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Chlorprothixene is commonly used off-label in low doses for sedative-hypnotic purposes although it might carry a risk of cardiometabolic adverse events due to its pharmacodynamic profile. We investigated the risk of diabetes and major adverse cardiovascular events (MACE) with use of low-dose chlorprothixene, compared with use of low-dose quetiapine in a nationwide cohort study, including all new users of low-dose chlorprothixene (n = 81 328) and low-dose quetiapine (n = 91 163) in Denmark 2000–2017. Main outcomes were diabetes and MACE (myocardial infarction, stroke and death from cardiovascular causes). The association between cumulative dose of chlorprothixene and the outcomes was tested in a case–control analysis. Low-dose chlorprothixene use was associated with increased risk of diabetes (intention-to-treat [ITT]-hazard ratio [HR]: 1.16; 95% CI: 1.08–1.25), compared with low-dose quetiapine use. This association strengthened when follow-up was restricted to time on treatment (as-treated [AT]-HR: 1.34; 95% CI: 1.14–1.56). Low-dose chlorprothixene use was also associated with increased risk of MACE (ITT-HR: 1.12; 95% CI: 1.04–1.21) and stroke (ITT-HR: 1.21; 95% CI: 1.06–1.37) but not with myocardial infarction (ITT-HR: 1.11; 95% CI: 0.95–1.30) nor death from cardiovascular causes (ITT-HR: 1.07; 95% CI: 0.96–1.20). Cumulative dose of chlorprothixene ≥6000 mg was associated with increased risk of diabetes (OR: 1.15–1.63; test for trend: p < 0.001), whereas cumulative dose of chlorprothixene ≥1500 mg was associated with increased risk of MACE (OR: 1.10–1.85; test for trend: p < 0.001). In conclusion, low-dose chlorprothixene use is associated with increased risk of cardiometabolic adverse events compared with low-dose quetiapine use.

Drug, alcohol and tobacco use disorders are a global burden affecting millions of people. Despite decades of research, treatment options are sparse or missing, and relapse rates are high. Glucagon-like peptide 1 (GLP-1) is released in the small intestine, promotes blood glucose homeostasis, slows gastric emptying and reduces appetite. GLP-1 receptor agonists approved for treating Type 2 diabetes mellitus and obesity have received attention as a potential anti-addiction treatment. Studies in rodents and non-human primates have demonstrated a reduction in intake of alcohol and drugs of abuse, and clinical trials have been initiated to investigate whether the preclinical findings can be translated to patients. This review will give an overview of current findings and discuss the possible mechanisms of action. We suggest that effects of GLP-1 in alcohol and substance use disorders is mediated centrally, at least partly through dopamine signalling, but precise mechanisms are still to be uncovered. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Purpose/background The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). Methods/procedures Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. Findings/results One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. Implications/conclusions Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

Clinical studies report preliminary therapeutic effects of classic psychedelic drugs in several psychiatric conditions and international drug trends show increased use of these compounds. However, the epidemiology of classic psychedelic drug use in Scandinavian countries remains sparsely investigated. To this end, we investigated the patterns of use and the subjectively perceived acute and persisting effects of lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), and mescaline, among Danish adults.An anonymous online survey with 152 items was conducted using the secure survey web application REDCap. Results were presented descriptively and as comparisons between psychedelic drugs.Five-hundred participants (30.0% female, mean age 34.5 years) were included. Classic psychedelics were mostly used with therapeutic (28.0%) or spiritual (27.2%) intentions. Sixty-seven per cent used classic psychedelics once a year or less. Most participants (56.4%) preferred using psilocybin. Classic psychedelic use was for some individuals, associated with hazardous use of alcohol (39.4%). Among participants with a psychiatric treatment history, 80.9% reported subjective improvements in symptoms following classic psychedelic use. Participants' most memorable experiences were moderate-to-strong mystical-type experiences (MEQ30 mean ± SD 3.4 ± 1.0; range 1-5) and had positive persisting effects on well-being (mean ± SD 2.1 ± 1.0), social relationships (mean ± SD 1.7 ± 1.2), meaning of life (mean ± SD 1.9 ± 1.1), and mood (mean ± SD 1.8 ± 1.1); range -3 to 3. DMT users experienced significantly greater subjective positive effects.Classic psychedelics were mostly used therapeutically or spiritually and had self-reported positive persisting effects, but were also associated with hazardous use of alcohol, among Danish adults. DMT was associated with significantly greater positive effects compared to LSD and psilocybin.

IntroductionAlcohol use disorder (AUD) is a brain disorder linked to over 200 health conditions. Cognitive behavioural therapy (CBT) is considered the best practice in the treatment of AUD, but more than 60% of patients relapse within the first year after treatment. Psychotherapy combined with virtual reality (VR) has received increasing interest in the treatment of AUD. However, existing studies have primarily investigated the use of VR for cue reactivity. We therefore aimed to investigate the effect of VR-assisted CBT (VR-CBT).Methods and analysisThis study is an assessor-blinded, randomised clinical trial being conducted at three outpatient clinics in Denmark. We will randomise 102 patients to 14 individual sessions of either manualised VR-CBT or CBT. The VR-CBT group will receive exposure to immersive high-risk VR situations from a pub, bar/party, restaurant, supermarket and at-home (30 videos) to activate high-risk-related beliefs and cravings for subsequent modification using CBT techniques. The treatment period is 6 months, and follow-up visits will be performed 3, 6, 9 and 12 months after inclusion. The primary outcome measure is the change in total alcohol consumption from baseline to 6 months after inclusion, measured with the Timeline Followback Method. Key secondary outcome measures include changes in the number of heavy drinking days, alcohol cravings, cognition, and symptoms of depression and anxiety.Ethics and disseminationApproval has been obtained by the research ethics committee in the Capital Region of Denmark (H-20082136) and the Danish Data Protection Agency (P-2021-217). All patients will receive both oral and written information about the trial and written informed consent will be obtained from each patient before inclusion. The study results will be disseminated in peer-reviewed publications and conference presentations.Trial registration numberClinicalTrial.gov,NCT05042180.

Rationale: After alcohol ingestion, the brain partly switches from consumption of glucose to consumption of the alcohol metabolite acetate. In heavy drinkers, the switch persists after abrupt abstinence, leading to the hypothesis that the resting brain may be “starved” when acetate levels suddenly drop during abstinence, despite normal blood glucose, contributing to withdrawal symptoms. We hypothesized that ketone bodies, like acetate, could act as alternative fuels in the brain and alleviate withdrawal symptoms. Objectives: We previously reported that a ketogenic diet during alcohol exposure reduced acute withdrawal symptoms in rats. Here, our goals were to test whether (1) we could reproduce our findings, in mice and with longer alcohol exposure; (2) ketone bodies alone are sufficient to reduce withdrawal symptoms (clarifying mechanism); (3) introduction of ketogenic diets at abstinence (a clinically more practical implementation) would also be effective. Methods: Male C57BL/6NTac mice had intermittent alcohol exposure for 3 weeks using liquid diet. Somatic alcohol withdrawal symptoms were measured as handling-induced convulsions; anxiety-like behavior was measured using the light-dark transition test. We tested a ketogenic diet, and a ketone monoester supplement with a regular carbohydrate-containing diet. Results: The regular diet with ketone monoester was sufficient to reduce handling-induced convulsions and anxiety-like behaviors in early withdrawal. Only the ketone monoester reduced handling-induced convulsions when given during abstinence, consistent with faster elevation of blood ketones, relative to ketogenic diet. Conclusions: These findings support the potential utility of therapeutic ketosis as an adjunctive treatment in early detoxification in alcohol-dependent patients seeking to become abstinent. Trial registration: clinicaltrials.gov NCT03878225, NCT03255031

The muscarinic cholinergic M

Animal studies have related glucagon-like peptide 1 receptor agonists (GLP-1) to lower alcohol intake. We examined whether GLP-1 was associated with risk of alcohol-related events in a nationwide cohort study and a self-controlled case series analysis including all new users of GLP1 (n = 38 454) and dipeptidyl peptidase 4 inhibitors (DPP4) (n = 49 222) in Denmark 2009-2017. They were followed for hospital contacts with alcohol use disorder or purchase of drugs for treatment of alcohol dependence in nationwide registers from 2009 to 2018. Associations were examined using Cox proportional hazard and conditional Poisson regression. During follow-up of median 4.1 years, 649 (0.7%) of participants were registered with an alcohol-related event. Initiation of GLP-1 treatment was associated with lower risk of an alcohol-related event (Hazard ratio = 0.46 (95%CI: 0.24-0.86) compared with initiation of DPP4 during the first 3 months of follow-up. Self-controlled analysis showed the highest risk of alcohol-related events in the 3-month pretreatment period (incidence rate ratio [IRR] = 1.25 (1.00-1.58)), whereas the risk was lowest in the first 3-month treatment period (IRR = 0.74 (0.56-0.97). In conclusion, compared with DPP4 users, individuals who start treatment with GLP-1 had lower incidence of alcohol-related events both in cohort and self-controlled analyses. Thus, there might be a transient preventive effect of GLP1 on alcohol-related events the first months after treatment initiation.

The muscarinic cholinergic M4 receptor subtype (M4 mAChR) is densely expressed in brain areas known to be involved in the reinforcing effects of drugs of abuse and we were the first to show that mice lacking M4 mAChRs exhibit elevated operant responding for alcohol and reduced capacity to extinguish this alcohol-seeking behaviour. Here we explore possible underlying determinants of this phenotype. We subjected M4 mAChR knockout mice and their littermate wildtype controls to tests of spontaneous activity, learning and memory, novelty seeking, as well as anxiety and examined the relationship of a newly discovered “disinhibited” endophenotype of these mice with voluntary alcohol consumption and relapse. We found a positive correlation between “disinhibited” behaviour on the plus maze and alcohol preference as well as relapse to alcohol drinking after a period of abstinence. Taken together, these data point to M4 mAChRs as a potential target for improved treatment strategies for alcohol use disorder. This receptor should be further investigated for its involvement in modulating behavioural inhibition in relation to loss of control over consumption of alcohol.

IntroductionClozapine and olanzapine are some of the most effective antipsychotics, but both are associated with weight gain and relevant metabolic disturbances, including pre-diabetes and diabetes. Non-pharmacological/behavioural interventions have had limited effects counteracting these adverse effects. Semaglutide, a glucagon-like peptide 1 receptor agonist, is approved for the treatment of type 2 diabetes and obesity. We will investigate the long-term effects of add-on treatment with semaglutide once a week versus placebo once a week on the metabolic status in pre-diabetic (glycated haemoglobin A1c (HbA1c) 35–47 mmol/mol (5.4%–6.4%) and diabetic (HbA1c 48–57 mmol/mol (6.5%–7.4%)) patients diagnosed with a schizophrenia spectrum disorder who initiated clozapine or olanzapine treatment within the last 60 months.Methods and analysisThis is a 26-week, double-blinded, randomised, placebo-controlled trial. Altogether, 104 patients diagnosed with a schizophrenia spectrum disorder, aged 18–65 years, with pre-diabetes or diabetes will be randomised to injections of 1.0 mg semaglutide once a week or placebo for 26 weeks. The primary endpoint is change from baseline in HbA1c. Secondary endpoints include changes in body weight, hip and waist circumference and plasma levels of insulin, glucagon, glucose, and C-peptide, insulin sensitivity, beta cell function, hepatic function, fibrosis-4 score, lipid profile, incretin hormones, bone markers, body composition, bone density, proteomic analyses and oxidative stress markers. Together with alcohol, tobacco and drug use, potential effects on the reward value of a sweet–fat stimulus, psychopathology, level of activity and quality of life will also be assessed.Ethics and disseminationThis study is approved by the Danish Medicines Agency and the regional scientific ethics committee of the Capital Region of Denmark (committee C, #H-20019008) and will be carried out in accordance with International Council for Harmonisation Good Clinical Practice guidelines and the Helsinki Declaration. The results will be disseminated through peer-review publications and conference presentations.Trial registration numberNCT04892199.

The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs).Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed.One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms.Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

Introduction: The antipsychotic drug clozapine remains underutilized partly because of the risk of life-threatening adverse effects, such as neutropenia. Therefore, an extensive hematological monitoring program was set up to detect neutropenia. Methods: In this retrospective cohort study, we used registry-based data from the Capital Region of Denmark to investigate incidence rates of neutropenia among patients with a diagnosis of schizophrenia or other psychotic disorders and treated with clozapine for the first time. In a within-subject design, we compared rates of neutropenia in time periods where patients were exposed to clozapine versus time periods, where they were not exposed to clozapine. We also investigated whether the lengths of clozapine-associated neutropenia (CAN) were related to discontinuation of clozapine treatment. Results: Data from 520 clozapine users were included. The incidence rate of CAN was 3.2 cases per 100 person-years (95% confidence interval [CI]: 2.1–4.8) throughout the entire study. There was no significant difference in incidence rates of neutropenia during clozapine exposure and non-clozapine exposure, with an incidence rate ratio of 0.7 (95% CI: 0.4–1.3). One episode of severe neutropenia was detected. Episodes of CAN with only one sub-threshold neutrophil count were not associated with higher clozapine discontinuation (26%) than CAN episodes of more than one sub-threshold neutrophil count (28%). Conclusion: In the present study, we could not confirm that clozapine treatment was associated with neutropenia.

Glucagon-like-peptide-1 (GLP-1)-receptor agonists have been proposed as putative treatment for substance use disorders (SUD). The objective of this systematic review is to characterize the effects of GLP-1-receptor agonists on SUD-related behavioural effects of drugs, nicotine, and alcohol. The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A search was performed in PubMed and EMBASE on June 16, 2018. The inclusion criteria were primary studies investigating the use of GLP-1-receptor agonists on behavioural endpoints related to SUD. Seventeen studies were included, investigating the effect of the GLP-1-receptor agonists exendin-4, fluoro-exendin-4, liraglutide, AC3174 and GLP-1 (7–36) on SUD-related behavioural effects of ethanol, cocaine, amphetamine, and/or nicotine. All studies used rodents as subjects. Nine of the studies dealt with ethanol, six with cocaine, two with amphetamine, and two with nicotine. Most studies investigated acute treatment effects, finding a significant effect in all but one experiment. A few studies investigated more chronic effects, but only on ethanol. All the studies reported sustained effects. Eleven studies tested more than one dose, finding a dose-related response in ten out of thirteen experiments. Six studies report a central effect through intra-cerebral administration or by using mice in which the central GLP-1-receptors had been inactivated. In conclusion, a solid body of evidence documents acute effects of GLP-1-receptor agonist treatment on behavioural effects of alcohol, nicotine, amphetamine and cocaine. Documentation of effect of more chronic GLP-1-receptor stimulation on these behaviours is limited.

Clozapine is gold standard for the management of treatment-resistant schizophrenia. It can offer life-changing symptom reduction where other antipsychotics have failed, and for these patients, treatment with clozapine should be maintained, if in any possible way. However, treatment with clozapine comes with a risk of developing potentially fatal adverse reactions, for example, severe neutropenia or agranulocytosis, in which case, treatment must be discontinued. Here, we present a case of clozapine-related neutropenia that commenced after the addition of sodium valproate. A subsequent re-challenge to clozapine resulted in severe neutropenia and led to the permanent cessation of clozapine treatment. The patient had been tolerating clozapine for more than a year before the addition of sodium valproate. The awareness of an interaction between clozapine and sodium valproate could help reduce the risk of clozapine-induced neutropenia and subsequent clozapine discontinuation.

Alcohol use disorders (AUD) often occur together with other psychiatric disorders such as affective disorders, anxiety disorders, personality disorders, drug use disorders, attention deficit and hyperkinetic disorder, post-traumatic stress disorder and psychosis. This psychiatric comorbidity is a global health problem and often not recognised and successfully treated. Increased awareness of possible AUD among psychiatric patients is needed, e.g. by use of the screening tool The Alcohol Use Disorder Identification Test, which is described in this review.

Craving is a cause of relapse in patients suffering from a substance use disorder. Cue-exposure therapy builds on eliciting feelings of craving in patients in safe and controlled environments to condition them to control these feelings. Different efficient and resource-friendly methods of eliciting craving exist, (such as written material, still pictures, etc.). However, these methods create knowledge and skill transfer gaps between therapy sessions and real life scenarios. Virtual reality allows more true-to-life experiences, and research demonstrates its capabilities in eliciting craving in patients. Studies have identified different environments that elicits craving, suggesting bars to be one of the most effective ones. Research also suggests the presence of others to be an effective method of eliciting craving in users. However, the effect of social interaction has not yet been explored. Therefore, this paper presents a virtual bar with the purpose to investigate whether social interaction affects alcohol craving in users. The VR intervention is designed with close cooperation with a psychiatrist experienced in working with individuals suffering from alcohol use disorder. In this paper, we present the designed and developed VR intervention and discuss how an experiment can be conducted after the COVID-19 shutdowns.

A ketogenic diet lowered benzodiazepine use during withdrawal in patients with AUD and blunted alcohol administration in rats., Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower “wanting” and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.

This review describes the growing research in virtual reality (VR) for healthcare purposes. In recent years, the technological improvements have expanded the possibility of investigating VR in diagnostics as well as treatment of mental and behavioural disorders. The existing literature regarding phobia, post-traumatic stress disorder, addiction, psychotic, eating and affective disorders is summarised and discussed in terms of clinical applicability.

PURPOSE/BACKGROUND: Prolonged QT interval related to psychopharmacological treatment is a risk factor for potentially life-threatening arrhythmias. Electrocardiographic measurements are recommended in patients with cardiovascular risk factors before initiating treatment with potentially QT-prolonging medications, such as certain antidepressants or antipsychotics. In patients with left bundle branch block (LBBB) or right bundle branch block (RBBB), conventional QT-estimation methods will lead to overestimation of the QT interval, as the conduction defect, reflected by the QRS duration, will increase the QT interval without representing longer repolarization as in drug-induced QT prolongation.METHODS/PROCEDURES: We conducted a systematic review of methods to estimate QT interval in the presence of LBBB or RBBB. We searched electronic databases Embase and Medline (last search, August 12, 2020).FINDINGS/RESULTS: We found 8 different methods, including linear correction formulae with and without correction for heart rate, or simpler formula correcting QRS duration with empirically derived modifiers. Only 3 of 8 methods were applicable in the presence of RBBB, whereas all 8 methods could be applied in the presence of LBBB.IMPLICATIONS/CONCLUSIONS: The QT interval is overestimated in patients with LBBB or RBBB, when using conventional measurements. Several alternative correction formulae exist, which can be applied using standard measurements from ordinary electrocardiographic readings. However, it is currently unknown whether or not the QT prolongation observed in the presence of bundle branch block significantly increases the risk of arrhythmias, as these formulae have not been tested against patient-specific clinical outcomes.

The dopamine transporter (DAT) is part of a presynaptic multi-protein network involving interactions with scaffold proteins via its C-terminal PDZ-domain binding sequence. In a mouse model expressing DAT with mutated PDZ binding sequence (DAT-AAA), we previously demonstrated the importance of this binding sequence for striatal expression of DAT. Here we show by application of direct Stochastic Reconstruction Microscopy (dSTORM) not only that the striatal level of transporter is reduced in DAT-AAA mice, but also that the nanoscale distribution of the transporter is altered with a higher propensity of DAT-AAA to localize to irregular nanodomains in dopaminergic terminals. In parallel, we observe mesostriatal dopamine (DA) adaptations and changes in DA-related behaviors different from those seen in other genetic DAT mouse models. DA levels in striatum are reduced to ∼45% of wild type (WT), accompanied by elevated DA turnover. Nonetheless, Fast-Scan Cyclic Voltammetry recordings on striatal slices reveal a larger amplitude and prolonged clearance rate of evoked DA release in DAT-AAA mice compared to WT mice. Autoradiography and radioligand binding show reduced DA D2 receptor levels while immunohistochemistry and autoradiography show unchanged DA D1 receptor levels. In behavioral experiments, we observe enhanced self-administration of liquid food under both a fixed-ratio (FR1) and progressive-ratio (PR) schedule of reinforcement, but a reduction compared to WT when using cocaine as reinforcer. Summarized, our data demonstrate how disruption of PDZ-domain interactions causes changes in DAT expression and its nanoscopic distribution that in turn alter DA clearance dynamics.

To evaluate 1) whether early nonresponse to antipsychotics predicts nonresponse and nonremission, 2) patient and illness characteristics as outcome predictors, and 3) response prediction of 30-item Positive and Negative Syndrome Scale (PANSS-30) compared with 6-item PANSS (PANSS-6) and Clinical Global Impressions-Improvement Scale (CGI-I) in youths with first-episode psychosis.Post hoc analysis from a 12-week, double-blinded, randomized trial of aripiprazole vs extended-release quetiapine in adolescents (age 12-17 years) with first-episode psychosis was performed. Early nonresponse (week 2 or week 4) was defined as 20% symptom reduction (PANSS-30) (or 20% symptom reduction [PANSS-6] or CGI-I score 4-7 [less than "minimally improved"]). Nonresponse (week 12) was defined as 50% symptom reduction (PANSS-30). Nonremission (week 12) was defined as a score of3 on 8 selected PANSS-items. Positive/negative predictive values (PPV/NPV) and receiver operating characteristics, binary logistic regression models, and PPV/NPV using PANSS-6 and CGI-I were analyzed.Of 113 randomized patients, 84 were included in post hoc analysis (mean [SD] age = 15.7 [1.3] years; 28.6% male). The 12-week symptom decrease was 31.9% [27.9%], most pronounced within the first 2 weeks (61.1% of total PANSS reduction). Response (27.4%) and remission (22.6%) rates were low. Results indicated that early nonresponse reliably predicted 12-week nonresponse (PPV: week 2, 82.2%; week 4, 90.0%) and nonremission (PPV: week 2, 80.0%; week 4, 90.0%); early nonresponse at week 4 was a statistically significant baseline predictor for 12-week nonresponse; and PANSS-6 had similar predictive significance as PANSS-30. However, outcomes were heterogeneous using CGI-I.In youths with first-episode psychosis showing early nonresponse to aripiprazole or extended-release quetiapine, switching antipsychotic drug should be considered. PANSS-6 is a feasible and clinically relevant alternative to PANSS-30 to predict 12-week nonresponse/nonremission.Tolerance and Effect of Antipsychotics in Children and Adolescents With Psychosis; https://www.gov/; NCT01119014.

BackgroundTreatment with antipsychotics is associated with an increased risk of type 2 diabetes mellitus (T2D), and increased levels of inflammatory biomarkers are present in patients with T2D. We previously demonstrated that the glucagon-like peptide-1 receptor agonist liraglutide significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. This study aims to assess the involvement of cytokines in the therapeutic effects of liraglutide.MethodsSerum concentrations of 10 cytokines (interferon-γ [IFN-γ], tumor necrosis factor-α, interleukin 1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and IL-13) from fasting prediabetic and normal glucose-tolerant (NGT) patients with schizophrenia-spectrum disorders were measured using multiplexed immunoassays. Prediabetic patients were randomized to 16 weeks of treatment with liraglutide or placebo, and cytokines were measured again at the end of the treatment.ResultsIFN-γ (1.98 vs 1.17 pg/ml, P = .001), IL-4 (0.02 vs 0.01 pg/ml, P P ConclusionPrediabetic vs NGT patients with schizophrenia treated with clozapine or olanzapine had increased serum levels of several proinflammatory cytokines, further substantiating the link between inflammation and T2D. Treatment with liraglutide did not affect the investigated cytokines. Further testing of these findings in larger numbers of individuals is needed.

Studies have consistently shown that patients with epilepsy could benefit from ketogenic diets (KDs). Recent evidence suggests that KD could be used in the treatment of central nervous system (CNS) diseases. The aim of this systematic review was to investigate the use and efficacy of KD, modified Atkins diet (MAD) and medium-chain triglyceride (MCT) diet in infants, children, adolescents, and adults with CNS diseases.This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Main databases, i.e. EMBASE, PubMed and PsycINFO, were searched on 4 December 2019. Only randomized clinical trials (RCTs) were included and only if they reported KD, MCT or MAD interventions on patients with CNS diseases.Twenty-four publications were eligible for inclusion (In conclusion, various forms of KDs seem tolerable and effective as part of the treatment for epilepsy, AD and PD, although more investigation concerning the mechanism, efficacy and adverse events is necessary.

Background: Muscarinic acetylcholine receptor 4 (M4) modulates dopaminergic neurotransmission and is a target for novel treatments of schizophrenia, cognitive deficits, and addiction. Impulsive and compulsive behaviors are key traits of addiction, yet the importance of M4 receptor signaling to these traits is poorly understood. We investigated impulsive action and compulsivity by measuring premature and perseverative responses in the five choice serial reaction time task (5CSRTT). Furthermore, we hypothesized that inter-trial interval (ITI) initiation settings affected training durations and test performances in these experiments. Methods: M4 -/- and wildtype mice were trained and tested on two versions of the 5CSRTT with different ITI initiation settings. One setting, the head-in condition, allowed the ITI to start while the mouse's head remained in the reward receptacle (magazine). The other setting, the head-out condition, required the mouse to remove its head from the magazine to initiate the ITI. Results and discussion: We did not observe differences in premature or perseverative responses in M4 -/- mice in either condition, but found evidence of reward-related compulsive behavior in M4 -/- mice. In the head-in condition, M4 -/- mice were slower to acquire the 5CSRTT, had more omissions, and had longer correct response latencies than wildtype mice. In the head-out condition, genotypes did not differ in training, but M4 -/- mice showed small decreases in accuracy. Our findings demonstrate that ITI initiation settings contribute to different training durations and tested behaviors in M4 -/- mice, suggesting ITI initiation settings are an important consideration for the general use of the 5CSRTT.

Patients receiving psychiatric medication, like the antipsychotic drug haloperidol, are at an increased risk of sudden cardiac death (SCD). Haloperidol blocks the cardiac rapidly-activating delayed rectifier potassium current, thereby increasing electrical dispersion of repolarization which can potentially lead to arrhythmias. Whether these patients are also at a higher risk to develop SCD during an acute myocardial infarction (AMI) is unknown. AMI locally shortens action potential duration, which might further increase repolarization dispersion and increase the risk of arrhythmia in the presence of haloperidol compared to without. Our aim was to test whether treatment with haloperidol implies an increased risk of SCD when eventually experiencing AMI. Twenty-eight female Danish Landrace pigs were randomized into three groups: low dose haloperidol (0.1 mg/kg), high dose (1.0 mg/kg) or vehicle-control group. One hour after haloperidol/vehicle infusion, AMI was induced by balloon-occlusion of the mid-left anterior descending coronary artery and maintained for 120 min, followed by 60 min of reperfusion. VF occurred during occlusion in 7/11 pigs in the control group, 3/11 in the low dose (p = 0.198) and 2/6 in the high dose group (p = 0.335). High dose haloperidol significantly prolonged QT, and reduced heart rate, vascular resistance and blood pressure before and during AMI. Premature ventricular contractions in phase 1b during AMI were reduced with high dose haloperidol. AMI-induced arrhythmia was not aggravated in pigs with haloperidol treatment. Our results do not suggest that AMI is contributing to the excess mortality in patients treated with antipsychotic drugs seen in epidemiological studies. Keywords: Antipsychotic drugs, Haloperidol, Sudden cardiac death, Acute myocardial infarction, Ventricular fibrillation, Porcine model

The dopamine transporter (DAT) is part of a presynaptic multi-protein network involving interactions with scaffold proteins via its C-terminal PDZ-domain binding sequence. Using a mouse model expressing DAT with mutated PDZ binding sequence (DAT-AAA), we previously demonstrated the importance of this binding sequence for striatal expression of DAT. Here we show by application of direct Stochastic Reconstruction Microscopy (dSTORM) not only that the striatal level of transporter is reduced in DAT-AAA mice, but also that the nanoscale distribution of this transporter is altered with a higher propensity of DAT-AAA to localize to irregular nanodomains in dopaminergic terminals. In parallel, we observe mesostriatal dopamine (DA) adaptations and changes in DA-related behaviors distinct from those seen in other genetic DAT mouse models. DA levels in the striatum are reduced to ∼45% of that of wild type (WT), accompanied by elevated DA turnover. Nonetheless, Fast-Scan Cyclic Voltammetry (FSCV) recordings on striatal slices reveal a larger amplitude and prolonged clearance rate of evoked DA release in DAT-AAA mice compared to WT mice. Autoradiography and radioligand binding show reduced DA D2 receptor levels, while immunohistochemistry and autoradiography show unchanged DA D1 receptor levels. In behavioral experiments, we observe enhanced self-administration of liquid food under both a fixed-ratio (FR1) and progressive-ratio (PR) schedule of reinforcement, but a reduction compared to WT when using cocaine as reinforcer. In summary, our data demonstrate how disruption of PDZ-domain interactions causes changes in DAT expression and its nanoscopic distribution that in turn alter DA clearance dynamics and related behaviors.

Background: Psychiatric conditions and psychopharmacological treatments have been demonstrated to be important risk-factors for prolonged hospital length of stay, readmission and morbidity, following fast-track total hip (THA) and total knee arthroplasty (TKA). Aims: The aim of the study was to provide a detailed description of the preoperative psychiatric characteristics of a well-defined patient population undergoing THA and TKA, using the 90-item Symptom Checklist (SCL-90-R). Methods: A pre-surgical population of 2183 patients completed the full SCL-90-R prior to THA/TKA from 2015 to 2016. The SCL-90-R scale and total scores of the pre-surgical sample were compared to the scores of an age- and gender stratified Danish sample of healthy controls. A Mokken scalogram analysis was conducted to assess the scalability of the SCL-90-R in both samples. Results: The Mokken analysis yielded acceptable scalability coefficients above 0.30 in all subscales of the SCL-90-R except psycoticism (0.28). There was no clinically significant difference (effect size =

Glucagon-like peptide-1 (GLP-1) is a gut peptide that regulates food intake and glucose metabolism. GLP-1 is also produced and released in the brain, and GLP-1 receptors are expressed in brain regions important for alcohol and drug reward, and for the development of addiction. GLP-1 receptor agonists can decrease alcohol intake acutely in rodents. However, alcohol use disorder is a chronic condition that requires treatments to be effective in promoting abstinence from excessive alcohol consumption over time. Here, we assessed the effect of daily treatment with the GLP-1 receptor agonist Exendin-4 in an assay of relapse-like drinking in socially housed mice. Male C57BL/6NTac mice were allowed continuous access to alcohol without tastant in the home cage for 37days. Then, alcohol bottles were removed and Exendin-4 (1.5μg/kg/day) or saline was administered subcutaneously for 8days during alcohol deprivation. Treatment continued for 8 additional days after reintroducing access to alcohol. A high-precision automated fluid consumption system was used to monitor intake of alcohol and water, drinking kinetics, and locomotor activity. Exendin-4 prevented the deprivation-induced increase in alcohol intake observed in control mice, without significantly affecting total fluid intake, body weight, or locomotor activity. The reduced alcohol intake was caused by a protracted latency to the first drink of alcohol and a reduced number of drinking bouts, while bout size and duration were not affected. The effect was maintained undiminished throughout the treatment period. These findings support the possible use of GLP-1 receptor agonists in the treatment of alcohol use disorder.

BACKGROUND: Head-to-head trials to guide antipsychotic treatment choices for paediatric psychosis are urgently needed because extrapolations from adult studies might not be implementable. In this superiority trial with two-sided significance testing, we aimed to compare the efficacy and safety of quetiapine-extended release (quetiapine-ER) versus aripiprazole in children and adolescents with first-episode psychosis, to determine whether differences between the two treatments were sufficient to guide clinicians in their choice of one drug over the other.METHODS: In this multicentre, double-blind, randomised trial in seven Danish university clinics, we recruited children and adolescents aged 12-17 years with a diagnosis of ICD-10 schizophrenia-spectrum disorder, delusional disorder, or affective-spectrum psychotic disorder, and psychotic symptoms scoring at least 4 on at least one of the following Positive and Negative Syndrome Scale (PANSS) items: P1 (delusions), P2 (conceptual disorganisation), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution), and G9 (unusual thought content), and a total PANSS score greater than 60. Patients were randomly assigned (1:1) to 12 weeks of treatment with target doses of 600 mg/day of quetiapine-ER (starting from 50 mg/day) or 20 mg/day of aripiprazole (starting from 2·5 mg/day). The assigned drug was titrated over five levels, with 2 days at each dose, and the final dose achieved on day 9. Randomisation was done using a computer-generated concealed sequence with a block size of 8, and stratified by baseline PANSS positive score (≤20 points or >20 points) and age (12-14 years or 15-17 years). Study drugs were administered in identical capsules, and interventions, assessments, and data analysis were done masked. The primary outcome was PANSS positive score. Key adverse outcomes were bodyweight, homoeostatic model of insulin resistance (HOMA-IR), akathisia, and sedation. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01119014.FINDINGS: Between June 10, 2010, and Jan 29, 2014, 231 participants were assessed for elegibility, of whom 113 were randomly assigned to quetiapine-ER (n=55) or aripiprazole (n=58). PANSS positive score did not differ between groups after 12 weeks (adjusted mean change -5·05 [5·46] for quetiapine-ER, -6·21 [5·42] for aripiprazole; p=0·98), but decreased over time in both groups (pINTERPRETATION: This first head-to-head comparison of quetiapine-ER versus aripiprazole in early-onset psychosis showed no significant group differences in severity of psychopathology after 12 weeks of treatment. Quetiapine-ER was associated with more metabolic adverse events and aripiprazole with more initial akathisia and, unexpectedly, more sedation. The limited antipsychotic efficacy and high level of adverse events were noticeable. This trial provides novel information for the treatment of early-onset psychosis and highlights the importance of adverse event profiles when choosing among antipsychotics for children and adolescents who often require chronic treatment.FUNDING: The National Research Council for Health and Disease Foundation for Health Promotion, AP Møller Foundation, Rosalie Petersens Foundation, Stevn and Rindom Foundation, Foundation for the Promotion of Medical Science, The Capital Region Psychiatric Research Foundation, Tryg Foundation, Region of Southern Denmark Research Foundation, Danish Psychiatric Research Educational Fund, Psychiatry Foundation, Foundation of 17-12-1981, Psychiatric Research Foundation Region Zealand, Capital Region Strategic Research Foundation, Knud og Dagny Andresens Foundation, Psychiatric Research Foundation of 1967, The Capital Region Research Foundation, Dr Sofus Carl Emil Friis and Hustru Olga Friis Scholarship, Tømrerhandler Johannes Fogs Foundation, Brdr Hartmanns Foundation DKK, Aase and Ejnar Danielsens Foundation, Jacob Madsen and wife Olga Madsens Foundation, CC Klestrup and wife Scholarship, Lundbeck Foundation Scholarship, and Tømrermester Jørgen Holm and wife Elisas Scholarship.

Background Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that specific muscarinic M 4 receptor stimulation can attenuate the discriminative stimulus effects and conditioned rewarding effects of cocaine, measures believed to predict the ability of cocaine and cocaine-associated cues to elicit relapse to drug taking. Methods We tested the M 4 -selective positive allosteric modulators VU0152100 and VU0467154 in a drug discrimination assay and a conditioned place preference assay, including extinction and reinstatement of place preference. Specificity of the cocaine discrimination effect was verified using knockout mice lacking either M 1 or M 4 receptors (M 1 −/− , M 4 −/− ). We also replicated previous findings in cocaine-induced locomotor hyperactivity and striatal dopamine microdialysis assays. Results VU0152100 attenuated the discriminative stimulus effect of cocaine in wild-type mice and M 1 −/− mice, but not in M 4 −/− mice, without affecting rates of responding. As previously shown with VU0152100, VU0467154 almost eliminated cocaine-induced hyperactivity and striatal dopamine efflux. VU0467154 failed to attenuate acquisition of cocaine-conditioned place preference, but facilitated extinction and prevented reinstatement of the conditioned place preference. Conclusions These findings further support the notion that M 4 receptors are promising targets for the treatment of cocaine addiction, by showing that results can be replicated using distinct ligands, and that in addition to blocking reinforcing effects of cocaine relevant to ongoing drug taking, M 4 positive allosteric modulators can also attenuate subjective and conditioned effects relevant to relapse.

Objectives This study sought to describe the use of pharmacotherapy in a nationwide cohort of young patients with sudden cardiac death (SCD). Background Several drugs have been associated with an increased risk of SCD and sudden arrhythmic death syndrome (SADS). It remains unclear how pharmacotherapy may contribute to the overall burden of SCD in the general population. Methods This was a nationwide study that included all deaths that occurred between 2000 and 2009 and between 2007 and 2009 in people age 1 to 35 years and 36 to 49 years, respectively. Two physicians identified all SCDs through review of death certificates. Autopsy reports were collected. Pharmacotherapy prescribed within 90 days before SCD was identified in the Danish Registry of Medicinal Product Statistics. Results We identified 1,363 SCDs; median age was 38 years (interquartile range: 29 to 45 years), and 72% (n = 975) were men. Autopsy was performed in 55%. Overall, 58% of SCD cases (n = 786) received at least 1 drug within 90 days before death. The most common drugs were analgesic drugs (n = 239; 18%), antihypertensive drugs (n = 234; 17%), and antibiotic drugs (n = 218; 16%). After multivariable adjustment, prescription of “brugadogenic” drugs or >1 QT-prolonging drug was associated with an increased risk of SADS compared with explained SCD (odds ratio: 2.16 [95% confidence interval: 1.12 to 4.17] and 2.91 [95% confidence interval: 1.46 to 5.81], respectively). Conclusions Pharmacotherapy was identified in 58% of the SCD cases. After multivariable adjustment, there was a 2- and 3-fold increased risk of SADS compared with explained SCD in patients receiving brugadogenic drugs or >1 QT-prolonging drug, respectively. Identification of high-risk patients is warranted to lower the burden of SCD.