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

Abstract

Background: Anxiety disorders are common, associated with significant burden of disease, and have high levels of treatment resistance. Low-dose ketamine has been extensively studied in treatment-resistant depression, with fewer reports in treatment-resistant anxiety disorders. Aims: This systematic review and meta-analysis collected efficacy, safety, and tolerability data for ketamine as a treatment for anxiety spectrum disorders. Methods: We conducted a systematic search for randomized controlled trials (RCTs) of acute ketamine treatment for patients with anxiety disorders. Open-label trials of ketamine maintenance therapy were also considered. Qualitative and, where possible, quantitative syntheses of findings were performed using Review Manager software (RevMan). Acute dose-response and maintenance treatment data were also collected. Results: There were six eligible acute RCTs – two in social anxiety disorder (SAD), three in post-traumatic stress disorder (PTSD), and one in obsessive-compulsive disorder (OCD). Four of the six showed significant improvement in anxiety rating scores in ketamine compared with control groups. Pooled analysis showed ketamine was associated with an increased likelihood of treatment response for SAD (odds ratio (OR): 28.94; 95% confidence interval [CI]: 3.45–242.57; p = 0.002) but not for PTSD (OR: 2.03; 95% CI: 0.67–6.15; p = 0.21). A dose-response profile was observed for ketamine and changes in SAD symptoms, with doses ⩾0.5 mg/kg associated with greater reduction in anxiety rating scores than lower doses. Ketamine maintenance therapy was associated with sustained anxiolytic effects and improved social and/or work functioning. Conclusion: These preliminary analyses suggest that acute ketamine may be broadly effective across treatment-resistant anxiety spectrum disorders. These effects can be prolonged with maintenance treatment. Future studies will be needed to provide critical knowledge gaps around off-label use, side effects, and potential risks for abuse in clinical settings.

The effect of ketamine on cognition, anxiety, and social functioning in adults with psychiatric disorders: A systematic review and meta-analysis

“…With respect to anxiety, this is the largest meta-analysis of ketamine intervention for anxiety symptoms. Our total sample size is larger than the one included in the previous metaanalysis of ketamine intervention in anxiety spectrum disorders (Whittaker et al, 2021) (6 vs. 2 RCTs, corresponding to 432 vs. 59 participants), and we confirmed the direction of the effect favoring ketamine. Differently from the work by Whittaker et al, we assessed anxiety symptoms trans-diagnostically, because anxiety is often comorbid with depression and other mental disorders.…”

“…The antidepressant and anti-suicidal effects of ketamine seem to be not exclusive to major depression disorder (MDD), rather they are played also across other affective disorders, including bipolar depression, anxiety disorders, and possibly also on depression with psychotic features, despite its relative contraindication in psychosis (Witt et al, 2020 ; Cavenaghi et al, 2021 ; Lima et al, 2022 ; Souza-Marques et al, 2022 ). Furthermore, there is increasing interest in the possible application of ketamine in other disorders, such as anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder (Whittaker et al, 2021 ; Jumaili et al, 2022 ).…”

“…However, it has been demonstrated that glutamate and NMDARs are involved in the stress response and fear extinction (Davis and Myers, 2002 ) and changes in the glutamate pathway have been linked to the development of anxiety disorders (Freitas-Ferrari et al, 2010 ; Kormos and Gaszner, 2013 ). A recent meta-analysis suggests that ketamine may also have significant anxiolytic effects on patients with anxiety spectrum disorders, including treatment-refractory cases (Whittaker et al, 2021 ).…”

Real-world depression, anxiety and safety outcomes of intramuscular ketamine treatment: a retrospective descriptive cohort study

“…The PHQ-9 asks patients to rate the frequency of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition's (DSM-V) symptoms of MDD over the past 2 weeks [33]. The PHQ-9 total score ranges from 0 to 27, with scores representing minimal depression (0-4), mild depression (5)(6)(7)(8)(9), moderate depression (10)(11)(12)(13)(14), moderately severe depression (15)(16)(17)(18)(19), and severe depression (20)(21)(22)(23)(24)(25)(26)(27). Item 9 of the PHQ-9 is a brief SI measure.…”

“…Ketamine treatment has also demonstrated efficacy for patients with other mental illnesses besides MDD. It has been shown to reduce anxiety symptoms in patients with generalized anxiety disorder (GAD) and/or social anxiety disorder (SAD) [6][7][8], and preliminary evidence shows that ketamine treatment may reduce symptoms of substance use disorders [9][10][11][12], post-traumatic stress disorder (PTSD) [13], bipolar depression [14], and eating disorders [15].…”