Ketamine/esketamine pharmacotherapy for treatment of anxiety disorders and anxiety symptoms in depression: Systematic review

Background: Ketamine and esketamine (“es/ketamine”) treatment protocols have been investigated in patients’ samples with treatment-refractory anxiety disorders. We systematically reviewed publications in which es/ketamine was used to treat anxiety symptoms in the context of either Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) anxiety disorders or treatment-resistant depression (TRD). Method: The literature search of English-language studies combining each of the keywords “ketamine” or “esketamine” with various psychopathological terms produced 4086 results. Through the use of specific inclusion/exclusion criteria, a total of 78 studies were eligible for inclusion. Results: Eleven studies investigated ketamine pharmacotherapy (no esketamine study was found) of patients suffering primarily from a DSM-5 anxiety disorder. Additionally, we found 67 studies which: (a) reported es/ketamine pharmacotherapy for treating primarily unipolar/bipolar depression and secondarily assessed changes in anxiety symptoms ( N = 55); or (b) compared the outcome (depression/suicidality severity) of es/ketamine between “anxious” versus “non-anxious” TRD ( N = 12). These studies were notably heterogeneous, and included randomized controlled trials, crossover trials, open-label studies, and case reports. Methods of administration of ketamine varied, including subcutaneous, intravenous, intramuscular, and oral; outcome measures also varied. Study findings suggest that es/ketamine is associated with a reduction of anxiety in the context either of anxiety disorders or of unipolar/bipolar TRD. These effects are sustained, especially with repeated doses and maintenance treatment: however, after terminating maintenance treatment anxiety symptoms may soon re-emerge. The tablet formulation reduces anxiety more slowly, but with fewer side effects. Conclusion: There are indications that es/ketamine pharmacotherapy may reduce pathological anxiety, although relapse may follow its termination. More studies are needed to confirm these preliminary findings.