Browsing by Author "Vohs, Jennifer"

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    Are Selective Estrogen Receptor Beta Agonists Potential Therapeutics for Schizophrenia?
    (Oxford University Press, 2020-05-18) Breier, Alan; Liffick, Emily; Hummer, Tom; Vohs, Jennifer; Mehdiyoun, Nicole; Yang, Ziyi; Saykin, Andrew J.; McDonald, Brenna; Francis, Michael; Medicine, School of Medicine
    Background Estrogen therapies, such as estradiol, have shown promise as therapeutics for schizophrenia; however, safety and tolerability concerns, including feminization effects in men and cancer and stroke risk in pre-menopausal women, may limit their broader use. Estradiol binds to both the estrogen alpha (ERA) and beta (ERB) receptors. ERB receptors appear not to mediate many of the concerning side effects of estrogen therapies. In addition, beta receptors have unique localization in cortical regions (i.e., hippocampus), and improve social behaviors and cognition in some animal models, which has led to interests in these compounds for testing in schizophrenia. To our knowledge, there have been no previous clinical trials of selective ERB agonists in schizophrenia. LY500307 is a highly selective agent for beta receptors without effects on estrogen alpha receptors when doses are constrained. Doses that are too high may engage alpha receptors but the alpha engaging threshold dose has not been fully determined in patient groups. The purpose of this dose-response study was to determine: ERB selectivity doses of LY500307 (i.e., without engaging alpha receptors); safety and tolerability; brain target engagement; and effects on cognition and symptoms. Methods A two-staged, double-blind, 8-week, adjunctive to APDs, adaptive phase 1b/2a trial design was conducted in men with schizophrenia (women were not included because of the lack of toxicology, safety, phase 1 and clinical data supporting use in this population). Three LY500307 doses and placebo were evaluated: 25 mg/day, 75 mg/day, and 150 mg/day. The primary markers for estrogen beta receptor selectivity was lack of effects on total testosterone levels (TT) and no feminization signs. Target engagement was assessed with an N-back working memory fMRI task and the electrophysiology measure mismatch negativity (MMN). Cognitive effects were assessed by the MCCB Composite score. Negative and total symptoms were assessed by the NSA-16 and PANSS, respectively. The primary analyses included all subjects and compared the slope from the three LY500307 dosing arms to the placebo slope in order to evaluate the dose responses. The linear mixed model with random intercept was employed and secondary analyses assessed differences between mean changes of the two higher dose arms combined (75 mg and 150 mg) versus placebo. Results Ninety-four patients were randomized across the placebo and three LY500307 dosing arms. There were no effects on plasma TT levels and no evidence of feminization, suggesting all doses were selective for the beta receptor. No significant adverse events were observed. There were no significant differences between the slopes of the three drug doses versus placebo on the brain target engagement variables (fMRI/N-back: F=0.24, p=0.868; MMN (Duration): F=1.08, p=0.358; MMN (Frequency): F=0.89, p=0.446) or on the cognitive/symptom measures (MCCB composite: F=0.87, p=0.458; NSA-16: F=1.79, p=0.148; and PANSS Total: F=0.69, p=0.558.) Secondary analyses also failed to show any significant effects of LY500307 versus placebo on any of the study variables. Discussion Conclusions: This study indicates that the ERB agonist LY500307 was selective, safe, and well tolerated in patients with schizophrenia. This selective ERB agonist, however, failed to demonstrate any significant effects on brain targets, cognition, negative and total symptoms. Potential issues related to dosing and characteristics of the patient population will be discussed. These data suggest that estrogen alpha receptor activation may be necessary to yield positive results in this patient population. Future studies are needed to confirm these findings.
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    F247. Internalized Stigma Has a Stronger Relationship with Intrinsic Motivation Compared to Amotivation in Early Phase and Prolonged Schizophrenia
    (Oxford University Press, 2018-04) Firmin, Ruth; Luther, Lauren; Lysaker, Paul; Vohs, Jennifer; Psychiatry, School of Medicine
    Background Motivation deficits predict decreased functioning in schizophrenia. Recent work suggests deficits reflect challenges in separate domains: intrinsic motivation (one’s internal drive to engage in a behavior out of enjoyment or interest) and amotivation (one’s broader decrease in motivated behavior linked to avolition and anhedonia). Internalized stigma is another determinant of functioning for people with schizophrenia that may impact motivation. However, little is known about these relationships, including which aspects of motivation it may impact nor when these links emerge. Identifying the link between these constructs may help to identify whether internalized stigma may be a novel treatment target to facilitate improvements in motivation. Methods Forty adults with early phase schizophrenia and 66 adults with prolonged schizophrenia completed measures of internalized stigma, intrinsic motivation, and amotivation. Pearson’s correlations were examined followed by Fischer’s r-to-z transformations to compare differences in the magnitude of associations between internalized stigma and intrinsic motivation and internalized stigma and amotivation among the first episode and prolonged samples. Next, we conducted stepwise regressions to examine whether internalized stigma was associated with intrinsic motivation above and beyond associations with amotivation in each sample. Results In the early phase sample, the association between internalized stigma was greater with intrinsic motivation (r=-0.48, p=.00) compared to amotivation (r=0.27, p=0.10). Associations with internalized stigma in the prolonged sample were also greater with intrinsic motivation (r=-0.30, p=0.02) versus amotivation (r=0.19, p=0.12). The magnitude of the associations between internalized stigma and intrinsic motivation (z=1.03, p=0.15) and between internalized stigma and amotivation (z=0.41, p = 0.34) did not significantly differ when comparing phase of illness. Regression analyses indicated that, controlling for amotivation, internalized stigma predicted intrinsic motivation in both the prolonged sample (R2=0.09, F(1,64) =6.18, p=0.02) and the early phase schizophrenia sample (R2=0.23, F(1,37)=10.98, p=.00). Discussion Results suggest internalized stigma has a stronger relationship with intrinsic motivation separate from, and above and beyond, its association with amotivation. Findings support models of intrinsic and amotivation being distinct domains. Links between internalized stigma and motivation appear to emerge and persist from the early stages of schizophrenia, suggesting that targeting stigma in early intervention services may help to improve intrinsic motivation in people with schizophrenia.
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    O12.3.Effects of Fingolimod, A Potent Anti-Inflammatory Agent, On Brain Structure, Function, And Symptoms in Schizophrenia
    (Oxford University Press, 2019-04) Breier, Alan; Hummer, Tom; Vohs, Jennifer; Mehdyoun, Nicole; Liffick, Emily; Francis, Michael; Medicine, School of Medicine
    Background New medications with novel targets are needed for schizophrenia. Several lines of evidence indicate that inflammatory processes including aberrant lymphocytic activity may be related to the pathophysiology of this illness. These data suggest that agents with anti-inflammatory actions, including modulation of lymphocytes and their inflammatory substrates, may prove to be efficacious for schizophrenia. Fingolimod is a powerful anti-inflammatory agent that is used in the treatment of relapsing multiple sclerosis. It is a sphingosine-1-phosphate (S1P) receptor modulator that decreases circulating lymphocytes through sequestration in lymph tissues. In addition, evidence suggest that it stimulates oligodendrocytes and may enhance white matter integrity. The purpose of this study was to assess the effects of fingolimod in schizophrenia. Methods Subjects with schizophrenia (N=40) were recruited through the Indiana University Psychotic Disorders Programs and randomized 1:1 in a double-blind, eight-week clinical trial of fingolimod 0.5 mg/day and placebo. Circulating total lymphocytes were determined and effects were assessed on symptoms (PANSS), cognition (BACS), plasma cytokines, white matter integrity (DTI) and cortical connectivity (resting fMRI). Results Results revealed a significant decrease in lymphocytes in subjects taking fingolimod versus placebo (treatment x time; F = 61.2, p < 0.001). Fingolimod treated subjects had a mean maximal drop in lymphocytes from baseline of 79.2% with all fingolimod treated subjects experiencing decrements greater than 60%. There was a trend toward higher mean skeletal fractional anisotropy (FA) post-treatment in the fingolimod group. Within the fingolmiod group, there were significant or trend-level correlations between FA increase and decrease in lymphocytes in the genu and body of the corpus collosum and the right superior longitudinal fasciculus. There were also significant group-by-visit interactions in connectivity of left prefrontal cortical (PFC) seeds with clusters in the cerebellum, driven by higher PFC-cerebellum connectivity following fingolimod treatment. There were no improvements (treatment x time) in PANSS total (F = 0.66, p= 0.52), any of the PANSS subscales, or BACS composite score (F = 0.54, p = 0.44). Serious side effects were not observed, and a full safety report will be provided. Discussion Fingolimod produced a strong anti-inflammatory response with substantial reductions in circulating lymphocytes in all treated subjects. Brain effects were observed. However, this response was not accompanied by improvements in symptoms or cognition. These data suggest that fingolimod’s target of S1P modulation and robust anti-inflammatory warrant further investigation in schizophrenia.