Gut microbial diversity and functional characterization in people with alcohol use disorder: A case-control study.

Individuals with Alcohol Use Disorder (AUD) typically have comorbid chronic health conditions, including anxiety and depression disorders, increased sleep disruption, and poor nutrition status, along with gut microbial dysbiosis. To better understand the effects of gut dysbiosis previously shown in individuals with AUD, gut microbiome and metabolome were investigated between three cohorts. Two groups of individuals with AUD included treatment-seeking newly abstinent for at least six weeks (AB: N = 10) and non-treatment-seeking currently drinking (CD: N = 9) individuals. The third group was age, gender, and BMI-matched healthy controls (HC: N = 12). Deep phenotyping during two weeks of outpatient National Institutes of Health Clinical Center visits was performed, including clinical, psychological, medical, metabolic, dietary, and experimental assessments. Alpha and beta diversity and differential microbial taxa and metabolite abundance of the gut microbiome were examined across the three groups. Metabolites derived from the lipid super-pathway were identified to be more abundant in the AB group compared to CD and HC groups. The AB individuals appeared to be most clinically different from CD and HC individuals with respect to their gut microbiome and metabolome. These findings highlight the potential long-term effects of chronic alcohol use in individuals with AUD, even during short-term abstinence.

A Novel Method for Deriving Adverse Event Prevalence in Randomized Controlled Trials: Potential for Improved Understanding of Benefit-Risk Ratio and Application to Drug Labels.

INTRODUCTION: Adverse event (AE) data in randomized controlled trials (RCTs) allow quantification of a drug's safety risk relative to placebo and comparison across medications. The standard US label for Food and Drug Administration-approved drugs typically lists AEs by MedDRA Preferred Term that occur at ≥ 2% in drug and with greater incidence than in placebo. We suggest that the drug label can be more informative for both patients and physicians if it includes, in addition to AE incidence (percent of subjects who reported the AE out of the total subjects in treatment), the absolute prevalence (percent of subject-days spent with an AE out of the total subject-days spent in treatment) and expected duration (days required for AE incidence to be reduced by half). We also propose a new method to analyze AEs in RCTs using drug-placebo difference in AE prevalence to improve safety signal detection. METHODS: AE data from six RCTs in schizophrenia were analyzed (five RCTs of the dopamine D2 receptor-based antipsychotic lurasidone and one RCT of the novel trace amine-associated receptor 1 [TAAR1] agonist ulotaront). We determined incidence, absolute prevalence, and expected duration of AEs for lurasidone and ulotaront vs respective placebo. We also calculated areas under the curve of drug-placebo difference in AE prevalence and mean percent contribution of each AE to this difference. RESULTS: A number of AEs with the same incidence had different absolute prevalence and expected duration. When accounting for these two parameters, AEs that did not appear in the 2% incidence tables of the drug label turned out to contribute substantially to drug tolerability. The percent contribution of a drug-related AE to the overall side effect burden increased the drug-placebo difference in AE prevalence, whereas the percent contribution of a placebo-related AE decreased such difference, revealing a continuum of risk between drug and placebo. AE prevalence curves for drug were generally greater than those for placebo. Ulotaront exhibited a small drug-placebo difference in AE prevalence curves due to a relatively low incidence and short duration of AEs in the ulotaront treatment arm as well as the emergence of disease-related AEs in the placebo arm. CONCLUSION: Reporting AE absolute prevalence and expected duration for each RCT and incorporating them in the drug label is possible, is clinically relevant, and allows standardized comparison of medications. Our new metric, the drug-placebo difference in AE prevalence, facilitates signal detection in RCTs. We piloted this metric in RCTs of several neuropsychiatric indications and drugs, offering a new way to compare AE burden and tolerability among treatments using existing clinical trial information.

Investigating the relationship between early life adversity, inflammation and alcohol use.

Early life adversity (ELA) has long-lasting and potentially harmful effects on adult mental and physical health, including a higher likelihood of developing psychiatric conditions such as depression, anxiety and alcohol use disorder (AUD). It has been suggested that inflammation may play a role in linking ELA to the development of AUD. Here, we evaluated a number of predictive factors of high sensitivity C-reactive protein (hsCRP), a key inflammatory marker, and the potential mediating role of hsCRP in the relationship between ELA and alcohol misuse in adulthood. Data was collected from participants who participated in NIAAA screening protocols between January 2013 and December 2019. In this secondary analysis, we first tested, via multiple linear regression, potential predictors of hsCRP levels among adults with AUD (N = 781) and non-AUD (N = 440) individuals. We subsequently conducted mediation analyses to evaluate the potential role of hsCRP in the relationship between early life stress and alcohol use. Regression analysis showed that stress in early life, but not childhood trauma, significantly predicted increased hsCRP levels in adulthood (p < 0.05). Additionally, a greater amount of alcohol drinking, but not a diagnosis of AUD, significantly predicted increased hsCRP levels (p < 0.05). Furthermore, hsCRP mediated the relationship between early life stress and alcohol consumption. Early life stress and heavier alcohol drinking both predicted increased hsCRP levels; however, an AUD diagnosis did not. Elevated inflammation, due to and/or predicted by greater early life stress, may contribute to the development of unhealthy alcohol use in adulthood.

Therapeutic Drug Monitoring of Antidepressants: An Underused but Potentially Valuable Tool in Primary Care.

Depressive disorders are among the most burdensome diseases globally in terms of prevalence, as well as in terms of quality of life, morbidity, and mortality. Hence, it is becoming increasingly common for primary care physicians to administer and monitor the treatment of individuals affected by depressive disorders. In this framework, Therapeutic Drug Monitoring (TDM) comes to the forefront. TDM is the measurement of specific drugs in the blood or plasma/serum, and its usefulness lies in the fact that it allows physicians to assess drug levels to personalize and optimize treatments. TDM has been used for decades to measure several classes of psychotropic drugs, such as antiepileptics and antipsychotics, but the use of this tool is still in its infancy in regard to antidepressants. In the context of primary care, TDM of antidepressant drug treatment shows promise, as it can enable primary care physicians to monitor the safety and efficacy of the treatment, leaving to secondary care, i.e., psychiatrists, the management of the more complex clinical cases.

Anabolic androgenic steroids used as performance and image enhancing drugs in professional and amateur athletes: Toxicological and psychopathological findings.

OBJECTIVE: The use of anabolic androgenic steroids (AASs) as performance and image enhancing drugs (PIEDs), once restricted to professional athletes, now includes amateurs and regular gym visitors. AAS use is associated with psychopathology, yet this relationship is complex and not fully understood. We aimed to assess the presence of AASs and other misused substances in athletes' biological samples and link toxicological to psychopathological findings. METHODS: A multicentre, cross-sectional study in fitness centres in Italy recruited 122 professional and amateur athletes training in several sports (84 men; age range = 18-45 years). Athletes completed questionnaires, interviews, and toxicology testing for AASs, other PIEDs, illicit drugs, and non-prescribed psychotropics. Toxicology was conducted in blood, urine, and hair. RESULTS: Self-reported and toxicologically detected use rates of AASs and other misused substances showed slight-to-fair agreement (Fleiss' κ = 0.104-0.375). There was slight-to-moderate agreement among the three biological samples used for AAS testing (κ = 0.112-0.436). Thirty-one athletes (25.4%) tested positive for AASs. More sport hours/week, narcissistic or antisocial personality disorders, and higher nonplanning impulsiveness scores predicted AAS use (pseudo-R2  = 0.665). AAS users did not differ significantly from non-users in major psychopathology, but their Hypomania Checklist-32 score, which also predicted AAS use, was significantly higher (p < 0.001), suggesting increased odds for cyclothymic disorder or subthreshold hypomania. CONCLUSIONS: Our results have implications for studying AAS users, as they identify a cluster of variables that may be relevant in future understanding of AAS use risks (e.g., personality disorders). Possible disagreements between AAS assessment methods should be considered when implementing harm reduction interventions, such as needle and syringe distribution, health education, and counselling, as well as surveillance programmes.

Effects of body weight, smoking status, and sex on plasma concentrations of once-monthly paliperidone palmitate.

OBJECTIVES: Knowledge about the impact of body composition features on pharmacokinetics of newer long-acting injectable antipsychotics is limited. METHODS: We analyzed steady-state plasma concentrations of paliperidone in different body mass index (BMI), age, sex, and smoking status patient subgroups treated with once-monthly paliperidone palmitate (PP1M). Paliperidone plasma concentrations and dose-adjusted-plasma concentrations (C/D) from a therapeutic drug monitoring (TDM) database of PP1M-treated patients were compared among normal BMI, overweight, and obese patients as well as between females vs. males, elderly vs. non-elderly, and smokers vs. non-smokers using non-parametric tests. RESULTS: In a total of 183 PP1M-treated patients, we found highly variable paliperidone plasma concentrations between individuals but no significant effect of PP1M dose or dosing intervals (p> 0.05). C/D ratios were similar in 54 obese, 82 overweight, and 47 normal BMI patients (p> 0.05). Females had 13.7% higher C/D ratios compared to males, yet this difference was not significant (p> 0.05). No differences were found between elderly vs. non-elderly patients or for smokers vs. non-smokers (p> 0.05). CONCLUSION: Our findings suggest that age, sex, smoking, or body weight may not substantially affect pharmacokinetic indices of PP1M. The high interindividual variation of plasma concentrations implies that TDM may be helpful to enhance PP1M efficacy and tolerability.

A systematic review of caffeine-related suicides and an analysis of the controversial role of caffeine consumption in suicidal risk.

Caffeine is the most widely consumed psychoactive compound worldwide. Its mechanisms of action are dose-dependent and when caffeine overdosing occurs, neurologic, cardiovascular and renal systems are mainly affected. Serious toxicities such as seizure and cardiac arrhythmias, seen with caffeine plasma concentrations of 15 mg/L or higher, have caused poisoning or, rarely, death. Caffeine concentrations of 80-100 mg/L are considered lethal. The aim of this systematic review is to summarize data regarding suicides by caffeine administration and analyze the controversial role of caffeine assumption and suicidal risk. We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) indications in the identification and selection of studies and reviewed a series of fatal cases due intentional intoxication by caffeine. A total of 36 cases have been identified. Our results suggests caffeine seems to be negatively correlated with suicide. Even if some observations suggested that the consumption of caffeine may have beneficial effects against depression, and as a consequence against suicide risk, more in-depth studies are required. Data obtained from our study could support both clinicians and forensic pathologists in identifying possible unrecognized cases.

Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking.

A relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p's < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p's < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.

Are carboxyhaemoglobin levels and distance of the corpse from the site of explosion linked? Results from the retrospective analysis of a terroristic attack.

We present a retrospective analysis of a terrorist attack with incendiary grenades. We tried to analyse the correlation between carboxyhaemoglobin levels and distance of the corpse from the explosion site to check whether there is a direct relationship between them. In most fatal cases caused by grenade explosions reported in literature, death results from disruptive injuries or following multiorgan complications of the trauma, but here the terrorists used incendiary grenades causing serious burns to the victims with flames at the site of explosion. As a result, the external injuries were not fatal for most victims, especially those further from the explosion site where the flames and carbon monoxide from the fire played a significant role in causing death. The convergence of circumstantial data, autopsy results, and toxicological data led us to conclude that a direct link between the carboxyhaemoglobin level and distance from the site of explosion could not be made. Understanding the limitation of the value of linking such data is important both for police and forensic pathologists as this can reduce potential errors in reconstructing the dynamics of the event.

Effect of intravenous ghrelin administration, combined with alcohol, on circulating metabolome in heavy drinking individuals with alcohol use disorder.

BACKGROUND: Ghrelin may influence several alcohol-related behaviors in animals and humans by modulating central and/or peripheral biological pathways. The aim of this exploratory analysis was to investigate associations between ghrelin administration and the human circulating metabolome during alcohol exposure in nontreatment seeking, heavy drinking individuals with alcohol use disorder (AUD). METHODS: We used serum samples from a randomized, crossover, double-blind, placebo-controlled human laboratory study with intravenous (IV) ghrelin or placebo infusion in two experiments. During each session, participants received a loading dose (3 µg/kg) followed by continuous infusion (16.9 ng/kg/min) of acyl ghrelin or placebo. The first experiment included an IV alcohol self-administration (IV-ASA) session and the second experiment included an IV alcohol clamp (IV-AC) session, both with the counterbalanced infusion of ghrelin or placebo. Serum metabolite profiles were analyzed from repeated blood samples collected during each session. RESULTS: In both experiments, ghrelin infusion was associated with an altered serum metabolite profile, including significantly increased levels of cortisol (IV-ASA q-value = 0.0003 and IV-AC q < 0.0001), corticosterone (IV-ASA q = 0.0202 and IV-AC q < 0.0001), and glycochenodeoxycholic acid (IV-ASA q = 0.0375 and IV-AC q = 0.0013). In the IV-ASA experiment, ghrelin infusion increased levels of cortisone (q = 0.0352) and fatty acids 18:1 (q = 0.0406) and 18:3 (q = 0.0320). Moreover, in the IV-AC experiment, ghrelin infusion significantly increased levels of glycocholic acid (q < 0.0001) and phenylalanine (q = 0.0458). CONCLUSION: IV ghrelin infusion, combined with IV alcohol administration, was associated with increases in the circulating metabolite levels of corticosteroids and glycine-conjugated bile acids, among other changes. Further research is needed to understand the role that metabolomic changes play in the complex interaction between ghrelin and alcohol.

Pharmacokinetic Correlates of Once-Monthly Paliperidone Palmitate-Related Adverse Drug Reactions.

OBJECTIVE: The objective of this study was to investigate associations between pharmacokinetic correlates and once-monthly paliperidone palmitate (PP1M)-related adverse drug reactions (ADRs). METHODS: Plasma concentrations and dose-adjusted plasma concentrations ('concentration-by-dose' [C/D]) of paliperidone from a naturalistic therapeutic drug monitoring database of PP1M-treated patients were compared between patients with ADRs, classified according to the Udvalg for Kliniske Undersogelser side-effect rating scales categories, and patients without ADRs. Analyses included non-parametric tests and a logistic regression model with a significance level set at 0.05. RESULTS: In 172 patients, we found no differences in sex, age, smoking, body mass index, PP1M dose, paliperidone plasma concentrations, and C/D values (p > 0.05) between 44 patients with and 128 patients without PP1M-related ADRs. We did not detect differences when specifying for different types of ADRs (p > 0.05). Injection intervals were shorter in patients with vs patients without ADRs (p = 0.03). The logistic regression did not report effects for sex, plasma concentrations, or C/D values (p > 0.05). Post hoc analyses in male patients receiving PP1M every 28 weeks reported higher paliperidone concentrations and C/D values in patients with vs without ADRs (p = 0.049 and p = 0.022). Within the group of male patients, we found an odds ratio of 3.07 for PP1M-associated ADRs in patients with C/D values above 7.7 (ng/mL)/(mg/day). CONCLUSIONS: Our findings did not reveal distinct patterns of paliperidone concentrations in patients with PP1M-related ADRs. However, male patients receiving PP1M every 28 days with C/D values higher than 7.7 (ng/mL)/(mg/day) showed a higher risk for ADRs, implying that therapeutic drug monitoring may be useful in assessing the risk of PP1M-related ADRs.

Clinical response in patients treated with once-monthly paliperidone palmitate: analysis of a therapeutic drug monitoring (TDM) database.

To investigate pharmacokinetic correlates of clinical response in patients treated with once-monthly paliperidone palmitate (PP1M) injections at steady state. Plasma concentrations and dose-adjusted-plasma concentrations (C/D) of paliperidone from a naturalistic therapeutic drug monitoring (TDM) database were compared between responders and non-responders using the Clinical Global Impressions-Improvement scale (CGI-I) ratings. Analyses were based on the non-parametric Mann-Whitney U test and the Pearson Chi-squared test (χ2) with a significance level of 0.05. Subgroup analyses were performed separately in patients with schizophrenia spectrum, schizoaffective disorders and bipolar disorders. Comparing 93 responders with 80 non-responders, we detected no significant differences in the proportion of females, age, and body mass index (p's ranging 0.18-0.83); there were more smokers in the group of non-responders (p = 0.04), which also included more patients with bipolar disorders (p = 0.014). Despite the lack of differences for prescribed PP1M doses and dose intervals (p = 0.42 and p = 0.11, respectively), non-responders had higher paliperidone plasma concentrations and C/D levels (p = 0.033 and p = 0.021, respectively). Subgroup analyses did not yield differences for paliperidone plasma and C/D levels between non-responders and responders with schizophrenia spectrum (p = 0.099 and p = 0.14, respectively) and bipolar disorders (p = 0.95 and p = 0.75, respectively); dose-adjusted plasma concentrations were higher in non-responders compared to responders with schizoaffective disorders (p = 0.039), while no differences were reported for plasma levels (p = 0. 15). Our results show that paliperidone plasma concentrations over injection doses may be associated with patterns of clinical response suggesting potential utility of TDM as part of PP1M-based maintenance treatment.

Cardiovascular Consequences of Excessive Alcohol Drinking via Electrocardiogram: A Systematic Review.

ABSTRACT: There is a link between excessive alcohol drinking and an increased risk to develop cardiovascular disease, including alcoholic cardiomyopathy. This association warrants further research on the potential utility for the electrocardiogram (ECG) in the participatory management of the chronic consequences of alcohol use disorder (AUD). Our goal is to enhance understanding about the pernicious role alcohol plays on cardiac health using the ECG, an accessible, cost-effective, validated tool to inform novel targeted treatments for AUD. In this systematic review of human studies, we examine the relationship between abnormal clinically significant changes to ECG variables and excessive alcohol drinking with the goal of identifying key patterns specific to quantity of alcohol consumed. Three independent reviewers and one consensus reviewer, adhering to the PRISMA guidelines, conducted an initial review on studies published from database inception to April 19, 2019, using PubMed, Embase, CINAHL and COCHRANE databases. The initial search generated 2,225 articles. The final selected number included 153 original articles. This systematic review provides evidence of patterns of clinically significant changes to ECG variables as a consequence of excessive alcohol consumption. Future directions include investigating whether a real-time assessment, such as the ECG, in conjunction with other key behavioral and cardiac measures, can help clinicians and patients realize the progressive and insidious cardiac damage because of excessive alcohol consumption. This theory-guided nurse science review supports the development of personalized symptom monitoring to deliver tailored feedback that illuminate risk factors as a potentially transformative approach in the management of AUD.

Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotic Drugs.

BACKGROUND: The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, and in maintenance treatment. METHODS: The authors critically reviewed 3 types of data: (1) positron emission tomography data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, (2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and (3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics. RESULTS: Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations because these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including comedications and comorbidities. Reported data combined with positron emission tomography evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges. CONCLUSIONS: Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.

Lack of Smoking Effects on Pharmacokinetics of Oral Paliperidone-analysis of a Naturalistic Therapeutic Drug Monitoring Sample.

INTRODUCTION: Major smoking effects have been reported for a series of psychotropic agents, mainly including substrates of CYP450 1A2, although smoking may also affect alternative metabolic pathways. To our knowledge, smoking effects on paliperidone pharmacokinetics have not been assessed yet. METHODS: We compared plasma concentrations of paliperidone as well as dose-corrected-plasma concentrations (C/D) from a naturalistic database between smokers and nonsmokers using nonparametrical tests, such as the Mann-Whitney U-test (MWU). Additionally, we compared light and heavy smokers with nonsmokers separately. RESULTS: Comparing 55 smokers with 37 nonsmokers treated with oral paliperidone, no differences in the percentage of females, age, body weight, body mass index, and daily paliperidone dose were reported (p=0.709 for χ2, p=0.26, p=0.38, p=0.67, and p=0.8 for MWU). No differences were detected in plasma concentrations or C/D values (p=0.50 and p=0.96 for MWU). Likewise, differences in daily dose, plasma concentrations, or C/D values were not significant between light smokers (n=17) and nonsmokers (p=0.61, p=0.81, and p=0.33 for MWU) or heavy smokers (n=22) and nonsmokers (p=0.874, p=0.38, and p=0.59; MWU in all cases). DISCUSSION: Paliperidone is not affected by smoking, and paliperidone dose-adjustments in smokers may not be necessary. This may be seen as an essential difference to risperidone, whose cytochrome-mediated metabolism might be affected by smoking.

Efficacy of nicotine administration on obsessions and compulsions in OCD: a systematic review.

BACKGROUND: Preliminary studies have tested nicotine as a novel treatment for OCD patients who respond partially/incompletely or not at all to first and second-line treatment strategies, with the former represented by SSRIs or clomipramine, and the latter by switching to another SSRI, or augmentation with atypical antipsychotics, and/or combination with/switching to cognitive-behavioural therapy. Some studies found nicotine-induced reduction of obsessive thoughts and/or compulsive behaviour in OCD patients. We aimed to evaluate the efficacy of nicotine administration in OCD patients. METHODS: We searched the PubMed, ScienceDirect Scopus, CINHAL, Cochrane, PsycINFO/PsycARTICLES, and EMBASE databases from inception to the present for relevant papers. The 'Preferred Reporting Items for Systematic Review and Meta-Analyses' (PRISMA) standards were used. We included all studies focusing on the effects of nicotine administration on OCD patients' obsessions or compulsions. Studies could be open-label, cross-sectional, randomized controlled trials, case series or case reports. RESULTS: A total of five studies could be included. Nicotine administration may ameliorate behavioural features and recurrent thoughts of severe, treatment-resistant OCD patients; however, in one study it was not associated with OC symptom improvement or cognitive enhancement across various executive function subdomains. CONCLUSIONS: Although encouraging, the initial positive response from the use of nicotine in OCD needs testing in large controlled studies. This, however, raises ethical issues related to nicotine administration, due to its addiction potential, which were not addressed in the limited literature we examined. As an alternative, novel treatments with drugs able to mimic only the positive effects of nicotine could be implemented.

Differences in Sociodemographic and Alcohol-Related Clinical Characteristics Between Treatment Seekers and Nontreatment Seekers and Their Role in Predicting Outcomes in the COMBINE Study for Alcohol Use Disorder.

BACKGROUND: One of the challenges in early-stage clinical research aimed at developing novel treatments for alcohol use disorder (AUD) is that the enrolled participants are heavy drinkers, but do not seek treatment for AUD. AIMS: To compare nontreatment seekers with alcohol dependence (AD) from 4 human laboratory studies conducted at Brown University (N = 240; 65.4% male) to treatment seekers with AD from the multisite COMBINE study (N = 1,383; 69.1% male) across sociodemographic and alcohol-related clinical variables and to evaluate whether the variables that significantly differentiate the 2 samples predict the 3 main COMBINE clinical outcomes: time to relapse, percent days abstinent (PDA), and good clinical outcome. METHODS: Sample characteristics were assessed by parametric and nonparametric testing. Three regression models measured the association between the differing variables and the 3 main COMBINE clinical outcomes. RESULTS: The nontreatment seekers, compared to the treatment seekers, were more ethnically diverse, less educated, single, and working part-time or unemployed (p's < 0.05); they met fewer DSM-IV AD criteria and had significantly lower scores on alcohol-related scales (p's < 0.05); they were less likely to have a father with alcohol problems (p < 0.0001) and had a significantly earlier age of onset and longer duration of AD (p's < 0.05); they also had significantly more total drinks, drinks per drinking day, heavy drinking days (HDD), and lower PDA in the 30 days prior to baseline (p's < 0.0001 to <0.05). Having more HDD in the 30 days prior to baseline predicted all of the 3 COMBINE clinical outcomes. All the other characteristics mentioned above that differed significantly between the 2 groups predicted at least 1 of the 3 COMBINE clinical outcomes, except for level of education, age of onset, and duration of AD. CONCLUSIONS: The observed differences between groups should be considered in efforts across participant recruitment at different stages of the development of new treatments for AUD.

A systematic review of radiological and histological findings of septic myocardial calcifications.

Myocardial calcification is a life-threatening condition that is a recognised complication of ischaemic heart disease, cardiac surgery, rheumatic fever, myocarditis and sepsis. Only sparse data, reporting the clinical symptoms, the anatomo-pathological findings, the imaging findings have been published and no exhaustive analysis of all these factors exists in literature. To date, there have been 26 published cases in the medical literature in which myocardial calcifications is the consequence of a septic status. In this review, we will describe the main imaging and histological findings, with particular attention to the known and hypothesized mechanisms of myocardial calcifications. The results of this study may help clinicians and forensic pathologists to identify possible unrecognized cases and inspire the development of an international registry by which to coordinate further research.

Methylphenidate challenge test in adults with attention deficit/hyperactivity disorder (ADHD): Clinical effects and their predictors.

OBJECTIVE: Adult and children attention deficit/hyperactivity disorder (ADHD) share similar symptoms and responses to drugs such as methylphenidate (MPH). Yet, in Europe, these drugs remain unlicensed for adults. We aimed to assess the effects of an acute MPH challenge on the four dimensions concentration, impulsivity, tension, and general well-being in ADHD adults, and identify predictors of improvement. METHODS: Therapeutic Drug Monitoring was performed to measure MPH plasma levels. A Visual Analogue Scale was administered to patients before and after the acute MPH challenge to measure self-reported changes in the four dimensions. RESULTS: After the acute MPH challenge, our 71 patients showed significant improvement in concentration and tension. The MPH challenge dose correlated with lower patients' age, greater side effects, increased concentration (p = .008) and decreased tension (p = .001). At multiple linear regression MPH plasma levels and absence of postdose side effects predicted concentration improvement, MPH plasma levels predicted tension improvement. MPH plasma levels were significantly higher in patients who reported an improvement in concentration, tension, and impulsivity compared to nonimprovers (p's from .001 to .004). CONCLUSIONS: These findings point to the efficacy of MPH challenge in improving concentration and tension in adult ADHD, thus emphasizing the need for a broader treatment access for these patients.

Blood Levels to Optimize Antipsychotic Treatment in Clinical Practice: A Joint Consensus Statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie.

OBJECTIVE: The quantification of antipsychotic levels in blood, also known as therapeutic drug monitoring (TDM), is a potentially useful tool of modern personalized therapy that can be applied to augment antipsychotic use and dosing decisions. The application of TDM for antipsychotics can be helpful in numerous challenging clinical scenarios, such as lack of therapeutic response, relapse, or adverse drug reactions (ADRs) related to antipsychotic treatment. The benefits of TDM may be particularly evident in the treatment of highly vulnerable patient subgroups, such as children, adolescents, pregnant women, and the elderly. The main aim of this article is to aid clinicians who routinely prescribe antipsychotics to successfully apply TDM in routine clinical practice in order to help optimize the efficacy and safety of those antipsychotics. PARTICIPANTS: Participants were clinicians and researchers, members of the American Society of Clinical Psychopharmacology, and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association of Neuropsychopharmacology and Pharmacopsychiatry). EVIDENCE: TDM literature on antipsychotics was critically reviewed to provide a condensed clinical decision-making algorithm with therapeutic reference ranges for blood antipsychotic levels, within which patients are most likely to respond and tolerate treatment, although TDM is not equally recommended/supported for all antipsychotics. CONSENSUS PROCESS: A preliminary draft was prepared and circulated to the writing group members. Consensus was achieved in all cases, and resulting recommendations focused on following areas: steady-state and sampling time, levels of recommendations, indications, therapeutic reference ranges and laboratory alert levels, practical issues, and interpretation, as well as limitations. CONCLUSIONS: The utilization of TDM as a tool for problem solving in antipsychotic treatment offers a unique method to improve safety and efficacy. This consensus statement summarizes essential information on the routine use of TDM for antipsychotics and encourages clinicians to perform TDM with the appropriate indications as part of the clinical decision-making process.