior. Intermittent hypoxia, induced by cigarettes or e-cigarettes, synergistically promotes impulsivity and sensitization, exacerbating suicidality. Two other shared behavioral risks also develop negative urgency (combined impulsivity and negative affect) and cross-sensitization to stressors or to other addictive stimuli. Finally, early smoking onset, promoted by e-cigarettes in never-smokers, increases subsequent suicide risk. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Prevention or cessation of nicotine inhalation can strategically prevent suicidality and other potentially lethal behavior regardless of psychiatric diagnoses. Medications for reducing smoking and suicidality, especially in younger smokers, should consider the neurobehavioral mechanisms for acute impulsivity and longer-term sensitization, potentially modulated more effectively through glutamate antagonism rather than nicotine substitution. (Am J Addict 2021;30:316-329).

Cingulate Cortex Structural Alterations in Substance Use Disorder Psychiatric Inpatients.

BACKGROUND AND OBJECTIVES: Substance use disorder (SUD) includes maladaptive patterns of substance use despite negative consequences. Previous structural neuroimaging studies showed some structural alterations in SUD, but it remains unknown whether these alterations are specifically associated with SUD or common comorbidities. This study attempts to validate the findings of structural differences between SUD, healthy controls (HC), and psychiatric controls (PC). METHODS: We used HC (N = 86) matched for demographics, and PC (N = 86) matched for demographics and psychiatric diagnoses to a group of SUD patients (N = 86). We assessed the group differences of subcortical volumes, cortical volumes, thickness, and surface areas between SUD and HC. We then analyzed the group differences between SUD and PC within regions showing differences between SUD and HC. RESULTS: SUD had smaller left nucleus accumbens, right thalamus, right hippocampus, left caudal anterior cingulate cortex (ACC) volume, and larger right caudal ACC volume, and right caudal ACC, right caudal middle frontal gyrus (MFG), and right posterior cingulate cortex (PCC) surface than HC. Increased right caudal ACC volume and right PCC surface in SUD were the only findings when compared with PC. Several areas showed thickness alterations between SUD and HC, but none survived multiple comparisons vs PC. DISCUSSION AND CONCLUSIONS: Our findings suggest that cingulate structures may be altered in SUD compared with both HC and PC. SCIENTIFIC SIGNIFICANCE: These results are among the first to indicate that some structural alterations may be SUD-specific, and highlight a cautionary note about using HC in psychiatric biomarker research. (Am J Addict 2021;30:72-79).

Internet Addiction Increases in the General Population During COVID-19: Evidence From China.

BACKGROUND AND OBJECTIVES: COVID-19-related quarantine and stress have likely escalated the crisis of Internet addiction. This study aimed to determine the impact of the COVID-19 pandemic on Internet use and related risk factors among the general public in China. METHODS: A large-sample cross-sectional online survey was conducted from March 24 to April 30, 2020, in China, and 20,472 participants completed the survey. We investigated the prevalence and severity of Internet addiction based on the Internet Addiction Test (IAT), and explored the risk factors related to increases in time spent on Internet use and severity of Internet addiction, as well as severe Internet addiction. RESULTS: The overall prevalence of Internet addiction was 36.7% among the general population during the pandemic, and that of severe Internet addiction was 2.8%, according to IAT scores. Time spent on recreational Internet use had significantly increased during the pandemic, and almost half of participants reported increases in the severity of Internet addiction. Risk factors for increases in time spent on Internet use and severity of Internet addiction and severe Internet addiction included having fewer social supporters, perceiving pressure and impact on mental health status due to COVID-19, and being over-engaged in playing videogames. DISCUSSION AND CONCLUSIONS: The COVID-19 pandemic adversely impacted Internet use and increased the prevalence and severity of Internet addiction among the general population in China, especially in vulnerable populations. SCIENTIFIC SIGNIFICANCE: This study provides evidence for policymakers to refine public health policies to control the pandemic and make efforts to provide population-specific prevention and interventions for people at risk of developing Internet addiction. (Am J Addict 2021;00:00-00).

Mental health services for infectious disease outbreaks including COVID-19: a rapid systematic review.

The upsurge in the number of people affected by the COVID-19 is likely to lead to increased rates of emotional trauma and mental illnesses. This article systematically reviewed the available data on the benefits of interventions to reduce adverse mental health sequelae of infectious disease outbreaks, and to offer guidance for mental health service responses to infectious disease pandemic. PubMed, Web of Science, Embase, PsycINFO, WHO Global Research Database on infectious disease, and the preprint server medRxiv were searched. Of 4278 reports identified, 32 were included in this review. Most articles of psychological interventions were implemented to address the impact of COVID-19 pandemic, followed by Ebola, SARS, and MERS for multiple vulnerable populations. Increasing mental health literacy of the public is vital to prevent the mental health crisis under the COVID-19 pandemic. Group-based cognitive behavioral therapy, psychological first aid, community-based psychosocial arts program, and other culturally adapted interventions were reported as being effective against the mental health impacts of COVID-19, Ebola, and SARS. Culturally-adapted, cost-effective, and accessible strategies integrated into the public health emergency response and established medical systems at the local and national levels are likely to be an effective option to enhance mental health response capacity for the current and for future infectious disease outbreaks. Tele-mental healthcare services were key central components of stepped care for both infectious disease outbreak management and routine support; however, the usefulness and limitations of remote health delivery should also be recognized.

Brief Report: Increased Addictive Internet and Substance Use Behavior During the COVID-19 Pandemic in China.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic and control measures may have increased the risk of abusing addictive substances as well as addictive behaviors. METHODS: We present an initial online survey in 6416 Chinese about the relation between the COVID-19 pandemic and addictive behavior in China. RESULTS: During the COVID-19 pandemic, 46.8% of the subjects reported increased dependence on internet use, and 16.6% had longer hours of internet use. The prevalence (4.3%) of severe internet dependence rose up to 23% than that (3.5%) before the COVID-19 pandemic occurred, and their dependence degree rose 20 times more often than being declined (60% vs 3%). Relapses to abuse from alcohol and smoking abstinence were relatively common at 19% and 25%, respectively. Similarly, 32% of regular alcohol drinkers and 20% of regular smokers increased their usage amount during the pandemic. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: These three coping behaviors (internet, alcohol, and smoking) during this COVID-19-related crisis appear to have increased the risk for substance use disorders and internet addiction. (Am J Addict 2020;00:00-00).

Doxazosin treatment in cocaine use disorder: pharmacogenetic response based on an alpha-1 adrenoreceptor subtype D genetic variant.

Background: The α1 antagonist doxazosin reduces cocaine use in individuals with cocaine use disorder (CUD) through a functional polymorphism of the α1 adrenoreceptor. The regulatory role of the α1adrenoreceptor subtype D (ADRA1D) gene polymorphism in CUD is uncharacterized.Objectives: To study how the genetic variant of ADRA1D gene (T1848A, rs2236554) may affect the treatment efficacy of doxazosin in reducing cocaine use.Methods: This 12-week pilot trial included 76 participants with CUD with ADRA1D (T1848A, rs2236554) AA (N = 40) or AT/TT genotype (N = 36). Participants were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29), and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy.Results: The AA and the AT/TT groups had comparable baseline rates of cocaine positive urines at weeks 1-2 (~ 76%). In the placebo group, an increase of cocaine positive urines in the AT/TT group was found as compared to the AA group (24% vs. 9%). In the doxazosin group, a greater decrease in cocaine positive urines was found in the AT/TT group relative to the AA group. The difference between the doxazosin and placebo groups in cocaine negative urines became evident at weeks 5-6 and peaked at weeks 9-10 (~35% difference). The AT/TT group demonstrated a significant medication and time by medication effect (p < .001), whereas the AA group did not.Conclusion: The T-allele carriers showed a greater reduction of cocaine use after treatment with doxazosin in participants with the ADRA1D gene polymorphism (T1848A), suggesting that this SNP may serve as a pharmacogenetic marker in pharmacotherapy of CUD.

Insular resting state functional connectivity is associated with gut microbiota diversity.

The gut microbiota has recently gained attention as a possible modulator of brain activity. A number of reports suggest that the microbiota may be associated with neuropsychiatric conditions such as major depressive disorder, autism and anxiety. The gut microbiota is thought to influence the brain via vagus nerve signalling, among other possible mechanisms. The insula processes and integrates these vagal signals. To determine if microbiota diversity and structure modulate brain activity, we collected faecal samples and examined insular function using resting state functional connectivity (RSFC). Thirty healthy participants (non-smokers, tobacco smokers and electronic cigarette users, n = 10 each) were studied. We found that the RSFC between the insula and several regions (frontal pole left, lateral occipital cortex right, lingual gyrus right and cerebellum 4, 5 and vermis 9) were associated with bacterial microbiota diversity and structure. In addition, two specific bacteria genera, Prevotella and Bacteroides, were specifically different in tobacco smokers and also associated with insular connectivity. In conclusion, we show that insular connectivity is associated with microbiome diversity, structure and at least two specific bateria genera. Furthemore, this association is potentially modulated by tobacco smoking, although the sample sizes for the different smoking groups were small and this result needs validation in a larger cohort. While replication is necessary, the microbiota is a readily accessible therapeutic target for modulating insular connectivity, which has previously been shown to be abnormal in anxiety and tobacco use disorders.

Keeping Up with Clinical Advances: Opioid Use Disorder.

Opioid use disorder (OUD) is a disorder that can lead to several negative outcomes, including overdose and death. A variety of opioids can be abused by individuals including both prescribed and non-prescribed opioids. Continued opioid use can be driven by negative affective states associated with opioid withdrawal. Several treatments exist in the field including medication assisted treatments such as methadone, buprenorphine, and naltrexone. Treatments such as clonidine and lofexidine can also be used to assist with decreasing withdrawal symptoms. Increasing adherence to treatment can further improve patient outcomes and promote continuation with treatment. A variety of methods to reduce relapse can also be utilized such as opioid agonists and maintenance therapy. According to the Centers for Disease Control, opioid overdoses contributed to 67.8% of overdose deaths in 2017.

Pharmacogenetics of Dopamine ß-Hydroxylase in cocaine dependence therapy with doxazosin.

The α1 -adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine ß-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DßH's conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DßH levels. This 12-week, double-blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DßH levels from the DBH CC genotype and 27 with lower DßH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29) and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T-allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41 percent from baseline in the CT/TT group with low DßH and NE levels, as compared with no net reduction in the CC genotype group with normal DßH and NE levels. The DBH polymorphism appears play an important role in CUD patients' response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine.

Review article: Effective management of opioid withdrawal symptoms: A gateway to opioid dependence treatment.

BACKGROUND AND OBJECTIVES: The opioid crisis has taken an immense toll in the United States. On average, five lives are lost to an opioid overdose every hour of the day; estimated costs associated with opioid misuse exceed $500 billion annually. Illicit opioid discontinuation is the first step in the treatment of opioid use disorder (OUD), and transition to an opioid agonist may initiate treatment. However, discontinuation to abstinence from either OUD directly or following agonist treatment results in severely distressing opioid withdrawal symptoms (OWS). METHODS: This review evaluated studies on the etiology, burden, and management of OWS. RESULTS: Noradrenergic hyperactivity generates many OWS. These OWS can cause patients to relapse during early opioid discontinuation. While agonist therapies are generally first-line for moderate or severe OUD and reduce OWS, prescribing restrictions can limit their availability. DISCUSSION AND CONCLUSIONS: Non-opioid medications to treat OWS provides a gateway into long-term treatment with naltrexone or psychosocial therapies. For opioid dependent patients without OUD, non-opioid treatments like α-2 adrenergic agonists can facilitate opioid tapering. SCIENTIFIC SIGNIFICANCE: For the millions who are physically dependent on opioids, new treatments for OWS can enhance recovery from OUD and prevent relapse. (© 2019 The Authors. The American Journal on Addictions Published by Wiley Periodicals, Inc.;XX:1-8).