Hippocampal glutamatergic/NMDA receptor functioning in bipolar disorder: a combined MMN and 1H-MRS study

Disturbances in the hippocampal glutamate (Glu)/N-methyl-d-aspartate (NMDA) system have been implicated in the pathophysiology of bipolar disorder (BD). Here we aim to provide a targeted integration of two measures of glutamatergic functioning in BD; the association between mismatch negativity (MMN) and in vivo hippocampal-Glu measured via proton magnetic resonance spectroscopy ((1)H MRS). Participants comprised of 33 patients with BD and 23 matched controls who underwent a two-tone passive, duration deviant MMN paradigm and (1)H MRS. Levels of Glu/creatine (Cr) in the hippocampus were determined. Pearson's correlations were used to determine associations between MMN and Glu/Cr. In controls, MMN amplitude was positively associated with Glu/Cr at the left temporal site. We did not find any significant associations with Glu/Cr and frontocentral MMN nor did we find any significant associations in BD patients. The results provide further insight into the neurophysiology of MMN, with evidence supporting the role of hippocampal-Glu signalling through the NMDA receptor in temporal MMN. Our data also demonstrate that Glu/Cr regulation of MMN is dampened in BD, which may indicate a lack of tightly regulated hippocampal NMDA functioning. These findings provide insight into the underlying basis of glutamatergic transmission disturbances implicated in the disorder.NHMRC Australia Fellowship 46491

A longitudinal proton magnetic resonance spectroscopy study investigating oxidative stress as a result of alcohol and tobacco use in youth with bipolar disorder

Alcohol and tobacco have been suggested to be "aggravating factors" for neuroprogression in bipolar disorder (BD), however the impact of these substances on the underlying neurobiology is limited. Oxidative stress is a key target for research into neuroprogression in BD and in accordance with this model, our previous cross-sectional studies have found that risky alcohol and tobacco use in BD is associated with increased oxidative stress, investigated via in vivo glutathione (GSH) measured by proton magnetic resonance spectroscopy ((1)H-MRS) in the anterior cingulate cortex (ACC). What remains unknown is whether the negative impact on GSH levels can be modified as a result of limiting alcohol and tobacco use. Thirty BD patients were included in the study. (1)H-MRS and tobacco and alcohol measures were conducted at baseline and follow-up assessments (15.5±4.6 months apart). Pearson׳s correlations were performed between percentage change in GSH concentration and changes in alcohol/tobacco use. Regression analyses were then conducted to further explore the significant correlations. An increase in GSH was associated with a decrease in alcohol consumption (r=-0.381, p<0.05) and frequency of tobacco use (-0.367, p=0.05). Change in alcohol consumption, tobacco use and age were significant predictors of change in GSH concentration (F (3, 26)=3.69, p<0.05). Due to the high comorbidity of alcohol and tobacco use in the sample, the individual effects of these substances on GSH levels could not be determined. This study offers longitudinal evidence that changing risky drinking patterns and tobacco use early in the course of BD is associated with improvements in antioxidant capacity, and therefore may be specific targets for early intervention and prevention of neuroprogression in BD.NHMRC Australia Fellowship 46491

Alcohol use in bipolar disorder: A neurobiological model to help predict susceptibility, select treatments and attenuate cortical insult.

In a series of neurophysiological and neuroimaging studies we investigated the neurobiology related to alcohol use in young people with bipolar disorder. Impairments were identified across frontal and temporal representations of event-related potential and proton magnetic resonance spectroscopy markers; mismatch negativity and in vivo glutathione, respectively. We propose these findings reflect impairments in the N-methyl-D-aspartate receptor and antioxidant capacity. This review seeks to place these findings within the broader literature in the context of two propositions: 1. Pathophysiological impairments in N-methyl-D-aspartate receptor functioning in bipolar disorder contribute to susceptibility toward developing alcohol problems. 2. Alcohol aggravates bipolar disorder neuroprogression via oxidative stress. A neurobiological model that incorporates these propositions is presented, with a focus on the potential for N-methyl-D-aspartate receptor antagonism and glutathione augmentation as potential adjunctive pharmacotherapies to treat the comorbidity. While this review highlights the importance of alcohol monitoring and reduction strategies in the treatment of bipolar disorder, the clinical impact of the proposed model remains limited by the lack of controlled trials of novel pharmacological interventions.NHMRC Australia Fellowship 46491

Discontinuities and disruptions in drug dosage guidelines for the paediatric population

AIMSThis study investigates paediatric drug dosage guidelines withthe aim of investigating their agreement with body surface area(BSA) scaling principles.METHODSA total of 454 drug dosage guidelines listed in the AMH-CDC 2015 were examined. Data extracted included the administration,frequency and dose per age bracket from 0 to 18 years. Drug treatments were categorized as follows: (1) The same dose rec-ommendation in milligrams per kilogram (mg kg 1) for all age/weights; (2) Change in the mg kg 1dosing according toage/weight; (3) Change in dose in mg according to age/weight; (4) Change from mg kg 1dosing to a dose in mg according toage/weight; (5) The same recommendation for all age/weight groups in mg; or (6) BSA dosing. Example drugs were selected toillustrate dose progression across ages.RESULTSMost drug treatments (63%) have the same mg kg 1dose for all age/weight groups, 14% are dosed in mg kg 1across all ageswith dose changes according to age/weight, 13% were dosed in mg across all ages with dose changes, 10% switched frommg kg 1to a set dose in mg, 4.2% have the same dose in mg for all age and weight groups and 2.2% are dosed according to BSA.CONCLUSIONSPaediatric dosage guidelines are based on weight-based formulas, available dosing formulations and prior patterns of use. Sub-stantial variation from doses predicted by BSA scaling are common, as are large shifts in recommended doses at age thresholds.Further research is required to determine if better outcomes could be achieved by adopting biologically based scaling of paedi-atric doses.NHMR

Alcohol-related suicide across Australia : a geospatial analysis

Background: The acute effects of alcohol consumption are a major risk factor for suicide. Positive blood alcohol concentrations are present in almost one-third of all suicides at time of death. These suicides are defined as alcohol-related suicides. This cross-sectional study examines the geospatial distribution/clustering of high proportions of alcohol-related suicides and reports on socioeconomic and demographic risk factors. Methods: National Coronial Information System (NCIS) data were used to calculate proportions of suicides with alcohol present at the time of death for each level 3 statistical areas (SA3) in Australia. A density analysis and hotspot cluster analysis were used to visualise and establish statistically significant clustering of areas with higher (hotspots) and lower (coldspots) proportions. Subsequently, socioeconomic and demographic risk factors for alcohol use and suicide were reported on for hot and cold spots. Results: Significant clustering of areas with higher proportions of alcohol-related suicide occurred in northern Western Australia, the Northern Territory and Queensland, as well as inland New South Wales and inland Queensland. Clustering of SA3s with significantly lower proportions occurred in major city and inner regional Sydney and Melbourne. Conclusion and implications for public health: Results from this study identify areas in which prevention strategies should target alcohol use and can be used to inform prevention strategy design. Additionally, hotspots and coldspots identified in this study can be used for further analysis to better understand contextual risk factors for alcohol-related suicide

[In Press] Antidepressant treatment trajectories and suicide attempt among Australians aged 45 years and older : a population study using individual prescription data

Introduction: Meta-analyses show antidepressant initiation has increased risk of suicidal behavior <25 years, no difference 25–64 years and reduced risk 65+ years. Estimating risks from RCTs has limitations and real-world population estimates are uncommon. Methods: A self-controlled case series reporting incidence rate ratio (IRR) between exposed and control periods for antidepressants associated with suicide attempt, in Australian older age adults. We included all cases with suicide attempt [hospital data for ICD codes (X60–X84)] and any antidepressant use (n = 689) by participants in the “45 and Up Study”. Results: For all antidepressants the IRR for suicide attempt was elevated across all exposures, declining from 7.44 (95%CI 5.57–9.94) during the first 30 days, to 2.21 (1.73–2.81) at 91+ days. All four antidepressant sub-groups had higher IRRs for the first 30 day exposure: 2.43 (1.37–4.29) for TCAs, 4.06 (2.78–5.93) for SSRIs, 4.15 (2.65–6.50) for other antidepressants, and 4.92 (3.30–7.34) for SNRIs. Increased IRR persisted for 61- to 90-day exposures for SSRIs 2.42 (1.18–4.98) and SNRIs 2.66 (1.34–5.27). Conclusion: Some older adults have increased risk of suicide attempt with antidepressant exposure, which may persist for months. Clinical guidelines should recommend a period of monitoring for treatment-emergent suicidal thoughts and behaviors in older adult patients

A systematic review and meta-analysis of magnetic resonance imaging measurement of structural volumes in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a debilitating condition associated with mild to moderate cognitive impairment and with a prevalence rate of up to 22% in veterans. This systematic review and quantitative meta-analysis explore volumetric differences of three key structural brain regions (hippocampus, amygdala and anterior cingulate cortex (ACC)), all of which have been implicated in dysfunction of both salience network (SN) and default mode network (DMN) in PTSD sufferers. A literature search was conducted in Embase, Medline, PubMed and PsycINFO in May 2013. Fifty-nine volumetric analyses from 44 articles were examined and included (36 hippocampus, 14 amygdala and nine ACC) with n=846 PTSD participants, n=520 healthy controls (HCs) and n=624 traumatised controls (TCs). Nine statistical tests were performed for each of the three regions of interest (ROIs), measuring volume differences in PTSD subjects, healthy and traumatised controls. Hippocampal volume was reduced in subjects with PTSD, with a greater reduction in the left hippocampus. A medium effect size reduction was found in bilateral amygdala volume when compared with findings in healthy controls; however, no significant differences in amygdala volume between PTSD subjects and trauma-exposed controls were found. Significant volume reductions were found bilaterally in the ACC. While often well matched with their respective control groups, the samples of PTSD subjects composed from the source studies used in the meta-analyses are limited in their homogeneity. The current findings of reduced hippocampal volume in subjects with PTSD are consistent with the existing literature. Amygdala volumes did not show significant reductions in PTSD subjects when compared with volumes in trauma-exposed controls—congruous with reported symptoms of hypervigilance and increased propensity in acquisition of conditioned fear memories—but a significant reduction was found in the combined left and right hemisphere volume analysis when compared with healthy controls. Bilateral volume reductions in the ACC may underpin the attentional deficits and inabilities to modulate emotions that are characteristically associated with PTSD patients.33 page(s

Co-ingested alcohol and the timing of deliberate self-poisonings

Objective: Investigating diurnal variation in the timing of suicidal behaviours offers opportunity to better understand its various proximal risk factors. Acute use of alcohol is a potent proximal risk factor for suicidal behaviour, though the nature of this risk is poorly understood. The aim of this study was to compare the diurnal variation in time of poison ingestion between deliberate self-poisonings that involve alcohol versus those that do not.Methods: A retrospective analysis of consecutive presentations to a toxicology service following deliberate self-poisoning, 1996-2016. An independent samples Kolmogorov-Smirnov test was performed to test the null hypothesis that the diurnal distribution of poison ingestion time was equal across self-poisonings that did and did not involve alcohol co-ingestion. Presence of circadian rhythmicity was established using cosinor analysis.Results: A total of 11,088 deliberate self-poisoning records, for 7467 patients (60.8% females), were included in the analysis. In all, 31.3% of the total records involved alcohol co-ingestion. Distribution of exposure time was significantly different between deliberate self-poisonings that did and did not involve alcohol (

Trends in recreational poisoning in Newcastle, Australia, between 1996 and 2013

Background: Poisoning that occurs as the result using alcohol or drugs for recreational purposes or to induce rewarding psychoactive effects ("recreational poisoning") represents significant harm attributed to drug use. There has been limited focus on recreational poisoning separately from hospital admissions for general harms related to alcohol or drug use. This study aims to detail the drug trends and patient population represented in recreational poisonings in Newcastle, Australia.Methods: Naturalistic analysis of consecutive hospital presentations following poisoning between January, 1996 and December, 2013 was conducted using data from the Hunter Area Toxicology Service (HATS). 13805 patient records were included (aged 18-98), 1209 (8.8%) of those were recreational poisonings.Results: Compared to non-recreational poisonings, recreational poisonings were more likely to occur in males than females (OR=2.87, 95% CI: 2.44-3.40, p < 0.001) and in patients under the age of 30 compared to their older counterparts (OR=1.58, 95% CI: 1.35-1.85,p < 0.001). Hospital presentations for recreational poisonings were more likely to occur between 0300 and 0600h than 0900-1700h (OR=3.07, 95% CI: 2.29-4.11, p < 0.001) and more likely to occur on the weekend than on a Monday. Overall, recreational poisoning admissions declined over time.Conclusions: Overall, the trends reported in this analysis reflect general use and availability of alcohol and illicit substances in Australia over the time period. Looking at specific sub-types of alcohol and drug-related harm, like poisoning, is important for service planning and government initiatives. (C) 2015 Elsevier Ireland Ltd. All rights reserved

Acute alcohol co-ingestion and hospital-treated deliberate self-poisoning; is there an effect on subsequent self-harm?

The aim of this study was to determine the relationship between alcohol co-ingestion in an index deliberate self-poisoning (DSP) episode with repeated DSP and subsequent suicide. A retrospective cohort study was conducted involving 5,669 consecutive index presentations to a toxicology service following DSP between January 1, 1996, and October 31, 2010. Records were probabilistically matched to National Coronial Information System data to identify subsequent suicide. Index DSPs were categorized on co-ingestion of alcohol, and primary outcomes analyzed were repetition of any DSP, rates of repeated DSP, time to first repeat DSP, and subsequent suicide. Co-ingestion of alcohol occurred in 35.9% of index admissions. There was no difference between those who coingested alcohol (ALC+) and those who did not co-ingest alcohol (ALC ) in terms of proportion of repeat DSP, number of DSP events, or time to first repeat DSP event. Forty-one (1.0%) cases were probabilistically matched to a suicide death; there was no difference in the proportion of suicide between ALC+ and ALC- at 1 or 3 years. There was no significant relationship between the coingestion of alcohol in an index DSP and subsequent repeated DSP or suicide. Clinically, this highlights the importance of mental health assessment of patients that present after DSP, irrespective of alcohol co-ingestion at the time of event