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In 2005 two patients were presented at the 9^th European Federation of Neurological Societies Congress in Athens, Greece (4). The first patient was a male 54 year old decorator, two years after a left temporo-parietal haemorrhage with impaired reading, expressive language, verbal comprehension and object recognition. An impaired auditory brainstem response (ABR) in both ears improved one hour after zolpidem. Mood, memory and cognitive function also improved for the duration of drug action of four hours. Decreased frontal and thalamic cerebral blood flow normalised on Brain SPECT.

The second patient was a 56 year old male retired bank manager with impaired speech comprehension 15 months after left temporo-parietal infarction. He lip-read and read subtitles to follow TV programmes. He was moody, with poor memory and had difficulty coping with his children. On zolpidem, he could cope and was able to understand what was said on TV. A grossly abnormal baseline ABR improved after zolpidem. Neuropschycometry showed cognitive, mood and memory improvement for the duration of drug action. Decreased left temporal cerebral blood flow normalised on brain SPECT. In a follow up study in 2010, the patient showed improvements on MEG activity in affected brain regions following zolpidem (5).

 

In a pilot study by Nyakale et al, brain SPECT changes were correlated with Barthel Index scores in patients on zolpidem treatment after stroke (6). 12 Patients after stroke, with confirmed post-ischaemic brain damage and a Barthel Index of less than 100/100 were selected for the study. All were prescribed zolpidem by their treating doctors. Two brain SPECT scans were completed using the radiopharmaceutical 99mTc HMPAO (Hydroxy methyl propylamine oxime) the first before starting 10mg daily zolpidem treatment and the second 1 hour after 10mg zolpidem application, within two weeks of starting treatment. A follow up Barthel Index was done at 6 months. There was significant improvement in brain perfusion and in the clinical condition of patients after treatment with zolpidem. The overall improvement on the Barthel Index score was significant (p=0097), improving from a mean of 60.8 (SD 30.88) to a mean of 74.58 (SD 29.88). 8/12 patients improved on Brain SPECT scan and 4/12 did not. The mean score of the 8/12 SPECT improvers increased from 65 (SD 28.3) to 83 (SD19.8) (p=0.0295) while the score of the 4/12 SPECT non improvers changed only slightly, from 52.5 (SD 38.6) to 56.3 (SD 41.1), p = 0.1615. 

 

Zolpidem’s proposed  mode of action is the modulation of ‘abnormal’ GABA receptors that are responsible for Brain suppression and dormancy after brain damage, also called the neurodormant state (7). The neurodormant state is the manifestation of a re-modulated GABA receptor status that occurs in areas of the brain after injury. A previous study has shown that certain types of brain suppression are associated with an altered composition of GABA(A) receptor subunits (8). In another study, this suppression was associated with reorganisation of GABA mediation in the cerebellum (9). With normal or borderline GABA levels, GABA receptors remain functioning normally, but in depleted regions such receptors presumably undergo molecular modifications or changes in abundance, possibly due to gene expression, as found in other ischaemic brain conditions (10,11).

 

For further information on neurodormancy, please click on -Brain dormancy theory- in the main menu. 

 

  

References

1        Cohen L, Chaaban B, Haberl M-O. Transient improvement of aphasia with zolpidem. N Engl J Med  2004; 350(9): 949-950.

2        Clauss RP, Nel HW. The effect of zolpidem on brain injury and diaschisis as detected by 99mTc HMPAO Brain SPECT in humans. Arzneim.-Forsch./Drug Res 2004; 54(10): 641- 646.

3        Ginsberg DL. Zolpidem treatment of Chronic Aphasia. Primary Psychiatry 2004, 11(4) 12-17.

4        Clauss RP, Jayarajan V, Nel HW, Saunders E. Evidence for zolpidem efficacy in auditory impairment. 9^th European Federation of Neurological Societies Congress

5        Hall SD,  Yamawaki N, Fisher AE, Clauss RP, Woodhall GL, Stanford IM. Desynchronization of pathological low-frequency brain activity by the hypnotic drug zolpidem. Nature Precedings 2008; hdl:10101/npre.2008.1966.1     

6        Nyakale NE, Clauss RP, Nel HW, Sathekge MM. Clinical and Brain SPECT Changes in Stroke Patients on Zolpidem Therapy. Journal of Functional Neurology, Rehabilitation, and Ergonomics 2011, 1(3).

7        Clauss RP, Nel HW. Drug induced arousal from the permanent vegetative state.NeuroRehabilitation 2006; 21 (1): 1-6.

8        Niimura K, Chugani DC, Muzik O and Chugani HT, Cerebellar reorganization following cortical injury in humans: effects of lesion size and age, Neurology.1999, 10: 792-797.

9        Witte OW and Stoll G, Delayed and remote effects of focal cortical infarctions:secondary damage and reactive plasticity, Adv Neurol. 1997, 73: 207-227.

10      Brinton RD, Thompson RF, Foy MR, Baudy M, Wang JM, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J. Progesterone receptors: Form and function in brain. Frontiers in Neuroendocrinology 2008; 29: 313- 39.

11    Aviles-Reyes RX, Angelo MF, Villarreal A, Rios H, Lazarowski A and Ramos  AJ, Intermittent hypoxia during sleep induces reactive gliosis and limited neuronal death in rats: Implications for sleep apnea, J Neurochem 2010, 112: 854-69.