A Review of Cholinergic Agents in the Treatment of Neurobehavioral Deficits Following Traumatic Brain Injury

Abstract

Although traumatic brain injury (TBI) frequently results in significant handicap, empirical investigations of pharmacological treatment of the neurobehavioral sequelae of TBI are rare. This review presents evidence that supports hypotheses of a cholinergic mechanism underlying some neurobehavioral sequelae of TBI, as well as a critical review of the preliminary evidence supporting the efficacy of cholinergic agents in TBI. Despite numerous methodological limitations, preliminary evidence exists for the efficacy of cholinergic agents in ameliorating attention and memory deficits following TBI. The authors highlight the need for large, randomized, double-blind, placebo-controlled trials that include a broad range of cognitive and behavioral outcome measures.

Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial

“…For one, our sample of chronic, disabled patients may be particularly refractory to the intervention. Furthermore, we excluded patients with a history of traumatic brain injury Griffin et al 2003). Similarly, elderly schizophrenic patients with comorbid dementia would be another patient group where procholinergic agents would be a rational choice.…”

Call for an Integrative and Multi-Disciplinary Approach to Traumatic Brain Injury (TBI)

“…4) Neurotransmitter systems and TBI a) Dysregulation of glutamatergic, dopaminergic, and cholinergic systems. Given the frontal-temporal pathophysiology of TBI, with particular vulnerability of the basal ganglia, amygdala-hippocampal-fornix formation, and hypothalamic-pituitary axis, as well as, central midline structures, including pontine tegmentum, periaqueductal gray, substantia nigra and thalamus, it is not surprising that dysregulation in the glutamatergic, dopaminergic, and cholinergic systems have been implicated with TBI (Griffin, van Reekum, & Masanic, 2003;Wheaton, Mathias, & Vink, 2009;Writer & Schillerstein, 2009). Traditionally, research in recovery of function after TBI has focused on preventing cellular events related to brain trauma, including blocking glutamate induced excitotoxicity, inhibiting apoptosis and reducing oxidative stress, with the premise that sparing neuronal cell death and axonal damage would result in improved functional outcome.…”

“…The psychostimulant, dextroamphetamine, may also have the added benefit of reducing the variability in performance in tasks of attention and working memory (Hornstein, Lennihan, Seliger, Lichtman, & Schroeder, 1996), but the studies at this time are limited. Cholinesterase inhibitors, initially developed in treating dementia, as donepezil and physostigmine, have been useful in treating the memory deficits and improving attention following TBI (Cardenas et al, 1994;Griffin et al, 2003;Taverni, Seliger, & Lichtman, 1998;Zhang et al, 2004). Other drugs in this pharmacological class as, rivastigmine and galantamine, as well as, other drugs used in treating dementia, as the NMDA antagonist, memantine, need to be more systematically studied in future studies.…”

Cognition-Enhancing Effects of Donepezil in Traumatic Brain Injury

“…Administration of acetylcholine precursors to patients with TBI improves post-traumatic amnesia [9], as well as attention and memory performance [10, 11]. However, despite their potential interest for TBI, the clinical use of such agents is limited by their short half-life and side effects.…”

“…Central acetylcholinesterase (AchE) inhibitors constitute a different class of drugs which increase synaptic acetylcholine in the brain and is accepted as relatively safe and effective in some neurodegenerative diseases [12]. For instance, they were shown to enhance cognition and improve global functioning in mild to moderate Alzheimer’s patients [13] and also to act on behavioural disorders including apathy [9]. Accordingly, it has been suggested that behavioural deficits common to other disorders associated with cholinergic loss, such as TBI, may also be treatable with AchE inhibitors [14].…”