Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders

Anxiety disorders (including specific phobia, social anxiety disorder [SAD], generalized anxiety disorder [GAD], panic disorder, and agoraphobia) are highly prevalent and often treatment-resistant, producing substantial burden worldwide. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has established rapid-onset antidepressant effects in treatment-resistant depression, but clinical research on ketamine for treatment-resistant anxiety disorders is comparatively sparse. The introduction highlights potential mechanistic reasons to target the glutamate system in anxiety—glutamate’s roles in fear extinction, stress-responsive neuropeptide regulation, and synaptic plasticity—and notes ketamine’s complex pharmacology beyond NMDAR antagonism, as well as the absence of consistent definitions for treatment resistance in anxiety and limited regulatory development in this area. Whittaker and colleagues set out to systematically review and meta-analyse randomized controlled trials (RCTs) of acute ketamine treatment for anxiety spectrum disorders, with supplementary consideration of open-label maintenance studies and acute dose–response data. The review aimed to summarise efficacy, safety, tolerability, and dose and maintenance effects across disorders commonly associated with anxiety symptoms, including SAD, GAD, post‑traumatic stress disorder (PTSD), and obsessive‑compulsive disorder (OCD).

The review protocol was prospectively registered on PROSPERO (CRD42020190282). The investigators searched MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), the Cochrane Library, and Google Scholar (first 200 hits) using ketamine‑and‑anxiety related keywords and mapped terms to indexed subject headings; full search details were reported in supplementary materials. Eligible studies for the meta-analysis were prospective acute treatment RCTs comparing ketamine (any route: oral, subcutaneous, intramuscular, intravenous) with a control (psychoactive or inactive) administered by the same route; case reports and case series were excluded. Adults with anxiety spectrum diagnoses (DSM‑5) including SAD, GAD, specific phobia, panic disorder, agoraphobia, separation anxiety disorder, PTSD, or OCD were eligible per the review criteria. Two researchers independently screened studies, extracted data using standardised tables, and assessed risk of bias with the Cochrane risk‑of‑bias tool for randomized trials. The authors synthesised findings narratively and performed random‑effects meta-analyses for appropriate binary outcomes using odds ratios with 95% confidence intervals, assessing statistical heterogeneity with chi-square and I-squared statistics. Where available, acute dose–response and maintenance treatment data were also extracted and presented as percent change from baseline. The review included additional unpublished data provided by trial authors when necessary; because included trials had prior ethics approval, no new ethics approval was required for the review.

From 3,127 records screened, 37 full texts were assessed and eight studies met inclusion criteria. The included corpus comprised six double‑blind acute RCTs (five crossover, one parallel), one acute dose–response analysis incorporating open‑label and double‑blind data, and one open‑label maintenance trial. Acute treatment trials covered SAD/GAD (two papers), PTSD (three papers), and OCD (one paper). Performance bias related to likely unblinding from ketamine’s dissociative effects was noted, and crossover designs were judged at higher risk of bias due to potential carryover. For SAD, Glue et al. (n = 12) used an ascending subcutaneous schedule (0.25, 0.5, 1 mg/kg) with a psychoactive midazolam control; Taylor et al. (n = 18) used a single 0.5 mg/kg IV infusion with saline control. Pooled responder analysis—using study‑specific responder definitions—found ketamine recipients were more likely to be responders than controls (OR = 28.94; 95% CI: 3.45–242.57; p = 0.002). GAD data were limited and overlapped with SAD comorbidity; Glue et al. reported a significant benefit in their small comorbid GAD subgroup (6/10 responders on ketamine vs 0/10 on control; OR = 30.33; 95% CI: 1.39–660.76; p = 0.03), but pooled GAD analysis was not possible due to insufficient data. Three RCTs examined PTSD. Feder et al. (n = 41) compared 0.5 mg/kg IV ketamine with midazolam and reported greater improvement in IES‑R scores at 24 h (mean difference 12.7; 95% CI: 2.5–22.8; p = 0.02). Dadabayev et al. used ketamine versus ketorolac in participants with chronic pain and comorbid PTSD; both groups improved and no significant difference in IES‑R change at 24 h was found (mean difference −0.34; 95% CI: −11.95–11.27; p = 0.95). Pradhan et al. employed a modified crossover design and found large improvements in both ketamine and saline phases with no significant between‑group difference in first‑phase outcomes. Pooled responder analysis across the three PTSD trials showed no statistically significant difference in odds of treatment response (OR = 2.03; 95% CI: 0.67–6.15; p = 0.21). Rodriguez et al. conducted the only eligible acute OCD trial (crossover, n = 15) comparing 0.5 mg/kg IV ketamine with saline. First‑phase OCD‑VAS scores showed significant reductions mid‑infusion, at 230 minutes, and at 7 days favouring ketamine; a higher proportion of responders (≥35% Y‑BOCS reduction at 7 days) was reported in the ketamine first‑phase group (50% vs 0%). Using published first‑phase data, the investigators calculated a non‑significant greater reduction in Y‑BOCS at 7 days after ketamine (mean difference −5.79; 95% CI: −11.94 to 0.36; p = 0.07), and supplementary data gave a non‑significant OCD‑VAS difference at 7 days (mean difference −2.50; 95% CI: −5.19 to 0.19; p = 0.07). Safety and tolerability analyses showed transient increases in Clinician‑Administered Dissociative States Scale (CADSS) scores after ketamine that returned toward baseline by 120 minutes, peaking around 30–40 minutes. Pooled analyses indicated markedly higher odds of subjective dissociation (feeling spaced out/disconnected) with ketamine versus control (OR = 104.13; 95% CI: 13.92–799.06; p < 0.0001), and elevated odds of nausea/vomiting (OR = 14.22; 95% CI: 2.53–79.98; p = 0.003) and dizziness/light‑headedness (OR = 8.65; 95% CI: 1.40–53.49; p = 0.02). Sympathomimetic effects with increases in heart rate and blood pressure were consistently reported. One subgroup (participants with comorbid PTSD and chronic pain) reported minimal dissociative effects, possibly related to comorbid physiology or concomitant medications, per the original trialists. Dose‑response data (from Glue et al. and secondary analysis by Truppman Lattie et al.) showed a dose–response relationship for anxiety scales (FQ, HAM‑A, SSAI) in SAD/GAD patients: 0.5 mg/kg and 1 mg/kg produced greater reductions than 0.25 mg/kg, with 0.5 mg/kg appearing to provide most of the benefit and little additional gain at 1 mg/kg. Maintenance data came from an open‑label study by Glue et al. in 20 responders receiving 1 mg/kg subcutaneous injections once or twice weekly; 18/20 patients reported improved social and/or work functioning. Truppman Lattie et al. reported maintenance trajectories over 14 weeks with pre‑dose improvements approaching an asymptote at about 3–4 weeks (HAM‑A, SSAI) and 7–8 weeks (FQ), plus consistent ~50% further reductions in scores one hour post‑dose across 14 weeks.

Whittaker and colleagues interpret their review as the first systematic review and meta‑analysis of controlled acute ketamine trials across anxiety spectrum disorders. The pooled and individual trial data led the investigators to conclude that ketamine shows preliminary evidence of anxiolytic effects across several disorders: a statistically significant increased likelihood of acute treatment response in SAD (OR = 28.94; 95% CI: 3.45–242.57; p = 0.002), and in the small comorbid GAD subgroup from Glue et al. (OR = 30.33; 95% CI: 1.39–660.76; p = 0.03). Pooled PTSD data did not demonstrate a significant benefit over controls. The authors also highlight positive findings in OCD first‑phase data and individual PTSD studies, noting heterogeneity in outcomes across scales and designs. The discussion emphasises a dose–response relationship, with doses ≥0.5 mg/kg typically associated with greater anxiolytic effects, and reports that maintenance dosing may sustain clinical benefit and improve social or occupational functioning. Safety considerations centred on transient dissociative and sympathomimetic effects; dissociation tended to resolve within two hours and may attenuate with repeated dosing. The authors advise practical mitigations such as monitoring the first hour post‑dose and pre‑treatment antiemetics to reduce nausea. Limitations acknowledged include the small number of eligible RCTs and small sample sizes (four of six RCTs had n < 20), heterogeneity in study protocols (control type, dosing, route), predominance of crossover designs with carryover risk, potential functional unblinding from ketamine’s psychoactive effects even when psychoactive controls were used, and clinical heterogeneity due to comorbidity. The absence of standardised operational definitions for treatment‑resistant anxiety is noted as a broader limitation in the field. The authors conclude that while findings are promising, they remain tentative; further parallel‑arm RCTs, clarification of optimal dosing and maintenance strategies, and longer‑term safety data are needed before routine clinical adoption, and off‑label use should involve careful clinical decision‑making and discussion of current evidence gaps.