In this secondary analysis of a multisite, double-blind RCT (n=174) in treatment‑resistant depression, subcutaneous racemic ketamine given twice weekly for 4 weeks at flexible, response‑guided doses (35-63mg/70kg) produced a significant short‑term reduction in anxiety (HAM‑A) versus midazolam, whereas a fixed low dose (35mg/70kg) did not. The anxiolytic effect was mediated by antidepressant response and was not maintained 4 weeks after the end of treatment.
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Background
Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties.
Aims
To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD.
Method
The Ketamine for Adult Depression Study was a multisite 4-week randomised, double-blind, active (midazolam)-controlled trial. The study initially used fixed low dose ketamine (0.5 mg/kg, cohort 1), before protocol revision to flexible, response-guided dosing (0.5–0.9 mg/kg, cohort 2). This secondary analysis assessed anxiety using the Hamilton Anxiety (HAM-A) scale (primary measure) and ‘inner tension’ item 3 of the Montgomery–Åsberg Depression Rating Scale (MADRS), at baseline, 4 weeks (end treatment) and 4 weeks after treatment end. Analyses of change in anxiety between ketamine and midazolam groups included all participants who received at least one treatment (n = 174), with a mixed effects repeated measures model used to assess the primary anxiety measure. The trial was registered as (ACTRN12616001096448).
Results
In cohort 1 (n = 68) the reduction in HAM-A score was not statistically significant: −1.4 (95% CI [−8.6, 3.2], P = 0.37), whereas a significant reduction was seen for cohort 2 (n = 106) of −4.0 (95% CI [−10.6, −1.9], P = 0.0058), favouring ketamine over midazolam. These effects were mediated by total MADRS and were not maintained at 4 weeks after treatment end. MADRS item 3 was also significantly reduced in cohort 2 (P = 0.026) but not cohort 1 (P = 0.96).
Conclusion
Ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.
The paper frames anxious distress as a common and clinically important feature of major depressive disorder (MDD), noting that comorbid high levels of anxiety are associated with poorer antidepressant outcomes. Earlier studies and case reports have suggested that ketamine can produce rapid reductions in depressive and anxiety symptoms, but the literature is limited by small samples, open-label designs, variable dosing and mixed patient populations. Few trials have specifically examined ketamine's anxiolytic effects in people with treatment-resistant depression (TRD), and prior TRD studies that reported anxiety change used single infusions or small samples, leaving uncertainty about dose, durability and whether anxiety improvements are independent of mood improvement. Mills and colleagues set out to examine whether subcutaneous racemic ketamine administered twice weekly for 4 weeks reduces anxiety in people with TRD. Using data from the Ketamine for Adult Depression Study (KADS), a multicentre randomised, double-blind, active (midazolam) controlled trial, the authors report secondary analyses with the Hamilton Anxiety Rating Scale (HAM-A) as the primary anxiety measure and MADRS item 3 (inner tension) as a supplementary measure. Specific hypotheses were that ketamine would reduce HAM-A and MADRS item 3 scores versus midazolam, that effects would be larger in participants with comorbid anxiety disorders independent of antidepressant effects, and that higher ketamine doses would produce greater anxiolytic effects.
KADS was a multi-centre double-blind RCT in seven centres in Australia and New Zealand investigating subcutaneous ketamine administered twice weekly for 4 weeks for people with TRD. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2013. All procedures involving human participants/patients were approved by the Sydney Local Health District (RPAH Zone) Human Research Ethics Committee (Australia X16-0146 and HREC/16/RPAH/168) and the Southern Health and Disability Ethics Committee (New Zealand; 16/STH/104). Written informed consent was obtained from all participants. The KADS protocol, including information on the two cohorts, has been published previously.Study participants in cohort 1 received a fixed dose of the study drug (ketamine 0.5 mg/kg, or midazolam 0.025 mg/kg). Following a recommendation from a routine Data Safety Monitoring Board meeting owing to concerns about lack of efficacy (observed in blinded data reports in the whole sample), flexible dose titration of the study drug was used in cohort 2, with dose up-titration guided by MADRS response (ketamine 0.5-0.9 mg/kg; or midazolam 0.025-0.045 mg/kg). The psychoactive placebo (midazolam) was identical in appearance and volume to ketamine and was also administered subcutaneously.
All analyses were conducted in R (version 4.1.3 for Windows, R Core Team; Vienna, Austria;). As the KADS RCT was not designed to explicitly address these analyses, all results are considered exploratory and so are not corrected for multiple comparisons. Future research is required to confirm the findings presented in this study.
In this randomised, double-blind trial, uncorrected results showed a significant reduction in total HAM-A score at the end of the RCT, favouring the group treated with ketamine. This was evident in the combined cohorts and in cohort 2 (where response-guided titration to higher doses was implemented). This finding that showed evidence of mediation by change in total MADRS score from baseline to end treatment, however, remained significant when change in total MADRS scores across the end treatment and 4 weeks after treatment end was included as a covariate, suggesting the improvement in depression did not completely account for the improvement in anxiety. However, the reduction in total HAM-A score observed in the ketamine group at the end of treatment was not maintained over the 4-week follow-up period (i.e. at the 4 weeks after treatment end visit) with no further treatment. The lower dose used in cohort 1 and the time to achieve an adequate dose in cohort 2 could possibly have contributed to the lack of enduring effects of ketamine. A significant decrease in MADRS item 3 score across the end treatment and 4 weeks after treatment end was also observed in cohort 2, favouring ketamine. This MADRS item 3 outcome suggests the change in total HAM-A score is unlikely to be entirely because of lower scores for HAM-A items (such as insomnia and mood) that overlap with depressive symptoms. As with total HAM-A score, the reduction in MADRS item 3 score in cohort 2 did not persist to the 4 weeks after treatment end visit. In our subgroup analyses of HAM-A factors, the decrease in HAM-A score was largely seen in the 'psychic' factor, with a significant difference favouring ketamine for this subscale, but no difference between treatment arms for the 'somatic' factor during the RCT (uncorrected results). We are unaware of published TRD studies that have examined change in the psychic and somatic subscales of the HAM-A scale in response to ketamine. A study of esketamine in TRD measured total HAM-A scores at baseline, 1 month after treatment commencement and 3 months after treatment commencement.Of the 116 participants,a post hoc analysis of the 30 participants aged 65 years or older found a significant reduction in total HAM-A score at 1 and 3 months after treatment commencement; however, the analysis of HAM-A score did not control for change in total MADRS score.In the combined cohorts, there was also a significant reduction in total HAM-A and MADRS item 3 scores at the end of the RCT in the group with a comorbid anxiety disorder, favouring ketamine. Few studies with limited samples have investigated ketamine as a potential treatment for anxiety disorders in individuals who are not currently depressed. A double-blind trial in 18 individuals with SAD found an improvement in ratings on the Liebowitz Social Anxiety Scale in the ketamine group.Blinding was an issue, and all but one participant correctly guessed their allocated treatment group of ketamine or placebo.An open-label study of ketamine also found a reduction in anxiety in individuals with SAD and/or treatmentresistant GAD who were not currently depressed, with a greater effect of ketamine observed at higher doses.In our analysis of the effect of ketamine dose on anxiety measures, the difference in total HAM-A score reduction between the ketamine treatment group of cohort 1 and the ketamine group of cohort 2 did not reach statistical significance. However, the significant difference in reduction of HAM-A score in cohort 2 between the midazolam and ketamine groups suggests ketamine was effective in reducing anxiety measures when given at adequate dosage, which potentially has clinical relevance. Strengths of this study include the large sample, blinding using midazolam as the control group, use of anxiety measures at multiple time points, use of more than one measure of anxiety (HAM-A plus MADRS item 3 scores) and controlling for change in mood. Only a small number of study participants discontinued the RCT phase, so there were few missing data. There are some limitations regarding our investigation of change in anxiety measures in response to ketamine. Although we did not find evidence to suggest that those with comorbid anxiety were less likely to have an antidepressant response to ketamine, there were relatively few study participants with a comorbid anxiety disorder in some groups. We conducted exploratory analyses of secondary outcomes of the main study, with uncorrected outcomes reported. Therefore, the results should be interpreted with caution, as they are potentially prone to false positives. Further research is needed, including hypothesis-driven validation, to replicate and verify our findings. Directions for further research to examine the efficacy of ketamine in reducing anxiety measures in individuals with TRD could include trials with longer durations with individualised dosing titration, which also look at outcomes weeks after treatment discontinuation. As we found the benefits to anxiety measures were not maintained at the 4 weeks after treatment end visit, this research could extend to examining potential ways to prolong positive effects of ketamine, such as following a course of ketamine with cognitive-behavioural therapy (CBT)or psychotherapy during ketamine treatment. It is beyond the scope of the present analysis to speculate more broadly on the maintenance of ketamine effects. Given the exploratory nature of the analyses, further confirmation of our findings from future trials with directional hypotheses is required. If our findings are replicated, further research to examine the use of ketamine as a maintenance treatment could also be considered, with a view to contributing to clinical practice guidelines. In summary, ketamine was associated with a reduction in total HAM-A score in the RCT phase of this multi-centre study investigating the efficacy of ketamine in treatment of TRD. The decrease in total HAM-A score was seen in the combined cohorts and cohort 2, where response-guided dosing was used, but not in cohort 1, which used a lower fixed dosage. Reduction in anxiety was mediated by decrease in total MADRS score, but remained significant after controlling for this. Results also found significant improvement in anxiety for ketamine compared to midazolam in those with a comorbid anxiety disorder, but not in those without a comorbid anxiety disorder. Overall, this study found that ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.
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Salloum, N. C., Fava, M., Freeman, M. P. et al. · Depression and Anxiety (2018)
Daly, E. J., Turkoz, I., Salvadore, G. et al. · Depression and Anxiety (2021)
Glue, P., Medlicott, N. J., Harland, S. et al. · Journal of Psychopharmacology (2017)
Wilkinson, S. T., Taeho, G., Rhee et al. · Psychotherapy and Psychosomatics (2021)
KADS was a multi-centre, double-blind randomised controlled trial conducted across seven sites in Australia and New Zealand. Adults with treatment-resistant major depressive disorder were randomised to receive subcutaneous racemic ketamine or an active psychoactive placebo, midazolam, administered twice weekly for 4 weeks. The trial operated in two sequential cohorts: cohort 1 used a fixed low ketamine dose (0.5 mg/kg; midazolam 0.025 mg/kg), whereas cohort 2 used flexible, response-guided titration (ketamine 0.5–0.9 mg/kg; midazolam 0.025–0.045 mg/kg) with up-titration guided by MADRS response. Ethics approvals and written informed consent were obtained; the protocol and cohort procedures have been published previously. Anxiety was assessed with the 14-item HAM-A (total score and psychic versus somatic subscales) at baseline, end of treatment (4 weeks) and 4 weeks after treatment end. MADRS item 3 (inner tension) was measured at the same time points and was analysed as an ordinal outcome. Presence of comorbid anxiety disorders was determined by DSM-5 diagnosis during a psychiatrist-conducted screening interview. The authors treated these anxiety analyses as secondary and exploratory. Statistical approaches included mixed effects repeated measures models (MRMM) for continuous HAM-A outcomes with fixed effects for Time, Group and their interaction and baseline HAM-A as a covariate; participants were included as a random effect. A cumulative link mixed model (CLMM) was used for ordinal MADRS item 3. Mediation analyses estimated the indirect effect of change in total MADRS score (baseline to end treatment) on HAM-A outcomes, reporting average causal mediation effects (ACME), average direct effects (ADE) and proportion mediated. Subgroup analyses examined psychic versus somatic HAM-A factors and outcomes in participants with versus without comorbid anxiety disorders. Dose–response exploratory analyses compared ketamine-treated participants across cohorts and used linear regression to test associations between ketamine dose (mg/kg and mg) and change in HAM-A, adjusting for potential confounders. Analyses were conducted in R; results are reported uncorrected for multiple comparisons and labelled exploratory.
Of 184 participants randomised, 174 received at least one dose of study drug and 167 had HAM-A assessed at both baseline and end treatment. Baseline HAM-A scores averaged roughly 20–22, corresponding to the upper end of moderate anxiety. Across the combined cohorts and in cohort 2, MRMMs showed a significant difference favouring ketamine over midazolam in change in total HAM-A across end treatment and 4 weeks after treatment end (combined cohorts P = 0.0071; cohort 2 P = 0.0058). No significant group difference was observed in cohort 1. Post hoc testing indicated the ketamine–midazolam difference was present at end treatment but not at 4 weeks after treatment end. In the combined cohorts the end-treatment difference was significant (P = 0.0093; Cohen's d = 0.53) but absent at 4 weeks (P = 0.80; Cohen's d = 0.05). In cohort 2 the end-treatment difference was also significant (P = 0.004; Cohen's d = 0.77) and non-significant at 4 weeks (P = 0.46; Cohen's d = 0.20). Thus, anxiolytic effects were short-lived without further treatment. Mediation analyses examined whether changes in depression (total MADRS) explained the HAM-A effect. In the combined cohorts the indirect effect via MADRS change was significant (ACME = -1.2, 95% CI [-1.9, -0.5], P < 0.0001) while the ADE (direct effect) was non-significant (0.1, 95% CI [-1.4, 1.7], P = 0.90). Cohort 2 showed a similar pattern (ACME = -1.4, 95% CI [-2.5, -0.6], P < 0.0001; ADE = -0.5, 95% CI [-2.7, 1.8], P = 0.68). Linear regression also found that reductions in HAM-A were associated with reductions in total MADRS during the RCT (β = 0.48, s.e. = 0.090, P < 0.0001). The authors conclude that much of the ketamine–anxiety relationship is mediated by antidepressant benefit, although group effects remained significant in some models after controlling for MADRS change. Analyses of MADRS item 3 (inner tension) found no significant difference in cohort 1 or in the combined cohorts across end treatment and 4 weeks after treatment end, but a significant advantage for ketamine in cohort 2 (P = 0.026), driven by end-treatment differences (P = 0.0027). Subscale analyses of HAM-A showed a significant Group effect for the psychic subscale in the combined cohorts (P = 0.011), driven by end-treatment differences (P = 0.011; Cohen's d = 0.54), whereas the somatic subscale showed no significant Group effect. In participants with a comorbid anxiety disorder, ketamine also outperformed midazolam on total HAM-A across end treatment and 4 weeks after treatment end (P = 0.019), with a post hoc end-treatment difference (P = 0.016; Cohen's d = 0.82) that did not persist at 4 weeks. Mediation in this subgroup again showed a significant indirect effect via MADRS change (ACME = -1.3, 95% CI [-2.8, -0.3], P = 0.008) with a non-significant ADE. MADRS item 3 differed between groups in those with comorbid anxiety (P = 0.016), driven by end-treatment differences (P = 0.018). When MADRS item 3 was removed from the total MADRS score among ketamine recipients, depression scores did not differ significantly between those with and without comorbid anxiety (P = 0.13). Exploratory dose analyses found a larger mean HAM-A decrease in cohort 2 ketamine recipients versus cohort 1 ketamine recipients, but the cohort comparison within the ketamine arm did not reach statistical significance (β = -4.00, P = 0.14). Regression analyses testing maximum ketamine dose (mg/kg or mg) against HAM-A change were non-significant (P = 0.49 and P = 0.51 respectively), suggesting no clear dose–response in these exploratory tests. Overall, anxiolytic effects were apparent at end treatment in adequately dosed participants but were not maintained at 4 weeks after treatment cessation.
Mills and colleagues interpret their findings as supporting an anxiolytic effect of subcutaneous ketamine in people with treatment-resistant depression when administered at adequate doses. The effect was evident at the end of the 4-week treatment course in the combined sample and in cohort 2 (response-guided, higher dosing), but not in cohort 1 (fixed lower dose), and was not maintained at the 4-week post-treatment follow-up without further intervention. While mediation analyses indicated a substantial indirect effect of ketamine on anxiety via reduction in depressive symptoms, the group effect on HAM-A remained significant in models controlling for MADRS change, suggesting antidepressant response does not entirely account for anxiolytic effects. The reduction was concentrated in the HAM-A 'psychic' factor and was mirrored by improvements on MADRS item 3 in cohort 2. The authors place their findings in context with prior ketamine and esketamine studies that reported anxiolytic effects, noting the literature is limited by small samples and methodological variability. They highlight strengths of the present analysis: a relatively large randomised sample, active blinding with midazolam, repeated anxiety measurements, multiple anxiety outcome measures and control for mood change. Limitations acknowledged include that these analyses were secondary and exploratory with uncorrected multiple comparisons, relatively small numbers in some subgroups (notably participants with comorbid anxiety in certain comparisons), and the sequential cohort design that complicates inference about dose effects. The authors also note that the lack of durability at 4 weeks could relate to initial dosing strategy and time to reach adequate dose in cohort 2. For future research the study team recommends hypothesis-driven trials to replicate these findings, longer treatment durations with individualised titration, investigation of maintenance strategies and trials combining ketamine with psychotherapies such as cognitive-behavioural therapy to prolong benefits. They caution that, given the exploratory nature of the present analyses, confirmation in subsequent trials is required before changes to clinical practice or guideline recommendations are considered.