Youth Mental Health Screening and Linkage to Care.

One Mind, in partnership with Meadows Mental Health Policy Institute, convened several virtual meetings of mental health researchers, clinicians, and other stakeholders in 2020 to identify first steps toward creating an initiative for early screening and linkage to care for youths (individuals in early adolescence through early adulthood, ages 10-24 years) with mental health difficulties, including serious mental illness, in the United States. This article synthesizes and builds on discussions from those meetings by outlining and recommending potential steps and considerations for the development and integration of a novel measurement-based screening process in youth-facing school and medical settings to increase early identification of mental health needs and linkage to evidence-based care. Meeting attendees agreed on an initiative incorporating a staged assessment process that includes a first-stage brief screener for several domains of psychopathology. Individuals who meet threshold criteria on the first-stage screener would then complete an interview, a second-stage in-depth screening, or both. Screening must be followed by recommendations and linkage to an appropriate level of evidence-based care based on acuity of symptoms endorsed during the staged assessment. Meeting attendees proposed steps and discussed additional considerations for creating the first nationwide initiative for screening and linkage to care, an initiative that could transform access of youths to mental health screening and care.

Preliminary evidence supporting the practice of psychosis-risk screening within an inpatient psychiatric setting serving adolescents.

Evidence supports the use of brief psychosis-spectrum screening measures to identify individuals at elevated risk for psychosis, however, there is limited research on psychosis-spectrum screening among adolescents hospitalized for acute mental health concerns. Given the psychiatric vulnerability of this population, screening efforts within inpatient settings may help identify adolescents at greatest risk for ongoing mental health concerns including psychosis. This study investigates the use of two brief screening tools to identify psychosis-spectrum symptoms in psychiatrically hospitalized adolescents. Upon intake, adolescents completed two screening measures, the PRIME Screen-Revised and the Youth Self-Report Thought Problems scale, followed by a brief interview to evaluate psychosis-spectrum diagnoses. Associations between screening scores and diagnostic status were explored to evaluate the use of these tools to identify psychosis-spectrum conditions in this population. The sample included 57 adolescents, 28 of whom met psychosis-spectrum criteria. Psychosis-spectrum status was strongly correlated with PRIME scores (r = 0.59) and Thought Problems T scores (r = 0.55). Logistic regression analyses indicated that both screening measures demonstrate promising accuracy (74-81%) for identifying adolescents meeting psychosis-spectrum criteria. The PRIME and Thought Problems scale may be appropriate screening tools for use in adolescent inpatient settings to identify those experiencing clinically significant psychosis-spectrum symptoms.

Evidence for Differential Predictive Performance of the Prime Screen Between Black and White Help-Seeking Youths.

OBJECTIVE: Self-report screening instruments for emerging psychosis have the potential to improve early detection efforts by increasing the number of true positives among persons deemed to be at "clinical high risk" of the disorder, but their practical utility depends on their validity across race. This study sought to examine whether a commonly used self-report screening tool for psychosis risk performed equally among black and white youths in its ability to predict clinical high-risk status. METHODS: Black (N=58) and white (N=50) help-seeking individuals ages 12-25 (61% female) were assessed with the Prime Screen and the Structured Interview for Psychosis-Risk Syndromes (SIPS). A logistic regression model estimated race differences in the strength of the relation between Prime Screen scores and SIPS-defined risk status. RESULTS: Higher Prime Screen scores significantly predicted clinical high-risk status among white (p<.01) but not black participants. Among black youths without clinical high risk, self-reported Prime Screen scores more closely resembled scores for youths (black or white) with clinical high risk than scores of white peers who were also without clinical high risk. CONCLUSIONS: Results suggest that consideration of race or ethnicity and associated cultural factors is important when screening for clinical high-risk status. Findings support the need to develop culturally valid early psychosis screening tools to promote appropriately tailored early intervention efforts.

Trauma and psychosis symptoms in a sample of help-seeking youth.

Although childhood trauma is generally considered to be a risk factor for later development of psychosis, the influence of trauma on the specific presentation of psychosis symptoms in high-risk and first-episode samples remains unclear. The current study aims to investigate the association of trauma with psychosis and psychosis-risk symptoms among patients with early indications of psychosis as well as in a comparison group receiving mental health services for non-psychosis concerns. Participants (N=125) were assessed for history of exposure to trauma using the KSADS-PL and psychosis-risk symptoms using the Structured Interview for Psychosis-Risk Syndromes (SIPS). Individuals were categorized as "clinical high risk/early psychosis" or "low-risk for psychosis" on the basis of SIPS criteria. The association of traumatic events with specific symptoms was explored within each group. Exposure to one or more traumatic events was more common within the early psychosis group (85%) relative to the low-risk group (65%). Within both groups, trauma significantly correlated with the severity of clinician-rated positive - but not negative, disorganized, or general - symptoms. Within the low-risk group, there was a significant association between violent traumas and heightened suspiciousness. Within the early psychosis group, both violent and non-violent traumas predicted elevated grandiosity. The prevalence of traumatic events within this adolescent and young adult clinical sample was high. Trauma history significantly predicted greater positive symptoms. The apparent influence of trauma exposure on specific symptoms was unique in each group.

Attitudes towards cannabis use and genetic testing for schizophrenia.

AIM: Within schizophrenia, genetic factors contribute greatly to risk, yet genetic testing for the disorder is not available. For some individuals with specific genotypes, cannabis use may increase risk of schizophrenia. It is possible that genetic tests could be offered in the future to inform individuals of the risk of schizophrenia if they use cannabis. Previous research, however, provides little guidance on how young adults might respond to such tests. METHODS: We assessed a group of young adults (n = 83) to determine how the perceived magnitude of increased risk for schizophrenia in the presence of cannabis use influences decisions to undergo genetic testing, as well as subsequent attitudes and intentions towards cannabis use. RESULTS: Participants were significantly more likely to indicate willingness to get tested if the results identified a 10% risk versus a 2% risk of schizophrenia. Participants also indicated that if the results of their test reflected increased risk due to cannabis use, it would be more important to avoid cannabis in the 10% risk scenario as compared to the 2% risk scenario. These findings remained consistent among a subset of participants who indicated cannabis use. CONCLUSIONS: Results suggest that cannabis users and non-users were positively influenced in terms of intentions to change behaviour based on the magnitude of risk conveyed by genetic testing. These findings provide an initial step towards understanding young people's attitudes towards genetic testing and may help prepare interventions specifically tailored around cannabis use reduction for people at risk for schizophrenia.

Psychosis risk screening in youth: a validation study of three self-report measures of attenuated psychosis symptoms.

Brief self-report questionnaires that assess attenuated psychosis symptoms have the potential to quickly and effectively screen many people who may benefit from clinical monitoring or early intervention. The current study sought to examine and compare the criterion validities of attenuated symptoms screening tools with diagnoses obtained from the clinician-administered Structured Interview for Psychosis Risk Syndromes (SIPS). Three screening questionnaires (Prime Screen, Prodromal Questionnaire-Brief, and Youth Psychosis At-Risk Questionnaire-Brief) were administered just prior to the SIPS interview in a sample of adolescents and young adults seeking mental health services. Using thresholds recommended by instrument authors as well as empirically derived optimal thresholds, the sensitivity, specificity, positive predictive value, and overall accuracy of each self-report measure with regard to SIPS diagnosis were obtained. Screeners correlated highly with the SIPS and demonstrated equivalent overall efficiency in capturing psychosis risk status. All three screeners appear to be useful and valid assessment tools for attenuated symptoms, with each instrument demonstrating relative benefits. The validation of attenuated symptoms screening tools is an important step toward enabling early, wide-reaching identification of individuals on a course toward psychotic illness.

Green tea polyphenols precondition against cell death induced by oxygen-glucose deprivation via stimulation of laminin receptor, generation of reactive oxygen species, and activation of protein kinase Cε.

As the development of synthetic drugs for the prevention of stroke has proven challenging, utilization of natural products capable of preconditioning neuronal cells against ischemia-induced cell death would be a highly useful complementary approach. In this study using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in PC12 cells, we show that 2-day pretreatment with green tea polyphenols (GTPP) and their active ingredient, epigallocatechin-3-gallate (EGCG), protects cells from subsequent OGD/R-induced cell death. A synergistic interaction was observed between GTPP constituents, with unfractionated GTPP more potently preconditioning cells than EGCG. GTPP-induced preconditioning required the 67-kDa laminin receptor (67LR), to which EGCG binds with high affinity. 67LR also mediated the generation of reactive oxygen species (ROS) via activation of NADPH oxidase. An exogenous ROS-generating system bypassed 67LR to induce preconditioning, suggesting that sublethal levels of ROS are indeed an important mediator in GTPP-induced preconditioning. This role for ROS was further supported by the fact that antioxidants blocked GTPP-induced preconditioning. Additionally, ROS induced an activation and translocation of protein kinase C (PKC), particularly PKCε from the cytosol to the membrane/mitochondria, which was also blocked by antioxidants. The crucial role of PKC in GTPP-induced preconditioning was supported by use of its specific inhibitors. Preconditioning was increased by conditional overexpression of PKCε and decreased by its knock-out with siRNA. Collectively, these results suggest that GTPP stimulates 67LR and thereby induces NADPH oxidase-dependent generation of ROS, which in turn induces activation of PKC, particularly prosurvival isoenzyme PKCε, resulting in preconditioning against cell death induced by OGD/R.

Green tea polyphenols potentiate the action of nerve growth factor to induce neuritogenesis: possible role of reactive oxygen species.

Exogenously administered nerve growth factor (NGF) repairs injured axons, but it does not cross the blood-brain barrier. Thus, agents that could potentiate the neuritogenic ability of endogenous NGF would be of great utility in treating neurological injuries. Using the PC12 cell model, we show here that unfractionated green tea polyphenols (GTPP) at low concentrations (0.1 µg/ml) potentiate the ability of low concentrations of NGF (2 ng/ml) to induce neuritogenesis at a level comparable to that induced by optimally high concentrations of NGF (50 ng/ml) alone. In our experiments, GTPP by itself did not induce neuritogenesis or increase immunofluorescent staining for ß-tubulin III; however, it increased expression of mRNA and proteins for the neuronal markers neurofilament-L and GAP-43. Among the polyphenols present in GTPP, epigallocatechin-3-gallate (EGCG) alone appreciably potentiated NGF-induced neurite outgrowth. Although other polyphenols present in GTPP, particularly epigallocatechin and epicatechin, lack this activity, they synergistically promoted this action of EGCG. GTPP also induced an activation of extracellular signal-regulated kinases (ERKs). PD98059, an inhibitor of the ERK pathway, blocked the expression of GAP-43. K252a, an inhibitor of TrkA-associated tyrosine kinase, partially blocked the expression of these genes and ERK activation. Antioxidants, catalase (cell-permeable form), and N-acetylcysteine (both L and D-forms) inhibited these events and abolished the GTPP potentiation of NGF-induced neuritogenesis. Taken together, these results show for the first time that GTPP potentiates NGF-induced neuritogenesis, likely through the involvement of sublethal levels of reactive oxygen species, and suggest that unfractionated GTPP is more effective in this respect than its fractionated polyphenols.

Negation of the cancer-preventive actions of selenium by over-expression of protein kinase Cepsilon and selenoprotein thioredoxin reductase.

Selenium prevents cancer in some cases but fails to do so in others. Selenium's failure in this respect may be due to the development of resistance to its chemopreventive actions. Selenocompounds induce a variety of cancer-preventive actions in tumor cells, but these actions may be limited by the low concentrations of free selenocompounds able to reach cells from the plasma. Therefore, we have sought to identify the chemopreventive action requiring the lowest concentration of the redox-active form of selenium, methylseleninic acid (MSA). At submicromolar concentrations, MSA inhibited the malignant transformation of RWPE-1 prostate epithelial cells. In contrast, in already transformed prostate cancer cells, selenium in the micromolar range was required to inhibit cell growth and invasion and to induce apoptosis. The role of protein kinase C (PKC) in these cellular processes, especially the moderately selenium-sensitive PKCepsilon, was demonstrated using PKC-specific inhibitors and small interfering RNA. PKCepsilon levels inversely correlated with cellular sensitivity to MSA. An over-expression of PKCepsilon minimized MSA-induced inhibition of RWPE-1 cell transformation and induction of apoptosis. Thioredoxin reductase (TR), a selenoprotein, reversed the MSA-induced inactivation of PKC isoenzymes. High TR expression in advanced prostate cancer cells correlated with resistance to MSA. Furthermore, inhibition of TR by its specific inhibitor, auranofin, resulted in increased sensitivity of prostate cancer cells to MSA. Collectively, these results suggest that the cancer-preventive actions of selenium may be negated both by an over-expression of PKCepsilon, which is a redox-sensitive target for MSA, and by the selenoprotein TR, which reverses PKC sulfhydryl redox modification.

Locally generated methylseleninic acid induces specific inactivation of protein kinase C isoenzymes: relevance to selenium-induced apoptosis in prostate cancer cells.

In this study, we show that methylselenol, a selenometabolite implicated in cancer prevention, did not directly inactivate protein kinase C (PKC). Nonetheless, its oxidation product, methylseleninic acid (MSA), inactivated PKC at low micromolar concentrations through a redox modification of vicinal cysteine sulfhydryls in the catalytic domain of PKC. This modification of PKC that occurred in both isolated form and in intact cells was reversed by a reductase system involving thioredoxin reductase, a selenoprotein. PKC isoenzymes exhibited variable sensitivity to MSA with Ca(2+)-dependent PKC isoenzymes (alpha, beta, and gamma) being the most susceptible, followed by isoenzymes delta and epsilon. Other enzymes tested were inactivated only with severalfold higher concentrations of MSA than those required for PKC inactivation. This specificity for PKC was further enhanced when MSA was generated within close proximity to PKC through a reaction of methylselenol with PKC-bound lipid peroxides in the membrane. The MSA-methylselenol redox cycle resulted in the catalytic oxidation of sulfhydryls even with nanomolar concentrations of selenium. MSA inhibited cell growth and induced apoptosis in DU145 prostate cancer cells at a concentration that was higher than that needed to inhibit purified PKC alpha but in a range comparable with that required for the inhibition of PKC epsilon. This MSA-induced growth inhibition and apoptosis decreased with a conditional overexpression of PKC epsilon and increased with its knock-out by small interfering RNA. Conceivably, when MSA is generated within the vicinity of PKC, it specifically inactivates PKC isoenzymes, particularly the promitogenic and prosurvival epsilon isoenzyme, and this inactivation causes growth inhibition and apoptosis.

A direct redox regulation of protein kinase C isoenzymes mediates oxidant-induced neuritogenesis in PC12 cells.

In this study, we have used the PC12 cell model to elucidate the mechanisms by which sublethal doses of oxidants induce neuritogenesis. The xanthine/xanthine oxidase (X/XO) system was used for the steady state generation of superoxide, and CoCl(2) was used as a representative transition metal redox catalyst. Upon treatment of purified protein kinase C (PKC) with these oxidants, there was an increase in its cofactor-independent activation. Redox-active cobalt competed with the redoxinert zinc present in the zinc-thiolates of the PKC regulatory domain and induced the oxidation of these cysteine-rich regions. Both CoCl(2) and X/XO induced neurite outgrowth in PC12 cells, as determined by an overexpression of neuronal marker genes. Furthermore, these oxidants induced a translocation of PKC from cytosol to membrane and subsequent conversion of PKC to a cofactor-independent form. Isoenzyme-specific PKC inhibitors demonstrated that PKCepsilon plays a crucial role in neuritogenesis. Moreover, oxidant-induced neurite outgrowth was increased with a conditional overexpression of PKCepsilon and decreased with its knock-out by small interfering RNA. Parallel with PKC activation, an increase in phosphorylation of the growth-associated neuronal protein GAP-43 at Ser(41) was observed. Additionally, there was a sustained activation of extracellular signal-regulated kinases 1 and 2, which was correlated with activating phosphorylation (Ser(133)) of cAMP-responsive element-binding protein. All of these signaling events that are causally linked to neuritogenesis were blocked by antioxidant N-acetylcysteine (both L and D-forms) and by a variety of PKC-specific inhibitors. Taken together, these results strongly suggest that sublethal doses of oxidants induce neuritogenesis via a direct redox activation of PKCepsilon.