Department of Psychiatry and Behavioral Health Stony Brook University Renaissance School of Medicine Stony Brook, New York
Acknowledgments The authors express great gratitude to Professor Max Fink for his characterization of delirious mania. We also thank Dr. Fink for his continued guidance and support during the preparation of this manuscript.
Disclosures The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.
Alterations in gamma-aminobutyric acid (GABA) transmission are known to occur in delirium and catatonia. In delirium, GABA signaling is increased, which disrupts the circadian rhythm and melatonin release, thus impairing the sleep-wake cycle.44 Deficiencies in acetylcholine and melatonin are seen as well as excess of other neurotransmitters, including norepinephrine and glutamate.45 Conversely, in catatonia, functional imaging studies found decreased GABA-A binding in orbitofrontal, prefrontal, parietal, and motor cortical regions.46 A study analyzing 10 catatonic patients found decreased density of GABA-A receptors in the left sensorimotor cortex compared to psychiatric and healthy controls.47
Other neurotransmitters, such as glutamate, at the N-methyl-d-aspartate receptors (NMDAR) have been hypothesized to be hyperactive, causing downstream dysregulation of GABA functioning.48 However, the exact connection between delirious mania and all these receptors and neurotransmitters remains unknown.
Encephalitis hypothesis. The relationship between delirious mania and autoimmune encephalitis suggests delirious mania has etiologies other than a primary psychiatric illness. In a 2020 retrospective study49 that analyzed 79 patients with anti-NMDAR encephalitis, 25.3% met criteria for delirious mania, and 95% of these patients had catatonic features. Dalmau et al50 found that in many cases, patients tend to respond to ECT; in a cases series of 3 patients, 2 responded to benzodiazepines.
COVID-19 hypothesis. The SARS-CoV-2 virion has been associated with many neuropsychiatric complications, including mood, psychotic, and neurocognitive disorders.51,52 There also have been cases of COVID-19–induced catatonia.53-55 One case of delirious mania in a patient with COVID-19 has been reported.21 The general mechanism has been proposed to be related to the stimulation of the proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, which the virus produces in large quantities.56 These cytokines have been linked to psychosis and other psychiatric disorders.57 The patient with COVID-19–induced delirious mania had elevated inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and D-dimer, which supports a proinflammatory state. This patient had a complete resolution of symptoms with ECT.21
Management: Benzodiazepines and ECT
A step-by-step algorithm for managing delirious mania is outlined in the Figure. Regardless of the underlining etiology, management of delirious mania consists of benzodiazepines (lorazepam and diazepam); prompt use of ECT, particularly for patients who do not improve with large doses of lorazepam; or (if applicable) continued treatment of the underlining medical condition, which does not preclude the use of benzodiazepines or ECT. Recent reports27,58 have described details for using ECT for delirious mania, highlighting the use of high-energy dosing, bilateral electrode placement, and frequent sessions.
