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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.
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.
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.
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.
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.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
This article compares two models of discharge for repudiation. The first – termed the “mirror image model” – has come to the fore only in recent years. It treats the applicable principles as the mirror image of those that govern discharge for failure to perform a contractual term. Under the second model – the “differentiated model” – repudiation is analysed in terms of various criteria that respond to conceptual diversity within the basis for discharge. The two models diverge, at the heart of the repudiation doctrine, when the issue is whether a reasonable person would regard the promisor as having refused to perform the contract. It is argued that the differentiated model is the better model, and also the preferred view of the common law.
Prediction of suicidal behaviour is an aspirational goal for clinicians and policy makers; with patients classified as ‘high risk’ to be preferentially allocated treatment. Clinical usefulness requires an adequate positive predictive value (PPV).
To identify studies of predictive instruments and to calculate PPV estimates for suicidal behaviours.
A systematic review identified studies of predictive instruments. A series of meta-analyses produced pooled estimates of PPV for suicidal behaviours.
For all scales combined, the pooled PPVs were: suicide 5.5% (95% CI 3.9–7.9%), self-harm 26.3% (95% CI 21.8–31.3%) and self-harm plus suicide 35.9% (95% CI 25.8–47.4%). Subanalyses on self-harm found pooled PPVs of 16.1% (95% CI 11.3–22.3%) for high-quality studies, 32.5% (95% CI 26.1–39.6%) for hospital-treated self-harm and 26.8% (95% CI 19.5–35.6%) for psychiatric in-patients.
No ‘high-risk’ classification was clinically useful. Prevalence imposes a ceiling on PPV. Treatment should reduce exposure to modifiable risk factors and offer effective interventions for selected subpopulations and unselected clinical populations.
The conflict between common law and equity on the question of when time should be regarded as being “of the essence” for the performance of a contract has often been debated, as has the impact of its resolution by the Judicature reforms in favour of equity's more relaxed approach. Even so, it is tolerably clear that the two approaches have been substantially assimilated within general principles of discharge for breach. If, as a matter of construction, a time stipulation is a condition, then time is of the essence. Alternatively, time may have become of the essence by an effective notice to perform served by a promisee. If the contract has been validly discharged on either basis, specific performance will not be ordered in favour of the promisor.1
Repetition of hospital-treated self-poisoning and admission to
psychiatric hospital are both common in individuals who self-poison.
To evaluate efficacy of postcard intervention after 5 years.
A randomised controlled trial of individuals who have self-poisoned:
postcard intervention (eight in 12 months) plus treatment as usual
v. treatment as usual. Our primary outcomes were
self-poisoning admissions and psychiatric admissions (proportions and
There was no difference between groups for any repeat-episode
self-poisoning admission (intervention group: 24.9%, 95% CI 20.6-29.5;
control group: 27.2%, 95% CI 22.8-31.8) but there was a significant
reduction in event rates (incidence risk ratio (IRR)=0.54, 95% CI
0.37-0.81), saving 306 bed days. There was no difference for any
psychiatric admission (intervention group: 38.1%, 95% CI 33.1-43.2;
control group: 35.5%, 95% CI 30.8-40.5) but there was a significant
reduction in event rates (IRR=0.66, 95% CI 0.47-0.91), saving 2565 bed
A postcard intervention halved self-poisoning events and reduced
psychiatric admissions by a third after 5 years. Substantial savings
occurred in general hospital and psychiatric hospital bed days.
Hospital-treated self-poisoning is common, with limited effective interventions for reducing subsequent suicidal behaviour.
To test the efficacy of a postcard intervention to reduce suicidal behaviour.
Randomised controlled trial of individuals who self-poisoned (n = 2300), the intervention consisted of nine postcards sent over 12 months versus usual treatment. Outcomes assessed at 12 months (n = 2113) were suicidal ideation, suicide attempts and self-cutting (proportion and event rates).
There was a significant reduction in any suicidal ideation (relative risk reduction (RRR) = 0.31, 95% CI 0.22–0.38), any suicide attempt (RRR = 0.42, 95% CI 0.11–0.63) and number of attempts (incidence rate ratios (IRR) = 0.64, 95% CI 0.42–0.97). There was no significant reduction in any self-cutting (RRR = 0.14, 95% CI −-0.29 to 0.42) or self-cutting events (IRR = 1.03 95% CI 0.76–1.39).
A postcard intervention reduced suicidal ideation and suicide attempts in a non-Western population. Sustained, brief contact by mail may reduce suicidal ideation and suicide attempts in individuals who self-poison.
The Canadian Emergency Department Triage and Acuity Scale (CTAS) is a 5-level triage tool used to determine the priority by which patients should be treated in Canadian emergency departments (EDs). To determine emergency physician (EP) workload and staffing needs, many hospitals in Ontario use a case-mix formula based solely on patient volume at each triage level. The purpose of our study was to describe the distribution of EP time by activity during a shift in order to estimate the amount of time required by an EP to assess and treat patients in each triage category and to determine the variability in the distribution of CTAS scoring between hospital sites.
Research assistants directly observed EPs for 592 shifts and electronically recorded their activities on a moment-by-moment basis. The duration of all activities associated with a given patient were summed to derive a directly observed estimate of the amount of EP time required to treat the patient.
We observed treatment times for 11 716 patients in 11 hospital-based EDs. The mean time for physicians to treat patients was 73.6 minutes (95% confidence interval [CI] 63.6–83.7) for CTAS level 1, 38.9 minutes (95% CI 36.0–41.8) for CTAS-2, 26.3 minutes (95% CI 25.4–27.2) for CTAS-3, 15.0 minutes (95% CI 14.6–15.4) for CTAS-4 and 10.9 minutes (95% CI 10.1–11.6) for CTAS-5. Physician time related to patient care activities accounted for 84.2% of physicians' ED shifts.
In our study, EPs had very limited downtime. There was significant variability in the distribution of CTAS scores between sites and also marked variation in EP time related to each triage category. This brings into question the appropriateness of using CTAS alone to determine physician staffing levels in EDs.
To report the 24-month outcomes of a non-obligatory postcard intervention (plus treatment as usual) compared with treatment as usual.
In a randomised-controlled trial (Zelen design) conducted in Newcastle, Australia, eight postcards were sent to participants over a 12-month period. The principal outcomes were the proportion of participants with one or more repeat episodes of self-poisoning and the number of repeat episodes per person.
No significant reduction was observed in the proportion of people repeating self-poisoning in the intervention group (21.2%, 95% CI 17.0–25.3) compared with the control group (22.8%, 95% CI 18.7–27.0; χ2=0.32, d.f. = 1, P= 0.57); the difference between groups was −1.7% (95% CI −7.5 to 4.2). There was a significant reduction in the rate of repetition, with an incidence risk ratio of 0.49 (95% CI 0.33–0.73).
A postcard intervention maintained the halving of the rate of repetition of hospital-treated self-poisoning events over a 2-year period, although it did not significantly reduce the proportion of individuals who repeated self-poisoning.
Objective: To examine the demographic, prescription, ingestion, and psychiatric diagnostic factors that distinguished elderly from nonelderly patients treated for deliberate self-poisoning (DSP). Method: A prospective case series study of 2,667 patients presenting to a regional referral center for poisoning (Newcastle Mater Hospital, NSW, Australia), January 1991 to July 1998. The sample was stratified into two groups, 65 years or greater (n = 110) and 64 years or less (n = 2,557) at the time of index admission. The groups were compared using a forward stepwise logistic regression model. Uncontrolled comparisons were analyzed by chi-square statistic with Bonferroni-adjusted p values and controlled comparisons by odds ratio (OR) with 95% confidence interval (CI). Results: The elderly group represented 4.1% of the total. The logistic regression analysis found the elderly DSP group was more likely to have a longer length of stay (OR 5.90, CI 3.87–9.00), to have been prescribed “other” drugs (neither benzodiazepines, mood treatment drugs, nor paracetamol) before admission (OR 5.32, CI 3.34–8.48), to have been prescribed benzodiazepines (OR 3.15, CI 2.03–4.89), and to be diagnosed with major depression (OR 2.17, CI 1.41–3.36) than the younger group. The elderly group was less likely to have ingested paracetamol (OR 0.28, CI 0.14–0.54) or “other” drugs (neither benzodiazepines nor mood treatment drugs) in the DSP episode (OR 0.33, CI 0.20–0.54). Discussion: Elderly DSP patients differ in several important respects from younger patients. They have higher morbidity as a result of the DSP. Major depression plays a more important role. The strong relationship between benzodiazepine prescription and DSP in the elderly raises questions and possible prevention strategies.
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