This ascending single-dose study (n=12) evaluates the dose-related effects of ketamine (18-70mg/70kg) on patients with anxiety symptoms with treatment-resistant anxiety disorders. Ten of the twelve participants (83%) found relief for up to seven days. The results support ketamine as a potential therapeutic alternative for patients with anxiety disorders.
The N-methyl-D-aspartate receptor antagonist ketamine has rapid onset activity in treatment-resistant depression, post-traumatic stress disorder and obsessive compulsive disorder. Due to similarities in brain network activity in depression and anxiety disorders, we hypothesized that ketamine might also be active in other refractory anxiety disorders. We evaluated the efficacy and safety of ketamine in 12 patients with refractory generalized anxiety disorder and/or social anxiety disorder who were not currently depressed, using an ascending single dose study design (0.25, 0.5, 1 mg/kg administered subcutaneously) at weekly intervals. Within 1 h of dosing, patients reported reduced anxiety, which persisted for up to seven days. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate, with minor changes at 0.25 mg/kg, and progressively greater and more durable changes at the higher doses. Ten of 12 patients were treatment responders at 0.5-1 mg/kg. Ketamine was safe and well tolerated in this population. Ketamine may be a potential therapeutic alternative for patients with refractory generalized anxiety disorder/social anxiety disorder. Along with its demonstrated effectiveness in patients with treatment-resistant depression, obsessive compulsive disorder and post-traumatic stress disorder, these data raise the intriguing possibility that ketamine may have broad efficacy in disorders characterized by negative emotional states, and that these disorders may share a common precipitating neurobiology.
Previous research has shown that low-dose ketamine produces rapidly acting antidepressant effects in treatment-resistant depression (TRD), and preliminary studies have reported rapid improvement in obsessive–compulsive disorder and post-traumatic stress disorder. However, at the time of this study there were no published data on ketamine’s effects in treatment-resistant generalized anxiety disorder (GAD) or social anxiety disorder (SAD), despite shared alterations in brain network activity, grey matter and glutamate signalling across depression and anxiety disorders. Glue and colleagues set out to assess whether ketamine reduces anxiety symptoms in patients with treatment-resistant GAD or SAD. The study aimed to evaluate the feasibility, safety and dose-related effects of ascending single subcutaneous ketamine doses on standard anxiety rating scales in this patient group.
This was an open-label, ascending single-dose feasibility study approved by a regional ethics committee and prospectively registered with the Australian New Zealand Clinical Trial Registry; the extracted text does not clearly report the full registration identifier. Adults with DSM-IV GAD and/or SAD who met severity thresholds (Hamilton Anxiety Rating Scale (HAM-A) score ≥20 and/or Liebowitz Social Anxiety Scale (LSAS) score ≥60 at screening) were eligible. Patients with severe medical disorders, pregnancy or lactation, current use of monoamine oxidase inhibitors, thyroxine or stimulants, active suicidal ideation, or a Montgomery–Åsberg Depression Rating Scale (MADRS) score ≥20 at screening were excluded. All participants provided informed consent and underwent screening laboratory and vital-sign checks. Participants were allowed to continue stable ongoing medications and psychotherapy but could not start new treatments or change doses during the study. Three ascending subcutaneous ketamine dose levels were given in fixed order (0.25, 0.5 and 1 mg/kg), each separated by one week. The investigators selected subcutaneous administration for perceived similar efficacy to intravenous dosing with better tolerability; dose selection was informed by prior work in TRD that suggested a threshold near 0.25–0.3 mg/kg and durability at higher doses. Safety and efficacy monitoring included vital signs predose and at 15, 30, 45, 60, 90 and 120 minutes post-dose. Anxiety was assessed using the Fear Questionnaire (FQ) and HAM-A at predose and at 1, 2, 24, 72 and 168 hours post-dose. Dissociative effects were measured with the Clinician Administered Dissociative States Scale (CADSS) predose and at 30 and 60 minutes. Adverse events were recorded throughout. For analysis, summary statistics described demographics, vital signs and scales. To account for repeated measures within participants and across the three doses, the investigators used linear mixed models with random effects for participant and participant-by-dose and fixed effects for time, dose and the time-by-dose interaction; residual maximum likelihood estimation was used. Conditional residuals were inspected and log transformations considered when appropriate. Statistical testing used Stata 14.1 with two-sided p<0.05 considered significant; as an exploratory study no adjustment was made for multiple comparisons. A responder analysis defined response as a ≥50% reduction in HAM-A or FQ total score after any dose.
Seventeen patients were screened and 12 were enrolled; all 12 completed the protocol. The sample comprised four females (33%) and eight males (67%), mean age 32 years (range 23–55), with a mean duration of anxiety disorders of 16.5 years (range 5–30). Ten participants (83%) met criteria for GAD and nine (75%) for SAD; five (42%) also had panic disorder and two had post-traumatic stress disorder. All patients were taking antidepressants and had not responded to prior antidepressant trials and psychotherapy. Eleven subjects (92%) had a lifetime history of major depressive disorder, but none appeared to be currently depressed (mean MADRS at screening 8.0, range 5–12). Baseline severity scores were consistent with marked illness: mean HAM-A at screening was 26 and mean LSAS was 89. On the FQ, mixed model analysis showed a significant dose-by-time interaction (p=0.033), with dose-related differences in the magnitude and duration of initial reductions. HAM-A profiles showed dose-related patterns for initial decrease and duration, but the time-by-dose interaction did not reach conventional significance (p=0.068), described by the investigators as a non-significant tendency. Overall, 10 of 12 patients (83%) achieved a ≥50% reduction on HAM-A and/or FQ after the 0.5 or 1 mg/kg doses. All participants reported dissociative symptoms beginning around 5 minutes post-injection, peaking at about 20–30 minutes and largely returning towards baseline by 60 minutes. CADSS scores demonstrated dose-dependent increases at 30 minutes with a significant dose-by-time interaction (p=0.008); after 1 mg/kg two participants rated the dissociative experience as very intense and feeling out of control. Two subjects experienced transient nausea at 30 minutes. Cardiovascular effects were dose related: after 1 mg/kg mean systolic and diastolic blood pressure rose by 9.4 mm Hg and 7.5 mm Hg respectively at 30 minutes, and heart rate increased by 4.5 beats per minute at 15 minutes. No participants withdrew for adverse events.
Glue and colleagues interpret these results as the first demonstration that ketamine can produce rapid anxiolytic effects in patients with severe, treatment-refractory GAD and/or SAD who are not currently depressed. The temporal pattern resembled that reported in TRD: rapid onset of effect with waning benefit over 3–7 days. The investigators report a dose–response relationship for both anxiolytic effects and dissociative side effects; 0.25 mg/kg appeared to be a threshold producing only brief reductions at 1 hour, whereas 0.5–1 mg/kg produced larger reductions and the longest duration of benefit appeared at 1 mg/kg. The authors acknowledge several important limitations. The open-label ascending-dose design means both participants and investigators knew ketamine was administered, which may introduce bias in reported outcomes. Sample size was small and diagnostic comorbidity common: seven patients met criteria for both GAD and SAD, six had current or prior panic disorder and almost all had prior major depressive disorder. Concomitant antidepressant medications were continued, which could confound attribution of effects to ketamine. The investigators note that this cohort reflects a ‘‘real-world’’ treatment-resistant population but that prior MDD could represent a phenotype particularly responsive to ketamine; this possibility and the suggestion that high baseline anxiety in TRD predicts ketamine response warrant testing in future randomised trials. In their concluding remarks the study team state that ketamine was generally safe and well tolerated in this small sample and suggest ketamine may offer a therapeutic alternative for patients with few options. They also raise the broader hypothesis that ketamine could have efficacy across disorders characterised by negative emotional states, but indicate that controlled studies are needed to confirm efficacy and define optimal dosing.
The initial report that low dose ketamine had rapidly acting antidepressant effects in treatment-resistant depression (TRD;has now been replicated in numerous randomized controlled trials (RCTs) and case series. Preliminary studies have reported rapid improvement in two disorders with prominent symptoms of anxiety: obsessive compulsive disorder (OCD;and post-traumatic stress disorder (PTSD;. To date there have been no data published on the effects of ketamine in treatment-resistant generalized anxiety disorder (GAD) or social anxiety disorder (SAD). We hypothesized that ketamine would improve anxiety ratings in GAD and SAD, based on overlapping alterations in brain network activity in depression and anxiety disorders, similar regional changes in grey matter volume, and alterations in glutamate signaling. The objective of this feasibility study was to evaluate the effect of ascending single doses of ketamine on anxiety ratings in patients with treatment-resistant GAD or SAD.
This study was approved by the Southern Health and Disabilities Ethics Committee (15/STH/86), and was registered prospectively with the Australian New Zealand Clinical Trial Registry (ACTRN Montgomery-Asberg Depression Rating Scale (MADRS;scores of ⩾20 at screening were excluded. All subjects provided signed informed consent prior to enrolment, and were assessed as suitable to participate based on review of medical history, safety laboratory tests, and vital signs. Patients were permitted to remain on current medication regimens and to continue with ongoing psychotherapy. However, no new treatments were to be started or doses/visit schedules changed. There were three ascending ketamine dose levels (0.25, 0.5 and 1 mg/kg, given in that order), injected subcutaneously in the upper arm, with one week between doses. Subcutaneous dosing was selected as it is as effective as IV dosing, however with better tolerability. The lowest dose was chosen as it appears to be a threshold dose in patients with TRD,, and we have found the 1 mg/kg dose to have the greatest durability of response in patients with TRD. Patients were monitored in the clinic for 2 h post-dose, with vital signs obtained predose, and 15, 30, 45, 60, 90, and 120 min post-dosing. Anxiety assessments included the Fear Questionnaire (FQ; score range 0-136;and the HAM-A (range 0-52;predose, at 1, 2, 24, 72, and 168 h post-dose. Tolerability assessments included reported adverse events throughout the study, and Clinician Administered Dissociative States Scale (CADSS;predose, 30, and 60 min post-dose. Summary statistics were calculated and reported for demographic, vital signs, and rating scale data. Categorical variables were reported using counts and percentages. In order to accommodate the repeated measures on patients from both the multiple measurements over time within a given dose and from the three doses received by each participant in this ascending dose design, linear mixed models were used with random participant and participant-dose effects along with fixed effects for time, dose, and the time-by-dose interaction. Residual maximum likelihood estimates were used. Histograms and scatter plots of conditional residuals were inspected and, where appropriate, natural logarithm transformations investigated to see if this improved satisfaction of model assumptions. Statistical analyses were performed using Stata 14.1 and two-sided p<0.05 was considered statistically significant. As this was an exploratory study, and to avoid reducing power to detect both beneficial and adverse effects, no adjustments for multiple comparisons were made. A responder analysis was performed based on the proportion of participants with 50% or greater reduction in HAM-A or FQ total score after any dose.
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Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
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Seventeen patients were screened; 12 patients were enrolled and all completed the study. The participants comprised four females (33%) and eight males (67%). Mean age was 32 years (range 23-55), and duration of their anxiety disorders was 16.5 years (range 5-30). Ten subjects met the criteria for GAD (83%), and nine for SAD (75%). There was significant comorbidity, with five subjects also having panic disorder (42%; see Supplementary Material, Figure). All patients were currently taking antidepressants and had not responded to prior trials of antidepressants and group or individual psychotherapy, including CBT (individual patient details are tabulated in Supplementary Material, Table ). Mean HAM-A at screening was 26 (indicative of severe anxiety), and mean LSAS at screening was 89 (threshold score for probable SAD is 60). Eleven subjects had had prior major depressive disorder (MDD) (92%), however none appeared to be currently depressed (mean screening MADRS=8.0, range= 5-12; threshold score for moderate depression is 20).
Mean FQ rating-time profiles are shown in Figure. Dose responses were noted in terms of magnitude of initial decrease and duration of reduced ratings. The mixed model analysis identified significant dose×time interaction (p=0.033). Mean HAM-A rating-time profiles are shown in Figure. Doseresponses were noted for magnitude of initial decrease, and duration of reduced scores. The mixed model analysis identified a non-significant tendency for a dose×time interaction (p=0.068). Overall 10 of 12 patients (83%) reported a >50% reduction in HAM-A and/or FQ scales after the 0.5 or 1 mg/kg doses.
All subjects reported dissociative symptoms, starting approximately 5 min after each injection, with peak intensity around 20-30 min. CADSS scores showed dose-dependent increases at 30 min and were returning towards baseline by 60 min (Figure). The mixed model analysis identified a significant dose×time interaction (p=0.008). After the 1 mg/kg dose, two subjects rated these experiences as very intense, feeling out of control. Two subjects also reported transient nausea at 30 min post dose. Dose-related increases in systolic and diastolic blood pressure were observed at 30 min, with mean change from baseline of 9.4 and 7.5 mm Hg after 1 mg/kg dosing. Heart rate increased by 4.5 beats/min at 15 min after 1 mg/kg dosing.
This is the first demonstration of anxiolytic effects of ketamine in patients with severe treatment-resistant GAD and/or SAD who were not currently depressed. The pattern of improvement was similar to that seen in patients with TRD, in that there was a rapid onset of anxiolytic effects, and that these effects wore off over 3-7 days. A dose-response profile was noted for anxiolytic effects and dissociative side effects. Ketamine was safe and well tolerated. Treatment-resistant anxiety disorders are a major clinical problem. Between 40-60% of patients with anxiety disorders may fail to respond to conventional drug or psychological treatments. Evidence to support specific treatment strategies for treatment-resistant anxiety is limited, and patients may remain functionally impaired. We have identified that ketamine has broad anxiolytic effects with GAD and/or SAD, with improvements in cognitive, emotional, and physical symptoms of anxiety, irrespective of diagnosis. We identified a dose response for ketamine in this patient group. 0.25 mg/kg appeared to be a threshold dose, associated with a brief reduction in anxiety ratings at 1 h post dose, which did not persist. The maximum reduction in anxiety appeared to be greater for 0.5-1 mg/kg, and the duration of anxiolytic effects appeared to be greatest at 1 mg/kg. There are limited dose-response data for ketamine in TRD. We have recently showed in an individual dose-titration study that 0.2-0.3 mg/kg is a threshold dose for reducing severity of depression in patients with TRD, and that higher doses (up to 0.5 mg/kg) appear to have more robust antidepressant effects. The efficacy of doses >0.5 mg/kg has not been systematically studied in TRD. There a number of limitations with the current study, including diagnostic comorbidity, use of concomitant medication, and the open-label study design. Seven patients met criteria for comorbid GAD and SAD, six had current or previous panic disorder, and two had PTSD (see Supplementary Table, online). Comorbidity of anxiety disorders is not uncommon in patients with treatment-resistant anxiety, and this cohort represents a real-world patient population. Almost all patients had had prior MDD. While none were depressed at the time of testing, it is possible that a history of prior MDD could represent a clinical phenotype responsive to ketamine. Also potentially of relevance is the finding that TRD patients with high baseline anxiety levels may be more responsive to ketamine than nonanxious TRD patients. This could be explored in future treatment trials in anxious patients with and without prior MDD. Although patients were not responding to ongoing antidepressant therapies, we decided not to change these prior to ketamine treatment, consistent with our earlier study in TRD. The study design involved open-label ascending doses of ketamine, where both patients and investigators knew they were receiving ketamine, which potentially introduced reporting and measurement bias issues. Subject numbers were small. Since this was the first study to evaluate the efficacy and safety of ketamine in this patient population, we believe that this design was fit for purpose. In conclusion, this study provides the first evidence that ketamine improves symptoms of anxiety in patients with treatment refractory GAD and SAD who are not currently depressed, and is safe and well tolerated. Ketamine has the potential to provide a therapeutic alternative for this patient group with few treatment alternatives. Along with its demonstrated effectiveness in patients with TRD, OCD, and PTSD, these data raise the intriguing possibility that ketamine may have broad efficacy in disorders characterized by negative emotional states, and that these disorders may share a common precipitating neurobiology.