An analysis of views about supported reduction or discontinuation of antipsychotic treatment among people with schizophrenia and other psychotic disorders.

BACKGROUND: Antipsychotic medication can reduce psychotic symptoms and risk of relapse in people with schizophrenia and related disorders, but it is not always effective and adverse effects can be significant. We know little of patients' views about continuing or discontinuing antipsychotic treatment. AIMS: To explore the views of people with schizophrenia and other psychotic disorders about continuing their antipsychotic medication or attempting to reduce or discontinue this medication with clinical support. METHODS: We collected quantitative and qualitative data by conducting semi-structured interviews in London, UK. Factors predicting a desire to discontinue medication were explored. Content analysis of qualitative data was undertaken. RESULTS: We interviewed 269 participants. 33% (95% CI, 27 to 39%) were content with taking long-term antipsychotic medication. Others reported they took it reluctantly (19%), accepted it on a temporary basis (24%) or actively disliked it (18%). 31% (95% CI, 25 to 37%) said they would like to try to stop medication with professional support, and 45% (95% CI, 39 to 51%) wanted the opportunity to reduce medication. People who wanted to discontinue had more negative attitudes towards the medication but were otherwise similar to other participants. Wanting to stop or reduce medication was motivated mainly by adverse effects and health concerns. Professional support was identified as potentially helpful to achieve reduction. CONCLUSIONS: This large study reveals that patients are commonly unhappy about the idea of taking antipsychotics on a continuing or life-long basis. Professional support for people who want to try to reduce or stop medication is valued.

A qualitative exploration of family members' perspectives on reducing and discontinuing antipsychotic medication.

BACKGROUND: Antipsychotics are routinely prescribed to people diagnosed with schizophrenia or psychosis on a long-term basis. Considerable literature explores service users' opinions and experiences of antipsychotics, but studies investigating family members' views are lacking. AIMS: To explore family members' perspectives on antipsychotics, particularly their views on long-term use, reduction and discontinuation of antipsychotics. METHODS: Semi-structured interviews were conducted with 11 family members of people experiencing psychosis. Participants were recruited through community support groups and mental health teams. Interviews were analysed thematically. RESULTS: The majority of family members valued antipsychotic medication primarily in supporting what they saw as a fragile stability in the person they cared for. Their views of medication were ambivalent, combining concerns about adverse effects with a belief in the importance of medication due to fears of relapse. They described a need for constant vigilance in relation to medication to ensure it was taken consistently, and often found changes, particularly reduction in medication difficult to contemplate. CONCLUSIONS: Findings highlight that family members' attitudes to medication sometimes conflict with those of the people they care for, impacting on their health and the caring relationship. Family members may need more support and could be usefully involved in medication decision-making.

My Personal Experience of Orthodox Psychiatry and Alternative Approaches.

Ruth Smith's incisive and moving account of her experiences with orthodox psychiatry as delivered by the UK National Health Service sets the scene for this special section. She gives a detailed description of her own twelve years' experience as a Carer to her daughter, diagnosed with psychosis at age 24 years. She explains how they struggled to comply with the psychiatric services and cope with the, often traumatic, treatment provided to them. Clearly, we need to do better, but how? Smith explains how her study of critical texts and research papers on the subject helped to form her own critical viewpoint.

The Intersection of Racial-Ethnic Socialization and Adolescence: A Closer Examination at Stage-Salient Issues.

The literature on parental racial-ethnic socialization (RES) has established the multiple protective effects of RES on developmental outcomes. Although the majority of this literature examines RES processes in adolescence, with the exception of identity processes this literature has not specifically tackled how these messages intersect with specific adolescent developmental processes. We review the literature on RES processes in non-White adolescents with a focus on the parent-adolescent relationship, risk-taking behaviors, romantic relationships, and different contexts (i.e., extracurricular, work, and social media settings). We propose that developmental science needs to account for how parental RES may not only change in adolescence, but in particular responds to the perceived risks associated with this developmental period and interacts with normative developmental tasks and milestones.

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases.

Non-substrate-like inhibitors of glycosyltransferases are sought after as chemical tools and potential lead compounds for medicinal chemistry, chemical biology and drug discovery. Here, we describe the discovery of a novel small molecular inhibitor chemotype for LgtC, a retaining α-1,4-galactosyltransferase involved in bacterial lipooligosaccharide biosynthesis. The new inhibitors, which are structurally unrelated to both the donor and acceptor of LgtC, have low micromolar inhibitory activity, comparable to the best substrate-based inhibitors. We provide experimental evidence that these inhibitors react covalently with LgtC. Results from detailed enzymological experiments with wild-type and mutant LgtC suggest the non-catalytic active site residue Cys246 as a likely target residue for these inhibitors. Analysis of available sequence and structural data reveals that non-catalytic cysteines are a common motif in the active site of many bacterial glycosyltransferases. Our results can therefore serve as a blueprint for the rational design of non-substrate-like, covalent inhibitors against a broad range of other bacterial glycosyltransferases.

Statistical approach to establish equivalence of unabbreviated mass spectra.

RATIONALE: In many legal and regulatory applications, mass spectral comparison of an unknown or questioned sample to a reference standard or database is used for identification; however, no statistical confidence level or error rate is determined. Therefore, a simple and rapid method to establish the statistical equivalence of mass spectra is needed. METHODS: The standard deviation of the abundance at each m/z ratio was determined from replicate measurements or from a statistical model. These standard deviations were used in an unequal variance t-test to compare two spectra at every m/z ratio over the entire scan range. If determined to be statistically indistinguishable at every m/z ratio, the random-match probability (RMP) that the specific mass spectral fragmentation pattern occurred by chance was calculated. RESULTS: n-Alkane and alkylbenzene standards of varying concentrations were analyzed on the same instrument at different ionization voltages. Using the proposed method, replicate spectra were successfully associated at the 99.9% confidence level, with RMP values less than 10(-29). Despite the similarity in fragmentation patterns, spectra were distinguished from others in the homologous series. Moreover, the n-alkane spectra were appropriately associated to and discriminated from those in a standard reference database at the 99.9% confidence level. CONCLUSIONS: A simple and rapid method to assign statistical significance to the comparison of mass spectra was developed and validated. This method may be useful for legal and regulatory applications, such as the identification of controlled substances, environmental pollutants, and food and drug contaminants.

A low-cost phantom design for evaluating spine SABR calculations in the presence of prosthetic vertebral stabilization.

Dose-perturbation characteristics are important to consider during the calculation of radiation therapy protocols for patients who are going to receive high doses that would reach the tolerance limits of the spinal cord [1]. Several studies have investigated dose perturbations introduced by metal implants in close proximity to spine SABR treatments [2-7]. However, there is a lack of work assessing this effect using the RayStation TPS [8]. We present an initial design for a low-cost phantom to evaluate spine stereotactic ablative radiotherapy (SABR) in the presence of prosthetic vertebral stabilization. The phantom is modular, allowing the prosthetic at the centre of the phantom to be removed by exchanging the central block. It also includes space to insert ion chamber and film. The agreement of the RayStation TPS (v8.0B) collapsed cone convolution (CCC) calculation and measurement was determined for phantom versions with and without prosthetic. There was little to no change in the agreement between the measured and calculated dose when introducing metallic hardware. This suggests that our Raystation-based SABR planning approach for patients with spinal hardware meets clinical expectations. Departments without access to anthropomorphic phantoms may find this design useful but should test their phantom design in typical clinical settings to ensure it is robust to real world situations.

Early diagnosis and treatment of HIV infection: magnitude of benefit on short-term mortality is greatest in older adults.

BACKGROUND: the number and proportion of adults diagnosed with HIV infection aged 50 years and older has risen. This study compares the effect of CD4 counts and anti-retroviral therapy (ART) on mortality rates among adults diagnosed aged ≥50 with those diagnosed at a younger age. METHODS: retrospective cohort analysis of national surveillance reports of HIV-diagnosed adults (15 years and older) in England, Wales and Northern Ireland. The relative impacts of age, CD4 count at diagnosis and ART on mortality were determined in Cox proportional hazards models. RESULTS: among 63,805 adults diagnosed with HIV between 2000 and 2009, 9% (5,683) were aged ≥50 years; older persons were more likely to be white, heterosexual and present with a CD4 count <200 cells/mm(3) (48 versus 32% P < 0.01) and AIDS at diagnosis (19 versus 9%, P < 0.01). One-year mortality was higher in older adults (10 versus 3%, P < 0.01) and especially in those diagnosed with a CD4 <200 cells/mm(3) left untreated (46 versus 15%, P < 0.01). While the relative mortality risk reduction from ART initiation at CD <200 cells/mm(3) was similar in both age groups, the absolute risk difference was higher among older adults (40 versus 12% fewer deaths) such that the number needed to treat older adults to prevent one death was two compared with eight among younger adults. CONCLUSIONS: the magnitude of benefit from ART is greater in older adults than younger adults. Older persons should be considered as a target for HIV testing. Coupled with prompt treatment, earlier diagnosis is likely to reduce substantially deaths in this group.

Identifying reliable ions for the statistical differentiation of structurally similar fentanyl analogs.

Definitive identification of fentanyl analogs based on mass spectral comparison is challenging given the high degree of structural and, hence, spectral similarity. To address this, a statistical method was previously developed in which two electron-ionization (EI) mass spectra are compared using the unequal variance t-test. Normalized intensities of corresponding ions are compared, testing the null hypothesis (H0 ) that the difference in intensity is equal to zero. If H0 is accepted at all m/z values, the two spectra are statistically equivalent at the specified confidence level. If H0 is not accepted at any m/z value, then there is a significant difference in intensity at that m/z value between the two spectra. In this work, the statistical comparison method is applied to distinguish EI spectra of valeryl fentanyl, isovaleryl fentanyl, and pivaloyl fentanyl. Spectra of the three analogs were collected over a 9-month period and at different concentrations. At the 99.9% confidence level, the spectra of corresponding isomers were statistically associated. Spectra of different isomers were statistically distinct, and ions responsible for discrimination were identified in each comparison. To account for inherent instrument variations, discriminating ions for each pairwise comparison were ranked based on the magnitude of the calculated t-statistic (tcalc ) value. For a given comparison, ions with higher tcalc values are those with the greatest difference in intensity between the two spectra and, therefore, are considered more reliable for discrimination. Using these methods, objective discrimination among the spectra was achieved and ions considered most reliable for discrimination of these isomers were identified.

Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial.

BACKGROUND: Maintenance antipsychotic medication is recommended for people with schizophrenia or recurrent psychosis, but the adverse effects are burdensome, and evidence on long-term outcomes is sparse. We aimed to assess the benefits and harms of a gradual process of antipsychotic reduction compared with maintenance treatment. Our hypothesis was that antipsychotic reduction would improve social functioning with a short-term increase in relapse. METHODS: RADAR was an open, parallel-group, randomised trial done in 19 National Health Service Trusts in England. Participants were aged 18 years and older, had a diagnosis of recurrent, non-affective psychotic disorder, and were prescribed an antipsychotic. Exclusion criteria included people who had a mental health crisis or hospital admission in the past month, were considered to pose a serious risk to themselves or others by a treating clinician, or were mandated to take antipsychotic medication under the Mental Health Act. Through an independent, internet-based system, participants were randomly assigned (1:1) to gradual, flexible antipsychotic reduction, overseen by treating clinicians, or to maintenance. Participants and clinicians were aware of treatment allocations, but assessors were masked to them. Follow-up was for 2 years. Social functioning, assessed by the Social Functioning Scale, was the primary outcome. The principal secondary outcome was severe relapse, defined as requiring admission to hospital. Analysis was done blind to group identity using intention-to-treat data. The trial is completed and has been registered with ISRCTN registry (ISRCTN90298520) and with ClinicalTrials.gov (NCT03559426). FINDINGS: 4157 people were screened, of whom 253 were randomly allocated, including 168 (66%) men, 82 (32%) women, and 3 (1%) transgender people, with a mean age of 46 years (SD 12, range 22-79). 171 (67%) participants were White, 52 (21%) were Black, 16 (6%) were Asian, and 12 (5%) were of other ethnicity. The median dose reduction at any point during the trial was 67% in the reduction group and zero in the maintenance group; at 24 months it was 33% versus zero. At the 24-month follow-up, we assessed 90 of 126 people assigned to the antipsychotic dose reduction group and 94 of 127 assigned to the maintenance group, finding no difference in the Social Functioning Scale (ß 0·19, 95% CI -1·94 to 2·33; p=0·86). There were 93 serious adverse events in the reduction group affecting 49 individuals, mainly comprising admission for a mental health relapse, and 64 in the maintenance group, relating to 29 individuals. INTERPRETATION: At 2-year follow-up, a gradual, supported process of antipsychotic dose reduction had no effect on social functioning. Our data can help to inform decisions about the use of long-term antipsychotic medication. FUNDING: National Institute for Health Research.

Forensic analysis of Salvia divinorum using multivariate statistical procedures. Part I: discrimination from related Salvia species.

Salvia divinorum is a hallucinogenic herb that is internationally regulated. In this study, salvinorin A, the active compound in S. divinorum, was extracted from S. divinorum plant leaves using a 5-min extraction with dichloromethane. Four additional Salvia species (Salvia officinalis, Salvia guaranitica, Salvia splendens, and Salvia nemorosa) were extracted using this procedure, and all extracts were analyzed by gas chromatography-mass spectrometry. Differentiation of S. divinorum from other Salvia species was successful based on visual assessment of the resulting chromatograms. To provide a more objective comparison, the total ion chromatograms (TICs) were subjected to principal components analysis (PCA). Prior to PCA, the TICs were subjected to a series of data pretreatment procedures to minimize non-chemical sources of variance in the data set. Successful discrimination of S. divinorum from the other four Salvia species was possible based on visual assessment of the PCA scores plot. To provide a numerical assessment of the discrimination, a series of statistical procedures such as Euclidean distance measurement, hierarchical cluster analysis, Student's t tests, Wilcoxon rank-sum tests, and Pearson product moment correlation were also applied to the PCA scores. The statistical procedures were then compared to determine the advantages and disadvantages for forensic applications.

Forensic analysis of Salvia divinorum using multivariate statistical procedures. Part II: association of adulterated samples to S. divinorum.

Salvia divinorum is a plant material that is of forensic interest due to the hallucinogenic nature of the active ingredient, salvinorin A. In this study, S. divinorum was extracted and spiked onto four different plant materials (S. divinorum, Salvia officinalis, Cannabis sativa, and Nicotiana tabacum) to simulate an adulterated sample that might be encountered in a forensic laboratory. The adulterated samples were extracted and analyzed by gas chromatography-mass spectrometry, and the resulting total ion chromatograms were subjected to a series of pretreatment procedures that were used to minimize non-chemical sources of variance in the data set. The data were then analyzed using principal components analysis (PCA) to investigate association of the adulterated extracts to unadulterated S. divinorum. While association was possible based on visual assessment of the PCA scores plot, additional procedures including Euclidean distance measurement, hierarchical cluster analysis, Student's t tests, Wilcoxon rank-sum tests, and Pearson product moment correlation were also applied to the PCA scores to provide a statistical evaluation of the association observed. The advantages and limitations of each statistical procedure in a forensic context were compared and are presented herein.

Optical and spectroscopic characterization of crystalline structures in cannabis extracts.

Marijuana and hemp represent two broad classes of Cannabis sativa plants that are distinguished based on the concentration of the psychoactive cannabinoid delta-9-tetrahydrocannabinol (Δ9 -THC). In this work, solvent extracts derived from marijuana and hemp were characterized using optical and spectroscopic techniques. The crystalline components of the solvent extracts were first analyzed using polarized light microscopy to determine optical properties, namely, crystal system, optical sign, and principle refractive indices. Crystals from the marijuana-derived extracts exhibited an orthorhombic crystal system and were optically negative, with nß between 1.6320 and 1.6330 ± 0.0002. In contrast, crystals from hemp-derived extracts exhibited a monoclinic crystal system and were optically positive, with nß between 1.600 and 1.6040 ± 0.0002. Crystals were further distinguished through infrared spectroscopy, which highlighted structural differences between the two sample types, primarily based on differences in O-H stretching. Finally, single-crystal X-ray diffraction was used to definitively identify the crystalline components, confirming the presence of tetrahydrocannabinolic acid in marijuana-derived extracts and cannabidiol in hemp-derived extracts. Given the differences in crystal structure identified between marijuana-derived and hemp-derived solvent extracts, optical characterization provides a screening method to differentiate visually similar samples prior to confirmatory analysis.

Diagnostic accuracy of Achenbach scales in detecting youths' substance use disorders.

It is vital to identify substance use disorders (SUDs) in youths and adults early and accurately. Previous studies have investigated the validity and reliability of the Achenbach Child Behavior Checklist (CBCL) and Youth Self Report (YSR) for other related anxiety, mood, and behavior problems. The present study tested if the CBCL and YSR substance use items can discriminate adolescents with versus without a SUD diagnosis accurately enough to justify clinical application within an evidence-based assessment framework. N = 422 outpatient adolescents (age 9-18) and their caregivers completed semistructured diagnostic interviews. Caregivers completed CBCL, and adolescents completed the YSR. K-SADS-PL + diagnoses indicated that 34 youths met Diagnostic and Statistical Manual (DSM)-IV criteria for SUDs. Receiver Operating Characteristics (ROC) models estimated the likelihood of having Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (KSADS-PL) + SUDs based on substance use scores of CBCL or YSR. Scores on all scales significantly identified KSADS-PL-diagnosed SUDs in adolescents: Area under the curve (AUCCBCL = .90, p < .0005; AUCYSR = .84, p < .0005). There was no significant difference in the accuracy comparing each informant used separately; CBCL showed incremental value above the YSR report when both were included in logistic regression models. CBCL and YSR substance items demonstrated diagnostic and clinical utility in identifying SUDs in adolescents. Findings suggest that Achenbach Scales could be a valuable intake instrument in detecting adolescents SUDs. A supplemental clinical vignette illustrates the clinical application of the study findings. It will be important for future research to replicate use of these measures across varying clinical scenarios and settings. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Priorities for future research on reducing and stopping psychiatric medicines using a James Lind Alliance priority setting partnership: The PROTECT study protocol.

Background: There is a growing number of service users looking to discontinue use of psychiatric medicines. Tapering is the recommended approach for reducing and/or discontinuing the use of psychiatric medicines. This involves gradually reducing the dose over time to minimise the potential for withdrawal symptoms. However, many uncertainties exist regarding the process of reducing and stopping psychiatric medicines. This study will use a James Lind Alliance Priority Setting Partnership to determine the Top 10 unanswered questions and uncertainties about reducing and stopping psychiatric medicines. Methods : The Priority Setting Partnership will be conducted using the James Lind Alliance methodology. It will involve seven stages: (i) creating an international Steering Group of representatives from key stakeholder groups that will include people with lived experience of taking and/or stopping psychiatric medicines, family members, carers/supporters and healthcare professionals, and identifying potential partners to support key activities (e.g. dissemination); (ii) gathering uncertainties about reducing and stopping psychiatric medicines from key stakeholders using an online survey; (iii) data processing and summarising the survey responses; (iv) checking the summary questions against existing evidence and verifying uncertainties; (v) shortlisting the questions using a second online survey; (vi) determining the Top 10 research questions through an online prioritisation workshop; (vii) disseminating results. Conclusions : This study will use a Priority Setting Partnership to generate a Top 10 list of research questions and uncertainties about reducing and stopping psychiatric medicines. This list will help to guide future research and deliver responsive and strategic allocation of research resources, with a view to ultimately improving the future health and well-being of individuals who are taking psychiatric medicines.

Measuring evaporation rate constants of highly volatile compounds for use in predictive kinetic models.

A kinetic model was previously developed in our laboratory to predict evaporation of compounds as a function of gas chromatographic retention index (IT). To define the initial model, evaporation rate constants were experimentally determined for compounds in the range IT = 800-1400 at temperatures from 5 to 35 °C. While the predictive accuracy was demonstrated, broader application of the model requires extension of the IT range to include more volatile compounds. However, such extension requires experimental determination of rate constants, which is challenging due to the explosive hazard and rapid evaporation of volatile compounds. In this work, rate constants of highly volatile compounds were experimentally determined and used to extend the kinetic model to predict evaporation. Prior to experimental evaporations, theoretical calculations were performed to optimize experimental parameters and to ensure that the vapor generated remained below the lower flammability limit for each compound. Compounds were then experimentally evaporated at three different temperatures (10, 20, and 30 °C) and analyzed by gas chromatography-mass spectrometry. The evaporation rate constants for each compound, corrected for condensation, were determined by regression to a first-order rate equation. These rate constants were combined with previously collected data to extend the kinetic model at each temperature. Comparison of predicted and experimentally determined chromatograms of an evaporated validation mixture indicated good model performance, with correlation coefficients ranging from 0.955 to 0.997 and mean absolute percent errors in predicting abundance ranging from 3 to 26%.

Brain-derived neurotrophic factor levels in newly diagnosed patients with bipolar disorder, their unaffected first-degree relatives and healthy controls.

BACKGROUND: Brain-derived neurotrophic factor (BDNF), which facilitates neuroplasticity and synaptogenesis, may be decreased in bipolar disorder, but has not been systematically investigated in people with newly diagnosed bipolar disorder and unaffected first-degree relatives. AIMS: To compare BDNF levels in patients with newly diagnosed bipolar disorder, their unaffected first-degree relatives and healthy controls. METHOD: The study investigated plasma BDNF levels in patients (n = 371) with newly diagnosed bipolar disorder, their unaffected first-degree relatives (n = 98) and healthy controls (n = 200) using enzyme-linked immunosorbent assay. We further investigated associations between BDNF levels and illness-related variables and medication status. RESULTS: BDNF levels were found to be 22.0% (95% CI 1.107-1.343) higher in patients with bipolar disorder compared with healthy controls (P < 0.001) and 15.6% higher in unaffected first-degree relatives compared with healthy controls (95% CI 1.007-1.327, P = 0.04), when adjusting for age and gender. Further, BDNF levels were positively associated with duration of illness at a trend level (P = 0.05), age (P = 0.001) and use of anti-epileptic medication (P = 0.05). CONCLUSIONS: These findings suggest that BDNF levels are not decreased in the early stages of bipolar disorder and in unaffected first-degree relatives contrasting with prior findings during later stages of the illness.