Psychedelic research at a crossroads.

There is an urgent need to develop better treatments for mental health conditions that affect one in every eight people in the world. To combat this concern, psychedelic drugs have been combined with psychotherapy and studied in clinical trials in the United States and Europe. Psychedelics are hallucinogenic drugs that alter brain activity and facilitate altered states of consciousness. The proposed benefits of psychedelic-assisted therapy (PAT) include relatively short treatment times and stronger effects compared to other treatments. Although results of trials using MDMA for trauma or psilocybin for depression are promising, PAT is controversial because many questions about its safety and effectiveness are unanswered. This is evident in the recent ruling by the US Food and Drug Administration against the approval of MDMA therapy for post-traumatic stress disorder and the retraction of several papers about MDMA trials owing to unethical conduct by study therapists and data integrity, among other concerns. This field is at a crossroads, and the research community must address several obstacles to transition from exploratory trials to established, evidence-based treatments while avoiding pitfalls that can hinder advancement.

Cariprazine in Psychiatry: A Comprehensive Review of Efficacy, Safety, and Therapeutic Potential.

This article provides a comprehensive review of recent developments regarding a new atypical antipsychotic drug - cariprazine - considering the mechanism of action, efficacy, safety, and promising therapeutic option for various psychiatric disorders, including schizophrenia and bipolar disorder, therapy of addictions, and treatment in the pediatric population. Its distinct pharmacological profile, characterized by partial agonism at dopamine D2 and D3 receptors, as well as serotonin receptors - 5HT1A with a preference for the D3 receptor - sets it apart from other antipsychotics. The unique mechanism of action contributes to cariprazine's positive impact on negative symptoms in schizophrenia and an antidepressant effect. Its relatively low risk of adverse effects, such as sedation, metabolic issues, and hypotension, enhances its tolerability. In bipolar affective disorder, cariprazine exhibits effectiveness in managing both depressive and manic episodes. Ongoing research in pediatric populations suggests potential benefits in schizophrenia, bipolar I disorder, and autism spectrum disorder, but further research is necessary to establish safety and efficacy. Moreover, cariprazine shows promise in addiction therapy, particularly with coexisting psychiatric disorders. Continued research and clinical exploration may discover additional insights, broadening its use in diverse patient populations. This article aims to review the role of cariprazine, a dopamine D2/D3 and serotonin 5-HT1A receptor partial agonist, in the management of psychotic illnesses, including schizophrenia, bipolar disorder, addiction therapy, and pediatric treatment.

Effect of pharmacological treatment of attention-deficit/hyperactivity disorder on later psychiatric comorbidity: a population-based prospective long-term study.

BACKGROUND: Psychiatric comorbidity is frequent among persons with attention-deficit/hyperactivity disorder (ADHD). Whether pharmacological treatment of ADHD influences the incidence of psychiatric comorbidity is uncertain. OBJECTIVE: To investigate associations and causal relations between pharmacological treatment of ADHD and incidence of subsequent comorbid psychiatric diagnoses. METHODS: We employed registry data covering all individuals aged 5-18 years in Norway who were diagnosed with ADHD during 2009-2011 (n=8051), followed until 2020. We used linear probability models (LPM) and instrumental variable (IV) analyses to examine associations and causal effects, respectively, between pharmacological treatment and subsequent comorbidity. FINDINGS: From time of ADHD diagnosis to 9 years of follow-up, 63% of patients were registered with comorbid psychiatric disorders. For males, LPM showed associations between ADHD medication and several incident comorbidities, but strength and direction of associations and consistency over time varied. For females, no associations were statistically significant. IV analyses for selected categories isolating effects among patients 'on the margin of treatment' showed a protective effect for a category of stress-related disorders in females and for tic disorders in males for the first 2 and 3 years of pharmacological treatment, respectively. CONCLUSIONS: Overall, LPM and IV analyses did not provide consistent or credible support for long-term effects of pharmacological treatment on later psychiatric comorbidity. However, IV results suggest that for patients on the margin of treatment, pharmacological treatment may initially reduce the incidence of certain categories of comorbid disorders. CLINICAL IMPLICATIONS: Clinicians working with persons with ADHD should monitor the effects of ADHD medication on later psychiatric comorbidity. TRIAL REGISTRATION NUMBER: ISRCTN11891971.

CCNP Innovations in Neuropsychopharmacology Award: The psychopharmacology of psychedelics: where the brain meets spirituality.

For 3000 years, psychedelics have been used in religious contexts to enhance spiritual thinking, well-being, and a sense of community. In the last few years, a renaissance in the use of psychedelic drugs for mental disorders has occurred in Western society; consequently, a pressing scientific need to elucidate the intricate mechanisms underlying their actions has arisen. Psychedelics mainly bind to serotonin (5-HT) receptors, particularly 5-HT2A receptors, but may also bind to other receptors. Unlike conventional psychotropic drugs used in psychiatry, psychedelics introduce a distinctive complexity. They not only engage in receptor activation, but also exert influence over specific neural circuits, thereby facilitating transformative cognitive experiences and fostering what many have identified as a spiritual contemplation or mystical experience. This comprehensive review describes clinical studies that have examined the propensity of psychedelics to enhance spiritual, mystical, and transcendent cognitive states. This multifaceted nature, encompassing diverse components and paradigms, necessitates careful consideration during the investigation of psychedelic mechanisms of action to avoid oversimplification. The present review endeavours to elucidate the mechanisms underlying the actions of 2 principal psychedelic substances, psilocybin and lysergic acid diethylamide (LSD), with a focus on monoamine and glutamate receptor mechanisms; molecular aspects, such as neuroplasticity and epigenetics; as well as the impact of psychedelics on brain circuits, including the default mode network and the cortico-striato-thalamo-cortical network. Given their distinctive and intricate mechanisms of action, psychedelics necessitate a novel conceptual framework in psychiatry, offering insight into the treatment of mental health disorders and facilitating the integration of the realms of brain, mind, and spirituality.

Prescription of psychotropic drugs by non-psychiatrist specialists in Morocco: current practices and educational needs.

INTRODUCTION: Mental health is considered a major public health issue. Non-psychiatric physicians often engage in the treatment of mental disorders. The aim of this study was to describe psychiatric drug prescription knowledge and practices among non-psychiatric specialists and evaluate their training needs. METHODS: A descriptive cross-sectional study was conducted from September 1st to October 15th, 2021, in 3 Moroccan healthcare facilities and among private practitioners in Kenitra. We asked non-psychiatric specialists about their knowledge and current practices regarding psychotropic drugs, and their needs in psychiatric training. RESULTS: The study included a total of 150 participants. The majority of participants demonstrated insufficient knowledge regarding the selection of psychotropic drugs and the duration of pharmacotherapy. Specifically, 61.3% were unaware of the average duration of treatment for depression. 22.7% of participants did not feel comfortable when prescribing psychotropic drugs. Anxiolytics were the most commonly prescribed class of psychotropic drugs, accounting for 30.7% of prescriptions. The most common indications for psychotropic drugs prescription were anxiety (35.3%), followed by insomnia (34.7%) and depression (31.3%). The majority of participants (72%) reported receiving clinical training in psychiatry, with 74.7% expressing varying levels of satisfaction with their undergraduate psychiatry training, while 7.3% expressed dissatisfaction. Regarding CME, only 11.3% of participants engaged in at least one psychiatry-related CME session in the past two years. 54.7% of participants expressed interest in expanding their knowledge of prescribing psychotropic drugs. Around 40% of participants preferred trainings in psychotropic drugs prescription related to their specialty, while 34% were not interested in receiving further training. CONCLUSIONS: Our study shows gaps in knowledge of non-psychiatric specialists, which raises concern regarding their ability to care for mental disorders. Educational efforts should be made to improve teaching of psychiatry from the undergraduate level. Continuing Medical Education should be tailored to the specific needs and preferred learning methods of non-psychiatric physicians.

Cannabis Laws and Utilization of Medications for the Treatment of Mental Health Disorders.

Importance: Mental health disorders are prevalent yet undertreated health conditions in the US. Given perceptions about the potential effect of cannabis on individuals with mental health disorders, there is a need to understand the association of cannabis laws with psychotropic use. Objective: To investigate the association of medical and recreational cannabis laws and dispensary openings with the dispensing of psychotropic medications used to treat mental health disorders in the US. Design, Setting, and Participants: This cross-sectional study of 10 013 948 commercially insured patients used a synthetic control method to examine the association of cannabis policies with prescribing. Data on all patients dispensed prescriptions for each of the 5 classes of psychotropic medications from January 1, 2007, to December 31, 2020, were extracted from Optum's deidentified Clinformatics Data Mart Database. Statistical analysis was performed from September 2022 to November 2023. Exposures: The 4 exposure variables measured were whether medical or recreational cannabis laws were in effect and whether medical or recreational cannabis dispensaries were open in each state and calendar quarter. Main Outcome and Measures: One measure of the extensive margins of dispensing and 2 measures of the intensive margins of dispensing were constructed for 5 medication classes (benzodiazepines, antidepressants, antipsychotics, barbiturates, and sleep medications). Results: The primary sample (the benzodiazepine sample) included 3 848 721 patients (mean [SD] age, 46.1 [11.4] years; 65.4% women; 53.7% aged 35-54 years). Medical cannabis laws were associated with a 12.4% reduction in the benzodiazepine fill rate (average treatment effect on the treated [ATT], -27.4; 95% CI, -14.7 to 12.0; P = .001), recreational cannabis laws were associated with a 15.2% reduction in the fill rate (ATT, -32.5; 95% CI, -24.4 to 20.1; P = .02), and medical cannabis laws were associated with a 1.3% reduction in the mean number of benzodiazepine fills per patient (ATT, -0.02; 95% CI, -0.02 to 0.02; P = .04). Medical dispensaries were associated with a 3.9% reduction in mean days' supply per benzodiazepine fill (ATT, -1.7; 95% CI, -0.8 to 0.6; P = .001), while recreational dispensaries were associated with a 6.2% reduction (ATT, -2.4; 95% CI, -1.0 to 0.9; P < .001). Medical cannabis laws were associated with a 3.8% increase in antidepressant fills (ATT, 27.2; 95% CI, -33.5 to 26.9; P = .048), and medical dispensaries were associated with an 8.8% increase (ATT, 50.7; 95% CI, -32.3 to 28.4; P = .004). The mean number of antipsychotic medication fills per patient increased by 2.5% (ATT, 0.06; 95% CI, -0.04 to 0.05; P = .02) after medical cannabis laws and by 2.5% (ATT, 0.06; 95% CI, -0.04 to 0.04; P = .02) after medical dispensary openings. Findings for the other drug classes showed substantial heterogeneity by state and direction of association. Conclusions and Relevance: This cross-sectional study of commercially insured patients suggests that there may have been meaningful heterogeneous associations between cannabis policy and state and between cannabis policy and drug class (eg, decreases in dispensing of benzodiazepines but increases in dispensing of antidepressants and antipsychotics). This finding suggests additional clinical research is needed to understand the association between cannabis use and mental health. The results have implications for patient substance use and mental health-related outcomes.

Metabolic Syndrome among Patients Taking Atypical Antipsychotics: A Comparative Cross-Sectional Study at Erada and Mental Health Complex in Taif, Saudi Arabia.

Introduction: Second-Generation Antipsychotics (SGAs) are widely used for treating psychiatric disorders due to their favorable side effect profile compared to First-Generation Antipsychotics (FGAs). However, SGAs are associated with significant metabolic side effects. This study aims to explore the sociodemographic and health differences between individuals using SGAs and those not using them. Methods: A comparative cross-sectional study was conducted with 148 participants, including 102 SGA users and 46 non-users. Data were collected from patients and medical records, encompassing sociodemographic factors and health variables including diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, waist circumference, fasting blood glucose, cholesterol, triglycerides, HDL, LDL, and BMI. Statistical analyses included chi-square and Fisher's exact tests to compare the two groups. Results: SGA users had higher rates of overweight and obesity compared to non-users (p = 0.000), with 30.4% overweight and 29.4% obese among SGA users versus 21.7% overweight and 4.3% obese among non-users. A higher prevalence of cardiovascular disease was observed in SGA users (11.8% vs. 2.2%, p = 0.076). Although not statistically significant, trends indicated higher rates of diabetes mellitus and hyperlipidemia in non-users (30.4% vs. 18.6%, p = 0.110 and 7% vs. 0%, p = 0.083, respectively). Conclusion: This study highlights significant differences in BMI and cardiovascular disease prevalence between SGA users and non-users, reinforcing the need for comprehensive metabolic monitoring in patients treated with SGAs. The findings underscore the importance of considering sociodemographic factors in managing the health risks associated with SGA use. Further research with larger sample sizes and longitudinal designs is warranted to better understand these associations and develop targeted interventions.

New Psychoactive Substances Toxicity: A Systematic Review of Acute and Chronic Psychiatric Effects.

New psychoactive substances (NPSs) are a heterogenous group of psychotropic molecules and diverted pharmaceutical drugs sold worldwide as legal substitutes for controlled drugs. The psychiatric consequences of NPS use are relatively unknown, although evidence of related psychotic symptoms has been described in the literature. We sought to summarize the available evidence on NPS-related psychiatric disorders, to facilitate the interpretation of the molecular mechanism underlying their specific pathologies. A literature search of Scopus, PubMed and Google Scholar was conducted including studies published between 2013 and 2024, in which a correlation between NPS consumption and psychiatric symptoms was reported. Furthermore, the short- and long-term psychopathological effects were included. The literature search resulted in 109 NPS-related intoxication cases in which acute or chronic psychiatric symptoms were reported, mostly related to synthetic cannabinoids, followed by synthetic cathinones, hallucinogens, natural NPSs and stimulants. The most common acute symptoms were hallucinations, aggressiveness, and psychotic and bizarre behavior, related to the molecular disbalance of neurotransmitters in the central nervous systems, with different mechanisms. The lack of clear diagnostic criteria and toxicological analyses has resulted in crucial complications in psychiatric diagnoses related to NPS intoxication. Hence, the implementation of toxicological screening procedures in emergency rooms, including the main NPS classes, should support the diagnosis of acute intoxication and its proper therapeutic treatment. Finally, proper follow-up should be implemented to assess the chronic sequelae.

Multi-Omics Integration Analysis Pinpoint Proteins Influencing Brain Structure and Function: Toward Drug Targets and Neuroimaging Biomarkers for Neuropsychiatric Disorders.

Integrating protein quantitative trait loci (pQTL) data and summary statistics from genome-wide association studies (GWAS) of brain image-derived phenotypes (IDPs) can benefit in identifying IDP-related proteins. Here, we developed a systematic omics-integration analytic framework by sequentially using proteome-wide association study (PWAS), Mendelian randomization (MR), and colocalization (COLOC) analyses to identify the potentially causal brain and plasma proteins for IDPs, followed by pleiotropy analysis, mediation analysis, and drug exploration analysis to investigate potential mediation pathways of pleiotropic proteins to neuropsychiatric disorders (NDs) as well as candidate drug targets. A total of 201 plasma proteins and 398 brain proteins were significantly associated with IDPs from PWAS analysis. Subsequent MR and COLOC analyses further identified 313 potentially causal IDP-related proteins, which were significantly enriched in neural-related phenotypes, among which 91 were further identified as pleiotropic proteins associated with both IDPs and NDs, including EGFR, TMEM106B, GPT, and HLA-B. Drug prioritization analysis showed that 6.33% of unique pleiotropic proteins had drug targets or interactions with medications for NDs. Nine potential mediation pathways were identified to illustrate the mediating roles of the IDPs in the causal effect of the pleiotropic proteins on NDs, including the indirect effect of TMEM106B on Alzheimer's disease (AD) risk via radial diffusivity (RD) of the posterior limb of the internal capsule (PLIC), with the mediation proportion being 11.18%, and the indirect effect of EGFR on AD through RD of PLIC, RD of splenium of corpus callosum (SCC), and fractional anisotropy (FA) of SCC, with the mediation proportion being 18.99%, 22.79%, and 19.91%, respectively. These findings provide novel insights into pathogenesis, drug targets, and neuroimaging biomarkers of NDs.

[Pharmacological effects of fonturacetam (Actitropil) and prospects for its clinical use]. / Farmakologicheskie effekty fonturatsetama (Aktitropil) i perspektivy ego klinicheskogo primeneniya.

Phenylpiracetam (PP) is a nootropic drug with additional pharmacological effects, including anxiolytic, antiasthenic, antidepressant, anti-inflammatory and anticonvulsant effects. The paper presents the results of an analysis of experimental and clinical studies, which indicate the prospects for the use of PP in cerebral ischemia, neurodegenerative pathologies, epilepsy, asthenia, and mental disorders. The adaptogenic properties and mitochondrial protective effect of PP are considered, assessments of the possible effect of PP on neurotransmitter systems, regulation of carbohydrate and fat metabolism with the prospects for the use of PP in patients with metabolic syndrome.

Orexin receptor antagonists in the treatment of insomnia associated with psychiatric disorders: a systematic review.

Insomnia is highly comorbid in patients with psychiatric disorders, including depression, bipolar disorder, and substance use disorders, and should be treated as an independent condition. Dual orexin receptor antagonists (DORAs) have been investigated as a treatment for chronic insomnia. The objective of this systematic review was to examine evidence for two DORAs, lemborexant and suvorexant, as treatments for insomnia comorbid with a psychiatric disorder. We searched PubMed, Cochrane, and Embase from their inception until January and April 2023, and included studies examining suvorexant and lemborexant for treating insomnia comorbid with psychiatric disorders. We also manually searched clinical trial registries ( https://clinicaltrials.gov and https://www.umin.ac.jp/ctr ). Randomized clinical trials and observational/cohort studies were included. We identified 18 studies from PubMed, Cochrane, and Embase and three studies from clinicaltrials.gov and UMIN. Of the 21 reports, four were completed/terminated randomized clinical trials, eight were ongoing clinical trials, and nine were observational studies. We identified evidence for switching from benzodiazepine receptor agonists to a DORA, or using a DORA as add-on therapy and, therefore, discuss this topic as well. Two studies examined switching to or adding on a DORA in patients being treated with a benzodiazepine receptor agonist. DORAs may be as effective and safe for treating psychiatric comorbid insomnia (for most psychiatric conditions) as they are for treating primary insomnia. However, the evidence is limited to a few small studies. Further investigation of DORAs for the treatment of comorbid insomnia in those with coexisting psychiatric conditions is warranted.

Pharmacogenomic scores in psychiatry: systematic review of current evidence.

In the past two decades, significant progress has been made in the development of polygenic scores (PGSs). One specific application of PGSs is the development and potential use of pharmacogenomic- scores (PGx-scores) to identify patients who can benefit from a specific medication or are likely to experience side effects. This systematic review comprehensively evaluates published PGx-score studies in psychiatry and provides insights into their potential clinical use and avenues for future development. A systematic literature search was conducted across PubMed, EMBASE, and Web of Science databases until 22 August 2023. This review included fifty-three primary studies, of which the majority (69.8%) were conducted using samples of European ancestry. We found that over 90% of PGx-scores in psychiatry have been developed based on psychiatric and medical diagnoses or trait variants, rather than pharmacogenomic variants. Among these PGx-scores, the polygenic score for schizophrenia (PGSSCZ) has been most extensively studied in relation to its impact on treatment outcomes (32 publications). Twenty (62.5%) of these studies suggest that individuals with higher PGSSCZ have negative outcomes from psychotropic treatment - poorer treatment response, higher rates of treatment resistance, more antipsychotic-induced side effects, or more psychiatric hospitalizations, while the remaining studies did not find significant associations. Although PGx-scores alone accounted for at best 5.6% of the variance in treatment outcomes (in schizophrenia treatment resistance), together with clinical variables they explained up to 13.7% (in bipolar lithium response), suggesting that clinical translation might be achieved by including PGx-scores in multivariable models. In conclusion, our literature review found that there are still very few studies developing PGx-scores using pharmacogenomic variants. Research with larger and diverse populations is required to develop clinically relevant PGx-scores, using biology-informed and multi-phenotypic polygenic scoring approaches, as well as by integrating clinical variables with these scores to facilitate their translation to psychiatric practice.

Lifestyle and mood correlates of cardiometabolic risk in people with serious mental illness on second-generation antipsychotic medications.

INTRODUCTION: Cardiovascular morbidity and mortality are high in people with serious mental illness (SMI). This problem is mediated, at least in part, by metabolic side effects of second-generation antipsychotics (SGAs) and by unhealthy lifestyle behaviors. We asked whether oral glucose tolerance testing (oGTT) or hemoglobin A1c (HbA1c) is superior in identifying people with SMI at high cardiometabolic risk and whether this risk is shaped by mood, cognition, or lifestyle habits. METHODS: We evaluated 40 patients with schizophrenia, schizoaffective, or bipolar disorder receiving SGAs by oGTT, HbA1c, comprehensive metabolic and lipid panels, and CRP. Mood was assessed using the Patient Health Questionnaire (PHQ-9), and cognition was assessed using the Saint Louis University Mental Status examination. Diet was assessed using the UK Diabetes and Diet Questionnaire (UKDDQ), and physical activity was assessed using daily step counts. RESULTS: Most patients had prediabetes (preDM) or diabetes mellitus (DM), 72.5% by oGTT, and 52.5% by HbA1c criteria. Pulse rates and insulin resistance indices (Homeostatic Model Assessment of Insulin Resistance, HOMA IR; Matsuda) were significantly different between patients classified as normal or with preDM/DM, using either oGTT or HbA1c criteria. Patients with preDM/DM by HbA1c but not oGTT criteria also had higher waist/hip ratios, triglyceride, and CRP levels (p<0.05). A strong negative correlation was found between average daily step counts and CRP levels (rho = -0.62, p<0.001). Higher UKDDQ scores, or unhealthier diet habits, were associated with higher fasting plasma glucose (rho = 0.28, p = 0.08), triglyceride levels (rho = 0.31, p = 0.05), and insulin resistance (HOMA IR: rho = 0.31, p = 0.06). Higher PHQ-9 scores correlated with lower 2h-oGTT glucose levels (rho = -0.37, p<0.05). CONCLUSIONS: OGTT screening is superior to HbA1c screening in detecting preDM and DM early. Patients identified with preDM/DM by oGTT or HbA1c screening are insulin-resistant and have higher pulse rates. Abdominal obesity, unfavorable lipid profiles, and higher CRP levels were noted in patients screened by HbA1c, but not by oGTT. Low physical activity, low depression scores, and unhealthy diet habits were associated with higher CRP and higher glucose and triglyceride levels, respectively. Future studies should assess the impact of specifically tailored individual lifestyle counseling and medical management interventions in this high-risk population.

Factors Associated with Readmission within 30 Days of Hospital Discharge of Psychiatric Patients: Case-Control Study.

BACKGROUND: Readmission, defined as any admission after discharge from the same hospital, has negative implications for health outcomes. This study aims to identify the sociodemographic and clinical factors associated with hospital readmission among psychiatric patients. METHODOLOGY: This case-control study analyzed 202 clinical records of patients admitted to a psychiatric hospital between 2019-2021. The sample was selected using simple random sampling. Qualitative variables were presented using frequencies, percentages, and chi-square tests for association. Quantitative variables were described using central tendency measures and dispersion of data, investigated with the Kolmogorov-Smirnov test, Student's t-test or Wilcoxon test as appropriate. Regression analysis was conducted to determine factors linked to readmission. p < 0.05 was considered. RESULTS: Women accounted for a higher readmission rate (59%). Patients diagnosed with schizophrenia had a higher readmission rate (63%), experienced longer transfer times to the hospital during readmissions, and had shorter hospital stays. Polypharmacy and pharmacological interactions were associated with readmission. Olanzapine treatment was identified as a risk factor for readmission (ExpB = 3.203, 95% CI 1.405-7.306, p = 0.006). CONCLUSIONS: The findings suggest avoiding polypharmacy and medications with high side effect profiles to reduce readmissions. This study offers valuable insights for clinical decision-making from admission to discharge planning, aiming to enhance the quality of care.

Expanding the therapeutic potential of neuro(active)steroids: a promising strategy for hyperdopaminergic behavioral phenotypes.

Imbalances in dopamine activity significantly contribute to the pathophysiology of several neuropsychiatric disorders, including addiction, ADHD, schizophrenia, impulse control disorders, and Parkinson's Disease. Neuro(active)steroids, comprising endogenous steroids that finely modulate neuronal activity, are considered crucial regulators of brain function and behavior, with implications in various physiological processes and pathological conditions. Specifically, subclasses of Neuro(active)steroids belonging to the 5α reductase pathway are prominently involved in brain disorders characterized by dopaminergic signaling imbalances. This review highlights the neuromodulatory effects of Neuro(active)steroids on the dopamine system and related aberrant behavioral phenotypes. We critically appraise the role of pregnenolone, progesterone, and allopregnanolone on dopamine signaling. Additionally, we discuss the impact of pharmacological interventions targeting 5α reductase activity in neuropsychiatric conditions characterized by excessive activation of the dopaminergic system, ranging from psychotic (endo)phenotypes and motor complications to decision-making problems and addiction.

Mental health related adverse events of cytisine and varenicline in smokers with and without mental health disorders: Secondary analysis of a randomized controlled trial.

INTRODUCTION: Little is known about the adverse events (AEs) of cytisine versus varenicline among individuals with mental health disorders (MHDs), highlighting the necessity for further exploration to inform clinical practice. This secondary analysis of clinical trial data aimed to investigate the effect of varenicline vs. cytisine regarding mental-health-related AEs (MH-related AEs) on smokers with and without MHDs. METHODS: Australian daily smokers interested in quitting were randomised to varenicline (84 days) or cytisine (25 days) and categorised by self-reported MHD diagnosis or treatment in the past year (MHD or non-MHD groups). Treatment adherence was assessed by self-reported number of doses taken during the active treatment phase via two check-in calls (at one month), while AEs were evaluated through four phone interviews: two check-in calls (one month) and follow-up calls at four and seven months. Logistic regression analysis compared MH-related AEs between groups, including only participants taking at least one dose. RESULTS: Of 1452 smokers 246 reported MHDs, 725 received cytisine and 727 received varenicline. Median number of doses taken was comparable between MHD (34 cytisine and 12 varenicline) and non-MHD (33 cytisine and 13 varenicline) groups. MH-related AEs were: 14.1 % (n = 30) in MHD (12.5 % in cytisine and 15.4 % in varenicline), and 11.8 % (n = 126) in non-MHD group (10.9 % in cytisine and 13.7 % in varenicline). No significant difference in MH-related AE occurrence was identified between medication groups (aOR=0.96, 95 % CI 0.4 to 2.2, p-value = 0.94). CONCLUSION: Comparable MH-related AEs were observed between smokers with and without MHDs, suggesting that cytisine, like varenicline, may be well-tolerated by those with MHDs. However, larger clinical trials focused on MH-related AEs are needed for more conclusive evidence.

Adherence to psychopharmacological treatment in patients with severe and persistent mental disorders: A systematic review.

INTRODUCTION: It is known that non-adherence to psychiatric medications has harmful consequences for both patients and society. OBJECTIVE: To collect information on the incidence of non-adherence, and the factors and causes affecting adherence to psychopharmacological treatment in patients with severe and persistent mental disorders. METHODS: A systematic review of scientific articles on adult patients (>17 years) published in the last five years (2015-2020) on specialised databases such as PubMed, Scopus, Scielo and BioMed. Original articles from indexed journals with an impact factor >0.5, in English or Spanish, with an analytical, prospective, retrospective, cross-sectional and randomised design were included. Once the articles were identified, they were analysed, extracting the information necessary to answer the research questions. RESULTS: Fifteen articles were included. Of these, 40% (n = 6) were published in 2020, 20% (n = 3) were produced in China and 53.3% (n = 8) had an observational design. A total of 5,837 patients were included, of which 50.6% were men (n = 2,955), with moderate adherence (n = 10; 66.7%) reported in 10 investigations. Non-adherence varies from 7.7% to 60.6%. The factors that affect adherence are specific to the patient (age and sex), their family support network, and related to the disease or the treatment. The main cause of non-adherence is lack of insight. CONCLUSIONS: Adherence to treatment with psychotropic drugs is multifactorial. Access to mental health services should be improved, with an emphasis placed on patient education and providing greater knowledge of mental illness. Interventions to promote education and interaction with the psychiatrist could be beneficial.

The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy.

It has been unequivocally established that kynurenic acid has a number of actions in a variety of cells and tissues, raising, in principle, the possibility of targeting its generation, metabolism or sites of action to manipulate those effects to a beneficial therapeutic end. However, many basic aspects of the biology of kynurenic acid remain unclear, potentially leading to some confusion and misinterpretations of data. They include questions of the source, generation, targets, enzyme expression, endogenous concentrations and sites of action. This essay is intended to raise and discuss many of these aspects as a source of reference for more balanced discussion. Those issues are followed by examples of situations in which modulating and correcting kynurenic acid production or activity could bring significant therapeutic benefit, including neurological and psychiatric conditions, inflammatory diseases and cell protection. More information is required to obtain a clear overall view of the pharmacological environment relevant to kynurenic acid, especially with respect to the active concentrations of kynurenine metabolites in vivo and changed levels in disease. The data and ideas presented here should permit a greater confidence in appreciating the sites of action and interaction of kynurenic acid under different local conditions and pathologies, enhancing our understanding of kynurenic acid itself and the many clinical conditions in which manipulating its pharmacology could be of clinical value.