ZOLPIDEM: THE "ECCITATORY INHIBITOR". Recovery in Disorder of Consciousness

Date: 11/12/2013


For many years it was assumed by clinicians and researchers that patients suffering from prolonged disorders of consciousness (DOC, i.e., the vegetative and minimally conscious states) were not candidates for any meaningful treatments. In recent years, however, glimmers of optimism have begun to emerge, fuelled by several interrelated lines of research.

Can Zolpidem wake people from coma

Disorders of consciousness (DOC) include coma, vegetative state (VS) and minimally conscious state (MCS). 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), which means a complete absence of wakefulness and awareness, whereas VS is characterized by a lack of awareness despite a preserved wakefulness. VS, in fact, 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, which needs long time intervals (months, years, and sometimes, decades) 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. In biochemical terms, the recovery of consciousness that is seen in some patients after therapeutic interventions could be due to the action of some pharmacological agents on functions of those neurotransmitters playing a decisive role in neural synaptic plasticity and functional connectivity of consciousness networks, even if the underlying mechanisms accounting for the wide variance in recovery patterns and in the efficacy of therapeutic interventions are not still well understood.
In recent years, there has been increasing interest in the scientific community with regard to the possible effects of pharmacological agents that act on the GABA system, showing an intriguing apparently paradoxical effect.

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

In 1999 it was first observed that a person in a coma appeared to respond to Zolpidem, the most used GABA agonist, with increased consciousness. Researchers report it was observed that 15 minutes after application of the drug the patient awoke from his semi-comatose condition and remained awake for the next 3-4 hours. When drug action subsided he returned to his semi-comatose state.

Extraordinary arausal from semi-comatose state on Zolpidem. A case report


Zolpidem is a GABA agonist, which means it activates the neurotransmitter GABA (gamma-amino butyric acid). GABA is the primary inhibitory neurotransmitter in the brain, so it decreases or inhibits neuronal firing. For this reason it is commonly use to treat seizures or abnormal nerve pain, by decreasing the activity of hyperactive or hyper excitable neurons. How, then, could it increase brain activity ?

Zolpidem is a non-benzodiazepine drug belonging to the imidazopiridine class, chemically distinct from sedatives such as barbiturates, antihistamines, benzodiazepines and cyclopyrrolones.

It is absorbed quickly, and that makes it very suitable to induce sleep rapidly. It has a short half life of 2.4 hours with no active metabolite; it does not accumulate with following administering.
In the liver, the drug is oxidised and hydroxylated in order to inactive metabolites that are eliminated primarily through renal excretion.

Zolpidem perform on GABA recptors ; GABA systems involve various receptors and subtypes. The GABA (A) receptor chloride channel macromolecular complex is implicated in sedative, anticonvulsant, anxiolytic and myorelaxant drug properties. Its major modulating site is located on the alpha sub-unit, on the omega receptor and there are at least three subtypes. Though benzodiazepines bind non-selectively to these, zolpidem binds preferentially to omega 1 receptors, which are situated in the globus pallidus area of the brain.


Incidence of clinically significant responses to Zolpidem among patients with disorders of consciousness has been shown in a preliminary placebo controlled trial by Whyte and Myers (Evidence for Zolpidem efficacy in brain damage, SA Fam Pract 2005;47(3): 49-50): in their study, in has been demonstrated the evidence for the efficacy of Zolpidem in a wide range of brain pathology. At the end of the observations, of fifteen patients, there resulted in one clinically significant response to Zolpidem; patient went from vegetative state (as a result of brain injury sustained from a motor vehicle accident four years prior to the study) to minimally conscious state.
Thanks to the neuro-imaging techniques, it was clearly shown the astounding findings
in this patient, such as the return to his semi-comatose state after the lapse of drug action and the subsequent reawakening from semi-coma after renewed drug application, and also the findings of improved perfusion in previously supposed dead brain tissue.

Figure 1: Changes in cerebral metabolism associated with zolpidem administration in minimally conscious state as a result of severe brain injury. In the off drug state (top panels) marked anterior forebrain hypo metabolism is noted bilaterally in frontal/prefrontal cortex, thalami and striatum. Following zolpidem administration (bottom panels) broad increases of metabolic rates are observed in these regions Similar observations in another zolpidem responsive patient link increases of cerebral metabolism in the frontal cortex, striatum and thalamus to changes in the shape of the spectral content of the EEG (removing abnormal low frequency component) and the coherence architecture (reducing marked low frequency coherence in the off drug state).

Evidence for Zolpidem efficacy in brain damage

Sedative to cure somnolence. Awakening response to zolpidem from a comatose state

Trial studies are conducted comparing zolpidem and placebo treatment in injured patients. Results include sensitive assessment of brain structure and function. Brain structural measures are obtained including based morphometric measures of focal and diffuse atrophy, and diffusion tensor imaging measures of white matter integrity. Brain function will be assessed with both functional MRI and event related potentials. Specifically, researchers search patterns of resting perfusion via arterial spin labelling, and regional activation in response to passive language stimulation via BOLD MRI imaging.

Zolpidem treatment of disorders of consciousness


As far the improved functionality is concerned, it is important underline that forebrain dysfunction causing brain injury may arise as a result of at least three general mechanisms:

  • widespread death of forebrain neurons (i.e. sufficient to produce brain death or permanent VS),
  • widespread de-afferentation and disconnection of neurons,
  • “circuit”-level functional disturbances due to the loss of these neuronal connections

The first one is clearly irreversible; late structural alterations in the brain may arise, altering the effects of the second mechanism. The third mechanism is likely caused by global decreases of excitatory neurotransmission producing overall changes in cerebral background activity levels (as produced by anaesthesia or direct effects on the function of certain cell types; e.g. hypoxia). It may represent the common denominator in disturbances of consciousness in severe brain injuries. The primary result of disturbances of this network may be to effectively produce a broad decrease in background synaptic activity and excitatory neurotransmission.

Schiff, in his report ( Recovery of consciousness after brain injury: a mesocircuit hypothesis ), has proposed a "mesocircuit hypothesis" to explain the paradoxical arousing effects of GABAergic agents on patients with disorders of consciousness characterized by circuit - level disturbance.

It is known that at a neuronal subpopulation level, the medium spiny neurons (MSN) of the striatum have a key role in maintaining activity in the anterior forebrain through their inhibitory projections to the globus pallidus interna, which, in turn, inhibits the central thalamus. Activation of MSN projections results in a disinhibition of central thalamic neurons, re-establishes the outflow of thalamocortical transmission and likely promotes a rebound of high frequency thalamocortical activity.

The thalamocortical projections from the central thalamus strongly innervate the frontal cortex and have in some instances a joint thalamostriatal projection back to the MSNs; recent studies demonstrate that thalamocortical projections to cortex have a stronger impact on driving excitation within the cortex than cortico-cortical projections; down-regulation of thalamic output, moreover, can be expected to have broad effects across cortical regions. It means that loss of excitatory inputs from the frontal cortex to the median spiny neurons in the striatum diminishes normal striatal inhibition of the globus pallidus.

Neurons from the central thalamus (both central lateral nucleus and parafasicularis nucleus) strongly project to the MSNs and diffusely innervate the striatum. These thalamostriatal projections use glutamate transmitter proteins with a high probability of synaptic release; it may have a strong role in modulating background activity in the striatum. The MSNs have a ‘high threshold’ UP-state that keeps them below their firing threshold unless sufficient levels of dopamine neuromodulation are present and there is a high level of spontaneous background synaptic activity arising from excitatory corticostriatal and thalamostriatal inputs.

Thus, diffuse brain injuries may lead to a sharp reduction of MSN output: a diffuse deafferentation produces withdrawal of both direct excitatory striatal projections from the central thalamus and down-regulation of the frontocortical regions that provide the main corticostriatal input.

The mesocircuit model organizes and rationalizes recent observations of the response of severely brain-injured subjects to pharmacological and electrophysiological interventions as well as some aspects of normal brain function.

The primary implication is that frontocortico-striatopallidal-thalamocortical loop frontal systems are selectively vulnerable at the ‘circuit’ level in many types of multi-focal brain injury. This accounts for the observations that selective metabolic depression of the anterior forebrain specifically grades with severity of behavioural impairment following diffuse axonal injury. (In addition, the well-known response to dopaminergic agents of severely brain-injured patients with markedly slowed behavioural response is consistent with the mesocircuit model. Dopaminergic facilitation of the output of the MSNs or direct modulation of mesial frontal cortical neurons would explain the restoration of anterior forebrain activity within the loop connections of the frontal cortex, striatum, pallidum and central thalamus).

Of particular interest, the mesocircuit model offers an explanation of a surprising and puzzlingly paradoxical phenomenon recently described about the use of Zolpidem in improving alertness and behavioural responsiveness in some severely brain injured patients. Consonant with the model of Schiff, it was proposed the following mechanism for this paradoxical response: under normal circumstances, the MSN's dis-inhibit the central thalamus via the GPi (globus pallidus inhibition).Thus, when MSN activity is reduced as a consequence of brain injury, central thalamic activity is also reduced. Since zolpidem directly inhibits the GPi, it can substitute for the normal inhibition of the GPi from MSN's, and thus permit a more normal level of central thalamic activity. The GABA-A alpha-1 subunit is expressed in large quantities in the globus pallidus interna and experimental studies support this mechanism of action. Of note, the MSNs are uniquely vulnerable to cellular dysfunction after hypoxia and several of the reported cases of paradoxical response have followed hypoxic-ischemic injuries


Figura 2. If normal striatal inhibition of the globus pallidus internal is lost, the globus pallidus internal tonically inhibits the thalamus. Zolpidem may bind to GABAA1 receptors in the globus pallidus interna, blocking its inhibitory inputs to the thalamus. As a result, excitatory cortical inputs from the thalamus are restored, causing paradoxical excitation.


The benefit of zolpidem in brain injured patients is transient and it occurs for the duration of drug action only. However, after first application and proof of efficacy in a controlled environment, it can be used daily for many years in brain injured patients, without adverse effects in our experience. Dosages can be reduced without compromising the effect of the drug on brain damage. The drug remains potent even after many years of constant treatment.

These recent research findings appropriately encourage further treatment studies, but it is unrealistic to hope that any treatment will be of benefit to all patients with DOC. In progressive disease however, as in progressive supranuclear palsy, effects may wane. This is probably due to the progressive nature of the disease with less and less dormant tissue available for reversal as the disease progresses. Zolpidem reverses symptoms due to brain dormancy but does not change those due to necrotic or scarred brain tissue.

A recent study (by Du et al.) showed good efficacy of zolpidem in VS patients after brain injury, especially in those whose brain damage was in non-brainstem areas. The authors suggested that slight damage to non-brainstem areas may lead to a condition of ‘brain dormancy’ rather than cellular apoptosis. Conversely, severe brainstem injury may lead to an apoptotic process and cell death, resulting in irreversible disruption of important functional areas. This implies the presence of neuronal systems that are dysfunctional but are not permanently destroyed and thus are subject to pharmacologic reactivation. This could be the reason why zolpidem is not effective in all patients with DOCs, as seen in some cases. Further placebo-controlled studies should be planned in order to evaluate the effects of zolpidem on ‘neurodormancy’ in larger groups of patients, taking into account the type and severity of brain damage and its cause.

Recovery of consciousness after brain injury: a mesocircuit hypothesis


In addition to accounting for the paradoxical response to zolpidem, the mesocircuit model provides a plausible framework for related observations in normal subjects. Of note, the model provides an explanation for the observation of the most robust changes in regional cerebral blood flow during the transitions during the sleep-wake cycle are in the striatum. Specifically, increases during the transition from slow wave sleep to rapid eye movement sleep (REM) and decreases in the transition from wakefulness to non-REM sleep. Similar recovery patterns in metabolic activity of the anterior forebrain are seen during early wakefulness as sleep inertia dissipates. The model suggesting interesting links with unusual behaviours (somnambulism, amnesic hyperphagia—nocturnal binge eating without memory trace) arising during sleep specifically associated zolpidem treatment. Finally, this mesocircuit model can also account for the common finding of the early selective metabolic down regulation in the mesial frontal and thalamic systems with different anaesthetics and variety of specific changes across the induction and recovery from general anaesthesia.

Recovery of consciousness after brain injury: a mesocircuit hypothesis


Understanding the circuit mechanisms associated with recovery of consciousness following severe brain injuries will open many directions for future researches in order to develop new diagnostic tools, based on neuroimaging and electrophysiological measurements, to guide longitudinal assessments of brain function.
Using drugs like zolpidem is only one approach. Researchers are also looking into implantable electrodes that can stimulate key brain regions, such as those that are normally activating and necessary for the maintenance of the waking state.

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