O12.3.Effects of Fingolimod, A Potent Anti-Inflammatory Agent, On Brain Structure, Function, And Symptoms in Schizophrenia

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

PSYCHOSIS IN HINDSIGHT: A COLLECTIVE RECOLLECTION OF THE ONSET OF PSYCHOSIS

poster abstractPsychotic disorders cause marked cognitive, perceptual, and social impairments and may lead to significant disability. Those affected with these illnesses may have great difficulty in educational, occupational, and social functioning; especially troubling is the fact that these illness often strike when those afflicted should be entering into some of the most productive years of their lives. The primary purpose of this study is to ascertain the perspective of subjects with psychotic disorders on the mental health system and treatment, stigmatization, social functioning, and symptom experience. This information will be of use in improving treatment engagement, compliance, and education of providers. Fifty subjects with nonaffective psychoses in each of two arms (new onset psychosis and chronic psychosis) will be enrolled and asked to complete a self-administered questionnaire. After subjects complete the questionnaire, investigators will review medical records to confirm subject age and diagnosis, compare subject report with symptomatology, and look for trends or topics of interest in comparing patient survey reports with medical records which may provide for useful insight upon further investigation

Functional neuroanatomical correlates of episodic memory impairment in early phase psychosis

Studies have demonstrated that episodic memory (EM) is often preferentially disrupted in schizophrenia. The neural substrates that mediate EM impairment in this illness are not fully understood. Several functional magnetic resonance imaging (fMRI) studies have employed EM probe tasks to elucidate the neural underpinnings of impairment, though results have been inconsistent. The majority of EM imaging studies have been conducted in chronic forms of schizophrenia with relatively few studies in early phase patients. Early phase schizophrenia studies are important because they may provide information regarding when EM deficits occur and address potential confounds more frequently observed in chronic populations. In this study, we assessed brain activation during the performance of visual scene encoding and recognition fMRI tasks in patients with earlyphase psychosis (n = 35) and age, sex, and race matched healthy control subjects (n = 20). Patients demonstrated significantly lower activation than controls in the right hippocampus and left fusiform gyrus during scene encoding and lower activation in the posterior cingulate, precuneus, and left middle temporal cortex during recognition of target scenes. Symptom levels were not related to the imaging findings, though better cognitive performance in patients was associated with greater right hippocampal activation during encoding. These results provide evidence of altered function in neuroanatomical circuitry subserving EM early in the course of psychotic illness, which may have implications for pathophysiological models of this illness

Are Selective Estrogen Receptor Beta Agonists Potential Therapeutics for Schizophrenia?

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

Characterization of white matter abnormalities in early-stage schizophrenia

Aim White matter abnormalities have been reported in schizophrenia and may indicate altered cortical network integrity and structural connectivity, which have been hypothesized as key pathophysiological components of this illness. In this study, we aimed to further characterize the nature and progression of white matter alterations during the early stages of the disorder. Methods We employed diffusion tensor imaging (DTI) approaches to investigate fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) in 40 patients with schizophrenia and related psychotic disorders (aged 18–30 years) who were within 5 years of illness, along with an age-, sex- and race-matched sample of 21 healthy controls. Relationships with illness duration, lifetime antipsychotic medication exposure and symptom levels were examined. Results Patients had lower FA and higher RD than controls in numerous white matter tracts, including the corpus callosum (CC) and the superior longitudinal fasciculus. Illness duration was associated with lower FA and higher RD, most prominently in the CC. No group differences or relationships to illness duration were detected with AD, and no relationships between any DTI measurements and lifetime antipsychotic medication use were found. Conclusions This investigation provides evidence of widespread disruptions to structural connectivity in the early stages of schizophrenia. The relationship to illness duration, coupled with an absence of relationships to AD or antipsychotic drug exposure, provides evidence of a progressive disease process, although prospective assessments with repeated DTI measurements are needed to fully characterize the trajectory of white matter abnormalities in this illness