Faculty Bibliography

Background: Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (previously known as TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/ refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea. Methods: An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential secondline treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measurable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if identified, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m²) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m²) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS with a one-sided alpha of 0.025. The first patient was enrolled in June 2014; recruitment is ongoing

Background: Difficulties with affect regulation and impulse control have a strong influence on violence. The objective of this study was to determine whether baseline depression and impulsivity predict aggression and whether they predict differential response to antiaggressive treatment. This is important, as we lack knowledge as to the selection of antipsychotics for the treatment of aggression. Methods: Physically aggressive inpatients with schizophrenia who received an evaluation of depression and impulsivity at baseline were randomly assigned in a double-blind, parallel group, 12-week trial to clozapine, olanzapine, or haloperidol. Trait impulsivity was measured by the Barratt Impulsiveness Scale; depression by the Positive and Negative Syndrome Scale Depression factor. The number and severity of aggressive events, as measured by the Modified Overt Aggression Scale (MOAS), were the outcome measures. Results: Baseline depression and impulsivity predicted higher levels of aggression, as measured by the MOAS total score, over the 12-week treatment period across all 3 medication groups. In addition, there was a strong interaction effect between baseline depression/impulsivity and medication grouping in predicting MOAS score. In particular, when higher depression and impulsivity were present at baseline, patients on haloperidol presented with more aggression than patients on the other 3 medications. Conclusions: Depression and impulsivity are important predictors of aggression and of differential response to antiaggressive treatment. This is most likely due to the medications' dissimilar neurotransmitter profiles. By identifying patients who will respond better to a given medication, we will be able to develop individualized strategies for the treatment of violent behavior.

Response inhibition deficits are well-documented in drug users, and are related to the impulsive tendencies characteristic of the addictive phenotype. Addicts also show significant motivational issues that may accentuate these inhibitory deficits. We investigated the extent to which these inhibitory deficits are present in abstinence. Salience of the task stimuli was also manipulated on the premise that emotionally-valenced inputs might impact inhibitory efficacy by overcoming the blunted responses to everyday environmental inputs characteristic of this population. Participants performed response inhibition tasks consisting of both neutral and emotionally valenced stimuli while high-density event-related potentials (ERPs) were recorded. Electrophysiological responses (N2/P3 components) to successful inhibitions in abstinent abusers (N = 20) and non-using participants (N = 21) were compared. In contrast to previous work in current users, our abstinent cohort showed no detectable behavioral or electrophysiological differences in their inhibitory responses, and no differences on self-reports of impulsivity, despite their long histories of chronic use (mean = 10.3 years). The current findings are consistent with a recovery of inhibitory control processes as a function of abstinence. Abstinent former users, however, did show a reduced modulation, relative to controls, of their ERPs to valenced input while performing successful inhibitions, although contrary to our hypothesis, the use of valenced inputs had no impact on inhibitory performance. Reduced ERP modulation to emotionally valenced inputs may have implications for relapse in emotional contexts outside the treatment center.

Individuals with schizophrenia are more prone to violent behaviors than the general population. It is increasingly recognized that processing of emotionally valenced stimuli is impaired in schizophrenia, a deficit that may play a role in aggressive behavior. Our goal was to establish whether patients with a history of violence would show more severe deficits in processing emotionally valenced inputs than nonviolent patients. Using event-related-potentials, we measured how early during processing of emotional valence, evidence of aberrant function was observed. Forty-two schizophrenia patients (21 with history of violence;21 without) and twenty-eight healthy controls were tested. Participants performed an inhibitory control task, making speeded responses to pictorial stimuli. Pictures occasionally repeated twice and participants withheld responses to these repeats. Valenced pictures from the International Affective Picture System were presented. Results in controls showed modulations during the earliest phases of sensory processing (<100ms) for negatively valenced pictures. A cascade of modulations ensued, involving sensory and perceptual processing stages. In contrast, neither schizophrenia group showed early differentiation. Non-violent patients showed earliest modulations beginning approximately 150ms. For violent patients, however, earliest modulations were further delayed and highly attenuated. The current study reveals sensory-perceptual processing dysfunction for negatively valenced inputs, which is particularly pronounced in aggressive patients.

BACKGROUND: There is no literature investigating denial of aggression in schizophrenia. Our goal was to study this phenomenon and to determine what deficits are associated with it. METHODS: 102 inpatients with schizophrenia were divided into three groups: (1) patients with a documented history of violent crime who denied it on extensive interviews ("deniers"); (2) those with such a history who admitted to it; and (3) those without violent crime. Patients were administered a psychometrically validated self-report scale of aggression, the Buss-Perry Aggression Questionnaire (BPAQ), the Positive and Negative Syndrome Scale and a comprehensive neurocognitive battery. They were followed for twelve weeks during which all violent incidents were recorded. RESULTS: The deniers were significantly more impaired in executive function, but not in any other cognitive domain. They did not evidence more severe psychotic symptoms or greater lack of insight in their psychosis, but this lack of insight was strongly related to hostility and suspiciousness. Their denial of aggression was also evidenced in a significantly lower self-reported BPAQ aggression score. In the patients who admitted to violent crimes, baseline BPAQ aggression score predicted subsequent aggression; in the deniers, it was negatively related to subsequent aggression. CONCLUSION: Denial of aggression is associated with executive dysfunction which facilitates a misappraisal of the surrounding world as threatening and hostile. For those who admit to crimes, self-reported aggression predicts future aggression. In contrast, in the deniers, the extent of denial is related to future aggression. The denial itself is a marker of greater aggressive tendencies.

Visual processing studies have repeatedly shown impairment in patients with schizophrenia compared to healthy controls. Electroencephalography (EEG) and, specifically, visual evoked potential (VEP) studies have identified an early marker of this impairment in the form of a decrement in the P1 component of the VEP in patients and their clinically unaffected first-degree relatives. Much behavioral and neuroimaging research has implicated specific dysfunction of either the subcortical magnocellular pathway or the cortical visual dorsal stream in this impairment. In this study, EEG responses were obtained to the contrast modulation of checkerboard stimuli using the VESPA (Visual Evoked Spread Spectrum Analysis) method. This was done for a high contrast condition and, in order to bias the stimuli towards the magnocellular pathway, a low contrast condition. Standard VEPs were also obtained using high contrast pattern reversing checkerboards. Responses were measured using high-density electrical scalp recordings in 29 individuals meeting DSM-IV criteria for schizophrenia and in 18 control subjects. Replicating previous research, a large (Cohen's d=1.11) reduction in the P1 component of the VEP was seen in patients when compared with controls with no corresponding difference in the VESPA response to high contrast stimuli. In addition, the low-contrast VESPA displayed no difference between patients and controls. Furthermore, no differences were seen between patients and controls for the C1 components of either the VEP or the high-contrast VESPA. Based on the differing acquisition methods between VEP and VESPA, we discuss these results in terms of contrast gain control and the possibility of dysfunction at the cortical level with initial afferent activity into V1 along the magnocellular pathway being intact when processing is biased towards that pathway using low contrast stimuli.

OBJECTIVE: Despite extensive experience with antipsychotic medications, we have limited capacity to predict which patients will benefit from which medications and for what symptoms. Such prediction is of particular importance for the proper treatment of violence. Our goal was to determine whether executive function predicts outcome of treatment for aggressive behavior and whether such prediction varies across medication groups. METHOD: Ninety-nine physically aggressive inpatients (aged 18-60 years) with schizophrenia or schizoaffective disorder (diagnosed according to DSM-IV) who completed tests of executive function were randomly assigned in a double-blind, parallel-group, 12-week trial to clozapine (n = 32), olanzapine (n = 32), or haloperidol (n = 35). The number and severity of aggressive events as measured by the Modified Overt Aggression Scale (MOAS) were the outcome measures. Psychopathology and medication side effects were also assessed. The study was conducted from 1999 to 2004. RESULTS: Poor executive function predicted higher levels of aggression, as measured by MOAS scores over the 12-week period, in all 3 medication groups (F(1,98) = 222.2, P < .0001). There was, however, a significant interaction effect between medication grouping and executive function (F(1,98) = 15.32, P < .001): clozapine exerted an antiaggression effect even in the presence of executive dysfunction. CONCLUSIONS: Executive function was a strong predictor of response to antiaggression treatment in all medication groups, but clozapine still retained clinical efficacy in the presence of poor executive functioning. Olanzapine was particularly efficacious in the absence of executive dysfunction. These findings have important implications for a targeted approach to the treatment of aggression in patients with schizophrenia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01123408.

OBJECTIVE: A positive relationship between cholesterol levels and cognition has been reported in various human and animal studies, but has never been investigated in schizophrenia. The goal of this study was to examine this relationship in schizophrenic patients randomized to clozapine, olanzapine or haloperidol. METHOD: This was a double-blind randomized prospective 12-week study. Participants received a baseline evaluation including a cognitive battery consisting of an evaluation of psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. Their fasting serum cholesterol level was also assessed. The participants were then randomized to clozapine, olanzapine, or haloperidol. They were evaluated at the end of 12weeks. A general cognitive index (GCI) derived from the cognitive battery was the primary variable. RESULTS: 82 patients had both baseline and endpoint neurocognitive assessments and cholesterol levels. There was a statistically and clinically significant positive association between change in cholesterol levels and change in GCI. This association was especially pronounced for verbal memory. There was no interaction between medication grouping and cholesterol level; the positive association was observable separately in each medication group. It was very robust and remained significant after we controlled for glucose and triglyceride levels, anticholinergic side effects, medication serum levels, cholesterol lowering medications, and pre-study antipsychotic medications. CONCLUSIONS: Cholesterol levels show a strong association with cognition in schizophrenia in all medication groups. Further research on the role of lipid metabolism in cognition may suggest new treatments for this core deficit of schizophrenia