(Proposal) How does a patient suddenly wake up after 3 years of being in vegetative state with the effect of a sleeping pill?

Why is this research proposal critical?

After different insults to the brain, including trauma, stroke etc., the patients can be diagnosed with disorders of consciousness such as coma, vegetative state (now called unresponsive wakefulness syndrome, UWS), or minimally conscious state. In 2000, a patient who had been in UWS for 3 years suddenly woke up and communicated with his family for 15 minutes after administration of a drug called Zolpidem (R. P. Clauss, Güldenpfennig, Nel, Sathekge, & Venkannagari, 2000). After this case report, several other studies were able to reproduce similar effects using Zolpidem in patients with disorders of consciousness (%5-7) (Whyte & Myers,2009).

Zolpidem is a hypnotic drug, most commonly used for sleep induction in people experiencing sleep related problems due to its low dependency risk profile compared to other sleeping pills. Paradoxical effects such as arousal, increased attention, increased alertness, etc. have been also reported in the general population. However, currently, the literature is lacking prevalence studies regarding Zolpidem use and its paradoxical responses in people who take it.
Understanding the prevalence of Zolpidem use and the paradoxical response to the drug will pave the way for future genetic research and machine learning algorithms to profile the paradoxical responders so that physicians can decide which disorders of consciousness patients can possibly benefit from treatment with Zolpidem. This is of very critical importance since this will have huge impact on patients’ quality of life as well as end-of-life decisions the caregivers are faced to make every day. On the other hand, this research will shed light on theories which try to understand the mechanism behind recovery of consciousness, such as ‘mesocircuit hypothesis’ (Nicholas D. Schiff, 2010a).

We will use a longitudinal study design with 2 surveys for our research questions.
The first survey will assess the prevalence of Zolpidem use in the general population, and thus will serve as a screening survey, asking basic demographical questions (age, sex, country of residence, job, education, etc.) and in a couple complementary questions whether the participants have used Zolpidem or not (1-2minutes).

Those participants who took Zolpidem will be followed up with a more detailed survey (8 minutes) asking about their experience with Zolpidem.

The data collected will be analyzed to 1)calculate the prevalence of Zolpidem use, 2) calculate the prevalence of paradoxical response to Zolpidem, 3)compare the doses to see which ones elicit paradoxical responses, 4)look for associations between the reason for Zolpidem use and the paradoxical response, 5)calculate how prevalent each different kind of paradoxical responses are, 6) look whether the paradoxical responses are more prevalent in certain age groups, 7)whether there are any associations between participants’ neuropsychiatric medical and drug use history and their response to Zolpidem.

Sample size and study costs
We completed a pilot study on Profilic this year to assess the feasibility of our study design and research question to be applied through a longitudinal study approach on the platform and improved our study design according to feedbacks gathered during the pilot studies until we got reliable results. Also, this gave us insight about our target sample size for our actual study, since there are no prevalence studies available regarding the use of Zolpidem and its paradoxical effects in the general population. We used the methodology presented by Arya et al. in 2012 to calculate our sample size.
1st survey target population size: 20,000
Survey duration: 1 minute
Total cost: £3,466.67
2nd survey estimated population: 800
Survey duration: 8 minutes
Total cost: £1,066.67

The pre-registration of our study will be shortly available on AsPredicted.org under the title ‘Paradoxical response to Zolpidem in general population: a prevalence study’.
The findings, study materials, analysis code and data will be openly available at Open Science Foundation website.


Arya R, Antonisamy B, Kumar S. Sample size estimation in prevalence studies. Indian J Pediatr. 2012 Nov;79(11):1482-8. doi: 10.1007/s12098-012-0763-3. Epub 2012 May 6. PMID: 22562262.

Clauss, R. P., Güldenpfennig, W. M., Nel, H. W., Sathekge, M. M., & Venkannagari, R. R. (2000).
Extraordinary arousal from semi-comatose state on zolpidem. South African Medical Journal, 90(1), 68–72.

Schiff, Nicholas D. (2010a). Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends in Neurosciences, 33(1), 1–9. Redirecting

Whyte, J., & Myers, R. (2009). Incidence of clinically significant responses to zolpidem among patients withdisorders of consciousness: A preliminary placebo controlled trial. American Journal of Physical
Medicine and Rehabilitation, 88(5), 410–418. https://doi.org/10.1097/PHM.0b013e3181a0e3a0