A Tale of (at Least) Two Drugs: Ketamine in the Setting of Catatonia

Background/Significance: Ketamine is a complex compound with an increasingly broad array of applications relevant to consultation-liaison psychiatry. Catatonia is a complex neuropsychiatric syndrome whose etiology can be attributed to multiple aberrations in neurotransmission (Carrol, 2000). Here, we will report two patient cases where catatonia improved after addition of ketamine, review the latter’s pharmacology, and potential mechanisms of action in catatonia in contrast to depression.
Case/

Methods: Two cases of excited catatonia were admitted to the medical hospital. In the first case, ketamine was initially used as an adjuvant anesthetic to facilitate ECT, whereas it was used for pre-procedural agitation in the latter. Catatonia dramatically improved in both cases, which is especially striking given previously poor response to treatment in the first case. To characterize catatonia's response to ketamine, PubMed and Web of Science were systematically reviewed for English-language studies and case reports of humans discussing both ketamine and catatonia. Dosages of ketamine, temporal relationship to catatonia symptoms, concomitant therapies, and outcome were collected when available. The references of selected papers were also reviewed.

Results: After manual removal of papers that were irrelevant or not meeting inclusion criteria, the authors noted 4 case reports. In two reports, anesthetic-dose ketamine was used to facilitate ECT with a good outcome. In the other two studies, low-dose ketamine successfully treated catatonia in settings where lorazepam was ineffective and/or unavailable.

Discussion: Ketamine has been used with varying goals for catatonia treatment across treatment settings, from management of agitation in the ED to facilitation of seizures during ECT, and catatonic symptoms were attributed to ketamine in other contexts. Antagonism of the NMDA receptor on GABA-ergic interneurons can lead to disinhibition of glutaminergic signaling in some circuits, which is a putative antidepressant mechanism of ketamine (Zanos et al, 2018). Ketamine can also directly antagonize other excitatory circuits in the prefrontal cortex and basal ganglia, which is consistent with treatment of catatonia. This is likely how other NMDA antagonists like memantine are effective in the treatment of catatonia, though ketamine is notably faster acting (Carroll et al, 2007). These findings suggest that ketamine may ameliorate catatonic symptoms via NMDA receptor antagonism, but further prospective studies are required to replicate this finding.
Conclusion/Implications: Ketamine has a small but compelling evidence base for use across catatonia-spectrum illness. Ketamine may be a promising addition to catatonia treatments, especially in settings where high-dose benzodiazepines limit efficacy of ECT. However, further research is needed to corroborate these findings.

References:
1. Carroll BT. The universal field hypothesis of catatonia and neuroleptic malignant syndrome. CNS Spectr. 2000;5(7):26–33.
2. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: Insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621–60.
3. Carroll BT, Goforth HW, Thomas C, Ahuja N, McDaniel WW, Kraus MF, et al. Review of Adjunctive Glutamate Antagonist Therapy in the Treatment of Catatonic Syndromes. J Neuropsychiatr. 2007;19(4):406–12.