Search

As Faculty of the British Association for Psychopharmacology course on child and adolescent psychopharmacology, we present here what we deem are the most common pitfalls, and how to avoid them, in child and adolescent psychopharmacology. In this paper, we specifically addressed common pitfalls in the pharmacological treatment of autism and intellectual disability, eating disorders, neuropsychiatric correlates of epilepsy, and psychosis. Pitfalls in relation to the treatment of other disorders are addressed in a separate paper (Part I). [ABSTRACT FROM AUTHOR]

As Faculty of the British Association for Psychopharmacology course on child and adolescent psychopharmacology, we present here what we deem are the most common pitfalls, and how to avoid them, in child and adolescent psychopharmacology. In this paper, we specifically addressed common pitfalls in the pharmacological treatment of attention-deficit/hyperactivity disorder, anxiety, bipolar disorder, depression, obsessive-compulsive disorder and related disorders, and tic disorder. Pitfalls in the treatment of other disorders are addressed in a separate paper (part II). [ABSTRACT FROM AUTHOR]

Some recent research and commentary have suggested that most or all the effects reported by people who microdose psychedelics may be explained by expectations or placebo effects. In this rapid review, we aimed to evaluate the strength of evidence for a placebo explanation of the reported effects of microdosing. We conducted a PubMed search for all studies investigating psychedelic microdosing with controlled doses and a placebo comparator. We identified 19 placebo-controlled microdosing studies and summarised all positive and null findings across this literature. Risk of bias was assessed using the Cochrane risk-of-bias tool for randomised trials. The reviewed papers indicated that microdosing with LSD and psilocybin leads to changes in neurobiology, physiology, subjective experience, affect, and cognition relative to placebo. We evaluate methodological gaps and challenges in microdosing research and suggest eight reasons why current claims that microdosing is predominately a placebo are premature and possibly wrong: (1) there have been only a small number of controlled studies; (2) studies have had small sample sizes; (3) there is evidence of dose-dependent effects; (4) studies have only investigated the effects of a small number of doses; (5) the doses investigated may have been too small; (6) studies have looked only at non-clinical populations; (7) studies so far have been susceptible to selection bias; and (8) the measured impact of expectancy is small. Considering the available evidence, we conclude that it is not yet possible to determine whether microdosing is a placebo. [ABSTRACT FROM AUTHOR]

Background: There is a growing interest in studying ibogaine (IBO) as a potential treatment for substance use disorders (SUDs). However, its clinical use has been hindered for mainly two reasons: First, the lack of randomized, controlled studies informing about its safety and efficacy. And second, IBO's mechanisms of action remain obscure. It has been challenging to elucidate a predominant mechanism of action responsible for its anti-addictive effects. Objective: To describe the main targets of IBO and its main metabolite, noribogaine (NOR), in relation to their putative anti-addictive effects, reviewing the updated literature available. Methods: A comprehensive search involving MEDLINE and Google Scholar was undertaken, selecting papers published until July 2022. The inclusion criteria were both theoretical and experimental studies about the pharmacology of IBO. Additional publications were identified in the references of the initial papers. Results: IBO and its main metabolite, NOR, can modulate several targets associated with SUDs. Instead of identifying key targets, the action of IBO should be understood as a complex modulation of multiple receptor systems, leading to potential synergies. The elucidation of IBO's pharmacology could be enhanced through the application of methodologies rooted in the polypharmacology paradigm. Such approaches possess the capability to describe multifaceted patterns within multi-target drugs. Conclusion: IBO displays complex effects through multiple targets. The information detailed here should guide future research on both mechanistic and therapeutic studies. [ABSTRACT FROM AUTHOR]

Background: Medication adherence is a prerequisite to achieving beneficial treatment outcomes. In major depressive disorder, many patients fail to complete medication regimens, raising concern for poor treatment outcomes. It is usual to experience adverse drug reactions (ADRs) while taking antidepressants, and relative discomfort is reported by patients. Aims: The present review focuses on the presence of antidepressant-related side effects and the subsequent relationship with medication non-adherence. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Following the preliminary research, the research question and eligibility criteria were created based on the PICO framework. All articles retrieved from the selected databases were exported to Covidence, a Systematic Review managing software tool. Two reviewers assessed the papers to identify the risk of bias using the Joanna Briggs Institute critical appraisal tool for cross-sectional studies. Seven studies with a low–moderate risk of bias fulfilled the eligibility criteria and were conducted from 2013 to 2020 in Europe, Africa and Asia. Results: The results demonstrated high levels of suboptimal adherence ranging from 46% to 83% amongst the studied population. A variety of side effects were reported by a significant number of participants predominantly with moderate severity. A correlation between the presence of ADRs and suboptimal rates of adherence to antidepressants was found. Somnolence and headaches among other unspecified ADRs were found to increase the dropout rates for selective serotonin reuptake inhibitors. Conclusions: The present study elucidates the need for effective interventions to facilitate antidepressant adherence and enhance doctor–patient communication, benefiting both the individuals and the healthcare system and leading to better clinical outcomes and reduction of relapse-related costs. [ABSTRACT FROM AUTHOR]

Background: The classical psychedelics psilocybin, peyote, ayahuasca/ N, N-dimethyltryptamine, and lysergic acid diethylamide can temporarily produce altered states of consciousness, characterized by changes in sensory perception, thought, mood, and the sense of self-reality and meaning. It is important to have reliable instruments for quantifying these altered states in trials, due to a plausible link between the acute subjective experience and treatment outcome. Methods: We conducted a review of outcome measures applied in research on classical psychedelics to assess one or more dimensions of the acute subjective psychedelic experience. Three relevant databases were searched electronically. Two reviewers independently conducted article selection and data extraction regarding the instruments, dimensions, geography, population, and psychedelic substance investigated in the included studies. We identified the five most utilized instruments for the most recent 6 years, as well as the five most utilized instruments for each psychedelic. Results: We included 93 papers, which reported on 93 unique trials and utilized 17 different rating scales. Of these, the most utilized were the Five-Dimensional Altered States of Consciousness Questionnaire, visual analog or Likert scales specially developed for the trials, the Hallucinogen Rating Scale, the States of Consciousness Questionnaire, and the Abnormer Psychischer Zustand. Discussion: Considerable variability was found in the instruments utilized in clinical trials on classical psychedelics. We advise and encourage the development of a core outcome set for psychedelic research to enable altered state comparisons across compounds, participants, and settings. We further advise that instruments be designed to assess the "setting" of a psychedelic experience. [ABSTRACT FROM AUTHOR]

Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers, comprising an international team of researchers from academia and industry, convened in 2021 to discuss how to improve the translational relevance and interpretation of findings from animal models that are used in preclinical psychopharmacology. The following paper distils the outcomes of the working group's discussions into 10 key considerations for the planning and reporting of behavioural studies in animal models relevant to psychiatric disorders. These form the iTRIPP guidelines (Improving Translational Relevance In Preclinical Psychopharmacology). These guidelines reflect the key considerations that the group thinks will likely have substantial impact in terms of improving the translational relevance of behavioural studies in animal models that are used to study psychiatric disorders and their treatment. They are relevant to the research community when drafting and reviewing manuscripts, presentations and grant applications. The iTRIPP guidelines are intended to complement general recommendations for planning and reporting animal studies that have been published elsewhere, by enabling researchers to fully consider the most appropriate animal model for the research purpose and to interpret their findings appropriately. This in turn will increase the clinical benefit of such research and is therefore important not only for the scientific community but also for patients and the lay public. [ABSTRACT FROM AUTHOR]

Background: The classical psychedelics, psilocybin, peyote, ayahuasca/ N,N -dimethyltryptamine, and lysergic acid diethylamide are considered promising new treatments for psychiatric illnesses, such as depression, anxiety, addiction, and obsessive-compulsive disorders. However, their profound and characteristic subjective effects raise concern for distinctive biases in randomized clinical trials. Methods: We performed a systematic literature search to identify all clinical trials on classical psychedelics with patient populations to examine descriptive data and determine the risk of bias. Two independent reviewers searched three databases (PubMed, Embase, and APA PsycNet) and extracted information on study design, study population, use of active or inactive placebo, dropouts, evaluation of blinding of intervention, and reporting of expectancy and therapeutic alliance. Results: We included 10 papers reporting on 10 unique trials. The trials generally included populations that were predominantly white and highly educated. The trials had small samples and considerable dropout. Blinding was either unsuccessful or not reported regardless of type of placebo. Few trials published protocols, statistical analysis plans (SAPs), and outcomes relating to psychotherapy fidelity. All trials but one were rated as high risk of bias. Conclusion: Successful blinding of intervention is a significant challenge in this field. To better accommodate this, we suggest that future trials use a parallel-group design and utilize an active placebo on a psychedelic-naïve population. Future trials should publish trial protocol and SAPs, use clinician-rated outcomes accessed by a blinded rater, evaluate blinding of intervention, and consider measuring expectancy and therapeutic fidelity. [ABSTRACT FROM AUTHOR]

Background: Clinical trials are currently investigating the potential of substance-assisted psychotherapy (SAPT) as treatment for several psychiatric conditions. The potential therapeutic effects of SAPT may be influenced by contextual factors including preparation prior to and integration after the substance-assisted therapy sessions. Aims: This systematized review outlines recommendations for current practice in preparatory sessions in SAPT including safety measures and screening procedures, preparation of set and setting, session contents, methods, and roles, prerequisites, and appropriate conduct of therapists. Methods: A systematized review of the literature was conducted based on PRISMA guidelines. MEDLINE (OVID), PsycINFO (OVID), and Cochrane Library were searched and clinical trials, treatment manuals, study protocols, case studies, qualitative studies, descriptive studies, theoretical papers, reviews, book chapters, and conference proceedings published until February 1, 2022 were retrieved. Results: The final synthesis included k = 83 sources. Information about safety measures including screening of participants, set and setting, contextual-, physiological-, and psychological preparation, roles, competencies, prerequisites, and characteristics of the therapists, and the establishment of a therapeutic relationship were summarized and discussed. Conclusion: It is concluded that there is a consensus in the literature about the importance of adequate preparation before the administration of psychoactive substances in SAPT. However, the extent and approaches for these sessions vary across different models and there is a need for timelier and more rigorous qualitative and quantitative investigations assessing different approaches and techniques for the optimal preparation of clients in SAPT. [ABSTRACT FROM AUTHOR]

The 9-item Concise Health Risk Tracking – Self-Report (CHRT-SR9) is a widely used patient-reported outcome measure of suicidal risk. The goal of this article is to provide an evidence-based interpretation of the CHRT-SR9 total score in terms of four clinically actionable categories of suicidal risk (none, mild, moderate, and severe).Data from two large programs involving adolescents and adults were combined in this paper. In these studies, the CHRT-SR9 was anchored against an independent measure of suicidal risk, the suicide item (Item #9) in the Patient Health Questionnaire (PHQ-9), with categories 0 (none), 1 (mild), 2 (moderate), and 3 (severe). In the combined data (n = 1945), we calculated the cumulative percentage of data across these four categories and the percentile score of the CHRT-SR9 total score that corresponded to these percentages; from this, we developed ranges of the CHRT-SR9 total score that corresponded to the four categories of Item #9 of PHQ-9. We also calculated similar ranges for two broad subscales of the CHRT-SR9 total score; Propensity and Suicidal Thoughts. To assess the robustness of our findings, we repeated the analysis at another timepoint across studies.Findings indicated that the CHRT-SR9 total score (range: 0–36) can be categorized as none (0–14), mild (15–21), moderate (22–26), and severe (27–36). Similar categories were calculated for the Propensity and Suicidal Thoughts subscales. The findings were the same when repeated at another timepoint.This categorization of the CHRT-SR9 total score can place patients into clinically meaningful and actionable categories of suicidal risk. [ABSTRACT FROM AUTHOR]

Drugs used to treat psychotic disorders ('antipsychotics') have been widely used in psychiatry since the introduction of chlorpromazine in the mid-1950s. The categorization of these drugs evolved in a piecemeal way, relying initially on grouping by chemical structure (e.g. phenothiazines, butyrophenones), then by epoch of introduction (e.g. first generation ('conventional') vs second generation ('atypical')). As psychopharmacological expertise has advanced, it has become possible to quantify affinities for each drug in this class for relevant receptors including dopamine D2, 5HT2A, 5HT2C, histamine H1 and others. However, until the recent emergence of a new generation of agents known collectively as dopamine D2 receptor partial agonists (e.g. aripiprazole, brexpiprazole and cariprazine), there had been little reference in drug classification to specific pharmacological properties. An overview of data on receptor affinities across multiple drugs and receptor types would permit categorization according to binding affinities and putative pharmacological mechanisms. In this paper, we have attempted to construct a 'subway map' of 32 drugs used for treatment of psychotic disorders. This design allows a visualization of both the historical classifications by structure and epoch of introduction, and of the binding affinities for key receptors based on appraisal of scientific literature. The map represents a step towards categorization by mechanism, allowing prescribers and patients to understand which drugs share common biological features and the extent to which drugs may have similarities and differences in their mechanisms. In addition, this approach may encourage more logical groupings of drugs to be used in systematic reviews and meta-analyses. [ABSTRACT FROM AUTHOR]

The author comments on the article "The Broad Spectrum of Bipolar Disorder: Implications for Research and Practice," published within the issue of the journal. He agrees with the thesis suggested by the article's authors regarding the importance of bipolar disorder and the diagnostic concerns hindering its early recognition and treatment. However, he disagrees the observation of the author regarding the treatment of bipolar disorders with antidepressants.

Background: Most people often consume alcohol cumulatively and gradually. Yet almost scientific knowledge about alcohol's acute effects on cognition, behavior, and affect stems from laboratory studies that employ a single beverage administration procedure. Objective: This study tests the hypothesis that alcohol's acute effects depend on both methods of administration and alcohol blood level. We introduce a new laboratory procedure for studying cumulative alcohol drinking and examine alcohol's effects on emotion recognition as a function of both alcohol administration method and alcohol blood level. Methods: Participants were recruited for one of two studies. One study employed a between-subject design using a single alcoholic dose. Participants were randomly assigned to drink either placebo (0.00%), low (0.03%), moderate (0.06%), or high (0.09%) alcohol levels. The second study employed a within-subject design using a cumulative alcoholic administration method, in which each participant drank four drinks (placebo, followed by three alcoholic drinks). Both groups reached similar breath alcohol concentrations. In both studies, participants attended a single study session, in which emotion recognition was examined following alcohol administration. Results: Single alcoholic beverage administration method caused greater impairment in emotion recognition ability, specifically for anger, happiness, and fear, as compared with cumulative administration method, even though breath alcohol levels were similar in both conditions. Conclusions: This paper presents questions concerning the internal validity of previous laboratory studies that use a single beverage administration procedure. Insights into the effects of alcohol on behavior, as well as regarding our knowledge about models of addiction are presented. [ABSTRACT FROM AUTHOR]

7: 64-77. 12 Rafizadeh R, Danilewitz M, Bousman CA, et al (2023a) Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis. On a similar theme is an interesting case-control study in people taking clozapine, suggesting that metabolic effects of clozapine (e.g. on body mass index) are related to response, that is, side effects are required to have effects ([4]). A second clozapine paper examines the role of clozapine in rates of relapse and abstinence in those with schizophrenia and co-morbid amphetamine use ([13]). [Extracted from the article]

Background: Psilocybin is the psychoactive component in Psilocybe mushrooms ('magic mushrooms'). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outcomes is currently under investigation, for example, in therapeutic applications. However, to date, no meta-analysis has investigated the dose-dependency of subjective experiences across available studies. Aim: Establishing dose–response relationships of the subjective experiences induced by psilocybin in healthy study participants and a comparison of patient groups. Method: We applied a linear meta-regression approach, based on the robust variance estimation framework, to obtain linear dose–response relationship estimates on questionnaire ratings after oral psilocybin administration. Data were obtained from the Altered States Database, which contains data extracted from MEDLINE-listed journal articles that used standardized and validated questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire and the Hallucinogen Rating Scale. Results: Psilocybin dose positively correlated with ratings on most factors and scales, mainly those referring to perceptual alterations and positively experienced ego dissolution. Measures referring to challenging experiences exhibited small effects and were barely modulated by dose. Conclusion: Psilocybin intensified almost all characteristics of altered states of consciousness assessed with the given questionnaires. Because subjective experiences are not only determined by dose, but also by individual and environmental factors, the results may only apply to controlled laboratory experiments and not to recreational use. This paper may serve as a general literature citation for the use of psilocybin in experimental and clinical research, to compare expected and observed subjective experiences. [ABSTRACT FROM AUTHOR]

This paper introduces a new construct, the 'pivotal mental state', which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation. [ABSTRACT FROM AUTHOR]

Comment on 'Characteristics of poisonings involving ketamine in the United States, 2019-2021' We read with interest the paper by [1] on the 'Characteristics of poisonings involving ketamine in the United States, 2019-2021'. In recent years, ketamine use has become more widespread in the United States, which can be attributed, in part, to the increasing availability of ketamine in psychiatric treatment settings which subsequently could have led to increased interest in nonmedical use. [Extracted from the article]

Background: Anorexia nervosa (AN) is the psychiatric disorder with the highest mortality rate, with a standard mortality ratio of 5.86. Despite the large use of psychotropic drugs in the clinical setting, Food and Drug Administration has not approved any psychoactive treatment for AN.Aims: The aim of this study was to perform an updated systematic review and meta-analysis of published randomized controlled trials (RCTs) investigating psychopharmacological treatment in acute-phase AN.Methods: The present paper follows the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. An extensive literature search was performed. All RCTs enrolling patients with acute-phase AN, comparing at least one psychotropic drug with another drug, placebo, treatment-as-usual or no treatment were included. The main outcome was the effect of psychoactive drugs on body mass index (BMI); data on psychopathological outcomes were also collected when available.Results: A total of 19 RCTs met all specified criteria. Of these, 11 were excluded from quantitative analyses. Of the eight studies included in the meta-analyses, five reported data on BMI, showing no significant difference between olanzapine and placebo for weight recovery. No significant result was found for AN psychopathology, depressive and anxious symptoms for any of the molecules studied.Conclusions: RCTs published in this field display methodological biases, low sample sizes and short follow-up periods. Further research efforts are needed in this field as no evidence has been demonstrated for the use of any psychotropic drug in acute-phase AN neither for weight recovery, nor for comorbid psychiatric symptoms. [ABSTRACT FROM AUTHOR]

The lifetime risk of dying by suicide in schizophrenia and related psychoses has been estimated to be approximately between 5% and 7%, though some have estimated that the number is closer to 10%. The highest risk for suicide occurs within the first year after presentation, when patients have a 12 times greater risk of dying by suicide than the general population, or a 60% higher risk compared with patients in other phases of psychosis, although the risk continues for many years. Some 31% of all deaths in first and early episode samples are due to suicide. Studies in individuals at clinical high-risk for psychosis (CHR) or with attenuated positive symptoms also demonstrate that suicidality is common and problematic in these individuals. Therefore, suicide in psychosis is a particularly severe problem. In order to develop interventions aimed at reducing the risk of suicide in psychotic individuals, it will be critical to understand the neurobiology of suicide in psychosis. In this paper, I report on the results of a systematic review of the work done to date on the neurobiology of suicide in psychosis and on suicidality in the CHR period. I will also identify gaps in knowledge and discuss future strategies for studying the neurobiology of suicidality in psychosis that may help to disentangle the links between suicide and psychosis and, by doing so, allow us to gain a greater understanding of the relationship between suicide and psychosis, which is critical for developing interventions aimed at reducing the risk of suicide in psychotic individuals. [ABSTRACT FROM AUTHOR]

Our 1992 paper, 'The neural substrates of sensorimotor gating of the startle reflex: a review of recent findings and their implications', reviewed a series of (then) new and preliminary findings from cross-species studies of prepulse inhibition of the startle reflex, and commented on their implications. At the time that the report was composed, PubMed listed about 40 citations for studies using the search term 'prepulse inhibition'. In the ensuing 25 years, the field has added about 2700 such reports, reflecting the substantial growth in interest in prepulse inhibition and its utility across a number of different experimental applications. The 30th anniversary of the Journal of Psychopharmacology provides an opportunity to comment briefly on what was described in that 1992 report, how the field has progressed in the subsequent decades, and the paths forward for studies of prepulse inhibition and its use as an operational measure of sensorimotor gating. Among these future paths, we highlight the use of prepulse inhibition as: an endophenotype for genomic studies, and a biomarker for healthy brain circuitry, which may predict sensitivity to psychotherapeutics. Our 1992 report was highly speculative and based on paper-thin empirical data, yet viewed in a certain light, it appears to have contained a basic roadmap for a journey spanning the next 25 years of prepulse inhibition research… and 'what a long, strange trip it's been'. [ABSTRACT FROM AUTHOR]

The 2002 paper "Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine" by Bell and colleagues - reprinted in this issue of the Journal - reports on a study undertaken in the halcyon days of David Nutt's Psychopharmacology Unit at the University of Bristol, England. In this invited commentary authors of the original work discuss the impact of this paper on the field of acute tryptophan depletion research (especially in the field of clinical anxiety disorders) and the development of disorder-specific anxiogenic provocations over the past decade. [ABSTRACT FROM AUTHOR]

Background: In the past few years, the issue of 'microdosing' psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is.Aim: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies.Approach: Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned.Conclusion: It is concluded that while most anecdotal reports focus on the positive experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clinical studies including biological (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential negative consequences microdosing could have. [ABSTRACT FROM AUTHOR]

Background: Generalized anxiety disorder is a common psychiatric condition that is associated with decreased quality of life and significant disability. Benzodiazepines are anti-anxiety drugs used widely in the treatment of generalized anxiety disorder. This study examines the influence of several variables on benzodiazepine efficacy in generalized anxiety disorder.Method: We performed a systematic review of placebo-controlled randomized controlled trials with benzodiazepines in generalized anxiety disorder. Fifty-eight studies were deemed eligible to include in the meta-analysis. The studies dated from 1977 to 2013 and included over 5400 participants. From each paper, we extracted: benzodiazepine name and dose, dosing regimen, baseline Hamilton Anxiety Scale (HAM-A) score, change in HAM-A score at study endpoint, drop-out rate, year of study publication, diagnostic criteria used, study size, study duration, location, any conflicts of interest and side-effect profile. We then assessed the influence, direct and indirect, of individual variables on the primary outcome (mean difference at endpoint, HAM-A score).Results: Three factors were shown to be associated statistically with change in HAM-A; baseline HAM-A for benzodiazepine arm, baseline HAM-A for the placebo arm, and duration of the study. A higher baseline HAM-A in both arms was associated with a greater mean difference in HAM-A. A shorter study length was also associated with a greater mean difference.Discussion: The major factors determining benzodiazepine response was baseline anxiety level for the benzodiazepine arm and study duration. In any design of further meta-analyses and clinical trials for generalized anxiety disorder we suggest that these should be considered these as confounding factors. [ABSTRACT FROM AUTHOR]

Available antipsychotics show different efficacy on manic symptoms of bipolar patients, but few studies have investigated the speed of action of the various compounds. For this reason, purpose of the present paper was to compare antipsychotic mono-therapies in terms of speed of action in a sample of manic bipolar patients. In total, 155 bipolar patients, treated with antipsychotic mono-therapy and followed-up in Inpatient Psychiatry Clinic of University of Milan, were included in this single-blind comparative study. Clinical response was defined as a reduction of Young Mania Rating Scale (YMRS) scores ⩾50%, while remission as a YMRS score <10. After 4 days patients who had been treated with asenapine, were more likely to have achieved a clinical response than those in treatment with haloperidol ( p = 0.001). After 7 days, a more frequent clinical response was achieved by patients treated with asenapine than those who had been treated with haloperidol ( p < 0.001) or olanzapine ( p = 0.047). Asenapine appears to be faster in determining treatment response in manic patients compared with haloperidol and less markedly with olanzapine. [ABSTRACT FROM AUTHOR]

Understanding factors that contribute to eating disorders, which affect 13% of females, is critical to developing effective prevention and treatment programs. In this paper, we summarize results from prospective studies that identified factors predicting onset and persistence of eating disorders and core symptom dimensions. Next, implications for intervention targets for prevention, and treatment interventions from the risk- and maintenance-factor findings are discussed. Third, given that evidence suggests eating disorders are highly heritable, implying biological risk and maintenance factors for eating disorders, we offer working hypotheses about biological factors that might contribute to eating disorders, based on extant risk factor findings, theory, and cross-sectional studies. Finally, potentially fruitful directions for future research are presented. We suggest that it would be useful for experimental therapeutics trials to evaluate the effects of reducing the risk factors on future onset of eating pathology and on reducing maintenance factors on the risk for persistence of eating pathology, and encourage researchers to utilize prospective high-risk studies so that knowledge regarding potential intervention targets for prevention and treatment interventions for eating disorders can be advanced. Using the most rigorous research designs should help improve the efficacy of prevention and treatment interventions for eating disorders. [ABSTRACT FROM AUTHOR]

Despite its importance in regulating emotion and mental wellbeing, the complex structure and function of the serotonergic system present formidable challenges toward understanding its mechanisms. In this paper, we review studies investigating the interactions between serotonergic and related brain systems and their behavior at multiple scales, with a focus on biologically-based computational modeling. We first discuss serotonergic intracellular signaling and neuronal excitability, followed by neuronal circuit and systems levels. At each level of organization, we will discuss the experimental work accompanied by related computational modeling work. We then suggest that a multiscale modeling approach that integrates the various levels of neurobiological organization could potentially transform the way we understand the complex functions associated with serotonin. [ABSTRACT FROM AUTHOR]

Background: Cannabis-induced psychotic disorder (CIPD) is a psychiatric disorder induced by cannabis consumption. The psychological and psychophysiological features of this disorder are still unknown. We aimed to examine the psychological, personality and psychophysiological features of patients with CIPD. This study is an analytical extension of our previously published data, which previously found prepulse inhibition (PPI) deficits in the CIPD group used in this current paper.Methods: We used a sample of 45 patients with CIPD. After 9 months of follow up, these patients were assessed with a Symptom Checklist-90-R (SCL-90-R) questionnaire of psychopathology, with the Eysenck Personality Questionnaire, and with a psychophysiological paradigm of inhibition of the startle reflex (PPI). These results were compared with a group of patients with schizophrenia and cannabis abuse (SCHZ) ( n = 54); patients with cannabis dependence (CD) ( n = 21); and healthy controls ( n = 50).Results: CIPD patients obtained significant higher scores in the SCL-90-R subscale of neuroticism. These patients showed PPI percentages similar to SCHZ patients within early attentional levels (30 ms). The variables with greater correlation, and that appeared in the CIPD group were interpersonal sensitivity, depression and phobia.Conclusions: Neurotic symptomatology and difficulties in inhibition of the startle reflex might be risk factors for developing CIPD. [ABSTRACT FROM AUTHOR]

Placebo response theory and set and setting theory are two fields which examine how non-biological factors shape the response to therapy. Both consider factors such as expectancy, preparation and beliefs to be crucial for understanding the extra-pharmacological processes which shape the response to drugs. Yet there are also fundamental differences between the two theories. Set and setting concerns itself with response to psychoactive drugs only; placebo theory relates to all therapeutic interventions. Placebo theory is aimed at medical professionals; set and setting theory is aimed at professionals and drug users alike. Placebo theory is primarily descriptive, describing how placebo acts; set and setting theory is primarily prescriptive, educating therapists and users on how to control and optimize the effects of drugs. This paper examines how placebo theory and set and setting theory can complement and benefit each other, broadening our understanding of how non-biological factors shape response to drugs and other treatment interventions. [ABSTRACT FROM AUTHOR]

Rationale: In recent decades, the use of ayahuasca (AYA) - a β-carboline- and dimethyltryptamine-rich hallucinogenic botanical preparation traditionally used by Northwestern Amazonian tribes for ritual and therapeutic purposes - has spread from South America to Europe and the USA, raising concerns about its possible toxicity and hopes of its therapeutic potential. Thus, it is important to analyze the acute, subacute, and long-term effects of AYA to assess its safety and toxicity.Objectives: The purpose of this study was to conduct a systematic review of human studies assessing AYA effects on psychiatric symptoms, neuropsychological functioning, and neuroimaging.Methods: Papers published until 16 December 2015 were included from PubMed, LILACS and SciELO databases following a comprehensive search strategy and pre-determined set of criteria for article selection.Results: The review included 28 full-text articles. Acute AYA administration was well tolerated, increased introspection and positive mood, altered visual perceptions, activated frontal and paralimbic regions and decreased default mode network activity. It also improved planning and inhibitory control and impaired working memory, and showed antidepressive and antiaddictive potentials. Long-term AYA use was associated with increased cortical thickness of the anterior cingulate cortex and cortical thinning of the posterior cingulate cortex, which was inversely correlated to age of onset, intensity of prior AYA use, and spirituality. Subacute and long-term AYA use was not associated with increased psychopathology or cognitive deficits, being associated with enhanced mood and cognition, increased spirituality, and reduced impulsivity.Conclusions: Acute, subacute, and long-term AYA use seems to have low toxicity. Preliminary studies about potential therapeutic effects of AYA need replication due to their methodological limitations. [ABSTRACT FROM AUTHOR]

Here, Reynolds and Neill describe the studies that preceded and followed publication of this paper, which reported a deficit in parvalbumin (PV), a calcium-binding protein found in GABA interneurons known to be reduced in schizophrenia patients, in conjunction with a deficit in reversal learning in an animal model for schizophrenia. This publication resulted from common research interests: Reynolds in the neurotransmitter pathology of schizophrenia, and Neill in developing animal models for schizophrenia symptomatology. The animal model, using a sub-chronic dosing regimen (sc) with the non-competitive NMDA receptor antagonist PCP (phencyclidine), evolved from previous work in rats (for PCP) and primates (for cognition). The hypothesis of a PV deficit came from emerging evidence for a GABAergic dysfunction in schizophrenia, in particular a deficit in PV-containing GABA interneurons. Since this original publication, a PV deficit has been identified in other animal models for schizophrenia, and the PV field has expanded considerably. This includes mechanistic work attempting to identify the link between oxidative stress and GABAergic dysfunction using this scPCP model, and assessment of the potential of the PV neuron as a target for new antipsychotic drugs. The latter has included development of a molecule targeting KV3.1 channels located on PV-containing GABA interneurons which can restore both PV expression and cognitive deficits in the scPCP model. [ABSTRACT FROM AUTHOR]

Despite the first reports concerning benzodiazepine dependence being published in the early 1960s literature, the risk of benzodiazepine addiction is still greatly debated. The severe discomfort and life threatening complications usually experienced by long-term benzodiazepine users who suddenly interrupt benzodiazepine intake have led to the development of several detoxification protocols. A successful strategy used by our Addiction Unit is abrupt benzodiazepine cessation by administering flumazenil slow subcutaneous infusion (FLU-SSI) with an elastomeric pump. Although some studies proved the efficacy of flumazenil infusion more than 20 years ago, only a few centres in the world offer this method to their patients. This paper reports the data related to 214 subjects addicted to high doses of benzodiazepine and treated with the FLU-SSI method between 2012 and 2014. This technique is less invasive and requires less nursing intervention than intravenous infusion. Our data support FLU-SSI as a possible efficient strategy for the treatment of patients with long-term, high-dose benzodiazepine addiction, and could become a routine therapy as long as the necessary further studies on dose, duration of infusion and safety issues are carried out. [ABSTRACT FROM AUTHOR]

Kirsch et al. (2008, Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5: e45), conducted a meta-analysis of data from 35 placebo controlled trials of four newer antidepressants. They concluded that while these drugs are statistically significantly superior to placebo in acute depression, the benefits are unlikely to be clinically significant. This paper has attracted much attention and debate in both academic journals and the popular media. In this critique, we argue that Kirsch et al.’s is a flawed analysis which relies upon unusual statistical techniques biased against antidepressants. We present results showing that re-analysing the same data using more appropriate methods leads to substantially different conclusions. However, we also believe that psychopharmacology has lessons to learn from the Kirsch et al. paper. We discuss issues surrounding the interpretation of clinical trials of antidepressants, including the difficulties of extrapolating from randomized controlled trials to the clinic, and the question of failed trials. We call for more research to establish the effectiveness of antidepressants in clinically relevant populations under naturalistic conditions, for example, in relapse prevention, in patients with co-morbidities, and in primary care settings. [ABSTRACT FROM PUBLISHER]

This paper explores chronologically the evolution of raised prolactin levels as an entity in psychiatric patients. Menstrual problems were described in patients with schizophrenia prior to the introduction of antipsychotic medication, but galactorrhoea and gynaecomastia were not commonly seen until the advent of antipsychotics. Following the introduction of antipsychotic medication single case reports of patients with galactorrhoea and gynaecomastia appeared. These were followed by a collection of case reports and the process reached today's data of laboratory defined rates of prolactin and sexual side effects. The paper also reviews the emerging research linking hyperprolactinaemia with increased risk of osteoporosis and possibly breast cancer. An overarching thread which runs throughout these publications, is the paucity of clinical research, which has only recently begun to be addressed. [ABSTRACT FROM PUBLISHER]

Since the wars in Iraq and Afghanistan, posttraumatic stress disorder (PTSD) has become a major area of research and development. The most widely accepted treatment for PTSD is prolonged exposure (PE) therapy, but for many patients it is intolerable or ineffective. ±3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MDMA-AP) has recently re-emerged as a new treatment option, with two clinical trials having been published and both producing promising results. However, these results have yet to be compared to existing treatments. The present paper seeks to bridge this gap in the literature. Often the statistical significance of clinical trials is overemphasized, while the magnitude of the treatment effects is overlooked. The current meta-analysis aims to provide a comparison of the cumulative effect size of the MDMA-AP studies with those of PE. Effect sizes were calculated for primary and secondary outcome measures in the MDMA-AP clinical trials and compared to those of a meta-analysis including several PE clinical trials. It was found that MDMA-AP had larger effect sizes in both clinician-observed outcomes than PE did (Hedges' g=1.17 vs. g=1.08, respectively) and patient self-report outcomes (Hedges' g=0.87 vs. g=0.77, respectively). The dropout rates of PE and MDMA-AP were also compared, revealing that MDMA-AP had a considerably lower percentage of patients dropping out than PE did. These results suggest that MDMA-AP offers a promising treatment for PTSD. [ABSTRACT FROM AUTHOR]

In recent years the recreational use of inhaled nitrous oxide gas (N2O) is becoming increasingly popular, yet little is known about the characteristics of its users or the effects they experience. This paper presents original research from the 2014 Global Drug Survey (GDS) (n=74,864). GDS runs the largest survey of recreational drug use in the world. The findings confirm N2O as a very common drug of use, in particular in the UK and US (38.6% and 29.4% lifetime prevalence). In the UK N2O was reported to be the eighth most commonly used substance. N2O was generally consumed via gas-filled balloons, at festivals and clubs where use of other substances was common. The vast majority of users use infrequently, and their use is not associated with significant harm. However, there appears to be a subpopulation of heavy users who may be using in a dependent pattern. Analysis of last year N2O users (n=4883), confirms that N2O is associated with hallucinations and confusion (which may be the desired effects) and persistent numbness and accidental injury (27.8%, 23.9%, 4.3% and 1.2% of last year users, respectively). Accidental injury is associated with the highest number of 'hits' per session, suggesting a dose-response relationship. The presence of significant harm is discussed in the light of public education on the risks of N2O use and harm-reduction strategies appropriate to N2O use. Further work needs to be completed to confirm the presence of persistent neurological symptoms in recreational users. [ABSTRACT FROM AUTHOR]

This paper reports on the effects of LSD on mental time travel during spontaneous mentation. Twenty healthy volunteers participated in a placebo-controlled crossover study, incorporating intravenous administration of LSD (75 μg) and placebo (saline) prior to functional magnetic resonance imaging (fMRI). Six independent, blind judges analysed mentation reports acquired during structured interviews performed shortly after the functional magnetic resonance imaging (fMRI) scans (approximately 2.5 h post-administration). Within each report, specific linguistic references to mental spaces for the past, present and future were identified. Results revealed significantly fewer mental spaces for the past under LSD and this effect correlated with the general intensity of the drug's subjective effects. No differences in the number of mental spaces for the present or future were observed. Consistent with the previously proposed role of the default-mode network (DMN) in autobiographical memory recollection and ruminative thought, decreased resting-state functional connectivity (RSFC) within the DMN correlated with decreased mental time travel to the past. These results are discussed in relation to potential therapeutic applications of LSD and related psychedelics, e.g. in the treatment of depression, for which excessive reflection on one's past, likely mediated by DMN functioning, is symptomatic. [ABSTRACT FROM AUTHOR]

The Cognitive Drug Research (CDR) System is a set of nine computerized tests of attention, information processing, working memory, executive control and episodic memory which was designed for repeated assessments in research projects. The CDR System has been used extensively in clinical trials involving healthy volunteers for over 30 years, and a database of 7751 individuals aged 18-87 years has been accumulated for pre-treatment data from these studies. This database has been analysed, and the relationships between the various scores with factors, including age, gender and years of full-time education, have been identified. These analyses are reported in this paper, along with tables of norms for the various key measures from the core tasks stratified by age and gender. These norms can be used for a variety of purposes, including the determination of eligibility for participation in clinical trials and the everyday relevance of research findings from the system. In addition, these norms provide valuable information on gender differences and the effects of normal ageing on major aspects of human cognitive function. [ABSTRACT FROM AUTHOR]

The 30-item revised Mystical Experience Questionnaire (MEQ30) was previously developed within an online survey of mystical-type experiences occasioned by psilocybin-containing mushrooms. The rated experiences occurred on average eight years before completion of the questionnaire. The current paper validates the MEQ30 using data from experimental studies with controlled doses of psilocybin. Data were pooled and analyzed from five laboratory experiments in which participants (n=184) received a moderate to high oral dose of psilocybin (at least 20 mg/70 kg). Results of confirmatory factor analysis demonstrate the reliability and internal validity of the MEQ30. Structural equation models demonstrate the external and convergent validity of the MEQ30 by showing that latent variable scores on the MEQ30 positively predict persisting change in attitudes, behavior, and well-being attributed to experiences with psilocybin while controlling for the contribution of the participant-rated intensity of drug effects. These findings support the use of the MEQ30 as an efficient measure of individual mystical experiences. A method to score a "complete mystical experience" that was used in previous versions of the mystical experience questionnaire is validated in the MEQ30, and a stand-alone version of the MEQ30 is provided for use in future research. [ABSTRACT FROM AUTHOR]

Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80-90% SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HT3 receptors in eliciting these differences. The 5-HT3 receptor antagonist ondansetron significantly reduced paroxetine's acute effects on ROL, while the 5-HT3 receptor agonist SR57227A significantly increased vortioxetine's acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HT3 receptor antagonism in mitigating these differences. [ABSTRACT FROM AUTHOR]

The concept of targeted therapies remains a holy grail for the pharmaceutical drug industry for identifying responder populations or new drug targets. Here we provide quantitative systems pharmacology as an alternative to the more traditional approach of retrospective responder pharmacogenomics analysis and applied this to the case of iloperidone in schizophrenia. This approach implements the actual neurophysiological effect of genotypes in a computer-based biophysically realistic model of human neuronal circuits, is parameterized with human imaging and pathology, and is calibrated by clinical data. We keep the drug pharmacology constant, but allowed the biological model coupling values to fluctuate in a restricted range around their calibrated values, thereby simulating random genetic mutations and representing variability in patient response. Using hypothesis-free Design of Experiments methods the dopamine D4 R-AMPA (receptor–alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor coupling in cortical neurons was found to drive the beneficial effect of iloperidone, likely corresponding to the rs2513265 upstream of the GRIA4 gene identified in a traditional pharmacogenomics analysis. The serotonin 5-HT3 receptor-mediated effect on interneuron gamma-aminobutyric acid conductance was identified as the process that moderately drove the differentiation of iloperidone versus ziprasidone. This paper suggests that reverse-engineered quantitative systems pharmacology is a powerful alternative tool to characterize the underlying neurobiology of a responder population and possibly identifying new targets. [ABSTRACT FROM AUTHOR]

There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species. In this paper we report the validation of a scopolamine based rodent pharmacological MRI provocation model. The effects of deemed procognitive agents (donepezil, vinpocetine, piracetam, alpha 7 selective cholinergic compounds EVP-6124, PNU-120596) were compared on the blood-oxygen-level dependent responses and also linked to rodent cognitive models. These drugs revealed significant effect on scopolamine induced blood-oxygen-level dependent change except for piracetam. In the water labyrinth test only PNU-120596 did not show a significant effect. This provocational model is suitable for testing procognitive compounds. These functional MR imaging experiments can be paralleled with human studies, which may help reduce the number of false cognitive clinical trials. [ABSTRACT FROM AUTHOR]

Cannabis use is associated with an increased risk of psychosis in vulnerable individuals. Cannabis containing high levels of the partial cannabinoid receptor subtype 1 (CB1) agonist tetrahydrocannabinol (THC) is associated with the induction of psychosis in susceptible subjects and with the development of schizophrenia, whereas the use of cannabis variants with relatively high levels of cannabidiol (CBD) is associated with fewer psychotic experiences. Synthetic cannabinoid receptor agonists (SCRAs) are full agonists and often more potent than THC. Moreover, in contrast to natural cannabis, SCRAs preparations contain no CBD so that these drugs may have a higher psychosis-inducing potential than cannabis. This paper reviews the general toxicity profile and the adverse effects of SCRAs with special emphasis on their psychosis-inducing risk. The review shows that, compared with the use of natural cannabis, the use of SCRAs may cause more frequent and more severe unwanted negative effects, especially in younger, inexperienced users. Psychosis and psychosis-like conditions seem to occur relatively often following the use of SCRAs, presumably due to their high potency and the absence of CBD in the preparations. Studies on the relative risk of SCRAs compared with natural cannabis to induce or evoke psychosis are urgently needed. [ABSTRACT FROM PUBLISHER]

Neural oscillations have received recently a great deal of interest in schizophrenia research because of the possibility to integrate findings from non-invasive electro/magnetoencephalographical recordings with pre-clinical research, which could potentially lead to the identification of pathophysiological mechanisms and novel treatment targets. In the current paper, we review the potential as well as the challenges of this approach by summarizing findings on alterations in rhythmic activity from both animal models and human data which have implicated dysfunctional neural oscillations in the explanation of cognitive deficits and certain clinical symptoms of schizophrenia. Specifically, we will focus on findings that have examined neural oscillations during 1) perceptual processing, 2) working memory and executive processes and 3) spontaneous activity. The importance of the development of paradigms suitable for human and animal models is discussed as well as the search for mechanistic explanation for oscillatory dysfunctions. [ABSTRACT FROM PUBLISHER]

There is a growing consensus that a symptomatology as complex and heterogeneous as schizophrenia is likely to be produced by widespread perturbations of brain structure, as opposed to isolated deficits in specific brain regions. Structural brain-imaging studies have shown that several features of the brain, such as grey matter, white matter integrity and the morphology of the cortex differ in individuals at high risk of the disorder compared to controls, but to a lesser extent than in patients, suggesting that structural abnormalities may form markers of vulnerability to the disorder. Research has had some success in delineating abnormalities specific to those individuals that transition to psychosis, compared to those at high risk that do not, suggesting that a general risk for the disorder can be distinguished from alterations specific to frank psychosis. In this paper, we review cross-sectional and longitudinal studies of individuals at familial or clinical high risk of the disorder. We conclude that the search for reliable markers of schizophrenia is likely to be enhanced by methods which amalgamate structural neuroimaging data into a coherent framework that takes into account the widespread distribution of brain alterations, and relates this to leading hypotheses of schizophrenia. [ABSTRACT FROM PUBLISHER]

Magnetoencephalography (MEG) is a neuroimaging technique that allows direct measurement of the magnetic fields generated by synchronised ionic neural currents in the brain with moderately good spatial resolution and high temporal resolution. Because chemical neuromodulation can cause changes in neuronal processing on the millisecond time-scale, the combination of MEG with pharmacological interventions (pharmaco-MEG) is a powerful tool for measuring the effects of experimental modulations of neurotransmission in the living human brain. Importantly, pharmaco-MEG can be used in both healthy humans to understand normal brain function and in patients to understand brain pathologies and drug-treatment effects. In this paper, the physiological and technical basis of pharmaco-MEG is introduced and contrasted with other pharmacological neuroimaging techniques. Ongoing developments in MEG analysis techniques such as source-localisation, functional and effective connectivity analyses, which have allowed for more powerful inferences to be made with recent pharmaco-MEG data, are described. Studies which have utilised pharmaco-MEG across a range of neurotransmitter systems (GABA, glutamate, acetylcholine, dopamine and serotonin) are reviewed. [ABSTRACT FROM AUTHOR]

Although substitution therapy with opiate agonist treatments such as methadone and buprenorphine has resulted in a reduction of illicit drug use related harm, such treatment has also resulted in severe problems in some countries where opioid-dependent individuals now inject illicitly sold buprenorphine or buprenorphine-naloxone instead of heroin. There is no approved treatment for buprenorphine dependence. Naltrexone is an opioid antagonist which has been used for the treatment of both alcohol and opioid dependencies. Although both buprenorphine and heroin resemble each other concerning their effects, buprenorphine has a higher affinity to opioid receptors than heroin. Therefore, it is not known if naltrexone can block the psychoactive effects of buprenorphine as it does for heroin. This paper presents observational case series data on the use of a sustained-release naltrexone implant for the treatment of buprenorphine dependence. To the authors’ knowledge this is the first use of sustained-release naltrexone for this indication. [ABSTRACT FROM AUTHOR]

Idiopathic hypersomnia (IH) is a rare sleep disorder, recently hypothesized to be related to the production of a molecule that facilitates the binding of gamma-aminobutyric acid (GABA) to the GABA receptor. This paper reports on the treatment of a patient with IH who was treated with a 96-hour continuous low dose (4 mg/day) infusion of a benzodiazepine antagonist, flumazenil, followed by a slow-release flumazenil implant. The use of flumazenil mitigated the patient’s IH symptoms including excessive daytime sleepiness, sleep drunkenness and self-reported cognitive problems. The case both provides a possible treatment and system for short (subcutaneous (SC) administration) and longer term (implant) flumazenil delivery. Current data supports the need for further research into the use of flumazenil for the treatment of IH and to develop long term flumazenil delivery systems. [ABSTRACT FROM PUBLISHER]

Previous comparative reviews of add-on therapies for patients with major depressive disorder (MDD) with an inadequate response to antidepressants have not used meta-analytic techniques to compare different drug classes and have included non-licensed therapies. This meta-analysis reviewed all published peer-reviewed evidence for the efficacy of EU-licensed therapies in patients with MDD and an inadequate response to antidepressant monotherapy. Papers concerning randomized clinical trials (RCTs) were identified using criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Add-on therapies reviewed were antidepressants, quetiapine XR, lithium, and S-adenosyl-l-methionine (SAMe). Seven RCTs that reported response and remission in a way that allowed quantitative analysis were included in this meta-analysis. Comparison of the different drug classes indicated that most interventions had similar efficacy. The likelihood of response was significantly greater with SAMe versus placebo and lithium and with quetiapine XR versus placebo. Most add-on interventions demonstrated comparable efficacy in patients with MDD and an inadequate response to initial antidepressants. However, there is currently a paucity of high-quality data regarding the use of add-on treatments in patients with MDD who are inadequate responders to antidepressants, with quetiapine XR presenting the most comprehensive evidence base to date. [ABSTRACT FROM PUBLISHER]

Electroconvulsive therapy is an important treatment option for major depressive disorders, acute mania, mood disorders with psychotic features, and catatonia. Several hypotheses have been proposed as electroconvulsive therapy’s mechanism of action. Our hypothesis involves many converging pathways facilitated by increased synthesis and release of tissue-plasminogen activator.Human and animal experiments have shown that tissue-plasminogen activator participates in many mechanisms of action of electroconvulsive therapy or its animal variant, electroconvulsive stimulus, including improved N-methyl-D-aspartate receptor-mediated signaling, activation of both brain-derived neurotrophic factor and vascular endothelial growth factor, increased bioavailability of zinc, purinergic release, and increased mobility of dendritic spines. As a result, tissue-plasminogen activator helps promote neurogenesis in limbic structures, modulates synaptic transmission and plasticity, improves cognitive function, and mediates antidepressant effects.Notably, electroconvulsive therapy seems to influence tissue-plasminogen activator metabolism. For example, electroconvulsive stimulus increases the expression of glutamate decarboxylase 65 isoform in γ-aminobutyric acid–releasing neurons, which enhances the release of tissue-plasminogen activator, and the expression of p11, a protein involved in plasminogen and tissue-plasminogen activator assembling.This paper reviews how electroconvulsive therapy correlates with tissue-plasminogen activator. We suggest that interventions aiming at increasing tissue-plasminogen activator levels or its bioavailability – such as daily aerobic exercises together with a carbohydrate-restricted diet, or normalization of homocysteine levels – be evaluated in controlled studies assessing response and remission duration in patients who undergo electroconvulsive therapy. [ABSTRACT FROM PUBLISHER]

Alcohol use is one of the top five causes of disease and disability in almost all countries in Europe, and in the eastern part of Europe it is the number one cause. In the UK, alcohol is now the leading cause of death in men between the ages of 16–54 years, accounting for over 20% of the total. Europeans above 15 years of age in the EU on average consume alcohol at a level which is twice as high as the world average. Alcohol should therefore be a public health priority, but it is not. This paper puts forward a new approach to reduce alcohol use and harms that would have major public health and social impacts. Our approach comprises individual behaviour and policy elements. It is based on the assumption that heavy drinking is key. It is simple, so it would be easy to introduce, and because it lacks stigmatising issues such as the diagnosis of addiction and dependence, it should not be contentious. [ABSTRACT FROM PUBLISHER]