Abuso de andrógenos: como o psiquiatra/sexólogo pode ajudar? / Androgen abuse: how can a psychiatrist/sexologist help?

Contexto e objetivo: o abuso de androgênios não se restringe mais a atletas, uma vez que é utilizado pela população geral para melhora da massa muscular e performance física. Tais doses supra fisiológicas causam vários efeitos colaterais, incluindo psiquiátricos e reprodutivos. Demonstrar a importância dos diagnósticos de quadros psiquiátricos e sexuais, bem como da escolha dos psicotrópicos mais adequados para cada paciente. Métodos: Trata-se de uma revisão narrativa acerca da importância do quadro, bem como seu tratamento. Discussão: Não basta fazer o diagnóstico de abuso de andrógenos. Pesquisar e tratar possíveis quadros psiquiátricos, disfunções sexuais (DS), transtornos parafílicos (TP) e outras doenças somáticas é primordial. Medicações psiquiátricas podem prejudicar a atividade sexual ou não. Transtorno do Comportamento Sexual Compulsivo (TCSC), Transtornos Parafílicos e outras condições sexuais de risco podem exigir psicotrópicos que inibam a função sexual. Porém, o favorecimento de uma atividade sexual saudável, sem sofrimento, pode demandar drogas que causem pouco ou nenhum prejuízo à sexualidade. Conclusão: Conhecer os diagnósticos sexuais, psiquiátricos e clínicos e tratá-los adequadamente é de suma importância. Os mecanismos moleculares e patológicos envolvidos nos efeitos colaterais neuropsiquiátricos dos andrógenos não são claros. Mais pesquisas são necessárias.

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.

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.

Prescription writing quality of psychotropic agents in MBBS interns in a private medical college hospital in Mangaluru.

Background: Rational prescription writing is an important skill to master during internship. This Quality Improvement (QI) project aimed to understand the state of prescription writing among interns posted in the Department of Psychiatry, analyze the causes responsible for errors in prescription writing and bring about a change in the current practice. Methods: The MBBS interns are posted in the Department of Psychiatry for 15 days. During day 1 to day 5 of their posting, a pre intervention phase was conducted wherein prescriptions written by interns in the Department of Psychiatry were collected. The prescriptions were scored based on 14 criteria which were selected based on World Health Organization (WHO) guidelines and Medical Council of India (MCI) ideal prescription format. During PDSA (Plan Do Study Act) Cycle 1, an educational handout was distributed to the interns containing the MCI ideal prescription format and WHO guidelines regarding prescription writing. The brochure was also verbally explained to the interns. From day 7 to day 15 of their posting, prescriptions written by the interns were collected. The prescriptions were scored using the same criteria. Results: During the pre intervention phase the mean total score of prescriptions was 9.54 ± 1.003. There was a significant improvement in the mean total score to 10.26 ± 0.746. There was a 7.54% improvement. There was also a significant improvement in several individual criteria. Conclusions: The first PDSA cycle was successful in improving the quality of prescription writing among interns posted in the Department of Psychiatry. There is a need to implement more PDSA cycles to improve the quality still further.

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.

Application of design of experiment for quantification of 71 new psychoactive substances in influent wastewater.

BACKGROUND: New psychoactive substances (NPS) are of public health concern due to their sporadic proliferation and the dearth of information on toxicity when consumed. In addition to seized data from forensic and toxicology reporting, wastewater analysis serves as a complimentary tool for NPS surveillance. A method to detect 71 NPS by simple filtration followed by liquid-chromatography tandem mass spectrometry was developed to detect multiclass NPS consisting of arylcyclohexylamines, designer benzodiazepines, synthetic cannabinoids, synthetic opioids, phenethylamines, synthetic cathinones, tryptamines, and indole alkaloids. RESULTS: In this work, the influential factors for electrospray ionisation were identified and optimised using the fractional factorial design and face-centred central composite design, respectively. The filtration loss during sample clean-up was assessed for all compounds. The final method was validated and applied to wastewater collected from a music festival held in Queensland in 2022. The validated method had linearity between 0.5 ng L-1 and 5000 ng L-1, the limit of quantification (LOQ) ranges from 0.6 ng L-1 to 70 ng L-1, precision within ±20 %, accuracy ranges from 70 % to 120 %, and matrix effect ranges from soft (0 %-20 %) to medium (20 %-50 %) for the majority of the compounds. NPS detected in the festival were 2-fluorodeschloroketamine, 7-hydroxymitragynine, mitragynine, N,N-dimethylpentylone, pentylone, phenibut, and O-desmethyltramadol. SIGNIFICANCE: Systematic electrospray ionisation optimisation using the design of experiment for a large method is practical and provides in-depth chemical information on studied compounds. The optimised method demonstrated the applicability of analysing samples collected from a festival in this work.

Research Progress on Detection of New Psychoactive Substance Piperazines in vivo.

Piperazines are a class of new psychoactive substances with hallucinogenic effects that affect the central nervous system by affecting the level of monoamine neurotransmitters. Abuse of piperazines will produce stimulating and hallucinogenic effects, accompanied by headache, dizziness, anxiety, insomnia, vomiting, chest pain, tachycardia, hypertension and other adverse reactions, and may even cause cardiovascular diseases and multiple organ failure and lead to death, seriously affecting human physical and mental health and public safety. The abuse of new psychoactive substance piperazines has attracted extensive attention from the international community. The study of its pharmacological toxicology and analytical methods has become a research hotspot in the field of forensic medicine. This paper reviews the in vivo processes, sample treatment and analytical methods of existing piperazines, in order to provide reference for forensic identification.

Development of a CZE-MS/MS method with dynamic pH junction sample pretreatment for analysis of kratom psychoactive alkaloids in urine.

BACKGROUND: Kratom is a herbal substance belonging to the group of new psychoactive substances. It contains psychoactive indole alkaloids mitragynine and 7-hydroxymitragynine. At low doses, they act as psychostimulants and at higher doses they mediate an opioid-like effect. The increasing misuse of kratom requires the development of analytical methods that will accurately and reliably identify and quantify its psychoactive alkaloids in biological samples. Therefore, the development of effective, precise, and reliable green analytical methods that are easy to implement in practice is of great importance. On-line combination of capillary zone electrophoresis with tandem mass spectrometry (CZE-MS/MS) seems to be a promising solution. RESULTS: We present a novel green approach based on capillary zone electrophoresis - tandem mass spectrometry (CZE-MS/MS) method with on-line dynamic pH junction sample pretreatment to identify and determine mitragynine and 7-hydroxymitragynine in urine samples. The separation was performed in a background electrolyte composed of 100 mM formic acid (pH 2.39). The dynamic pH junction was ensured by injection of a short plug of 12.5 % NH4OH before the sample. Under optimal conditions, the developed method was validated and parameters such as linearity (r2 > 0.99), precision (2.2-8.7 %), accuracy (89.2-102.5 %) or stability of the sample (86.6-114.7 %) met the defined FDA guideline criteria (%RSD and %RE values where within ±15 %). Introduction of a simple in-capillary preconcentration strategy based on dynamic pH junction enabled significant improvement in analytical signal intensity and also the applicability of the method. Applying the presented approach, high sensitivity was achieved as indicated by limit of detection values, which were 0.5 ng mL-1 and 2 ng mL-1 for mitragynine and 7-hydroxymitragynine, respectively. Greenness of the proposed approach was confirmed by the AGREE metrics (score 0.63). The application potential of the developed method was successfully verified using blinded urine model samples. SIGNIFICANCE: For the first time a fully validated CZE-MS/MS method for kratom alkaloids determination was introduced. The presented novel method is a cheaper and more ecological alternative to conventionally used chromatographic techniques what was clearly confirmed by its greenness evaluation and comparison with previously published liquid chromatography (LC) approaches. In-capillary sample pretreatment (dynamic pH junction) has been demonstrated to be an effective and fast tool in bioanalysis, minimizing the number of pretreatment steps and the manipulation with the sample. Moreover, LOD values comparable to those obtained by LC methods were recorded. High potential for the implementation of this approach into the toxicology environment in the near future is expected.

Determination of three ephedrine psychoactive substances in sewage using solid-phase extraction-ultra-performance liquid chromatography-tandem mass spectrometry.

RATIONALE: In recent years, ephedrine psychoactive substances have attracted much attention due to their prevalence in water bodies and potential threat to aquatic ecosystems. Psychoactive substances have been considered as a new type of environmental pollutant due to their unpredictable potential risks to the behavior and nervous system of non-target organisms. A rapid, sensitive, selective, and robust method for the quantification of three ephedrine psychoactive substances in sewage is needed. METHODS: An ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of three ephedrine psychoactive substances in water. The optimal processing conditions were determined by optimizing the chromatography-mass spectrometry and solid-phase extraction (SPE) conditions (e.g., the SPE column, sample pH, washing, and elution), and the treatment conditions were determined; this was achieved via positive ion scanning in multiple reaction monitoring mode. Poly-Sery MCX was selected as the extraction column, with samples loaded at pH 3. And 4-mL solution of 2% formic acid (FA) aqueous solution was used as the eluent; the target compounds were eluted with 5 mL of 5% NH4OH in acetonitrile (ACN) solution. The best results were obtained when the residue was resolubulization in ACN after nitrogen evaporation. RESULTS: The developed UPLC-MS/MS showed a good linear relationship in the range of 0-50.00 µg/L, with determination coefficients (R2) greater than 0.9990. The detection limit and quantitation limit were 0.05-0.10 and 0.20-0.50 µg/L, respectively. Recovery rates of the target compounds in blank sewage at three different concentrations ranged from 92.37% to 106.31%, with relative standard deviations (RSDs) of 0.77%-4.83% (n = 7). CONCLUSIONS: This method has been successfully applied to the analysis of surface water and domestic sewage, and the samples were processed stably, indicating that the method is practical for the determination of ephedrine psychoactive drugs in water bodies.

[Forensic toxicological characteristics of modern occupational injuries]. / Sudebno-meditsinskaya toksikologicheskaya kharakteristika sovremennogo proizvodstvennogo travmatizma.

OBJECTIVE: To analyze the contribution of alcohol and drug intoxication to fatal occupational injuries and sudden death at the workplace in Moscow. MATERIAL AND METHODS: A number of death cases of various organizations' employees equal 357 in Moscow in 2023 were investigated. The mean age of the deceased was 48.29±13.9 years, 92.4% of them were men. RESULTS: Ethanol in blood has been determined in 15% of the deceased. Narcotic drugs and psychotropic medications have been found in 6.7% of cases. Signs of chronic intoxication have been established in 16.5% of the deceased. Chronic intoxication accompanied or aggravated the course of 70% of cardiomyopathies. The proportion of deceased in an accident at an industry or construction site equal 23.9%, as well as 1/2 of the deceased in an accident on the street and in a residential building were impaired by alcohol. CONCLUSION: The study of the contribution of alcohol and drug consumption to occupational mortality will allow to plan measures for reducing the mortality of working-age population.

Lifetime Psychotropic Medication Use Among Service Members and Veterans With and Without History of Mild Traumatic Brain Injury: A Pilot Study.

INTRODUCTION: Military Service Members, Veterans, and other patient populations who experience traumatic brain injury (TBI) may have increased risk of early neurodegenerative diseases relative to those without TBI history. Some evidence suggests that exposure to psychotropic medications may play a role in this association. The Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) prospective longitudinal study provides an ideal setting to examine the effects of psychotropic medication exposure on long-term neurological health of those with and without mild TBI history. In this study, we sought to develop and pilot test a self-report electronic survey instrument to measure participants' psychotropic medication histories for use across LIMBIC-CENC study sites. MATERIALS AND METHODS: We developed a new survey instrument measuring psychotropic medication history and fielded it among Service Members and Veterans enrolled in a single site of the LIMBIC-CENC study to evaluate response rates and patterns, and to compare survey responses to prescription data extracted from participants' Veterans Affair (VA) records. Descriptive statistics estimated survey respondents' lifetime psychotropic medication exposures by their TBI history and other demographic and clinical characteristics of interest. We also compared survey responses to participants' VA outpatient prescription records to estimate sensitivity and negative predictive values (NPVs) for participants' self-reported medication exposures relative to this single prescription data source. RESULTS: Among 310 Veterans enrolled at the study site, 249 completed the survey (response rate = 80%), of whom 248 also had VA health records and were included in the analysis. Most (69%) had a history of mild TBI. Over three-fourths of survey respondents (78%) reported ever having used prescription opioids, 26% reported benzodiazepines, 50% reported muscle relaxants, 42% reported antidepressants, 13% reported non-benzodiazepine sedative-hypnotics, 15% reported stimulants, 7% reported mood stabilizers, and 6% reported antipsychotics. Veterans with, versus without, a history of mild TBI were more likely to self-report psychotropic medication history as well as have confirmed receipt of VA prescriptions for each medication class. Using VA records as a criterion standard, the sensitivity of the survey for detecting VA prescriptions ranged from 19% to 84%, while the NPVs ranged from 64% to 97%. Sensitivity and NPVs were similar for participants with, versus without, mild TBI history. CONCLUSIONS: Service Members and Veterans may receive psychotropic medications from multiple sources over their lifetimes. Valid methods to examine and quantify these exposures among those with a history of TBI are important, particularly as we evaluate causes of neurodegenerative disorders in this population over time. The measurement of Veterans' lifetime psychotropic medication exposures using a self-report survey, in combination with health care records, holds promise as a valid approach, but further testing and refinement are needed.

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.

Common mental health diagnoses arising from or coinciding with menopausal transition and prescribing of SSRIs/SNRIs medications and other psychotropic medications.

BACKGROUND: Women with menopausal transition (MT) have an elevated risk of experiencing common mental health diagnoses (CMHD: depression or anxiety). There is no recent data comparing the rate, and treatment, of CMHD between men and women. METHODS: In this population-based study, incidence rates (IR) per 100 person-years-at-risk (PYAR) for men and women ≥45 years registered with an UK primary care practice between 2010 and 2021 were estimated. Incidence rate ratios (IRR) with 95 % confidence intervals (CIs) of CMHD were estimated using men as a reference. We measured first prescriptions for psychotropic medications received within 12 months after CMHD. For selective serotonin reuptake inhibitors (SSRIs) /selective norepinephrine reuptake inhibitors (SNRIs), we measured the IR of prescribing per 100 PYAR, by 10-year bands. Proportion of SSRIs/SNRIs prescribing was estimated per 100 persons. RESULTS: Rates of anxiety and depressive disorders were 1.68 and 1.69 per 100 PYAR in women aged 45-54 years-old compared to 0.91 and 1.20 per 100 PYAR in men, with IRR of 1.84 (95 % CI 1.72-1.97) and 1.44 (1.35-1.53) respectively. SSRIs/SNRIs were the most prescribed medication; in 2021, IRs for SSRIs/SNRIs were 13.4 per 100 PYAR in both sexes. In 2021, the proportion of SSRIs/SNRIs prescribing was 50.67 per 100 women and 41.91 per 100 men. LIMITATIONS: MT is assumed based on women's age as menopause onset is rarely recorded in primary care databases. CONCLUSIONS: Women ≥45 years experienced more CMHD compared to men, especially 45-54 years-olds, which coincides with MT. The proportion of SSRIs/SNRIs prescribing was higher in women.

Variations in Dispensing Psychotropic Drugs to Adolescents Depending on School Periods: A French Nationwide Retrospective Study.

Seasonality patterns are reported for various psychiatric disorders. Concerning adolescents, there is an increased frequency of general emergency department visits for mental health disorders observed between March and May, as well as in October and November. We conducted a retrospective cohort study using the French health insurance medico-administrative database. We extracted psychotropic drug deliveries occurring between 2015 and 2019 for patients aged between 12 and 18 years old. Each drug delivery was classified as occurring during a school period (Sc), the summer holidays (SumH) or other shorter holidays periods (ShH). We compared the number of distinct patients, as well as the proportion of new consumers, according to week status. Anxiolytics and hypnotics were more frequently dispensed during the school periods and short breaks than during the summer holidays. Conversely, antidepressants were more commonly dispensed during the short breaks rather than school periods and summer holidays. The stressful effects induced by schooling appear to be addressed in the first line by anxiolytics and hypnotics, while antidepressants are more frequently introduced during school holidays.

AlphaFold accelerated discovery of psychotropic agonists targeting the trace amine-associated receptor 1.

Artificial intelligence is revolutionizing protein structure prediction, providing unprecedented opportunities for drug design. To assess the potential impact on ligand discovery, we compared virtual screens using protein structures generated by the AlphaFold machine learning method and traditional homology modeling. More than 16 million compounds were docked to models of the trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor of unknown structure and target for treating neuropsychiatric disorders. Sets of 30 and 32 highly ranked compounds from the AlphaFold and homology model screens, respectively, were experimentally evaluated. Of these, 25 were TAAR1 agonists with potencies ranging from 12 to 0.03 µM. The AlphaFold screen yielded a more than twofold higher hit rate (60%) than the homology model and discovered the most potent agonists. A TAAR1 agonist with a promising selectivity profile and drug-like properties showed physiological and antipsychotic-like effects in wild-type but not in TAAR1 knockout mice. These results demonstrate that AlphaFold structures can accelerate drug discovery.

Pathophysiological impacts of 5-MeO-MiPT on zebrafish (Danio rerio) via the Gαq/11-PLCß signaling pathway.

Novel Psychoactive Substances (NPS) derived from tryptamines has been detected in aquatic environments, leading to environmental toxicology concerns. However, the specific toxicological mechanism, underlying these NPS, remains unclear. In our previous work, we used 5-Methoxy-N-isopropyl-N-methyltryptamine (5-MeO-MiPT) as the representative drug for NPS, and found that, 5-MeO-MiPT led to obvious behavioral inhibition and oxidative stress responses in zebrafishes model. In this study, Zebrafish were injected with varying concentrations of 5-MeO-MiPT for 30 days. RNA-seq, qPCR, metabolomics, and histopathological analyses were conducted to assess gene expression and tissue integrity. This study confirms that 5-MeO-MiPT substantially influences the transcription and expression of 13 selected genes, including ucp1, pet100, grik3, and grik4, mediated by the Gαq/11-PLCß signaling pathway. We elucidate the molecular mechanism that 5-MeO-MiPT can inhibit DAG-Ca2+/Pkc/Erk, Pkc/Pla2/PLCs and Ca2+/Camk Ⅱ/NMDA, while enhance Ca2+/Creb. Those secondary signaling pathways may be the mechanisms mediating 5-MeO-MiPT inhibiting normal behavior in zebrafish. These findings offer novel insights into the toxicological effects and addiction mechanisms of 5-MeO-MiPT. Moreover, it presents promising avenues for investigating other tryptamine-based NPS and offers a new direction for diagnosing and treating liver-brain pathway-related diseases.

Challenging behaviour, the application of restrictive measures and psychotropic drug prescription in people with intellectual disabilities.

BACKGROUND: Prescribing of psychotropic drugs (PDs) and applying restrictive measures are both frequently used in managing challenging behaviour of people with intellectual disabilities (ID), which is not always according to guidelines or good clinical practice. AIMS: This study aimed to investigate the potential triangular relationship between challenging behaviour, the application of restrictive measures and PD prescription. METHODS AND PROCEDURES: In this cross-sectional study, data on challenging behaviour, PD prescription and restrictive measures were collected. We defined and compared four mutually exclusive groups of participants. OUTCOMES AND RESULTS: Challenging behaviour in the group in whom one or more PD were prescribed as a restrictive measures (PDRM) was more severe than in the other three groups. More severe challenging behaviour, a higher number of antipsychotics, antidepressants and anxiolytics/hypnotics prescriptions, a lower dosage, and more application of domotics as restrictive measure was shown in the PDRM compared to the group in whom PDs were prescribed according to guidelines (PDNRM). CONCLUSIONS AND IMPLICATIONS: We did not find indications for a triangular relationship of challenging behaviour, the application of restrictive measures and PD prescriptions. Future longitudinal research is needed to better understand this complex relationship and should investigate the indication and the effect of treatment. WHAT THIS PAPER ADDS?: This study is a first exploration of the potential triangular relationship between symptoms of challenging behaviour, psychotropic drug (PD) prescription, and the application of restrictive measures. Prescribing PDs and applying restrictive measures are two interventions which are commonly used to manage challenging behaviour in people with intellectual disabilities. Both have been subject of research separately in recent years. However, it is conceivable that the PD prescription in treatments for challenging behaviour could be a substitute for another form of a restrictive measure, for example a physical or mechanical restraint. For this purpose, we defined and compared four mutually exclusive groups of participants. We found no indication for this triangular relationship. On the other hand, we found the highest severity of challenging behaviour in the group who used PDs as restrictive measure next to other restrictive measures. Our results may suggest that both prescribing PDs and applying non-pharmacological restrictive measures are used simultaneously in managing challenging behaviour, are not sufficiently implemented or effective.

Psychotropic Medications Promote Time-Dependent Reduction of Suicidal Ideation in Mood Disorder: A Prospective Cohort Study.

BACKGROUND: Despite a plethora of research on the topic, there is still no solid evidence that pharmacological treatment actually reduces the risk of suicide in patients with mental illness. In this study, we aimed to assess the effect of psychotropic medications on suicidal ideation in patients with major depressive disorder (MDD) and bipolar disorder (BPD) in two age groups: less than 25 years and 25 years and older. METHODS: We analyzed 312 patients with mood disorders with current suicidal thoughts or recent suicide attempts. We followed the participants from baseline for 6 months and assessed changes in suicidal ideation with Columbia-Suicide Severity Rating Scale (C-SSRS). The effect of psychotropic drug administration on suicidal ideation over time was analyzed using a linear mixed model. RESULTS: In patients aged 25 years and older with mood disorders, suicidal ideation was more severe when using psychotropic drugs than when not using them. However, suicidal ideation decreased rapidly over time. The time-dependent reduction in suicidal ideation was accelerated when using antidepressants and sedatives/hypnotics in adult MDD, and when using mood stabilizers in adult BPD. However, this effect was not observed in participants aged less than 25 years. CONCLUSION: Adequate psychotropic medication may reduce suicidal ideation in patients with mood disorders aged 25 years and older. Additional research on psychotropic drugs is needed to effectively reduce the risk of suicide among children and adolescents with mood disorders.

Analysis of crude wastewater from two treatment plants in South Wales for 35 new psychoactive substances and cocaine, and cannabis.

This study investigates the presence of new psychoactive substances (NPS) and their metabolites in two wastewater treatment plants (WWTPs) situated in South Wales, UK (WWTP-1 and WWTP-2). Analysis was conducted for 35 NPS and metabolites, along with the inclusion of benzoylecgonine (main cocaine metabolite) and cannabis, the most detected illicit substances. Benzoylecgonine was identified as the predominant substance in both WWTPs. Epidemiological calculations revealed the average population consumption of cocaine to be 3.88 mg/d/1000 inhabitants around WWTP-1 and 1.97 mg/d/1000 inhabitants for WWTP-2. The removal efficiency of benzoylecgonine across both WWTPs was observed at an average of 73%. Subsequent qualitative analyses on randomly selected wastewater samples detected medicinal compounds including buprenorphine, methadone, and codeine in both WWTPs. An additional experiment employing enzymatic hydrolysis revealed the presence of morphine, an increased presence of codeine, and 11-Nor-9-Carboxy-THC (THC-COOH) post-hydrolysis. These findings underscore the significant presence of illicit substances and medicinal compounds in wastewater systems with the absence of NPS within the South Wales area, highlighting the necessity for enhanced monitoring and treatment strategies to address public health and environmental concerns.

In-stream attenuation and enantioselective fractionation of psychiatric pharmaceuticals in a wastewater effluent-dominated river basin.

Wastewater effluent is the main contributor of psychiatric pharmaceuticals (PPs) pollution in surface waters. However, little is known about its spatial evolution dynamics in effluent-dominated rivers. Herein, 10 representative PPs, including 6 chiral pharmaceuticals and 4 achiral pharmaceuticals, were explored in the Beiyun River, a typical wastewater effluent-dominated river, to explore their occurrence, in-stream attenuation and enantioselective fractionation behaviors at a watershed scale. Among the target substances, 8 and 9 drugs were detected in surface water and sediment samples with the ΣPPs concentrations ranging from 78.4 to 260.1 ng/L and 4.8 to 43.4 ng/g dw in surface water and sediments, respectively. Along the mainstream of the Beiyun River, only several PPs detected in surface water, e.g., citalopram, O-demethylvenlafaxine, and fluoxetine, exhibited in-stream attenuation behaviors when reaching rural area, while all PPs detected in sediments displayed in-stream attenuation behavior. Four chiral PPs detected in surface water exhibited an enantioselective attenuation phenomenon, while in sediments, only citalopram displayed an enantioselective fractionation behavior. The differences in the in-stream attenuation and enantioselective environmental behavior of individual PPs caused complex contaminant evolution along the stream reach. This work provides enantiomeric profiles of chiral pollutants for evaluating their in-stream attenuation processes, which would facilitate better understanding of the changing contaminant exposure conditions in complex natural environments.