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It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults.
Lipids were measured at baseline (1985–1986; age: 18–30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes.
There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C <100 mg/dL, 101–129 mg/dL, 130–159 mg/dL, and ≥160 mg/dL, respectively. Standardized differences in all cognitive function test scores ranged from 0.16 SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV.
Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.
A programmable borehole measurement system was deployed in hot water drilled ice holes during the ‘Bed Access and Monitoring of Ice Sheet History’ (BEAMISH) project to drill to the bed of the Rutford Ice Stream in West Antarctica. This system operates autonomously (no live data) after deployment, and records borehole diameter (non-contact measurement), water column pressure, heading and inclination. Three cameras, two sideways looking and one vertical, are also included for visual inspection of hole integrity and sediments. The system is small, lightweight (~35.5 kg) and low power using only 6 ‘D’ cell sized lithium batteries, making it ideal for transport and use in remote field sites. The system is 2.81 m long and 165 mm in diameter, and can be deployed attached to the drill hose for measurements during drilling or on its own deployment line afterwards. The full system is discussed in detail, highlighting design strengths and weaknesses. Data from the BEAMISH project are also presented in the form of camera images showing hole integrity, and sensor data used to calculate borehole diameter through the full length of the hole. These data are used to show confidence in hole verticality and subsurface cavity development and connection.
Psychiatrists may be daunted by the prospect of undertaking a neurological examination. In this article we briefly review the neurological signs that may be seen in the context of some common neurological disorders of cognition and movement which may present with neurobehavioural symptoms and therefore may be seen initially by psychiatrists. This approach emphasises that neurological examination is not simply an operationalised procedure but an interpretative process. We propose a minimum neurological examination suitable for use by psychiatrists. Many of the signs included are relatively simple to observe or elicit, require no special equipment, and the examination techniques involved are easy to master.
Depression is characterised by negative views of the self. Antidepressant treatment may remediate negative self-schema through increasing processing of positive information about the self. Changes in affective processing during social interactions may increase expression of prosocial behaviours, improving interpersonal communications.
To examine whether acute administration of citalopram is associated with an increase in positive affective learning biases about the self and prosocial behaviour.
Healthy volunteers (n = 41) were randomised to either an acute 20 mg dose of citalopram or matched placebo in a between-subjects double-blind design. Participants completed computer-based cognitive tasks designed to measure referential affective processing, social cognition and expression of prosocial behaviours.
Participants administered citalopram made more cooperative choices than those administered placebo in a prisoner's dilemma task (β = 20%, 95% CI: 2%, 37%). Exploratory analyses indicated that participants administered citalopram showed a positive bias when learning social evaluations about a friend (β = 4.06, 95% CI: 0.88, 7.24), but not about the self or a stranger. Similarly, exploratory analyses found evidence of increased recall of positive words and reduced recall of negative words about others (β = 2.41, 95% CI: 0.89, 3.93), but not the self, in the citalopram group.
Participants administered citalopram showed greater prosocial behaviours, increased positive recall and increased positive learning of social evaluations towards others. The increase in positive affective bias and prosocial behaviours towards others may, at least partially, be a mechanism of antidepressant effect. However, we found no evidence that citalopram influenced self-referential processing.
We examined demographic, clinical, and psychological characteristics of a large cohort (n = 368) of adults with dissociative seizures (DS) recruited to the CODES randomised controlled trial (RCT) and explored differences associated with age at onset of DS, gender, and DS semiology.
Prior to randomisation within the CODES RCT, we collected demographic and clinical data on 368 participants. We assessed psychiatric comorbidity using the Mini-International Neuropsychiatric Interview (M.I.N.I.) and a screening measure of personality disorder and measured anxiety, depression, psychological distress, somatic symptom burden, emotional expression, functional impact of DS, avoidance behaviour, and quality of life. We undertook comparisons based on reported age at DS onset (<40 v. ⩾40), gender (male v. female), and DS semiology (predominantly hyperkinetic v. hypokinetic).
Our cohort was predominantly female (72%) and characterised by high levels of socio-economic deprivation. Two-thirds had predominantly hyperkinetic DS. Of the total, 69% had ⩾1 comorbid M.I.N.I. diagnosis (median number = 2), with agoraphobia being the most common concurrent diagnosis. Clinical levels of distress were reported by 86% and characteristics associated with maladaptive personality traits by 60%. Moderate-to-severe functional impairment, high levels of somatic symptoms, and impaired quality of life were also reported. Women had a younger age at DS onset than men.
Our study highlights the burden of psychopathology and socio-economic deprivation in a large, heterogeneous cohort of patients with DS. The lack of clear differences based on gender, DS semiology and age at onset suggests these factors do not add substantially to the heterogeneity of the cohort.
The safety and tolerability of aripiprazole as adjunctive treatment was examined in patients with major depressive disorder (MDD) without psychotic features who had a major depressive episode and who did not respond adequately to standard antidepressant therapy (ADT).
Data from three identical short-term, double-blind, placebo-controlled studies (CN138139, CN138163, CN138165) were pooled. After a prospective phase with placebo plus ADT, patients without adequate response entered a 6-week, double-blind phase with placebo or aripiprazole plus ADT. Safety endpoints included death, serious adverse events (SAEs), treatment-emergent adverse events (AEs), Simpson-Angus Scale (SAS), Barnes Akathisia Global Clinical Assessment, Abnormal Involuntary Movement Scale (AIMS), clinical laboratory tests, vital signs and electrocardiograms.
In total, 538 patients were randomized to adjunctive placebo and 547 to adjunctive aripiprazole. AEs with an incidence ≥5% and at least twice the rate of placebo were akathisia (adjunctive aripiprazole, 22.7%; adjunctive placebo, 4.1%), restlessness (12.4% vs 2.2%), fatigue (8.6% vs 4.3%), insomnia (8.2% vs 3.2%), vision blurred (6.2% vs 1.5%), somnolence (5.9% vs 2.6%), and constipation (4.9% vs 2.4%). AEs that had a treatment difference of ≥2% included akathisia, somnolence, sedation, dizziness, disturbance in attention, extrapyramidal disorder, restlessness, insomnia, constipation, dyspepsia, fatigue, feeling jittery, vision blurred, weight increased, and dyspnea. SAEs occurred in 0.7% of patients in each treatment group. There were no deaths during the studies.
In this pooled analysis of patients with MDD and an inadequate response to ADT, adjunctive aripiprazole showed consistently high study completion rates and low discontinuation rates resulting from adverse events.
Available data suggest that sex hormone levels during puberty may affect symptom onset and expression, treatment responsiveness and outcomes in schizophrenia, whereas post-pubertal adolescents may have a similar clinical presentation and treatment response compared to adults with schizophrenia.
Post-hoc analyses were conducted to assess the similarity of short- and long-term efficacy between post-pubertal adolescents and adults with schizophrenia treated with aripiprazole.
Based on available European epidemiologic data, a cut-off age of 15 years was used to isolate a subgroup of mostly post-pubertal adolescents with schizophrenia in aripiprazole clinical studies. Outcome measures from this subgroup (ages 15-17; n=147) were then compared to outcomes from one adult study (n=853) on short and long-term measures of efficacy, including PANSS scores, response rates, and remission rates.
Comparable short and long-term treatment effects were observed on the PANSS total and subscale scores, demonstrated by overlapping 95% confidence intervals (mean change from baseline in PANSS total score (OC dataset): at week 6 in adults: -27,7; in adolescents 15-17 yr: -29,6; at week 30 in adults: -39,2; in adolescents 15-17 yr: -36). Percent of adolescents achieving response (defined as ≥ 30% decrease in PANSS total score from baseline) at 32 weeks (80,2%) on open label treatment was similar to that in adult studies at week 34 (80%) on double blind treatment (OC dataset).
Adolescents with schizophrenia (ages 15-17, mostly post-pubertal) demonstrate a positive treatment response in short-term and long-term studies which is similar to that observed in the adult patient population.
To evaluate the safety of aripiprazole as adjunctive treatment in major depressive disorder (MDD) without psychotic features within different patient subgroups.
Data were pooled from three multicentre, randomized, double-blind, placebo-controlled studies (CN138-139, CN138-163 and CN138-165). Patients who did not respond adequately to an 8-week course of standard ADT were randomized to receive adjunctive aripiprazole or placebo for a further 6 weeks. To assess differences in the adverse events (AE) profile of aripiprazole for demographic subgroups, the incidence of AEs was presented for the pooled placebo-controlled MDD studies by gender, age, and race. An odds ratio (OR) estimate was calculated and the ORs compared across all categories using the Breslow-Day test for AEs with incidence ≥5% in the pooled aripiprazole group.
In total, 14.3% of aripiprazole-treated patients and 12.5% of placebo-treated patients discontinued treatment. Treatment-emergent AEs were reported by 65.4% and 82.3% in the adjunctive placebo and adjunctive aripiprazole groups, respectively. Most aripiprazole-related AEs were, however, mild to moderate in severity. With the exception of blurred vision, which occurred in white patients only (p=0.002), there were no significant differences in the incidence of treatment-emergent AEs across different age groups, racial groups or between the genders in the aripiprazole- and placebo-treated groups.
Adjunctive aripiprazole was generally well tolerated and most treatment-emergent AEs were of mild to moderate severity. The AEs profile of adjunctive aripiprazole did not show significant variation in relation to age, gender or race, compared with that of placebo.
Aripiprazole has demonstrated efficacy for the treatment of paediatric patients (10–17 years) with a manic or mixed episode associated with bipolar I disorder in a clinical trial that utilised the Young Mania Rating Scale (YMRS) Total score as the primary outcome measure.
This analysis evaluated the profile of discrete symptom response using the YMRS and other measures.
Post-hoc analysis of individual items of the YMRS and the parent or subject version of the General Behaviour Inventory (GBI) Mania and Depression scales using data from a 4-week, double-blind, randomised trial that compared aripiprazole (10 or 30 mg/day, n = 197) with placebo (n = 99).
In total, 296 patients were randomised; 80% completed the study. Significant decreases at Week 4 (p < 0.05) were seen in eight YMRS items: elevated mood, increased motor activity/energy, need for sleep, irritability, speech (rate and amount), language/thought disorder, abnormal thought content and disruptive/aggressive behaviour. For the GBI, effect sizes for parent-reported mania items were medium to large (for example, 0.41 for ‘depressed but high energy’ to 0.78 for ‘rage combined with unusually happy’) but were consistently small on subject self-reported items of mania and depression and, for the overall scale, had the poorest agreement with clinician ratings.
Aripiprazole demonstrated improvements in some of the more troublesome symptoms of paediatric patients with bipolar I disorder experiencing an acute manic or mixed episode. Of note, irritability and aggression showed large treatment effects on both clinician and parent-reported measures, but less so for subject-reported measures.
Case management has been an integral part of psychiatric practice in the United States for over a decade and has generated a large body of literature. The application of case management principles to the care of people suffering from psychiatric disorders is becoming increasingly popular in the United Kingdom and Europe and literature is now beginning to be published. However, no definitive statements about the efficacy of case management have been made due to a range of conceptual and methodological problems. The present paper is a critical review of the case management outcome literature. Reported outcomes are reviewed in the context of study design and service characteristics. The authors conclude that case management practice can have at least some impact on patients' use of services (including marked decrease in in-patient bed days); satisfaction with services; engagement with services; and social networks and relationships when it is delivered as a direct, clinical service with high staff: patient ratios. A set of recommendations are suggested for the future practice and presentation of research into case management.
Optimal management of schizophrenia in adolescents is limited by the lack of available therapies. The efficacy and tolerability of aripiprazole was investigated in this patient population.
This 6-week, randomized, double-blind, placebo controlled trial was conducted at 101 international centers, with a safety monitoring board. 13-17 year-olds with a DSM-IV diagnosis of schizophrenia were randomized to placebo, or a fixed dose of aripiprazole 10 mg or 30 mg reached after a 5 or 11 day titration, respectively. The primary endpoint was mean change from baseline on the PANSS Total score at week 6. Secondary endpoints included the PANSS Positive and Negative subscales, and CGI Improvement score. Tolerabilility assessements included frequency and severity of adverse events, as well as blood chemistries, metabolic parameters and weight gain.
Over 85% of 302 patients completed this study. Both 10 mg and 30 mg doses were superior to placebo on the primary endpoint (PANSS total), with significant differences observed as early as Week 1 (30mg). Both doses showed significant improvement on the PANSS Positive and CGI-I scales; and the 10 mg dose group was superior on PANSS Negative score. Approximately 5% of aripiprazole patients discontinued due to AEs. Weight gain and changes in prolactin were minimal.
10mg and 30mg doses of aripiprazole were superior to placebo in the treatment of adolescents with schizophrenia. Aripiprazole was well tolerated, in general, with few discontinuations due to AEs. EPS was the most common AE. Change in body weight was similar to placebo.
There is limited published data from long-term pediatric bipolar clinical trials with which to guide appropriate treatment decisions. Long-term efficacy and safety of aripiprazole was investigated in this patient population.
296 youths, ages 10-17 year-old with a DSM-IV diagnosis of bipolar I disorder were randomized to receive either placebo or aripiprazole (10mg or 30mg) in a 4-week double-blind trial. Completers continued assigned treatments for an additional 26 weeks (double-blind). Efficacy endpoints included mean change from baseline to week 4 and week 30 on the Young Mania Rating Scale; Children's Global Assessment Scale, Clinical Global Impressions-Bipolar version severity scale, General Behavior Inventory, Attention Deficit Hyperactivity Disorders Rating Scale, and time to discontinuation. Tolerability/safety assessments included incidence and severity of AEs, blood chemistries and metabolic parameters.
Over the 30-week course of double-blind treatment, aripiprazole (10 mg and 30 mg) was superior to placebo as early as week 1 (p< 0.002) and at all scheduled visits from week 2 through week 30 on mean change from baseline in the Y-MRS total score (p<.0001; all visits). Significant improvements were observed on multiple endpoints including the CGAS, GBI, CGI-BP, ADHD-RS-IV total score, time to discontinuation, and response and remission rates. The 3 most common AEs were somnolence, extrapyramidal disorder, and fatigue. Mean change in body weight z-scores over 30 weeks was not clinically significant.
Over 30-weeks of treatment, both doses of aripiprazole were superior to placebo in the long term treatment of pediatric bipolar patients. Aripiprazole was generally well tolerated.
Evaluate the efficacy of aripiprazole combination with lithium/valproate vs. placebo combination in bipolar mania using a titration regimen with a low starting dose (5 mg/day).
Eligible adult patients with bipolar mania receiving lithium/valproate and a Young Mania Rating Scale (YMRS) Total score ≥16 who might benefit from combination treatment with aripiprazole, were randomized to aripiprazole (n=181) or placebo (n=189) with lithium/valproate. Primary endpoint was mean change from baseline to Week 12 in YMRS. Secondary endpoints were Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness score, response rate (≥50% improvement in YMRS Total score), and remission rate (YMRS ≤12). Safety and tolerability were also assessed. Enrolment yielded a 77% power to detect a 2.6-point change in YMRS Total score at endpoint.
At endpoint, the mean change in YMRS Total Score (last-observation-carried-forward [LOCF]) for aripiprazole vs. placebo was not significant (treatment difference [-2.04] in favour of aripiprazole (95% CI: -4.14, 0.07; p=0.058). Mean change from baseline to endpoint in CGI-BP showed a treatment difference (-0.30) in favour of aripiprazole vs. placebo (95% CI: - 0.59, -0.01; p=0.044). Response rates were 68.8% vs. 61.3% (p=0.128) and remission rates were 69.9% vs. 64.0% (p=0.211) for aripiprazole and placebo, respectively. No unexpected adverse events (AEs) occurred. Treatment-emergent AEs (≥5% and twice the rate of placebo) were akathisia, depression, and nausea.
The target sample size of 388 patients was not achieved in this study and the primary outcome did not reach statistical significance. Now new or unexpected AEs occurred.
Evaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.
Patients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed.
710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p< 0.0001, log-rank test). Discontinuations due to treatment-emergent adverse events (AEs) were: Phase 1, 3.8% (n=24/632); Phase 2, 3.0% (n=21/709); Phase 3, 4.9% (n=28/576); Phase 4, 7.1% (n=19/269). Most AEs were mild or moderate. Insomnia was the only AE >5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders.
ARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia1.
Brexpiprazole is a serotonin-noradrenaline-dopamine agent that binds with high affinity to multiple serotonin, norepinephrine and dopamine receptors. In particular, Brexpiprazole is a partial agonist at dopamine D2/D3 and 5-HT1A receptors and an antagonist at 5-HT2A and norepinephrine alpha1B receptors.
We assessed the efficacy and safety of brexpiprazole versus placebo as adjunctive therapy to anti-depressant therapy (ADT) in subjects with MDD who demonstrated inadequate response to ADT.
This trial had 3 phases: a screening phase (7-28 days); a prospective phase (Phase A): 8-week, single-blind placebo plus an investigator-determined, open-label ADT; a randomized phase (Phase B): 6-week, double-blind, adjunctive brexpiprazole (2 mg/day) vs. placebo in patients with an inadequate response to ADT.
The primary efficacy endpoint was the change from the end of Phase A (Week 8) to the end of Phase B (Week 14) in MADRS Total Score. The key secondary endpoint was the change in mean SDS score. Other secondary endpoints were mean change in CGI-S, IDS-R, HAMD and HAMA.
Of 379 randomized patients, completion rates at Week 14 were high (92.9%). Statistically significant improvements in mean MADRS Total score were observed for subjects receiving adjunctive brexpiprazole 2mg/day compared with placebo (p=0.0001) at endpoint. In addition, on all secondary endpoints Brexpiprazole showed a statistically significant advantage over placebo.
Commonly reported adverse events in the brexpiprazole group (>5% and more than twice placebo) were weight gain (8.0%), akathisia (7.4%).
Brexpiprazole was effective and well tolerated as adjunctive treatment for MDD patients with an inadequate response to ADT.
Animal assisted therapy (AAT) is becoming increasingly utilized for psychiatric patients with suboptimal response to traditional therapies. Larger animals, such as horses, may be especially effective therapy enhancers for some patients.
We have introduced AAT at a 500 bed psychiatric hospital in New Jersey. We previously conducted a randomized control trial (n=103) of ten weekly AAT group therapy sessions, comparing canine assisted therapy, equine facilitated therapy (EFT), enhanced psychosocial therapy, and standard treatment in highly regressed and/or violent patients. Initial analyses indicated that the EFT group had fewer violence-related incidents during the 3 months following the intervention compared with the other groups (p< 0.05).
We have initiated a second randomized controlled study comparing EFT with standard hospital treatment in a similar sample.
Based on observations that patients with trauma/abuse histories may find AAT beneficial, this partial replication study is assessing whether trauma history and perceptions relate to symptomatic and functional outcome with EFT.
Preliminary post-session interviews over several weeks for a subgroup of four patients with reported trauma histories (rates comparable to persons with PTSD on the Traumatic Life Events Questionnaire) elicited explicit trauma-related themes (e.g., recollection of past abuse) as well as putative indirect references such as identifying with the horses as understanding their pain and representing “hope.”
The presentation reviews the evolution and refinement of the intervention at our hospital, challenges to implementation, therapeutic course, preliminary outcome assessments, quantitative and qualitative, comparing EFT with standard treatment in the studies.
Evaluate the effectiveness of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.
Detailed methodology has been published previously1. Briefly, the study consisted of 4 phases: oral conversion to aripiprazole (Phase 1); oral aripiprazole stabilization (Phase 2); ARI-OM stabilization (Phase 3), with co-administration of oral aripiprazole for the first 2 weeks; and an ARI-OM maintenance phase (Phase 4). Effectiveness assessments included Investigator's Assessment Questionnaire (IAQ) scores, a scale that evaluates effectiveness of current treatment vs. pre-trial medication, where a negative change in score signals improvement, and Personal and Social Performance (PSP) scale scores, where negative change in score signals worsening.
710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo once-monthly [placebo- OM]=134). Mean IAQ Total scores remained stable in Phase 2 (31.3) and Phase 3 (30.6). During Phase 4, the mean change in IAQ Total score was +1.3 for ARI-OM vs. +3.8 for placebo-OM (p< 0.0001). Mean changes in PSP Total scale scores showed improvement during Phase 2 (3.0) and Phase 3 (2.6). Mean change in PSP scores during Phase 4 showed greater functional stability with ARI-OM (−1.7) compared with placebo-OM (−6.2) (p=0.0002 vs. placebo-OM).
Improvements in effectiveness, as assessed by the IAQ and PSP Total scale scores, in the Phases 2 & 3 were maintained in Phase 4 for ARI-OM compared with placebo-OM. Treatment with ARI-OM improved symptoms, overall response to treatment and functioning.
We used a combination of accelerator mass spectrometry (AMS) radiocarbon dating, optically stimulated luminescence (OSL) age estimates, and stratigraphic data from cores collected along the southern margin of the Green Bay Lobe (GBL) of the Laurentide Ice Sheet to provide new information on the timing and dynamics of the end of advance of the GBL and the dynamics of the ice sheet while very near its maximum position. Coring at multiple sites along the margin of the GBL indicate that ice had reached a stable position near its maximum extent by 24.7 ka; that ice advanced several kilometers to the Marine Isotope Stage 2 maximum position sometime shortly after 21.2 ka; and that ice remained at or beyond that position through the time interval represented by an OSL age estimate of 19.2 ± 3.2 ka. The timeline developed from these chronological data is internally consistent with, and further refines, AMS radiocarbon ages and OSL age estimates previously published for the southern margin of the GBL. It also provides new chronological control on the expansion of the GBL from its late Marine Isotope Stage (MIS) 3 extent to its MIS 2 maximum.