Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs?

Disorders of consciousness (DOC) include coma, vegetative state (VS) and minimally conscious state (MCS). Coma is a condition of unarousability with a complete absence of wakefulness and awareness, whereas VS is characterized by a lack of awareness despite a preserved wakefulness. Patients in coma are unconscious because they lack both wakefulness and awareness. Patients in a VS are unconscious because, although they are wakeful, they lack awareness. Patients in a MCS show minimal but definite behavioural evidence of self and environmental awareness. Coma results from diffuse bilateral hemispheric lesions or selective damage to the ascending reticular system (which is functionally connected to the cerebral cortex by intralaminar thalamic nuclei). VS is a syndrome that is considered to be the result of a disconnection of different cortical networks rather than a dysfunction of a single area or a global reduction in cortical metabolism. As revealed by functional imaging studies, clinical recovery is often associated with a functional restoration of cortico-thalamo-cortical connections. Depending on the amount of network restored, patients may regain full consciousness or remain in a MCS. Molecular and neural mediators may indirectly contribute to the above restoration processes owing to their role in the phenomenon of neural synaptic plasticity. Therefore, there is growing interest in the possible effects of drugs that act at the level of the CNS in promoting emergence from DOC. Sporadic cases of dramatic recovery from DOC after the administration of various pharmacological agents, such as baclofen, zolpidem and amantadine, have been recently supported by intriguing scientific observations. Analysis of the reported cases of recovery, with particular attention paid to the condition of the patients and to the association of their improvement with the start of drug administration, suggests that these treatments might have promoted the clinical improvement of some patients. These drugs are from various and diverging classes, but can be grouped into two main categories, CNS stimulants and CNS depressants. Some of these treatments seem to directly encourage a consciousness restoration, while others play a more determinant role in improving cognitive domains, especially in patients with residual cognitive impairment, than in the field of consciousness. Given the great interest recently generated in the scientific community by the increasing number of papers addressing this issue, further investigation of the above treatments, with particular attention paid to their mechanisms of action, the neurotransmitters involved and their effects on cortico-thalamo-cortical circuitry, is needed.