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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.
Public and patient expectations of treatment influence health behaviours and decision-making.
We aimed to understand how the media has portrayed the therapeutic use of ketamine in psychiatry.
We systematically searched electronic databases for print and online news articles about ketamine for psychiatric disorders. The top ten UK, USA, Canadian and Australian newspapers by circulation and any trade and consumer magazines indexed in the databases were searched from 2015 to 2020. Article content was quantitatively coded with a framework encompassing treatment indication, descriptions of prior use, references to research, benefits and harms, treatment access and process, patient and professional testimony, tone and factual basis.
We found 119 articles, peaking in March 2019 when the United States Food and Drug Administration approved esketamine. Ketamine treatment was portrayed in an extremely positive light (n = 82, 68.9%), with significant contributions of positive testimony from key opinion leaders (e.g. clinicians). Positive research results and ketamine's rapid antidepressant effect (n = 87, 73.1%) were frequently emphasised, with little reference to longer-term safety and efficacy. Side-effects were frequently reported (n = 96, 80.7%), predominantly ketamine's acute psychotomimetic effects and the potential for addiction and misuse, and rarely cardiovascular and bladder effects. Not infrequently, key opinion leaders were quoted as being overly optimistic compared with the existing evidence base.
Information pertinent to patient help-seeking and treatment expectations is being communicated through the media and supported by key opinion leaders, although some quotes go well beyond the evidence base. Clinicians should be aware of this and may need to address their patients’ beliefs directly.
Biobanks are a valuable resource for creating advancements in science through cutting-edge omics research. Twin research methods allow us to understand the degree to which genetics and environmental factors contribute to health outcomes.
The Sri Lankan Twin Registry biobank (SLTR-b) was established in 2015 as part of Colombo Twin and Singleton Follow-up Study. Venous blood and urine were collected from twins and comparative sample of singletons for clinical investigations and biobanking.
The SLTR-b currently houses 3369 DNA and serum samples. Biobank specimens are linked to longitudinal questionnaire data, clinical investigations, anthropometric measurements, and other data.
The SLTR-b aims to address gaps in health and genetics research. It will provide opportunities for academic collaborations, local and international, and capacity building of future research leaders in twin and omics research. This paper provides a cohort profile of the SLTR-b and its linked data, and an overview of the strategies used for biobanking.
Disability in older adults is associated with a need for support in work, education, and community activities, reduced independence, and poorer quality of life. This study examines potential determinants of disability in a clinical sample of older adults across the continuum of cognitive decline, including sociodemographic, medical, psychiatric, and cognitive factors.
This is a cross-sectional study.
Participants were recruited from a specialty clinic for adults “at risk” of or with early dementia (including subjective cognitive complaints, mild cognitive impairment, and early dementia).
Four hundred forty-two older adults (mean age = 67.11, SD = 9.33) underwent comprehensive medical, neuropsychological, and mood assessments.
Disability was assessed via the self-report World Health Organization Disability Assessment Schedule 2.0. A stepwise (forward) linear regression model was computed to determine factors that contribute to disability within this group.
Depressive symptoms were the largest predictor, uniquely explaining 31.8% of the variance. Other contributing factors in the model included younger age, medical burden, and sleep quality, with all factors together accounting for a total of 50.4% of the variance in disability. Cognitive variables did not contribute to the model.
Depressive symptoms account for a significant portion of the variance in disability, but other factors such as age, medical burden and sleep quality are also important contributors in older adults across the continuum of cognitive decline. The relative association of these variables with disability appears to differ for older (≥65 years) relative to younger (<65 years) participants. Given the relationship between disability and these risk factors, an integrative and multidisciplinary approach to risk reduction will likely be most effective, with potential carry over effects for physical and mental health.
Insomnia treatment using an internet-based cognitive–behavioural therapy
for insomnia (CBT-I) program reduces depression symptoms, anxiety
symptoms and suicidal ideation. However, the speed, longevity and
consistency of these effects are unknown.
To test the following: whether the efficacy of online CBT-I was sustained
over 18 months; how rapidly the effects of CBT-I emerged; evidence for
distinct trajectories of change in depressive symptoms; and predictors of
A randomised controlled trial compared the 6-week Sleep Healthy Using the
Internet (SHUTi) CBT-I program to an attention control program. Adults
(N=1149) with clinical insomnia and subclinical
depression symptoms were recruited online from the Australian
Depression, anxiety and insomnia decreased significantly by week 4 of the
intervention period and remained significantly lower relative to control
for >18 months (between-group Cohen's d=0.63, 0.47,
0.55, respectively, at 18 months). Effects on suicidal ideation were only
short term. Two depression trajectories were identified using growth
mixture models: improving (95%) and stable/deteriorating (5%) symptoms.
More severe baseline depression, younger age and limited comfort with the
internet were associated with reduced odds of improvement.
Online CBT-I produced rapid and long-term symptom reduction in people
with subclinical depressive symptoms, although the initial effect on
suicidal ideation was not sustained.
The Sri Lankan Twin Registry (SLTR), established in 1997, is a unique resource for twin and genetic research in a low- and middle-income country (LMIC). It comprises of a volunteer cohort of 14,120 twins (7,060 pairs) and 119 sets of triplets, and a population-based cohort of 19,040 (9,520 pairs) twins and 89 sets of triplets. Several studies have been conducted using this registry, including the Colombo Twin and Singleton Study (CoTaSS 1; 4,387 twins, 2,311 singletons), which have explored the prevalence and heritability of a range of psychiatric disorders as well as gene-environmental interplay. Currently, a follow-up study (CoTaSS 2) of the same cohort is underway, looking at the prevalence and interrelationship of key cardiovascular and metabolic risk markers (e.g., metabolic syndrome). A significant feature of CoTaSS 2 is the establishment of a biobank. Current SLTR work is extending beyond mental health and the interface between mental and physical health to new horizons, extending collaborations with the wider global twin research community. Ethics and governance have been given special emphasis in the initiative. Capacity building and public engagement are two crucial components. Establishment of a state-of-the-art genetic laboratory was a major accomplishment. SLTR is a classic showcase of successful North–South partnership in building a progressive research infrastructure in a LMIC.
Background: Somatic symptoms often co-occur with psychological symptoms but this overlap is poorly understood. Some aspects of this overlap differ in the South Asian context, but it is not clear whether this is a reporting effect or an underlying difference in experienced illness. Methods: Home interviews were administered to 4,024 twins randomly selected from a population-based twin register in the Colombo district of Sri Lanka (the CoTASS study). These included assessments of psychological, somatic and fatigue symptoms. The data were analyzed using factor analytic and quantitative genetic approaches. Results: Confirmatory factor analysis showed that the symptoms from the three scales represented three separate dimensions, rather than all tapping into a single dimension. However, familial correlations among the data were most consistent with a common pathway model. This implies that a portion of the underlying vulnerability is common across psychological, fatigue and somatic symptoms. There were sex differences in the etiology of this model, with shared environmental and genetic influences playing different roles in men and women. Conclusions: There is a complex etiological relationship between psychological, fatigue and somatic symptoms. This is similar in Sri Lanka to Western countries, but there may be a greater influence from the family environment, suggesting that care needs to be taken when generalizing research findings between countries. People who complain of certain fatigue or somatic symptoms may well also have psychological symptoms, or may have genetic or environmental vulnerabilities to such problems.
Fatigue is a common symptom in Western high-income countries but is often medically unexplained and little is known about its presentation in other populations.
To explore the epidemiology and aetiology of fatigue in Sri Lanka, and of its overlap with depression.
A total of 4024 randomly selected twins from a population-based register in Sri Lanka (Colombo district) completed home interviews including the Chalder Fatigue Questionnaire.
The prevalence of fatigue was similar to that in other countries, although prolonged fatigue may be less common. There was substantial comorbidity with a screen for lifetime depression. Non-shared environmental factors made the largest contributions, although genetic/family factors also contributed. The aetiology appeared consistent across the spectrum of severity.
The aetiology of fatigue is broadly similar in Sri Lanka and Western high-income countries. Abnormal experiences of fatigue appear to be the extreme form of more common fatigue, rather than representing independent entities with different genetic or environmental risk factors.
Susceptibility to depression results from genetic and non-familially shared environmental influences in high-income, Western countries. Environments may play a different role for populations in different contexts.
To examine heritability of depression in the first large, population-based twin study in a low-income country.
Lifetime depression and a broader measure of depression susceptibility (D-probe) were assessed in 3908 adult twins in Sri Lanka (the CoTASS study).
There were gender differences for the broad definition (D-probe), with a higher genetic contribution in females (61%) than males (4%). Results were similar for depression, but the prevalence was too low to estimate heritability for males.
Genetic influences on depression in women appear to be at least as strong in this Sri Lankan sample as in higher-income countries. Conclusions are less clear for men but suggest a larger role for environments rather than genes. The nature as well as the magnitude of environmental influences may also differ across populations.
Case–control studies are vulnerable to selection and information biases
which may generate misleading findings.
To assess the quality of methodological reporting of case–control studies
published in general psychiatric journals.
All the case–control studies published over a 2-year period in the six
general psychiatric journals with impact factors of more than 3 were
assessed by a group of psychiatrists with training in epidemiology using
a structured assessment devised for the purpose. The measured study
quality was compared across type of exposure and journal.
The reporting of methods in the 408 identified papers was generally poor,
with basic information about recruitment of participants often absent.
Reduction of selection bias was described best in the ‘pencil and paper’
studies and worst in the genetic studies. Neuroimaging studies reported
the most safeguards against information bias. Measurement of exposure was
reported least well in studies determining the exposure with a biological
Poor reporting of recruitment strategies threatens the validity of
reported results and reduces the generalisability of studies.
The outcome and impact of major depression in developing countries are
To describe the outcome of major depression and compare the disability
and patterns of service use among different outcome groups.
In a case cohort study, nested within a population-based survey of 68 000
participants using the Composite International Diagnostic Interview
(CIDI), 300 participants were randomly selected from those with current
major depression and 300 from those with no lifetime history.
Participants were re-interviewed after 18–62 months to ascertain current
diagnosis, psychological symptoms, disability and use of health
Of participants with major depression at baseline 26% also met criteria
for major depression at follow up. Mortality ratio standardised for age
and gender was 3.55 (95% CI 1.97 to 6.39). All indices of measure of
disability were significantly higher in the persistently depressed group
compared with the completely recovered group. Participants who had
recovered partially resembled participants with persistent depression.
Two-thirds of those with persistent depression had not sought any
Major depression was associated with mortality and disability Those with
residual symptoms remained disabled. Help-seeking was unusual.
To extract relevant information for clinicians from reported and/or accessible cases involving psychiatric illness brought under the Disability Discrimination Act 1995 (DDA). Institutional databases were searched for DDA cases and relevant guidance from case law extracted.
Over half the cases reaching higher courts involve psychiatric illness. A number of decisions provide guidance for clinicians wishing to aid their own patients, and those involved as expert witnesses. These cover which conditions are included as impairments (almost everything in ICD–10), what associated effects are to be considered, and the relevance of comorbidity and treatment. Cases often involve recovery of clinical documents that reveal interesting variation in professional standards.
Virtually all patients of psychiatrists in secondary care would be covered by the DDA. Knowledge of this Act could be used to enhance a patient's access to employment and services, and potentially overcome some of the effects of stigmatisation.