Huperzine A for the treatment of cognitive, mood, and functional deficits after moderate and severe TBI (HUP-TBI): results of a Phase II randomized controlled pilot study: implications for understanding the placebo effect.

Objective: To investigate the effect of Huperzine A on memory and learning in individuals with moderate-severe traumatic brain injury (TBI).Design: Randomized, double-blind, placebo-controlled Phase II clinical trial.Methods: Subjects were randomly assigned to receive Huperzine A or placebo for 12 weeks and were assessed during in-person visits at screening/baseline, and 6, 12, 24, and 52 weeks post-injury. Changes in memory and learning scores on the California Verbal Learning Test - 2nd Edition (CVLT-II) from baseline to week 12 were assessed using permutation tests and regression analyses.Results: There was no difference between the Huperzine A and placebo groups in memory performance after 12 weeks of treatment. In the placebo group, significant improvements were noted in learning and memory scores. Both groups showed clinically important improvements in depression on the Beck Depression Index.Conclusions: The clinically important improvements in cognitive and emotional outcomes observed in both the placebo and active treatment arms of this clinical trial of Huperzine A are best understood in the context of a placebo effect. Future trials involving patients with moderate-severe TBI in the subacute to chronic phases of recovery should be designed to account for placebo effects as failure to do so may lead to spurious conclusions.

Anger and Depression in Middle-Aged Men: Implications for a Clinical Diagnosis of Chronic Traumatic Encephalopathy.

OBJECTIVE: In recent years, it has been proposed that problems with anger control and depression define clinical features of chronic traumatic encephalopathy (CTE). The authors examined anger problems and depression in middle-aged men from the general population and related those findings to the proposed clinical criteria for CTE. METHODS: A sample of 166 community-dwelling men ages 40-60 was extracted from the normative database of the National Institutes of Health Toolbox. All participants denied prior head injury or traumatic brain injury (TBI). Participants completed scales assessing anger, hostility, aggression, anxiety, and depression. RESULTS: In response to the item "I felt angry," 21.1% of men reported "sometimes," and 4.8% reported "often." When asked "If I am provoked enough I may hit another person," 11.4% endorsed the statement as true. There were moderate correlations between anger and anxiety (Spearman's ρ=0.61) and between depression and affective anger (ρ=0.51), hostility (ρ=0.56), and perceived hostility (ρ=0.35). Participants were dichotomized into a possible depression group (N=49) and a no-depression group (N=117) on the basis of the question "I feel depressed," specific to the past 7 days. The possible depression group reported higher anxiety (p<0.001, Cohen's d=1.51), anger (p<0.001, Cohen's d=0.96), and hostility (p<0.001, Cohen's d=0.95). CONCLUSIONS: Some degree of anger and aggression are reported by a sizable minority of middle-aged men in the general population with no known history of TBI. Anger and hostility are correlated with depression and anxiety, indicating that all tend to co-occur. The base rates and comorbidity of affective dysregulation in men in the general population is important to consider when conceptualizing CTE phenotypes.