Pharmacodynamics of pemoline in attention deficit disorder with hyperactivity.

The onset, duration, and offset of pemoline action to improve cognitive performance is examined intensively in 25 prepubescent males suffering from attention-deficit disorder with hyperactivity (ADDH). The purpose was to characterize the pharmacodynamics of pemoline in ADDH patients through correlation of plasma pemoline concentration with psychometric measures of memory search efficiency and paired-associates learning, with the physiological effect of pemoline on dopaminergic transmission concurrently measured by analysis of plasma prolactin response. The effect of pemoline on neuroprocessing is apparent within the first 2 hours after administration with an inverse relationship between plasma pemoline and prolactin concentration present at hour one only (r = 0.84; p = 0.005). Pemoline therapy for 3 weeks does not significantly affect area under the curve for pemoline or prolactin nor did the effect on memory search efficiency decrease, suggesting no apparent tolerance.     

Expanding the donor pool: regional variation in pediatric organ donation rates

There are limited published data on pediatric organ donation rates. The aim of this study was to describe the trends in pediatric organ donation over time and to assess the regional variation in pediatric deceased organ donation. OPTN data were utilized to assess the trends in pediatric organ donation over time. The number of deceased pediatric organ donors was indexed using regional mortality data obtained from the National Center for Health Statistics and compared across UNOS regions and two different eras. The number of pediatric deceased organ donors has declined in the recent era, largely driven by fewer adolescent donors. For all age groups, there is significant regional variation in organ donation rates, with identifiable high‐ and low‐performing regions. Expansion of the donor pool may be possible by optimizing organ donation in regions demonstrating lower recruitment of pediatric donors. Using the region with the highest donation rate for each age group as the gold standard, we estimate a potential 24% increase in the number of donors if all regions performed comparably, equating to 215 new pediatric donors annually.     

The additive impact of cardio‐metabolic disorders and psychiatric illnesses on accelerated brain aging

Severe mental illnesses (SMI) including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD) elevate accelerated brain aging risks. Cardio‐metabolic disorders (CMD) are common comorbidities in SMI and negatively impact brain health. We validated a linear quantile regression index (QRI) approach against the machine learning “BrainAge” index in an independent SSD cohort (N = 206). We tested the direct and additive effects of SMI and CMD effects on accelerated brain aging in the N = 1,618 (604 M/1,014 F, average age = 63.53 ± 7.38) subjects with SMI and N = 11,849 (5,719 M/6,130 F; 64.42 ± 7.38) controls from the UK Biobank. Subjects were subdivided based on diagnostic status: SMI+/CMD+ (N = 665), SMI+/CMD− (N = 964), SMI−/CMD+ (N = 3,765), SMI−/CMD− (N = 8,083). SMI (F = 40.47, p = 2.06 × 10⁻¹⁰) and CMD (F = 24.69, p = 6.82 × 10⁻⁷) significantly, independently impacted whole‐brain QRI in SMI+. SSD had the largest effect (Cohen’s d = 1.42) then BD (d = 0.55), and MDD (d = 0.15). Hypertension had a significant effect on SMI+ (d = 0.19) and SMI− (d = 0.14). SMI effects were direct, independent of MD, and remained significant after correcting for effects of antipsychotic medications. Whole‐brain QRI was significantly (p < 10⁻¹⁶) associated with the volume of white matter hyperintensities (WMH). However, WMH did not show significant association with SMI and was driven by CMD, chiefly hypertension (p < 10⁻¹⁶). We used a simple and robust index, QRI, the demonstrate additive effect of SMI and CMD on accelerated brain aging. We showed a greater effect of psychiatric illnesses on QRI compared to cardio‐metabolic illness. Our findings suggest that subjects with SMI should be among the targets for interventions to protect against age‐related cognitive decline.     

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10^?3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = ?.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.     

ENIGMA-DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research

The ENIGMA-DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder-oriented working groups used the ENIGMA-DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA-defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross-diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large-scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross-diagnosis features.     

Multiple-dose pharmacokinetics of fluvoxamine in children and adolescents

OBJECTIVE: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. METHOD: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder or other disorder requiring fluvoxamine treatment. Serum samples were collected over 12 hours after 12 or more consecutive doses of 25, 50, 100, and 150 mg. RESULTS: Sixteen children (seven females, nine males) and 18 adolescents (nine females, nine males) were included in the pharmacokinetic analyses. Children demonstrated higher mean peak plasma concentration, higher mean area under the plasma concentration-time curve, and lower apparent oral clearance compared with adolescents. Compared with male children, female children had higher mean area under the plasma concentration-time curve, higher mean peak plasma concentration, and more reports of adverse events. However, the area under the plasma concentration-time curve was not directly correlated with frequency or severity of adverse events. Pharmacokinetics were nonlinear over the dose range studied. No pharmacokinetic differences were apparent between adolescents and adults on 150 mg b.i.d. CONCLUSIONS: These pharmacokinetic results suggest that children (especially females) have a higher exposure to fluvoxamine than adolescents, whereas adolescents and adults appear to have similar exposure to fluvoxamine.     

Adderall XR: long acting stimulant for single daily dosing

Adderall XR (SLI381) is the latest addition to the group of psychostimulant formulations, which provides the mixed amphetamine salts contained in Adderall as a single-daily dose formulation. Adderall XR is indicated for the treatment of attention deficit hyperactivity disorder in children and adolescents, with recent US Food and Drug Administration approval for attention deficit hyperactivity disorder in adults. Novel and important aspects of Adderall XR is its 12 h duration of action, relative superior efficacy to nonstimulant atomoxetine in a comparator trial, and significant quality of life impact in children, confirmed by the largest effectiveness trial yet to be performed for any attention deficit hyperactivity disorder therapy. Potentially important benefits of Adderall XR are proven safety and efficacy in adults with attention deficit hyperactivity disorder and positive postmarketing findings in treating oppositional defiant disorder -- the most common comorbidity in children with attention deficit hyperactivity disorder. This review summarizes the important properties of Adderall XR, to include a distinct two-stage delivery system and combination of active ingredients, offering unique advantages. Relevant clinical trials and the newest data from meeting reports are also discussed.     

Id proteins in cell growth and tumorigenesis

Since the gene encoding Id1 was cloned in 1990, Id proteins have been implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. The development of knockout and transgenic animal models for many members of the Id gene family has been particularly useful in sorting out the biologic relevance of these genes and their expression during normal development, malignant transformation, and tumor progression. Here we review the current understanding of Id gene function, the biologic consequences of Id gene expression, and the implications for Id gene regulation of cell growth and tumorigenesis.