International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators.

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; ß*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; ß*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630.

Online news media reporting of ketamine as a treatment for depression from 2000 to 2017.

OBJECTIVES: Since the first reporting of ketamine's antidepressant effects in 2000, there has been growing public interest in this novel rapid-acting treatment for depression despite its abuse potential. Online media is an increasingly popular way for the general public to source information. Our objective was to examine how online news outlets have portrayed ketamine as an antidepressant by ascertaining the volume and content of relevant articles and trends over time. METHODS: In this semi-quantitative study, we identified articles regarding ketamine's use in depression from the 30 most popular English-language online news-generating sources over 18 years (2000-2017). Articles were then blindly assessed by 2 independent raters, who analysed the texts by quantifying the presence/absence of 12 content items. RESULTS: We identified 97 articles, the number of which has increased since the first online news report in 2006. Most (69%) came from the USA and nearly all correctly stated the indications for ketamine. About half of the most recent articles mentioned abuse potential and 27% of articles referred to risks of unregulated use of ketamine. Just under 20% of articles referred to the lack of evidence regarding direct comparisons between ketamine and other currently available antidepressants. There was no difference in the overall level of detail within the articles during the study time period. CONCLUSIONS: Online news media articles have been generally positive about ketamine for treating depression but need to be interpreted with caution as many of them did not discuss negative aspects of ketamine and made unsubstantiated claims about ketamine.

Vascular endothelial growth factor and pigment epithelial-derived factor in the peripheral response to ketamine.

BACKGROUND: Ketamine is a rapid-acting antidepressant but its mechanism remains unclear. Vascular endothelial growth factor growth factor (VEGF) has been reported in the antidepressant action of ketamine in rodents. VEGF and pigment epithelial-derived factor (PEDF) signalling are closely linked and both are dysregulated in depression. We explored the effect of a single infusion of ketamine, with midazolam as comparison, on peripheral whole blood mRNA levels of vascular endothelial growth factor A (VEGFA) and PEDF, and the VEGFA/PEDF ratio, in patients with depression. METHODS: Twenty-five patients with depression were randomised to either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) infusions over 40 min. Blood plasma samples were taken 1 h before the first infusion and 4 h after the infusion start. mRNA was extracted and qRT-PCR performed to analyse gene expression. RESULTS: Single infusions of ketamine and midazolam both decreased depression scores (F(1,21) = 102.40, p < 0.000). There was a significant group × time interaction for VEGFA mRNA levels (F(1, 21) = 5.207, p = 0.029), with ketamine increasing VEGFA levels. There was no significant effect of either ketamine or midazolam on PEDF levels. There was a significant group × time interaction for VEGFA/PEDF mRNA ratio, with ketamine alone increasing this ratio (F(1, 11) = 12.085, p = 0.005). LIMITATIONS: Patients were on psychotropic medication and continued treatment as usual throughout the study. CONCLUSIONS: These preliminary results support a role for VEGF in the action of ketamine and suggest a novel role for VEGF/PEDF in the molecular response to ketamine.

Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial).

Background: Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response.  Methods: The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression.  The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick's Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up.  Results: In total, 1581 admissions to St Patrick's Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions: This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration: ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.

STRESS-testing clinical activity and outcomes for a combined prison in-reach and court liaison service: a 3-year observational study of 6177 consecutive male remands.

BACKGROUND: People with major mental illness are over-represented in prison populations however there are few longitudinal studies of prison in-reach services leading to appropriate healthcare over extended periods. AIMS: We aimed to examine measures of the clinical efficiency and effectiveness of a prison in-reach, court diversion and liaison service over a 3 year period. Secondly, we aimed to compare rates of identification of psychosis and diversion with rates previously reported for the same setting in the 6 years previously. We adopted a stress testing model for service evaluation. METHOD: All new male remand committals to Ireland's main remand prison from 2012 to 2014 were screened in two stages. Demographic and clinical variables were recorded along with times to assessment and diversion. The DUNDRUM Toolkit was used to assess level of clinical urgency and level of security required. Binary logistic regression was used to assess factors relevant to diversion. RESULTS: All 6177 consecutive remands were screened of whom 1109 remand episodes (917 individuals) received a psychiatric assessment. 4.1 % (95 % CI 3.6-4.6) had active psychotic symptoms. Levels of self-harm were low. Median time to full assessment was 2 days and median time to admission was 15.0 days for local hospitals and 19.5 days for forensic admissions. Diversion to healthcare settings outside prison was achieved for 5.6 % (349/6177, 95 % CI 5.1-6.3) of all remand episodes and admissions for 2.3 % (95 % CI 1.9-2.7). Both were increased on the previous period reported. Mean DUNDRUM-1 and DUNDRUM-2 Triage Security Scores were appropriate to risk and need. CONCLUSIONS: We found that a two-stage screening and referral process followed by comprehensive assessment optimised identification of acute psychosis. The mapping approach described shows that it is possible for a relatively small team to sustainably achieve effective identification of major mental illness and diversion to healthcare in a risk-appropriate manner. The stress-testing structure adopted aids service evaluation and may help advise development of outcome standards for similar services.