Aging of persons with schizophrenia: analysis of a national dataset.

OBJECTIVES: The number of older adults suffering from schizophrenia is increasing. Despite this, less than 1% of published studies about schizophrenia focus on those older than 65 years. Research indicates these individuals may age differently from the general population due to lifestyle, medication factors, and effects of the disease itself. We aimed to analyze whether schizophrenia was associated with a younger age at first assessment for social care as a proxy measure for accelerated aging. DESIGN: We analyzed the effect of schizophrenia diagnosis, demographics, mood, comorbidities, falls, cognition, and substance use on age at first assessment for social care using linear regression. PARTICIPANTS: We used data from 168,780 interRAI Home Care and Long-Term Care Facility (HC; LTCF) assessments completed from July 2013 to June 2020. RESULTS: When corrected for confounding factors, schizophrenia contributed to age at first assessment being 5.5 years younger (p = 0.0001 Cohen's D = 1.0) than in people free from schizophrenia. Its effect on age at first assessment was second only to smoking. People suffering from schizophrenia also required a higher level of care (long-term care facility rather than home care). People suffering from schizophrenia had significantly higher rates of diabetes mellitus and chronic obstructive pulmonary disease but otherwise had lower rates of comorbidity than people free from schizophrenia who required care. CONCLUSIONS: Aging with schizophrenia is associated with needing increased social care at a younger age. This has implications for social spending and developing policies to decrease frailty in this population.

Optimal sample selection applied to information rich, dense data.

Dense data can be classified into superdense information-poor data (type 1 dense data) and dense information-rich data (type 2 dense data). Arbitrary, random, or optimal thinning may be applied to type 1 dense data to minimise computational burden and statistical issues (such as autocorrelation). In contrast, a prospective or retrospective optimal design can be applied to type 2 dense data to maximise information gain from limited resources (capital and/or time). Here we describe a retrospective optimal selection strategy for quantification of unbound drug concentration from a discrete set of plasma samples where the total drug concentration has been measured.

Oral docetaxel plus encequidar - A pharmacokinetic model and evaluation against IV docetaxel.

The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency. METHODS:  A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision. RESULTS:  The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels. CONCLUSION:  The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Use of advance directives to promote supported decision-making in mental health care: Implications of international trends for reform in New Zealand.

Advance directives are advocated, in many jurisdictions, as a way to promote supported decision-making for people who use mental health services and to promote countries' compliance with their obligations under the United Nations Convention on the Rights of Persons with Disabilities. The United Nations Convention on the Rights of Persons with Disabilities promotes the use of tools to further personal autonomy which would include integrating the use of advance directives into mental health law, to clarify the effect (or force) an advance directive carries when its maker comes under the relevant mental health legislation. In addition, securing the active use of advance directives requires adoption of certain supportive practices and policies within health services. Here, we discuss a number of approaches taken to advance directives in revised mental health legislation, and the associated practices we think are required.

Maintenance ECT treatment in New Zealand: Local and national data.

OBJECTIVES: To retrospectively analyse patients receiving maintenance Electroconvulsive therapy (ECT), patterns of ECT treatment administration and impact on hospitalisation before and during treatment, in a single New Zealand District Health Board catchment. We also asked other District Health Boards in New Zealand for annual data on their use of maintenance ECT. METHODS: Regional analysis: retrospective analysis of patient-level data over 9 years. National analysis: survey of maintenance ECT/year. RESULTS: Regionally, 14 patients received maintenance ECT over 9 years. Patients were 50% male, with mean age 59 years, and principal diagnoses included schizophrenia, bipolar disorder and major depressive disorder. The time between ECT treatments tended to be shorter for patients with schizophrenia compared with those with mood disorders. Duration of time in hospital during maintenance ECT, compared with pre-ECT, was reduced by 52% for all patients, with greater reductions for patients with mood disorders compared with those with schizophrenia. Nationally, 19.7% of all ECT treatments in New Zealand (range 4-57%) were for maintenance treatment. DISCUSSION: Regional and national use patterns of maintenance ECT in New Zealand resemble those reported internationally. The RANZCP section of neurostimulation is planning ECT standards which would assist with ensuring coherence and quality of High-dose contrast-enhanced computed tomography/modified electroconvulsive therapy practice in New Zealand.

Aberrant salience and reward processing: a comparison of measures in schizophrenia and anxiety.

BACKGROUND: Aberrant salience may contribute to the development of schizophrenia symptoms via alterations in reward processing and motivation. However, tests of this hypothesis have yielded inconsistent results. These inconsistencies may reflect problems with the validity and specificity of measures of aberrant salience in schizophrenia. Therefore, we investigated relationships among measures of aberrant salience, reward, and motivation in schizophrenia and anxiety. METHOD: Individuals with schizophrenia (n = 30), anxiety (n = 33) or unaffected by mental disorder (n = 30) completed measures of aberrant salience [Aberrant Salience Inventory (ASI), Salience Attribution Test (SAT)], motivation (Effort Expenditure for Reward Task), and reinforcer sensitivity (Stimulus Chase Task). RESULTS: Schizophrenia participants scored higher than anxiety (d = 0.71) and unaffected (d = 1.54) groups on the ASI and exhibited greater aberrant salience (d = 0.60) and lower adaptive salience (d = 0.98) than anxious participants on the SAT. There was no evidence of a correlation between measures of aberrant salience. Schizophrenia was associated with related deficits in motivated behaviour and maladaptive reward processing. However, these differences in reward processing did not correlate with aberrant salience measures. CONCLUSIONS: The results suggest that key measures of aberrant salience have limited specificity and validity. These problems may account for inconsistent findings reported in the literature.

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review.

PURPOSE: Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects. METHODS: This was a structured review of published ketamine pharmacokinetics, safety and tolerability data for any ketamine formulation. The ratio of ketamine:norketamine was calculated from reported Cmax values, as a measure of first pass metabolism. The effect of formulation and route of administration on safety was evaluated by measuring mean changes in systolic blood pressure and tolerability by changes in dissociation ratings. Data were correlated using Spearman's method. RESULTS: A total of 41 treatment arms were identified from 21 publications, and included formulation development studies in healthy volunteers, and studies in clinical populations (patients undergoing anaesthesia, or being treated for pain or depression). Ketamine:norketamine ratios were strongly positively correlated with change in dissociation ratings (r = 0.89) and change in blood pressure (r = 0.96), and strongly negatively correlated with ketamine Tmax (r = - 0.87; p < 0.00001 for all). Ketamine Tmax strongly positively correlated with a change in dissociation ratings (r = - 0.96) and change in blood pressure (r = - 0.99; p < 0.00001 for all). CONCLUSION: Ketamine formulations that maximize first pass metabolism and delay Tmax will be better tolerated and safer than formulations which lack those characteristics.

The Great Escape. Centenarians' exceptional health.

BACKGROUND: Centenarians escapers are those who reached 100 years of age without the diagnosis of any of the common age-related diseases and exploring their characteristics will inform about successful ageing. No previous study has examined centenarians free of common chronic diseases amongst New Zealand centenarians. METHODS: Retrospective observational cross-sectional review of a national dataset determining the prevalence of depression, dementia, diabetes and hypertension, smoking, physical activity and social relationships among older adults (aged 60-99 years) and centenarians. Participants were all older New Zealanders living independently in the community who completed the international Residential Assessment Instrument-Home Care (interRAI-HC) assessment during the study's 5-year period (July 2013-June 2018). RESULTS: The assessments of 292 centenarians (mean age 101.03, SD 1.27 years) and 103,377 elderly (mean age 81.7, SD 5.7 years) were analysed. Compared to the elderly, centenarians were more likely to be female (74.7%, compared with 59.3% elderly, p < 0.001). Centenarians free of common chronic diseases did not differ from other centenarians on any of the analysed variables. Reduction in smoking rates and steady high rates of social engagement were associated with reaching a centenarian status free of common chronic diseases compared with older adults. CONCLUSIONS: Not smoking and being socially engaged throughout older age were associated with being a centenarian free of common chronic diseases. This study adds to our understanding the complexities of attaining exceptional longevity.

Progesterone loading as a strategy for treating postpartum depression.

Postpartum depression (PPD) is a severe disorder that adversely impacts both mothers and infants. It is associated with significant morbidity and mortality and reported prevalence is 11.5% (Ko, Rockhill, Tong, Morrow, & Farr. (2017). MMWR Morbidity and Mortality Weekly Report, 66(6), 153-158). Although PPD's fundamental pathophysiology remains to be fully illuminated, the influence of changes in perinatal hormones such as allopregnanolone (an endogenous progesterone metabolite) are most promising avenues of research. Conventional treatments for PPD are aligned with treatment strategies for depressive disorders. Brexanolone is a small molecule, neuroactive steroid GABAA receptor allosteric modulator consisting of synthetic allopregnanolone and a solubilizing agent. In early 2019, brexanolone received approval in the United States for the treatment of PPD. Brexanolone is only available through a restricted program and is costly. Animal models demonstrate that progesterone prevents depression-like behaviors. However, studies of progesterone's effects in women suffering from PPD are few and inconclusive. We hypothesize that orally dosed progesterone will increase concentrations of allopregnanolone in the central nervous system, which should relieve symptoms of PPD.

No country for older men: ageing male suicide in New Zealand.

OBJECTIVE: Suicide rates increase in late life. There is, however, a gap in understanding suicide in the very old. We aimed to underscore the evidence for high rates of death by suicide in the oldest-old men (age 85+) in New Zealand and to provide a conjectural discussion about factors driving these rates. METHOD: Provisional suicide data were obtained from the New Zealand Coronial Services website for the period 2011-2019. Yearly suicide rates for those aged 85+ were plotted over time. Mean suicide rates were calculated for three youth and young adult male cohorts, identified by the Coroner as having very high rates, and compared with the 85+ age cohort. RESULTS: Between 2011 and 2019, rates of death by suicide of older males remained consistently high never overlapping female suicide rates. Mean suicide deaths/100,000 population for all four age cohorts were comparable; 15-19 years: 23.5; 20-24 years: 29.0; 25-29 years: 27.0; 85+ years: 27.9. CONCLUSIONS: Deaths by suicide are very high for older males. In addition to established risk factors, psychosocial adversity as reflected by loneliness, poverty and shift to residential care may be major reasons for the high suicide rates. Research to inform about this vulnerable population and prevention are urgently needed.

Ketamine Effects on EEG during Therapy of Treatment-Resistant Generalized Anxiety and Social Anxiety.

BACKGROUND: Ketamine is swiftly effective in a range of neurotic disorders that are resistant to conventional antidepressant and anxiolytic drugs. The neural basis for its therapeutic action is unknown. Here we report the effects of ketamine on the EEG of patients with treatment-resistant generalized anxiety and social anxiety disorders. METHODS: Twelve patients with refractory DSM-IV generalized anxiety disorder and/or social anxiety disorder provided EEG during 10 minutes of relaxation before and 2 hours after receiving double-blind drug administration. Three ascending ketamine dose levels (0.25, 0.5, and 1 mg/kg) and midazolam (0.01 mg/kg) were given at 1-week intervals to each patient, with the midazolam counterbalanced in dosing position across patients. Anxiety was assessed pre- and postdose with the Fear Questionnaire and HAM-A. RESULTS: Ketamine dose-dependently improved Fear Questionnaire but not HAM-A scores, decreased EEG power most at low (delta) frequency, and increased it most at high (gamma) frequency. Only the decrease in medium-low (theta) frequency at right frontal sites predicted the effect of ketamine on the Fear Questionnaire. Ketamine produced no improvement in Higuchi's fractal dimension at any dose or systematic changes in frontal alpha asymmetry. CONCLUSIONS: Ketamine may achieve its effects on treatment-resistant generalized anxiety disorder and social anxiety disorder through related mechanisms to the common reduction by conventional anxiolytic drugs in right frontal theta. However, in the current study midazolam did not have such an effect, and it remains to be determined whether, unlike conventional anxiolytics, ketamine changes right frontal theta when it is effective in treatment-resistant depression.

Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression.

OBJECTIVE: To assess the efficacy and safety of subcutaneous ketamine for geriatric treatment-resistant depression. Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment. METHODS: In this double-blind, controlled, multiple-crossover study with a 6-month follow-up (randomized controlled trial [RCT] phase), 16 participants (≥60 years) with treatment-resistant depression who relapsed after remission or did not remit in the RCT were administered an open-label phase. Up to five subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (≥1 week apart), with one active control (midazolam) randomly inserted (RCT phase). Twelve ketamine treatments were given in the open-label phase. Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters. Remitters in each phase were followed for 6 months. RESULTS: Seven of 14 RCT-phase completers remitted with ketamine treatment. Five remitted at doses below 0.5 mg/kg. Doses ≥ 0.2 mg/kg were significantly more effective than midazolam. Ketamine was well tolerated. Repeated treatments resulted in higher likelihood of remission or longer time to relapse. CONCLUSION: Results provide preliminary evidence for the efficacy and safety of ketamine in treating elderly depressed. Dose titration is recommended for optimizing antidepressant and safety outcomes on an individual basis. Subcutaneous injection is a practical method for giving ketamine. Repeated treatments may improve remission rates (clinicaltrials.gov; NCT01441505).

Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis.

BACKGROUND: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. METHODS: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. RESULTS: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1-0.4 mg/kg i.v., and another assessed 0.1-0.5 mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6-7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2-5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7. CONCLUSION: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety.

Managing distance and covariate information with point-based clustering.

BACKGROUND: Geographic perspectives of disease and the human condition often involve point-based observations and questions of clustering or dispersion within a spatial context. These problems involve a finite set of point observations and are constrained by a larger, but finite, set of locations where the observations could occur. Developing a rigorous method for pattern analysis in this context requires handling spatial covariates, a method for constrained finite spatial clustering, and addressing bias in geographic distance measures. An approach, based on Ripley's K and applied to the problem of clustering with deliberate self-harm (DSH), is presented. METHODS: Point-based Monte-Carlo simulation of Ripley's K, accounting for socio-economic deprivation and sources of distance measurement bias, was developed to estimate clustering of DSH at a range of spatial scales. A rotated Minkowski L1 distance metric allowed variation in physical distance and clustering to be assessed. Self-harm data was derived from an audit of 2 years' emergency hospital presentations (n = 136) in a New Zealand town (population ~50,000). Study area was defined by residential (housing) land parcels representing a finite set of possible point addresses. RESULTS: Area-based deprivation was spatially correlated. Accounting for deprivation and distance bias showed evidence for clustering of DSH for spatial scales up to 500 m with a one-sided 95 % CI, suggesting that social contagion may be present for this urban cohort. CONCLUSIONS: Many problems involve finite locations in geographic space that require estimates of distance-based clustering at many scales. A Monte-Carlo approach to Ripley's K, incorporating covariates and models for distance bias, are crucial when assessing health-related clustering. The case study showed that social network structure defined at the neighbourhood level may account for aspects of neighbourhood clustering of DSH. Accounting for covariate measures that exhibit spatial clustering, such as deprivation, are crucial when assessing point-based clustering.

Psychosurgery Reduces Uncertainty and Increases Free Will? A Review.

OBJECTIVE: A definition of free will is the ability to select for or against a course of action to fulfill a desire, without extrinsic or intrinsic constraints that compel the choice. Free will has been linked to the evolutionary development of flexible decision making. In order to develop flexibility in thoughts and behavioral responses, learning mechanisms have evolved as a modification of reflexive behavioral strategies. The ultimate goal of the brain is to reduce uncertainty inherently present in a changing environment. A way to reduce the uncertainty, which is encoded by the rostral anterior cingulate, is to make multiple predictions about the environment which are updated in parallel by sensory inputs. The prediction/behavioral strategy that fits the sensory input best is then selected, becomes the next percept/behavioral strategy, and is stored as a basis for future predictions. Acceptance of predictions (positive feedback) is mediated via the accumbens, and switching to other predictions by the dorsal anterior cingulate cortex (ACC) (negative feedback). Maintenance of a prediction is encoded by the pregenual ACC. Different cingulate territories are involved in rejection, acceptance and maintenance of predictions. Free will is known to be decreased in multiple psychopathologies, including obsessive compulsive disorder and addictions. METHODOLOGY: In modern psychosurgery three target structures exist for obsessive compulsive disorder and addiction: the dorsal ACC, the nucleus accumbens, and/or the anterior limb of the internal capsula. Research in all three areas reports favorable results with acceptable side effects. Psychosurgical interventions seem to exert their effect by a common final common pathway mediated via the pregenual ACC. CONCLUSION: Successful neuromodulation increases the capacity to choose from different options for the affected individual, as well as inhibiting unwanted options, therefore increasing free will and free won't.

Signs and symptoms associated with synthetic cannabinoid toxicity: systematic review.

AIMS: Use of synthetic cannabinoids is associated with significant physical and psychological harms. This research quantified reported toxicities from published reports and assessed the influence of size of the reported study population on rates of symptom reporting. METHODS: Systematic review of published case reports and case series of toxicity associated with use of synthetic cannabinoids. RESULTS: Symptoms associated with synthetic cannabinoid toxicity were reported for 3695 individuals, predominantly young males. Symptoms included physiological (e.g. tachycardia, hypertension, nausea/vomiting), emotional (e.g. agitation, irritability, paranoia), behavioural (e.g. drowsiness, aggression) and perceptual (e.g. hallucinations) domains. Most common symptoms were tachycardia (30.2% of cases), agitation (13.5%), drowsiness (12.3%), nausea/vomiting (8.2%) and hallucinations (7.6%). Death or serious medical complications were uncommon (e.g. death 0.2%, stroke 0.1%, myocardial infarction 0.09%). Case reports/smaller case series (n<10) reported statistically significantly higher rates for 29/34 symptoms than larger case series (n≥10), which could represent selection bias. CONCLUSIONS: Symptoms of synthetic cannabinoid toxicity are variable and cover a number of physical and psychological domains. Symptom reporting varies by study population size. Due to the variable presenting symptoms of synthetic cannabinoid toxicity, clinicians in emergency services should consider synthetic cannabinoid toxicity when evaluating young adult male patients presenting with unexplained agitation or cardiovascular symptoms.