Amantadine treatment is associated with improved consciousness in patients with non-traumatic brain injury

Abstract

ObjectiveThis study determined the effect of amantadine treatment on consciousness in patients with non-traumatic brain injury.MethodsWe pooled individual patient data of five single-centre observational studies to determine the effect of amantadine treatment among patients with ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, community-acquired bacterial meningitis and status epilepticus, admitted between January 2012 and December 2015 and ventilated ≥7 days. Patient selection and multivariable regression modelling were used to adjust for differences in intergroup comparison and for parameters associated with consciousness. Improvement of consciousness 5 days after treatment initiation was defined as primary outcome. Secondary outcomes included Glasgow Coma Scale (GCS) at day 5 and GCS at day 10, rate of ICU delirium, epileptic seizures and all-cause mortality at 90 days.ResultsOverall, 84 of 294 (28.6%) eligible patients received amantadine. Amantadine treatment was associated with improvement of consciousness at day 5 (amantadine: 86.9% vs control: 54.0%; absolute difference: 32.9 (20.0–44.2); adjusted OR (aOR): 5.71 (2.50–13.05), p<0.001). Secondary outcomes showed differences in GCS 5 days (9 (8–11) vs 6 (3–9), p<0.001) and GCS 10 days (10(8–11) vs 9(6–11),p=0.003) after treatment initiation. There were no significant differences regarding all-cause mortality (aOR: 0.89 (0.44–1.82), p=0.758) and ICU delirium (aOR: 1.39 (0.58–3.31), p=0.462). Rate of epileptic seizures after initiation of amantadine treatment was numerically higher in the amantadine group (amantadine: 10.7% vs control: 3.0%; absolute difference: 7.7 (0.3–16.4); aOR: 3.68 (0.86–15.71), p=0.079).ConclusionsAmantadine treatment is associated with improved consciousness among patients with different types of non-traumatic brain injury in this observational cohort analysis. Epileptic seizures should be considered as potential side effects and randomised controlled trials are needed to confirm these findings.

Amantadine for NeuroenhaNcement in acutE patients Study - a protocol for a prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES)

“…Within the field of non-traumatic brain injuries, especially strokes, there only exists good clinical experience as well as promising retrospective and review [ 22 , 29 , 46 ] data. Hence, there is a significant unmet need for controlled and prospective datasets within clearly defined patient collectives.…”

“…Beyond this assumed individual benefit it is expected that the results of this study will be of significant long-term importance to improve therapeutic standards in acute neurointensive care unit patients in general. Indeed, recently, one of the first comprehensive studies in this field [ 46 ] has shown that amantadine medication leads to an improvement of vigilance even in patients with non-traumatic brain injuries (especially those with AIS, ICH and SAH) after five days of treatment. The authors concluded that these results should be confirmed in further studies also considering the functional outcome of patients which will be part of our secondary endpoints.…”

Whole-brain modelling supports the use of serotonergic psychedelics for the treatment of disorders of consciousness

“…We found that perturbing some receptors induced a significant shift in the dynamics of the DoC model as determined by the travelled distance as the scaling parameter increased. Of note, the least effective in terms of reaching a maximum change in the dynamics, were the dopaminergic receptors, which are currently used currently as treatment options (Giacino et al, 2012; Rühl et al, 2022). This discrepancy could arise due to downstream effects of dopaminergic stimulation not included in our model, or due to the fact that dopaminergic drugs used to treat DoC are non-specific with regards to the targeted dopamine receptor subtype.…”

“…Zolpidem restores consciousness in chronic patients due to a paradoxical effect (Bomalaski et al, 2017), and its effect wears off along with the drug (Whyte et al, 2014;Whyte & Myers, 2009). In contrast, Amantadine is a N-methyl-D-aspartate receptor antagonist and indirect dopamine agonist capable of inducing both short (5-10 days) and long-term (4-6 weeks) improvements (Rühl et al, 2022), and it was incorporated in DoC practical guidelines for clinicians (Giacino et al, 2018). Unfortunately, available drugs have modest therapeutic efficacy and act via unknown specific mechanisms, thus hindering the development of new options, while clinical trials are difficult to organise due to low number of participants and other limitations intrinsic to patients with conscious impairments (Marino & Whyte, 2022) In recent years, serotonergic psychedelics have been proposed as a potential new treatment to accelerate the recovery of DoC patients (Scott & Carhart-Harris, 2019).…”

Evaluation of Functional Recovery Following Thrombectomy in Patients With Large Vessel Occlusion and Prestroke Disability

“…Data on demographic characteristics (age and sex), comorbidities, status on hospital admission, and intrahospital parameters were obtained, as previously published. 12 , 13 , 14 Prestroke functional status was assessed at hospital admission using the modified Rankin Scale (mRS) based on information by patients, relatives, medical records, and if applicable, caregivers and referring physicians. 15 Prestroke disability was defined as a score on the mRS of 3 or 4.…”