Impact of BPRS interview length on ratings reliability in a schizophrenia trial

AbstractSignal detection in clinical trials relies on ratings reliability. We conducted a reliability analysis of site-independent rater scores derived from audio-digital recordings of site-based rater interviews of the structured Brief Psychiatric Rating Scale (BPRS) in a schizophrenia study. “Dual” ratings assessments were conducted as part of a quality assurance program in a 12-week, double-blind, parallel-group study of PF-02545920 compared to placebo in patients with sub-optimally controlled symptoms of schizophrenia (ClinicalTrials.gov identifier NCT01939548). Blinded, site-independent raters scored the recorded site-based BPRS interviews that were administered in relatively stable patients during two visits prior to the randomization visit. We analyzed the impact of BPRS interview length on “dual” scoring variance and discordance between trained and certified site-based raters and the paired scores of the independent raters.Mean total BPRS scores for 392 interviews conducted at the screen and stabilization visits were 50.4±7.2 (SD) for site-based raters and 49.2±7.2 for site-independent raters (t=2.34; p=0.025). “Dual” rated total BPRS scores were highly correlated (r=0.812). Mean BPRS interview length was 21:05±7:47min ranging from 7 to 59min. 89 interviews (23%) were conducted in less than 15min. These shorter interviews had significantly greater “dual” scoring variability (p=0.0016) and absolute discordance (p=0.0037) between site-based and site-independent raters than longer interviews.In-study ratings reliability cannot be guaranteed by pre-study rater certification. Our findings reveal marked variability of BPRS interview length and that shorter interviews are often incomplete yielding greater “dual” scoring discordance that may affect ratings precision

Recommendations for selection and adaptation of rating scales for clinical studies of rapid-acting antidepressants

The novel mechanisms of action (MOA) derived from some recently introduced molecular targets have led to regulatory approvals for rapid acting antidepressants (RAADs) that can generate responses within hours or days, rather than weeks or months. These novel targets include the N-methyl-D-glutamate receptor antagonist ketamine, along with its enantiomers and various derivatives, and the allosteric modulators of gamma-aminobutyric acid (GABA) receptors. There has also been a strong resurgence in interest in psychedelic compounds that impact a range of receptor sites including D1, 5-HT7, KOR, 5-HT5A, Sigma-1, NMDA, and BDNF. The RAADs developed from these novel targets have enabled successful treatment for difficult to treat depressed individuals and has generated a new wave of innovation in research and treatment. Despite the advances in the neurobiology and clinical treatment of mood disorders, we are still using rating instruments that were created decades ago for drugs from a different era (e.g., The Hamilton and Montgomery-Åsberg depression rating scales, HDRS, and MADRS) continue to be used. These rating instruments were designed to assess mood symptoms over a 7-day time frame. Consequently, the use of these rating instruments often requires modifications to address items that cannot be assessed in short time frames, such as the sleep and appetite items. This review describes the adaptative approaches that have been made with the existing scales to meet this need and examines additional domains such as daily activities, side effects, suicidal ideation and behavior, and role functioning. Recommendations for future studies are described, including the challenges related to implementation of these adapted measures and approaches to mitigation

HPA axis activity in patients with panic disorder: review and synthesis of four studies

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis may play a role in panic disorder. HPA studies in patients with panic disorder, however, have produced inconsistent results. Seeking to understand the inconsistencies, we reexamined endocrine data from four studies of patients with panic disorder, in light of animal data highlighting the salience of novelty, control, and social support to HPA axis activity. Patients with panic disorder were studied (1) at rest over a full circadian cycle, (2) before and after activation by a panicogenic respiratory stimulant (doxapram) that does not directly stimulate the HPA axis, and (3) before and after a cholecystokinin B (CCK-B) agonist that is panicogenic and does directly stimulate the HPA axis. Patients with panic disorder had elevated overnight cortisol levels, which correlated with sleep disruption. ACTH and cortisol levels were higher in a challenge paradigm (doxapram) than in a resting state study, and paradigm-related ACTH secretion was exaggerated in patients with panic disorder. Panic itself could be elicited without HPA axis activation. Patients with panic disorder showed an exaggerated ACTH response to pentagastrin stimulation, but this response was normalized by prior exposure to the experimental context or psychological preparation to reduce novelty and enhance sense of control. Novelty is one of a number of contextual cues known from animal work to activate the HPA axis. The HPA axis abnormalities seen in patients with panic disorder in the four experiments reviewed here might all be due to exaggerated HPA axis reactivity to novelty cues. Most of the published panic/HPA literature is consistent with the hypothesis that HPA axis dysregulation in panic is due to hypersensitivity to contextual cues. This hypothesis requires experimental testing. Depression and Anxiety 24:66–76, 2007. Published 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55906/1/20220_ftp.pd

The clinical global impression scale and the influence of patient or staff perspective on outcome

<p>Abstract</p> <p>Background</p> <p>Since its first publication, the Clinical Global Impression Scale (CGI) has become one of the most widely used assessment instruments in psychiatry. Although some conflicting data has been presented, studies investigating the CGI's validity have only rarely been conducted so far. It is unclear whether the improvement index CGI-I or a difference score of the severity index CGI-S_difis more valid in depicting clinical change. The current study examined the validity of these two measures and investigated whether therapists' CGI ratings correspond to the view the patients themselves have on their condition.</p> <p>Methods</p> <p>Thirty-one inpatients of a German psychotherapeutic hospital suffering from a major depressive disorder (age M = 45.3, SD = 17.2; 58.1% women) participated. Patients filled in the Beck Depression Inventory (BDI). CGI-S and CGI-I were rated from three perspectives: the treating therapist (THER), the team of therapists involved in the patient's treatment (TEAM), and the patient (PAT). BDI and CGI-S were filled in at admission and discharge, CGI-I at discharge only. Data was analysed using effect sizes, Spearman's <it>ρ </it>and intra-class correlations (ICC).</p> <p>Results</p> <p>Effect sizes between CGI-I and CGI-S _difratings were large for all three perspectives with substantially higher change scores on CGI-I than on CGI-S _dif. BDI_difcorrelated moderately with PAT ratings, but did not correlate significantly with TEAM or THER ratings. Congruence between CGI-ratings from the three perspectives was low for CGI-S _dif(ICC = .37; Confidence Interval [CI] .15 to .59; <it>F</it>_30,60= 2.77, <it>p </it>< .001; mean <it>ρ </it>= 0.36) and moderate for CGI-I (ICC = .65 (CI .47 to .80; <it>F</it>_30,60= 6.61, <it>p </it>< .001; mean <it>ρ </it>= 0.59).</p> <p>Conclusions</p> <p>Results do not suggest a definite recommendation for whether CGI-I or CGI-S _difshould be used since no strong evidence for the validity of neither of them could be found. As congruence between CGI ratings from patients' and staff's perspective was not convincing it cannot be assumed that CGI THER or TEAM ratings fully represent the view of the patient on the severity of his impairment. Thus, we advocate for the incorporation of multiple self- and clinician-reported scales into the design of clinical trials in addition to CGI in order to gain further insight into CGI's relation to the patients' perspective.</p

A cellular defense memory imprinted by early life toxic stress

Stress exposure early in life is implicated in various behavioural and somatic diseases. Experiences during the critical perinatal period form permanent, imprinted memories promoting adult survival. Although imprinting is widely recognized to dictate behaviour, whether it actuates specific transcriptional responses at the cellular level is unknown. Here we report that in response to early life stresses, Caenorhabditis elegans nematodes form an imprinted cellular defense memory. We show that exposing newly-born worms to toxic antimycin A and paraquat, respectively, stimulates the expression of toxin-specific cytoprotective reporters. Toxin exposure also induces avoidance of the toxin-containing bacterial lawn. In contrast, adult worms do not exhibit aversive behaviour towards stress-associated bacterial sensory cues. However, the mere re-encounter with the same cues reactivates the previously induced cytoprotective reporters. Learned adult defenses require memory formation during the L1 larval stage and do not appear to confer increased protection against the toxin. Thus, exposure of C. elegans to toxic stresses in the critical period elicits adaptive behavioural and cytoprotective responses, which do not form imprinted aversive behaviour, but imprint a cytoprotective memory. Our findings identify a novel form of imprinting and suggest that imprinted molecular defenses might underlie various pathophysiological alterations related to early life stress. © 2019, The Author(s)

Voting with their feet - predictors of discharge against medical advice in Aboriginal and non-Aboriginal ischaemic heart disease inpatients in Western Australia: an analytic study using data linkage

Background: Discharge Against Medical Advice (DAMA) from hospital is associated with adverse outcomes and is considered an indicator of the responsiveness of hospitals to the needs of Aboriginal and Torres Strait Islander Australians, the indigenous people of Australia. We investigated demographic and clinical factors that predict DAMA in patients experiencing their first-ever inpatient admission for ischaemic heart disease (IHD). The study focuse sparticularly on the differences in the risk of DAMA in Aboriginal and non-Aboriginal patients while also investigating other factors in their own right. Methods: A cross-sectional analytical study was undertaken using linked hospital and mortality data with complete coverage of Western Australia. Participants included all first-ever IHD inpatients (aged 25–79 years) admitted between 2005 and 2009, selected after a 15-year clearance period and who were discharged alive. The main outcome measure was DAMA as reflected in the hospital record. Multiple logistic regression was used to determine disparities in DAMA between Aboriginal and non-Aboriginal patients, adjusting for a range of demographic and clinical factors, including comorbidity based on 5-year hospitalization history. A series of additional models were run on subgroups of the cohort to refine the analysis. Ethics approval was granted by the WA Human Research and the WA Aboriginal Health Ethics Committees.Results: Aboriginal patients comprised 4.3% of the cohort of 37,304 IHD patients and 23% of the 224 DAMAs. Emergency admission (OR=5.9, 95% CI 2.9-12.2), alcohol admission history (alcohol-related OR=2.9, 95% CI 2.0-4.2) and Aboriginality (OR 2.3, 95% CI 1.5-3.5) were the strongest predictors of DAMA in the multivariate model. Patients living in rural areas while attending non-metropolitan hospitals had a 50% higher risk of DAMA than those living and hospitalised in metropolitan areas. There was consistency in the ORs for Aboriginality in the different multivariate models using restricted sub-cohorts and different Aboriginal identifiers. Sex, IHD diagnosis type and co-morbidity scores imparted different risks in Aboriginal versus non-Aboriginal patients. Conclusions: Understanding the risks and reasons for DAMA is important for health system policy and proactive management of those at risk of DAMA. Improving care to prevent DAMA should target unplanned admissions, rural hospitals and young men, Aboriginal people and those with alcohol and mental health comorbidities