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.

Establishing an esketamine clinic in Australia: Practical recommendations and clinical guidance from an expert panel.

BACKGROUND: Major depressive disorder (MDD) can have severe impacts on function and quality of life. Up to one third of patients will have an inadequate response to their first line of treatment, with subsequent lines of therapy associated with lower remission rates and higher relapse rates. Recently esketamine has become available for Australian patients, and this agent provides an additional treatment option for those with MDD who have had an inadequate response to two or more antidepressant therapies during the current moderate to severe depressive episode. This paper provides an expert panel's practical recommendations and clinical guidance for establishing esketamine clinics in Australia. METHODS: An expert panel (n = 11) comprising psychiatrists, mental health care nurses, pharmacists, and individuals with experience establishing esketamine clinics was convened in Sydney. The panel developed practical recommendations and clinical guidance, which were then further refined. RESULTS: Five key areas were identified: practical considerations for esketamine clinic set-up, including multidisciplinary care considerations; patient selection; administering esketamine; adverse event management and long-term follow-up. CONCLUSIONS: Guidance presented in this paper should assist Australian clinicians to set up an esketamine clinic, and provide practical advice on the infrastructure and clinical requirements for treatment of patients with this agent.

A systematic review of the print media representation of ketamine treatments for psychiatric disorders.

BACKGROUND: Public and patient expectations of treatment influence health behaviours and decision-making. AIMS: We aimed to understand how the media has portrayed the therapeutic use of ketamine in psychiatry. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Daily activities are associated with non-invasive measures of neuroplasticity in older adults.

OBJECTIVE: We aimed to determine the association between daily activities (sleep, sedentary behavior and physical activities) and neuroplasticity in older adults by measuring motor evoked potential amplitudes (MEPs) elicited after a single and spaced continuous theta burst stimulation (cTBS) paradigm, targeting the primary motor cortex. METHODS: MEPs were recorded from the right first dorsal interosseous muscle of 34 older adults (66.9 ± 4.5 years) by delivering single-pulse TMS before, between and at 0, 10, 20, 40 and 60 min after the application of spaced-cTBS separated by 10 min. Habitual activity was assessed by accelerometry for 24 h/day over 7-days. Multiple linear regression models determined if the time-use composition (sleep, sedentary behavior and physical activities) was associated with neuroplasticity response. RESULTS: More physical activity at the equal expense of sleep and sedentary behaviors was associated with greater motor cortical neuroplasticity. Associations appeared to be driven by more time spent in light- but not moderate-to-vigorous- physical activities. CONCLUSIONS: Engaging in light physical activity at the expense of sleep and sedentary behavior was associated with greater LTD-like motor cortex neuroplasticity (as measured with cTBS) in older adults. SIGNIFICANCE: These findings suggest the promotion of physical activity among older adults to support brain neuroplasticity.