Comparison of neuropsychological functioning in pediatric posterior fossa tumor survivors: Medulloblastoma, low-grade astrocytoma, and healthy controls.

BACKGROUND: Neuropsychological comparison of medulloblastoma (MB) and cerebellar low-grade astrocytoma (LGA) survivors to controls can clarify treatment-related neurocognitive late effects. While both brain tumor groups undergo surgery to the posterior fossa, children with MB additionally receive craniospinal irradiation with boost and chemotherapy. This study provides an updated comparison of neuropsychological functioning in these two groups and examines effects of demographic risk factors upon outcomes. PROCEDURE: Forty-two children (16 MB, nine LGA, and 17 controls) completed measures of intellectual functioning, verbal learning/memory, visual-motor integration, and fine-motor functioning. The effects of age at diagnosis, time since diagnosis, gender, fatigue, and social status on neuropsychological functioning were examined. RESULTS: MB survivors demonstrated the worst neurocognitive late effects, but they were less severe and extensive than in prior studies. LGA survivors' mean scores were below normative expectations in working memory, processing speed, and fine-motor functioning. In this overall sample, processing speed difficulties were independent of fine-motor functioning and fatigue. Higher parental education was associated with better intellectual functioning, working memory, delayed recall, and visual-motor integration. Neuropsychological function was not associated with gender, age at diagnosis, or time since diagnosis. CONCLUSION: The results support that contemporary treatment approaches with craniospinal irradiation plus boost and chemotherapy confer the greatest risk for late effects, while surgical resection is associated with subtle but important neurocognitive difficulties. Ultimately, this study furthers our understanding of factors impacting neuropsychological function in pediatric MB and LGA survivors and contributes to empirical support for close monitoring and targeted interventions into survivorship.

Long-term neuropsychological outcomes of survivors of young childhood brain tumors treated on the Head Start II protocol.

BACKGROUND: The Head Start treatment protocols have focused on curing young children with brain tumors while avoiding or delaying radiotherapy through using a combination of high-dose, marrow-ablative chemotherapy and autologous hematopoietic cell transplantation (AuHCT). Late effects data from treatment on the Head Start II (HS II) protocol have previously been published for short-term follow-up (STF) at a mean of 39.7 months post-diagnosis. The current study examines long-term follow-up (LTF) outcomes from the same cohort. METHODS: Eighteen HS II patients diagnosed with malignant brain tumors <10 years of age at diagnosis completed a neurocognitive battery and parents completed psychological questionnaires at a mean of 104.7 months' post-diagnosis. RESULTS: There was no significant change in Full Scale IQ at LTF compared to baseline or STF. Similarly, most domains had no significant change from STF, including verbal IQ, performance IQ, academics, receptive language, learning/memory, visual-motor integration, and externalizing behaviors. Internalizing behaviors increased slightly at LTF. Clinically, most domains were within the average range, except for low average mathematics and receptive language. Additionally, performance did not significantly differ by age at diagnosis or time since diagnosis. Of note, children treated with high-dose methotrexate for disseminated disease or atypical teratoid/rhabdoid tumor displayed worse neurocognitive outcomes. CONCLUSIONS: These results extend prior findings of relative stability in intellectual functioning for a LTF period. Ultimately, this study supports that treatment strategies for avoiding or delaying radiotherapy using high-dose, marrow-ablative chemotherapy and AuHCT may decrease the risk of neurocognitive and social-emotional declines in young pediatric brain tumor survivors.

The Impact of Sleep on the Relationship between Soccer Heading Exposure and Neuropsychological Function in College-Age Soccer Players.

OBJECTIVE: Soccer is the most popular sport worldwide and is the only sport where athletes purposely use their head to deflect the ball during play, termed "heading" the ball. These repetitive head impacts (RHI) are associated with worse neuropsychological function; however, factors that can increase risk of injury following exposure to such head impacts have been largely unexamined. The present study provided a novel examination of the modifying role of sleep on the relationship between RHI exposure and neuropsychological function in college-age soccer players. METHODS: Fifty varsity and intramural college soccer players completed questionnaires assessing recent and long-term heading exposure, a self-report measure of sleep function, and a battery of neuropsychological tests. RESULTS: A high level of recent heading exposure was significantly associated with poorer processing speed, independent of concussion history. With reduced sleep duration, a high level of recent heading exposure was related to worse sustained attention. However, with greater hours of sleep duration, heading exposure was related to preserved neuropsychological outcome in sustained attention. CONCLUSIONS: We replicated our earlier finding of an association between recent head impact exposure and worse processing speed in an independent sample. In addition, we found that sleep may serve as a risk or protective factor for soccer players following extensive exposure to head impacts. Ultimately, this study furthers the understanding of factors impacting neuropsychological function in soccer players and provides empirical support for sleep interventions to help ensure safer soccer play and recovery from injury.

Personality and Risk Taking in Sports: A Focus on Unintentional and Intentional Head Impacts in Amateur Soccer Players.

OBJECTIVE: In soccer, unintentional and intentional (heading) head impacts are associated with concussive symptoms and cognitive dysfunction. We examined whether personality traits were associated with these behaviors in soccer players. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Participants completed study visits at the Albert Einstein College of Medicine. A total of 307 adult amateur soccer players, recruited from New York City and the surrounding area, completed 737 HeadCount-2w questionnaires. PREDICTOR VARIABLES: Personality traits (intellect/imagination, conscientiousness, extraversion, agreeableness, and neuroticism) were assessed with the Mini-International Personality Item Pool questionnaire at the baseline study visit. MAIN OUTCOME MEASURES: Participants completed an online questionnaire (HeadCount-2w) to ascertain frequency of intentional head impacts and occurrence of unintentional head impacts every 3 to 6 months. Generalized estimating equations repeated-measures regressions determined whether personality predicted unintentional and intentional impacts. RESULTS: Personality traits were not associated with unintentional head impact(s) or frequency of intentional head impacts. CONCLUSIONS: These findings have important clinical implications, suggesting that personality is not driving the association between high levels of unintentional and intentional head impacts and worse neuropsychological functioning and concussive symptoms.

Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery-Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t32 = 0.11, p = 0.91, 95% CI [-7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.

Recent and Long-Term Soccer Heading Exposure Is Differentially Associated With Neuropsychological Function in Amateur Players.

OBJECTIVES: The present study examined the relative contribution of recent or long-term heading to neuropsychological function in amateur adult soccer players. PARTICIPANTS AND METHODS: Soccer players completed a baseline questionnaire (HeadCount-12m) to ascertain heading during the prior 12 months (long-term heading, LTH) and an online questionnaire (HeadCount-2w) every 3 months to ascertain heading during the prior 2 weeks (recent heading, RH). Cogstate, a battery of six neuropsychological tests, was administered to assess neuropsychological function. Generalized estimating equations were used to test if LTH or RH was associated with neuropsychological function while accounting for the role of recognized concussion. RESULTS: A total of 311 soccer players completed 630 HeadCount-2w. Participants had an average age of 26 years. Participants headed the ball a median of 611 times/year (mean=1,384.03) and 9.50 times/2 weeks (mean=34.17). High levels of RH were significantly associated with reduced performance on a task of psychomotor speed (p=.02), while high levels of LTH were significantly associated with poorer performance on tasks of verbal learning (p=.03) and verbal memory (p=.04). Significantly better attention (p=.02) was detectable at moderately high levels of RH, but not at the highest level of RH. One hundred and seven (34.4%) participants reported a lifetime history of concussion, but this was not related to neuropsychological function and did not modify the association of RH or LTH with neuropsychological function. CONCLUSION: High levels of both RH and LTH were associated with poorer neuropsychological function, but on different domains. The clinical manifestations following repetitive exposure to heading could change with chronicity of exposure. (JINS, 2018, 24, 147-155).

The promise of ketamine for treatment-resistant depression: current evidence and future directions.

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments for MDD primarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with the NIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants.

Ketamine safety and tolerability in clinical trials for treatment-resistant depression.

OBJECTIVE: Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD. METHOD: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation. RESULTS: The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information. CONCLUSIONS: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.

Neurocognitive effects of ketamine and association with antidepressant response in individuals with treatment-resistant depression: a randomized controlled trial.

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine displays rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the potential for adverse neurocognitive effects in this population has not received adequate study. The current study was designed to investigate the delayed neurocognitive impact of ketamine in TRD and examine baseline antidepressant response predictors in the context of a randomized controlled trial. In the current study, 62 patients (mean age = 46.2 ± 12.2) with TRD free of concomitant antidepressant medication underwent neurocognitive assessments using components of the MATRICS Consensus Cognitive Battery (MCCB) before and after a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Participants were randomized to ketamine or midazolam in a 2:1 fashion under double-blind conditions and underwent depression symptom assessments at 24, 48, 72 h, and 7 days post treatment using the Montgomery-Asberg Depression Rating Scale (MADRS). Post-treatment neurocognitive assessment was conducted once at 7 days. Neurocognitive performance improved following the treatment regardless of treatment condition. There was no differential effect of treatment on neurocognitive performance and no association with antidepressant response. Slower processing speed at baseline uniquely predicted greater improvement in depression at 24 h following ketamine (t = 2.3, p = 0.027), while controlling for age, depression severity, and performance on other neurocognitive domains. In the current study, we found that ketamine was devoid of adverse neurocognitive effects at 7 days post treatment and that slower baseline processing speed was associated with greater antidepressant response. Future studies are required to further define the neurocognitive profile of ketamine in clinical samples and to identify clinically useful response moderators.

A randomized controlled trial of intranasal ketamine in major depressive disorder.

BACKGROUND: The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. METHODS: In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. RESULTS: Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. CONCLUSIONS: This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.