by
Tiffany A. Greenwood;
Neal R. Swerdlow;
Joyce Sprock;
Monica E. Calkins;
Robert Freedman;
Michael F. Green;
Raquel E. Gur;
Ruben C. Gur;
Laura C. Lazzeroni;
Gregory A. Light;
Keith H. Nuechterlein;
Allen D. Radant;
Jeremy M. Silverman;
William S. Stone;
Catherine A. Sugar;
Debby W. Tsuang;
Ming T. Tsuang;
Bruce I. Turetsky;
David L. Braff;
Erica Duncan
Background
Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort.
Methods
Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1.
Results
980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973)=4.45, p=0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974)=3.92, p=0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p<0.0001), with heritability of 34–41% for latency and 45–59% for magnitude.
Conclusion
Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.
Background
Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD.
Methods/design
Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months’ duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks’ exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects.
Discussion
Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD.
Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Cocaine addicted men have low startle magnitude persisting during prolonged abstinence. Low startle rats show greater cocaine self-administration than high startle rats. Low startle may be a marker of a vulnerability to heightened cocaine-related behaviors in rats and similarly may be a marker of vulnerability to cocaine addiction in humans.
by
Kristin S. Cadenhead;
Erica Duncan;
Jean Addington;
Carrie Bearden;
Tyrone D. Cannon;
Barbara A. Cornblatt;
Dan Mathalon;
Thomas H. McGlashan;
Diana O. Perkins;
Larry J. Seidman;
Ming Tsuang;
Elaine Walker;
Scott W. Woods;
Peter Bauchman;
Ayse Belger;
Ricardo E. Carrion;
Franc Donkers;
Jason Johannesen;
Gregory Light;
Margaret Niznikiewicz;
Jason Nunag;
Brian Roach
Abstract: Biomarkers are important in the study of the prodromal period of psychosis because they can help to identify individuals at greatest risk for future psychotic illness and provide insights into disease mechanism underlying neurodevelopmental abnormalities. The biomarker abnormalities can then be targeted with treatment, with an aim toward prevention or mitigation of disease. The human startle paradigm has been used in translational studies of psychopathology including psychotic illness to assess preattentive information processing for over 50 years. In one of the largest studies to date in clinical high risk (CHR) for psychosis participants, we aimed to evaluate startle indices as biomarkers of risk along with the role of age, sex, treatment, and substance use in this population of high risk individuals. Methods: Startle response reactivity, latency, and prepulse inhibition (PPI) were assessed in 543 CHR and 218 Normal Comparison (NC) participants between the ages of 12 and 35. Results: At 1 year follow-up, 58 CHR participants had converted to psychosis. CHR and NC groups did not differ across any of the startle measures but those CHR participants who later converted to psychosis had significantly slower startle latency than did those who did not convert to psychosis, and this effect was driven by female CHR participants. PPI was significantly associated with age in the CHR, but not the NC, participants with the greatest positive age correlations present in those CHR participants who later converted to psychosis, consistent with a prior report. Finally, there was a significant group by cannabis use interaction due to greater PPI in cannabis users and opposite PPI group effects in users (CHR>NC) and non-users (NC>CHR). Discussion: This is the first study to demonstrate a relationship of startle response latency to psychotic conversion in a CHR population. PPI is an important biomarker that may be sensitive to the neurodevelopmental abnormalities thought to be present in psychosis prone individuals and the effects of cannabis. The significant correlations with age in this sample as well as the finding of greater PPI in CHR cannabis users replicate findings from another large sample of CHR participants.
Hemicrania continua is a headache characterized by chronic unremitting unilateral pain associated with ipsilateral autonomic findings. This type of headache responds to high-flow oxygen and indomethacin. This case report describes a male veteran with posttraumatic stress disorder (PTSD) and major depressive disorder who suffers from comorbid hemicrania continua. The psychiatric symptoms were recalcitrant to psychopharmacological intervention. However, when the patient's hemicrania continua was treated appropriately, the patient's psychiatric symptoms also abated. This case demonstrates the need to address physical comorbidities that may exacerbate psychiatric disorders, such as PTSD.
Baseline cue-dependent physiological reactivity may serve as an objective measure of posttraumatic stress disorder (PTSD) symptoms. Additionally, prior animal model and psychological studies would suggest that subjects with greatest symptoms at baseline may have the greatest violation of expectancy to danger when undergoing exposure based psychotherapy; thus treatment approaches which enhanced the learning under these conditions would be optimal for those with maximal baseline cue-dependent reactivity. However methods to study this hypothesis objectively are lacking. Virtual reality (VR) methodologies have been successfully employed as an enhanced form of imaginal prolonged exposure therapy for the treatment of PTSD.
Our goal was to examine the predictive nature of initial psychophysiological (e.g., startle, skin conductance, heart rate) and stress hormone responses (e.g., cortisol) during presentation of VR-based combat-related stimuli on PTSD treatment outcome. Combat veterans with PTSD underwent 6 weeks of VR exposure therapy combined with either D-cycloserine (DCS), alprazolam (ALP), or placebo (PBO). In the DCS group, startle response to VR scenes prior to initiation of treatment accounted for 76% of the variance in CAPS change scores, p < 0.001, in that higher responses predicted greater changes in symptom severity over time. Additionally, baseline cortisol reactivity was inversely associated with treatment response in the ALP group, p = 0.04. We propose that baseline cue-activated physiological measures will be sensitive to predicting patients' level of response to exposure therapy, in particular in the presence of enhancement (e.g., DCS).
by
Brian J. Roach;
Holly K. Hamilton;
Peter Bachman;
Aysenil Belger;
Ricardo E. Carrion;
Erica Duncan;
Jason Johannesen;
Joshua G. Kenney;
Gregory Light;
Margaret Niznikiewicz;
Jean Addington;
Carrie E. Bearden;
Emily M. Owens;
Kristin S. Cadenhead;
Tyrone D. Cannon;
Barbara A. Cornblatt;
Thomas H. McGlashan;
Diana O. Perkins;
Larry Seidman;
Ming Tsuang;
Elaine Walker;
Scott W. Woods;
Daniel H. Mathalon
Objectives
Mismatch negativity (MMN), an auditory event‐related potential sensitive to deviance detection, is smaller in schizophrenia and psychosis risk. In a multisite study, a regression approach to account for effects of site and age (12–35 years) was evaluated alongside the one‐year stability of MMN.
Methods
Stability of frequency, duration, and frequency + duration (double) deviant MMN was assessed in 167 healthy subjects, tested on two occasions, separated by 52 weeks, at one of eight sites. Linear regression models predicting MMN with age and site were validated and used to derive standardized MMN z‐scores. Variance components estimated for MMN amplitude and latency measures were used to calculate Generalizability (G) coefficients within each site to assess MMN stability. Trait‐like aspects of MMN were captured by averaging across occasions and correlated with subject traits.
Results
Age and site accounted for less than 7% of MMN variance. G‐coefficients calculated at electrode Fz were stable (G = 0.63) across deviants and sites for amplitude measured in a fixed window, but not for latency (G = 0.37). Frequency deviant MMN z‐scores averaged across tests negatively correlated with averaged global assessment of functioning.
Conclusion
MMN amplitude is stable and can be standardized to facilitate longitudinal multisite studies of patients and clinical features.
Fear conditioning methodologies have often been employed as testable models for assessing learned fear responses in individuals with anxiety disorders such as post-traumatic stress disorder (PTSD) and specific phobia. One frequently used paradigm is measurement of the acoustic startle reflex under conditions that mimic anxiogenic and fear-related conditions. For example, fear-potentiated startle is the relative increase in the frequency or magnitude of the acoustic startle reflex in the presence of a previously neutral cue (e.g., colored shape; termed the conditioned stimulus or CS+) that has been repeatedly paired with an aversive unconditioned stimulus (e.g., airblast to the larynx). Our group has recently used fear-potentiated startle paradigms to demonstrate impaired fear extinction in civilian and combat populations with PTSD. In the current study, we examined the use of either auditory or visual CSs in a fear extinction protocol that we have validated and applied to human clinical conditions. This represents an important translational bridge in that numerous animal studies of fear extinction, upon which much of the human work is based, have employed the use of auditory CSs as opposed to visual CSs. Participants in both the auditory and visual groups displayed robust fear-potentiated startle to the CS+, clear discrimination between the reinforced CS+ and non-reinforced CS-, significant extinction to the previously reinforced CS+, and marked spontaneous recovery. We discuss the current results as they relate to future investigations of PTSD-related impairments in fear processing in populations with diverse medical and psychiatric histories.
by
Maju Mathew Koola;
William A Brown Jr.;
Clifford Qualls;
Bruce Cuthbert;
Jeffrey P. Hollis;
Deanna L. Kelly;
Ngoc-Anh Le;
Jeffrey Raines;
Erica Duncan
Background: Peripheral arterial compliance is a measure of elasticity of the arteries that has been found to be a robust predictor of prevalent arteriosclerosis as well as incident stroke and myocardial infarction. Psychiatric diagnoses and second generation antipsychotics may contribute to cardiovascular risk and stroke, but effects on peripheral arterial compliance are unknown. This study compared peripheral arterial compliance in healthy male controls to male patients with psychiatric diagnoses who were treated with quetiapine or risperidone or off antipsychotics at time of testing. Methods: The groups consisted of 63 patients with mental illness taking quetiapine, risperidone, or no antipsychotics. There were 111 males in the control group. Mean thigh and calf arterial compliance among four groups were compared by ANCOVA, adjusting for body mass index and Framingham Risk Score. All patients were also compared to the control group. Compliance was measured with a computerized plethysmography device. Results: Patients (. n=. 63) had significantly lower arterial compliance in both thigh and calf than the controls. Arterial compliance in the calf was significantly lower in the subgroups of quetiapine (. n=. 16) and risperidone (. n=. 19) treated, and in unmedicated (. n=. 28) patients than in controls. In the thigh, patients taking either quetiapine or risperidone had significantly lower arterial compliance than controls. These subgroups did not differ from each other in arterial compliance. Conclusion: The presence of psychiatric diagnoses is associated with reduced arterial compliance. A large study may be required to measure any specific affects of antipsychotics such as quetiapine and risperidone on compliance compared to controls.
Patients with schizophrenia exhibit psychomotor deficits that are associated with poor functional outcomes. One pathway that may be associated with psychomotor slowing is inflammation. Inflammatory markers have been shown to be elevated in patients with schizophrenia and are associated with psychomotor deficits in both animal and human studies. Forty-three patients with schizophrenia and 29 healthy controls were recruited and underwent a battery of psychomotor tasks. The following immune measures in peripheral blood were assayed: IL-6, IL-1 beta, IL-10, TNF, MCP-1, IL-6sr, IL-1RA, and TNFR2. Generalized linear models were used to determine which immune markers, in addition to their interaction with diagnosis, were associated with performance on the psychomotor tasks. As expected, patients with schizophrenia demonstrated slower performance compared with healthy controls on the finger tapping test (FTT, tested on dominant and non-dominant hands), trail making test (TMT), and symbol coding test (SC). Interactive effects with diagnosis were found for TNF, IL-10, IL-6sr, and TNFR2 for the FTT (dominant), IL-10 and IL-6sr for FTT (non-dominant), TNF and IL-10 for TMT and TNF, IL-10, IL-6sr, TNFR2, and IL-1RA for SC. The results of this study provide evidence that peripheral inflammatory markers contribute to psychomotor slowing in patients with schizophrenia. These data are consistent with a growing literature, demonstrating that inflammation may target the basal ganglia to contribute to psychomotor deficits as is seen in other psychiatric disorders such as depression. These data also indicate that psychomotor speed may be a relevant construct to target in studies of the immune system in schizophrenia.