Zolpidem withdrawal induced uncoupling of GABA(A) receptors in vitro associated with altered GABA(A) receptor subunit mRNA expression.
Jembrek Maja Jazvinšćak,Vlainić Josipa,Šuran Jelena
Acta neurobiologiae experimentalis
Hypnotic zolpidem produces its effects via the benzodiazepine binding site in α1-containing GABAA receptors. The aim of the study was to assess the influence of duration of zolpidem treatment and its withdrawal, as well as the role of alpha1-containing GABAA receptors in the development of physical dependence and tolerance. Namely, recombinant receptors can be used to characterize mechanisms involved in different processes in the brain and to delineate the contribution of specific receptor subtypes. To address the influence of chronic zolpidem treatment we exposed HEK293 cells stably expressing alpha1beta2gamma2S recombinant GABAA receptors for seven consecutive days, while withdrawal periods lasted for 24, 48, 72 and 96 hours. Using radioligand binding studies we determined that chronic zolpidem treatment did not induce changes in either GABAA receptor number or in the expression of subunit mRNAs. We observed the enhancement of binding sites and upregulated expression of subunit mRNAs only following 96-hour withdrawal. Moreover, zolpidem treatment and its withdrawal (All time points) induced functional uncoupling between GABA and benzodiazepine binding sites in the GABAA receptor complex. Accordingly, it might be assumed that zolpidem withdrawal-induced uncoupling of GABAA receptors is associated with altered GABAA receptor subunit mRNA expression. The results presented here provide an insight into molecular and cellular mechanisms probably underlying adaptive changes of GABAA receptor function in response to chronic usage and withdrawal of zolpidem and perhaps the observed molecular changes could be linked to the tolerance and dependence produced upon prolonged treatment with other GABAergic drugs.
Extraordinary arousal from semi-comatose state on zolpidem. A case report.
Clauss R P,Güldenpfennig W M,Nel H W,Sathekge M M,Venkannagari R R
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde
A young semi-comatose male patient was investigated using 99mTc hexamethyl-propylene amine oxime (99mTc HMPAO) brain single photon emission computed tomography (SPECT) before and after administration of the gamma-aminobutyric acid (GABA) agonist zolpidem. 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. Brain SPECT before drug application showed large hypo-active areas in certain parts of the brain. Brain SPECT after drug application showed a generalised cortical activation relative to the cerebellum and a marked and amplified activation of the areas that were hypo-active before drug application.
The Effectiveness of Zolpidem for the Treatment of Disorders of Consciousness.
Tucker Calvin,Sandhu Kirsten
Approximately, five million people in the United States live with the residual effects of brain injury. The causes of acquired brain injury can be categorized as traumatic brain injury or non-traumatic brain injury. There are currently no treatments shown to consistently enhance recovery from disorders of consciousness (DOC). Sporadic recovery from DOC after the administration of various pharmacological agents has been described in several case reports. Increase in arousal after zolpidem administration is seen in patients with vegetative state or minimally conscious state for treatment of restlessness and disturbances of their sleep-wake cycle. The use of zolpidem could be reasonable in select patients with neurologic injury but promising integrity of brain structures, such as intact deep and superficial gray matter structures and white matter connections.
Functional and molecular plasticity of γ and α1 GABA receptor subunits in the dorsal motor nucleus of the vagus after experimentally induced diabetes.
Boychuk Carie R,Smith Katalin C,Smith Bret N
Journal of neurophysiology
Chronic experimentally induced hyperglycemia augments subunit-specific γ-aminobutyric acid A (GABA) receptor-mediated inhibition of parasympathetic preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV). However, the contribution of α1 or γ GABA receptor subunits, which are ubiquitously expressed on central nervous system neurons, to this elevation in inhibitory tone have not been determined. This study investigated the effect of chronic hyperglycemia/hypoinsulinemia on α1- and γ-subunit-specific GABA receptor-mediated inhibition using electrophysiological recordings in vitro and quantitative RT-PCR. DMV neurons from streptozotocin-treated mice demonstrated enhancement of both phasic and tonic inhibitory currents in response to application of the α1-subunit-selective GABA receptor-positive allosteric modulator zolpidem. Responses to low concentrations of the GABA receptor antagonist gabazine suggested an additional increased contribution of γ-subunit-containing receptors to tonic currents in DMV neurons. Consistent with the functional elevation in α1- and γ-subunit-dependent activity, transcription of both the α1- and γ2-subunits was increased in the dorsal vagal complex of streptozotocin-treated mice. Overall, these findings suggest an increased sensitivity to both zolpidem and gabazine after several days of hyperglycemia/hypoinsulinemia, which could contribute to altered parasympathetic output from DMV neurons in diabetes. Glutamate and GABA signaling in the dorsal vagal complex is elevated after several days of chronic hyperglycemia in a mouse model of type 1 diabetes. We report persistently enhanced GABA receptor-mediated responses to the somnolescent zolpidem in preganglionic vagal motor neurons. These results imply a broader impact of chronic hyperglycemia on central vagal function than previously appreciated and reinforce the hypothesis that diabetes effects in the brain can impact regulation of metabolic homeostasis.
Zolpidem-Induced Arousal by Paradoxical GABAergic Stimulation: A Case Report With F-18 Flumazenil Positron Emission Tomography and Single Photon Emission Computed Tomography Study.
Kim Changjae,Kwon Bum Sun,Nam Ki Yeun,Park Jin Woo,Lee Ho Jun
Annals of rehabilitation medicine
Zolpidem is a non-benzodiazepine drug that has selectivity for the gamma-aminobutyric acid (GABA) receptors. We experienced paradoxical effect of zolpidem in a 48-year-old male patient with hypoxic-ischemic brain injury after cardiac arrest. The patient was in stupor and could not communicate. His Glasgow Coma Scale (GCS) was E2M4V2 and Rancho Los Amigos (RLA) was grade III to IV. Zolpidem was prescribed to induce sedation but paradoxically, he became alert (GCS 15, RLA VII) and was able to communicate. The arousal lasted for 2 hours repeatedly following each administration of the medication. While he was alert, electroencephalogram showed the reversal of slow wave into beta range fast activity and F-18 flumazenil positron emission tomography (PET) showed increased GABAergic receptor activity in both frontoparietotemporal cortices. Single photon emission computed tomography (SPECT) also showed increased cerebral perfusion and reversal of cerebellar diaschisis.
Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons.
Prokic Emma J,Weston Cathryn,Yamawaki Naoki,Hall Stephen D,Jones Roland S G,Stanford Ian M,Ladds Graham,Woodhall Gavin L
Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15-30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage-clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states.
Zolpidem Activation of Alpha 1-Containing GABA Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons.
Neumann Elena,Rudolph Uwe,Knutson Daniel E,Li Guanguan,Cook James M,Hentschke Harald,Antkowiak Bernd,Drexler Berthold
Frontiers in pharmacology
High frequency neuronal activity in the cerebral cortex can be induced by noxious stimulation during surgery, brain injury or poisoning. In this scenario, it is essential to block cortical hyperactivity to protect the brain against damage, e.g., by using drugs that act as positive allosteric modulators at GABA receptors. Yet, cortical neurons express multiple, functionally distinct GABA receptor subtypes. Currently there is a lack of knowledge which GABA receptor subtypes would be a good pharmacological target to reduce extensive cortical activity. Spontaneous action potential activity was monitored by performing extracellular recordings from organotypic neocortical slice cultures of wild type and GABAR-α1(H101R) mutant mice. Phases of high neuronal activity were characterized using peri-event time histograms. Drug effects on within-up state firing rates were quantified via Hedges' g. We quantified the effects of zolpidem, a positive modulator of GABA receptors harboring α1-subunits, and the experimental benzodiazepine SH-053-2'F-S-CH3, which preferably acts at α2/3/5- but spares α1-subunits. Both agents decreased spontaneous action potential activity but altered the firing patterns in different ways. Zolpidem reduced action potential firing during highly active network states. This action was abolished by flumazenil, suggesting that it was mediated by benzodiazepine-sensitive GABA receptors. SH-053-2'F-S-CH3 also attenuated neuronal activity, but unlike zolpidem, failed to reduce high frequency firing. To confirm that zolpidem actions were indeed mediated via α1-dependent actions, it was evaluated in slices from wild type and α(H101R) knock-in mice. Inhibition of high frequency action potential firing was observed in slices from wild type but not mutant mice. Our results suggest that during episodes of scarce and high neuronal activity action potential firing of cortical neurons is controlled by different GABA receptor subtypes. Exaggerated firing of cortical neurons is reduced by positive modulation of α1-, but not α2/3/5-subunit containing GABA receptors.
An analysis of the effects of using Zolpidem and an innovative multimodal interdisciplinary team approach in prolonged disorders of consciousness (PDOC).
Delargy Mark,O'Connor Rebecca,McCann Alison,Galligan Irene,Cronin Heather,Gray Dee,O'Toole Caoimhe
Zolpidem has been used with mixed effects in patients presenting with Prolonged Disorders of Consciousness (PDOC). This single case report describes an interdisciplinary team (IDT) protocol combined with Zolpidem 10 mg in a single case of a patient in PDOC. 'Emily', a 44-year-old lady was admitted to a rehabilitation unit in Ireland one year post onset of subarachnoid haemorrhage. Standardized assessments diagnosed her as being in a minimally conscious state (MCS). An IDT protocol was devised to stimulate and record responses to sensory and pharmacological stimuli. The protocol was applied pre and post administration of Zolpidem 10 mg. Across standardized measures of awareness, improved results post-Zolpidem were recorded. Spontaneous, appropriate verbalization was the most significant change observed 30 min after administration of Zolpidem 10 mg. This ceased after approximately 2 h with Emily reverting to a non-verbal state. The combined effect of Zolpidem and the IDT protocol applied over an eight-week period resulted in durable functional and communicative gains for Emily, inferring neuro-plasticity. This report highlights the impact of a combined approach of intensive IDT intervention in conjunction with Zolpidem. The use of Zolpidem with this patient population warrants further investigation.
The effects of zolpidem in obstructive sleep apnea - An open-label pilot study.
Carberry Jayne C,Grunstein Ronald R,Eckert Danny J
Journal of sleep research
New knowledge on hypnotics and their effects on the phenotypic causes of obstructive sleep apnea indicate that zolpidem has therapeutic potential for certain patients. Specifically, zolpidem increases the threshold for arousal threshold and pharyngeal dilator muscle responsiveness. However, the effects of a standard dose of zolpidem (10 mg) on obstructive sleep apnea severity and symptoms have not been investigated. In an open-label pilot study, 12 unselected people with obstructive sleep apnea were recruited following a diagnostic in-laboratory sleep study. Participants then returned for a single-night sleep study in which 10 mg of zolpidem was given just prior to sleep. Tolerability, next-day sleepiness and the effects of zolpidem on polysomnography variables were assessed. Zolpidem was well tolerated and significantly improved the sleep efficiency compared with the no-drug night (77 ± 12% versus 84 ± 9%, p = 0.005). Individual responses on obstructive sleep apnea severity to zolpidem in this unselected obstructive sleep apnea patient population were variable with no overall systematic difference in apnea-hypopnea index (29 ± 18.2 events per hr versus 33 ± 28 events per hr, p = 0.45) or other key respiratory parameters (e.g. event duration or hypoxemia). Next-day sleepiness assessed via the Karolinska Sleepiness Scale was not different between visits (4 ± 1 versus 4 ± 2, p = 0.85). These findings provide the first insight into the effects of a standard dose of zolpidem in obstructive sleep apnea, and highlight its tolerability and potential to improve sleep quality. The variable effects on obstructive sleep apnea severity observed in this pilot also underscore the need for larger trials that incorporate phenotypic characterisation (e.g. arousal threshold, Pcrit and muscle responsiveness) to understand inter-individual heterogeneity and the therapeutic potential of zolpidem for certain people with obstructive sleep apnea.
Zolpidem and restoration of consciousness.
Whyte John,Rajan Riya,Rosenbaum Amy,Katz Douglas,Kalmar Kathleen,Seel Ron,Greenwald Brian,Zafonte Ross,Demarest David,Brunner Robert,Kaelin Darryl
American journal of physical medicine & rehabilitation
OBJECTIVE:Zolpidem has been reported to cause temporary recovery of consciousness in vegetative and minimally conscious patients, but how often and why this occurs are unknown. The authors aimed to determine the frequency of this phenomenon and whether it can be predicted from demographic and clinical variables. DESIGN:This is a placebo-controlled, double-blind, single-dose, crossover study performed by caregivers and replicated by trained professionals, for naive participants. Four previously identified responders were also studied to further characterize the clinical drug response. RESULTS:Eighty-four participants with traumatic and nontraumatic disorders of consciousness of at least 4 mos' duration were studied. Four "definite responders" were identified, but no demographic or clinical features were predictive of the response. Indicators of a drug response included increased movement, social interaction, command following, attempts at communication, and functional object use; typically lasted 1-2 hrs; and sometimes ended with increased somnolence. Adverse events were more common on zolpidem than placebo, but most were rated as mild. CONCLUSIONS:Approximately 5% (4.8%) of the participants responded to zolpidem, but the responders could not be distinguished in advance from the nonresponders. Future research is needed to understand the mechanism of zolpidem in enhancing consciousness and its potential role in treatment and research.
Residual effects of low-dose sublingual zolpidem on highway driving performance the morning after middle-of-the-night use.
Vermeeren Annemiek,Vuurman Eric F P M,Leufkens Tim R M,Van Leeuwen Cees J,Van Oers Anita C M,Laska Eugene,Rico Salvador,Steinberg Frank,Roth Thomas
STUDY OBJECTIVE:To evaluate next-morning driving performance after middle-of-the-night use of zolpidem 3.5 mg in a buffered sublingual formulation (ZST). DESIGN:Single-center, four-period, randomized, double-blind, placebo-controlled, crossover study. SETTING:Maastricht University, The Netherlands. PARTICIPANTS:Forty healthy volunteers (20 females). INTERVENTIONS:Single dose of ZST administered in the middle of the night at 3 and 4 h before driving, zopiclone 7.5 mg at bedtime 9 h before driving, and placebo. MEASUREMENTS:Performance in a 100-km standardized highway driving test in normal traffic measuring standard deviation of lateral position (SDLP) - an index of weaving. Drug-placebo changes in SDLP > 2.5 cm were considered to reflect clinically relevant driving impairment. RESULT:For ZST, Max McNemar symmetry analyses showed that the proportion of drivers classified as impaired was increased 3 h after dosing (P < 0.012), but not 4 h after dosing. Mean increases in SDLP from placebo, although statistically significant, were small (1.46 cm [P < 0.0001] at 3 h and 0.83 cm [P = 0.0174] at 4 h). The morning after zopiclone, 45% of the drivers were classified as impaired with a mean increase in SDLP of 2.46 cm (P < 0.0001). There were no significant sex differences in effects of ZST and zopiclone. CONCLUSION:Zolpidem 3.5 mg in a buffered sublingual formulation has a minimal risk of impairing driving performance in the morning ≥ 4 hours after middle-of-the night use. When taken 3 hours before driving, the drug may have impairing effects so caution should be exercised if medication is taken other than as indicated. CLINICAL TRIAL INFORMATION:ClinicalTrials.gov Identifier: NCT01106859; Trial Name: Driving Performance After Middle of the Night Administration of 3.5 mg Zolpidem Tartrate Sublingual Tablet; http://clinicaltrials.gov/ct2/show/NCT01106859.
Age-related changes in slow wave activity rise time and NREM sleep EEG with and without zolpidem in healthy young and older adults.
Chinoy Evan D,Frey Danielle J,Kaslovsky Daniel N,Meyer Francois G,Wright Kenneth P
OBJECTIVE:Whether there are age-related changes in slow wave activity (SWA) rise time, a marker of homeostatic sleep drive, is unknown. Additionally, although sleep medication use is highest among older adults, the quantitative electroencephalographic (EEG) profile of the most commonly prescribed sleep medication, zolpidem, in older adults is also unknown. We therefore quantified age-related and regional brain differences in sleep EEG with and without zolpidem. METHODS:Thirteen healthy young adults aged 21.9 ± 2.2 years and 12 healthy older adults aged 67.4 ± 4.2 years participated in a randomized, double-blind, within-subject study that compared placebo to 5 mg zolpidem. RESULTS:Older adults showed a smaller rise in SWA and zolpidem increased age-related differences in SWA rise time such that age differences were observed earlier after latency to persistent sleep. Age-related differences in EEG power differed by brain region. Older, but not young, adults showed zolpidem-dependent reductions in theta and alpha frequencies. Zolpidem decreased stage 1 in older adults and did not alter other age-related sleep architecture parameters. CONCLUSIONS:SWA findings provide additional support for reduced homeostatic sleep drive or reduced ability to respond to sleep drive with age. Consequences of reduced power in theta and alpha frequencies in older adults remain to be elucidated.
Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study.
Perlis Michael,Grandner Michael,Zee Jarcy,Bremer Erin,Whinnery Julia,Barilla Holly,Andalia Priscilla,Gehrman Phil,Morales Knashawn,Thase Michael,Bootzin Richard,Ader Robert
BACKGROUND AND AIM:At present, there is no consensus regarding how to medically manage chronic insomnia in the long term. The unstated standard of practice is for patients to use hypnotics intermittently. The present study aimed to compare a partial reinforcement strategy with nightly and intermittent dosing strategies for its potential as a maintenance therapy. METHODS:A mixed model was used in the study. One between-subjects factor: group (n = 4). One repeated-measures factor: time (12 weekly assessments). A total of 74 subjects with chronic Insomnia were treated with 10 mg zolpidem for 4 weeks. Treatment respondents were randomized to nightly dosing with 10 mg or 5 mg (QHS-10 and QHS-5), intermittent dosing with 10 mg (IDS-10 [3-5 days weekly]), or partial reinforcement dosing with 10 mg (PRS-10 [nightly pill use with 50% active medication and 50% placebos]) for 12 weeks. RESULTS:It was found, in compliant subjects (n = 55), that all four strategies evaluated maintained treatment response over time (ie, prevented or delayed relapse). For the subjects that remained in remission, the subjects in the intermittent dosing group (IDS-10) group exhibited poorer sleep continuity. CONCLUSIONS:While best considered a preliminary study, the present findings suggest that the partial reinforcement strategy may be a viable means toward maintaining treatment gains over time with less active medication.
Clinical correlates of zolpidem-associated complex sleep-related behaviors: age effect.
Chen Cheng-Sheng,Huang Mei-Feng,Hwang Tzung-Jeng,Chen Shao-Tsu,Ko Chih-Hung,Yen Chia-Nan,Chen Tzu-Ting,Su Po-Wen,Yeh Yi-Chun,Lin Jin-Jia,Yen Cheng-Fang
The Journal of clinical psychiatry
OBJECTIVE:Complex sleep-related behaviors (CSBs) are often associated with hypnotic use, especially zolpidem. The age effect on the occurrence of CSBs has not been adequately investigated. This study aimed to investigate and compare the clinical correlates of CSBs between adult and elderly subjects who were taking zolpidem. METHOD:A total of 253 adults (aged 20-55 years) and 64 elderly subjects (aged ≥ 65 years) who were administered zolpidem for at least 3 months were enrolled from psychiatric outpatient clinics from June 2011 to May 2012. The sociodemographic characteristics of the participants, the dose of zolpidem, and the occurrence of CSBs were collected. Logistic regression analysis was used to examine the clinical correlates of CSBs. RESULTS:In total, there were 62 members of the adult group (24.5%) and 11 elderly subjects (17.2%) with CSBs; however, the difference did not reach statistical significance. Logistic regression analysis showed that there was a main effect of zolpidem dose (≥ 10 mg; OR = 2.82, P = .038) and alcohol use (OR = 2.05, P = .026), but not sex or age group. There were interactive effects between age group and zolpidem dose (P = .043), indicating that a higher dose of zolpidem was associated with CSBs only in the adult group and not in the elderly group. Adults with CSBs used a higher dose of zolpidem than adults without (mean ± SD: 15.4 ± 6.8 mg vs 11.3 ± 5.7 mg), whereas elderly patients with CSBs did not use a higher dose of zolpidem than those without (12.2 ± 5.4 mg vs 11.9 ± 7.0 mg). CONCLUSIONS:A higher dose of zolpidem was correlated with CSBs only in the adult group and not in the elderly group. Future studies investigating the factors, other than dose, related to CSBs in the elderly will be performed.
Zolpidem reduces hippocampal neuronal activity in freely behaving mice: a large scale calcium imaging study with miniaturized fluorescence microscope.
Berdyyeva Tamara,Otte Stephani,Aluisio Leah,Ziv Yaniv,Burns Laurie D,Dugovic Christine,Yun Sujin,Ghosh Kunal K,Schnitzer Mark J,Lovenberg Timothy,Bonaventure Pascal
Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal's state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (∼ 65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders.
Higher-dose uses of zolpidem will increase the subsequent risk of developing benign brain tumors.
Harnod Tomor,Li Yu-Fen,Lin Cheng-Li,Chang Shih-Ni,Sung Fung-Chang,Kao Chia-Hung
The Journal of neuropsychiatry and clinical neurosciences
This study identified 37,810 patients with anxiety or sleep disorder (mean age=53.2 years, SD=16.0 years) who had zolpidem prescribed for at least 2 months from January 1, 2000 through December 31, 2009. Another non-zolpidem cohort was selected by 1:1 matching with the zolpidem cohort on the estimated probability (propensity score) of being treated. The zolpidem cohort had a higher incidence of benign brain tumors compared with the non-zolpidem cohort, particularly for elderly patients. The matched propensity score analysis showed that the highest risk of benign brain tumors occurred in participants with zolpidem exposure ≥520 mg/year (hazard ratio=1.85, 95% confidence interval=1.21-2.82) compared with those not taking zolpidem.
The association between zolpidem and infection in patients with sleep disturbance.
Huang Chih-Yuan,Chou Frank Hunag-Chih,Huang Yung-Sung,Yang Chang-Jen,Su Yu-Chieh,Juang Shiun-Yang,Chen Pin-Fan,Chou Pesus,Lee Ching-An,Lee Ching-Chih
Journal of psychiatric research
OBJECTIVE:Recent case reports suggest that zolpidem usage may be associated with infection events. The aim of this study was to determine the risk of infection events in patients with sleep disturbance taking zolpidem in a full 3-year follow-up study. METHODS:A total of 17474 subjects with a diagnosis of sleep disturbance in 2002 and 2003 were identified, of whom 5882 had used zolpidem after recruitment. A Cox proportional hazard model was used to estimate the 3-year infection event-free rates for the patients using zolpidem and those not using zolpidem after adjusting for confounding factors. To maximize case ascertainment, only patients hospitalized for infection events were included. RESULTS:A total of 646 patients had had infection events, 331 (5.63%) of whom had been taking zolpidem and 315 (2.71%) had not. Zolpidem usage increased the risk of infection events. After adjustments for gender, age, co-morbidities, and other medications, patients using zolpidem with cDDD 1-28, 29-84, and >84 had hazard ratios of 1.67 (95% CI, 1.32-2.11), 1.91 (95% CI, 1.47-2.49) and 1.62 (95% CI, 1.32-1.98) respectively, compared with patients who did not use zolpidem. CONCLUSIONS:Zolpidem increased the risk of infection events in sleep disturbance patients. This increased risk of infection should be explained to sleep disturbance patients, and prescriptions of zolpidem to chronic insomnia patients should be restricted.
Implication of mGlu5 receptor in the enhancement of morphine-induced hyperlocomotion under chronic treatment with zolpidem.
Shibasaki Masahiro,Ishii Kazunori,Masukawa Daiki,Ando Koji,Ikekubo Yuiko,Ishikawa Yutori,Shibasaki Yumiko,Mori Tomohisa,Suzuki Tsutomu
European journal of pharmacology
Long-term exposure to zolpidem induces drug dependence, and it is well known that the balance between the GABAergic and glutamatergic systems plays a critical role in maintaining the neuronal network. In the present study, we investigated the interaction between GABAA receptor α1 subunit and mGlu5 receptor in the limbic forebrain including the N.Acc. after treatment with zolpidem for 7 days. mGlu5 receptor protein levels were significantly increased after treatment with zolpidem for 7 days, and this change was accompanied by the up-regulation of phospholipase Cβ1 and calcium/calmodulin-dependent protein kinase IIα, which are downstream of mGlu5 receptor in the limbic forebrain. To confirm that mGlu5 receptor is directly involved in dopamine-related behavior in mice following chronic treatment with zolpidem, we measured morphine-induced hyperlocomotion after chronic treatment with zolpidem in the presence or absence of an mGlu5 receptor antagonist. Although chronic treatment with zolpidem significantly enhanced morphine-induced hyperlocomotion, this enhancement of morphine-induced hyperlocomotion was suppressed by treating it with the mGlu5 receptor antagonist MPEP. These results suggest that chronic treatment with zolpidem caused neural plasticity in response to activation of the mesolimbic dopaminergic system accompanied by an increase in mGlu5 receptor.
Hypnotics in insomnia: the experience of zolpidem.
MacFarlane James,Morin Charles M,Montplaisir Jacques
PURPOSE:One of the most commonly prescribed medications to treat insomnia is zolpidem, a nonbenzodiazepine compound that is available as an immediate-release oral tablet formulation, an extended-release oral formulation, an oral spray formulation, and as sublingual formulations. The purpose of this review was to summarize the data currently available on the efficacy and safety of zolpidem in the treatment of insomnia among adults. METHODS:Published studies on the use of zolpidem in the treatment of insomnia were identified by using combinations of relevant search terms in PubMed and Google Scholar. Studies were included if they were placebo- or active comparator-controlled studies, with the exception of trials on the long-term use of zolpidem. Studies were limited to those conducted in adults. Studies were not included if the patient population was small, if the study was not designed or powered to assess the efficacy or safety of zolpidem, if insomniac patients had a medical condition in addition to insomnia (with the exception of comorbid depression or anxiety for studies on comorbid insomnia), or if zolpidem was given concomitantly with any other therapy (with the exception of selective serotonin reuptake inhibitors for studies on comorbid insomnia). FINDINGS:Twenty-five studies designed to evaluate the efficacy of zolpidem in insomnia and 51 studies reporting the safety of zolpidem in insomnia were included in this review. IMPLICATIONS:The studies discussed in this review report the efficacy and safety of zolpidem in both young adults and the elderly. It can be used for either bedtime or middle-of-the-night administration, over the short or long term, with minimal risk of withdrawal or abuse. The use of zolpidem is associated with rebound insomnia, complex sleep-related behaviors, and next-day residual effects (after middle-of-the-night dosing) on driving ability, memory, and psychomotor performance.
A review of the evidence of zolpidem efficacy in neurological disability after brain damage due to stroke, trauma and hypoxia: A justification of further clinical trials.
Sutton J A,Clauss R P
During 15 years, 23 clinical reports and 6 studies have demonstrated associations between sub-sedative doses of zolpidem and recoveries from brain damage due to strokes, trauma and hypoxia. Clinical findings include unexpected awakenings from vegetative states and regressions of stroke symptoms after dosing that disappear during elimination and reappear on repeat dosing. Initially single-photon emission computed tomography scans showed improved perfusion within, around and distant from infarctions. Then positron emission tomography scans and electroencephalography detected renewed metabolic and neuronal activity. Placebo or a similar, gamma-aminobutyric acid (GABA)-ergic, sedative zopiclone has no such effect. The effect appears only several months after the injury, reflecting recent evidence in mice of substantial differences between the states of GABA receptors in acute and chronic repair phases of recovery. Zolpidem's good safety record and rapid absorption further indicate a need for more clinical trials. List of acronyms: BOLD, Blood-Oxygen-Level Dependent contrast imaging in MRI; CRS, Coma Recovery Scale; CRS-R, Coma Recovery Scale Revised; CSI, Cerebral State Index; CSM, Cerebral State Monitor; DOC, Disorder of Consciousness; EEG, Electro Encephalography; FDG-PET, FluoroDeoxyGlucose-Positron Emission Tomography; FTD, Frontotemporal dementia; GABA, Gamma-Aminobutyric Acid; MCS, Minimally Conscious State; M-EEG, Magneto-Encephalography; MRI, Magnetic Resonance Image; MSN, Median Spiny Neurones; PET, Positron Emission Tomography; PVS, Persistent Vegetative Sate; RLAC, Rancho Los Amigos Cognitive scores; SPECT, Single-photon emission computed tomography; TFES, Tinetti Falls Efficacy Scale; 99mTc HMPAO, Technetium hexamethylpropyleneamine oxime.
Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors: evidence of a novel benzodiazepine site in the α1-α1 interface.
Che Has Ahmad Tarmizi,Absalom Nathan,van Nieuwenhuijzen Petra S,Clarkson Andrew N,Ahring Philip K,Chebib Mary
Zolpidem is not a typical GABAA receptor hypnotic. Unlike benzodiazepines, zolpidem modulates tonic GABA currents in the rat dorsal motor nucleus of the vagus, exhibits residual effects in mice lacking the benzodiazepine binding site, and improves speech, cognitive and motor function in human patients with severe brain injury. The receptor by which zolpidem mediates these effects is not known. In this study we evaluated binary α1β3 GABAA receptors in either the 3α1:2β3 or 2α1:3β3 subunit stoichiometry, which differ by the existence of either an α1-α1 interface, or a β3-β3 interface, respectively. Both receptor stoichiometries are readily expressed in Xenopus oocytes, distinguished from each other by using GABA, zolpidem, diazepam and Zn(2+). At the 3α1:2β3 receptor, clinically relevant concentrations of zolpidem enhanced GABA in a flumazenil-sensitive manner. The efficacy of diazepam was significantly lower compared to zolpidem. No modulation by either zolpidem or diazepam was detected at the 2α1:3β3 receptor, indicating that the binding site for zolpidem is at the α1-α1 interface, a site mimicking the classical α1-γ2 benzodiazepine site. Activating α1β3 (3α1:2β3) receptors may, in part, mediate the physiological effects of zolpidem observed under distinct physiological and clinical conditions, constituting a potentially attractive drug target.
Zolpidem for the Treatment of Neurologic Disorders: A Systematic Review.
Bomalaski Martin N,Claflin Edward S,Townsend Whitney,Peterson Mark D
Importance:Given its selective action on the ω1 subtype of the γ-aminobutyric acid A receptor, zolpidem tartrate presents a potential treatment mechanism for other neurologic disorders. Objective:To synthesize studies that used zolpidem to treat neurologic disorders. Evidence Review:Eligibility criteria included any published English-language article that examined the use of zolpidem for noninsomnia neurologic disorders in humans for all dates up to March 20, 2015. Searched databases included PubMed, Scopus, Web of Science Core Collection, the Cochrane Library, EMBASE, CENTRAL, and clinicaltrials.gov. Publication bias was mitigated by searching clinicaltrials.gov for unpublished studies. Two rounds of screening were performed based on title and then abstract, and coding was performed by 2 coders. All methods followed the PRISMA Reporting Guidelines for systematic reviews of the literature. Findings:The initial search produced 2314 articles after removing duplicates. After exclusion based on a review of abstracts, 67 articles remained for full manuscript review. Thirty-one studies treated movement disorders, 22 treated disorders of consciousness, and 14 treated other neurologic conditions, including stroke, traumatic brain injury, encephalopathy, and dementia. Study designs included case reports (n = 28), case series (n = 8), single-patient interventional (n = 13), pretest and posttest (n = 9), randomized clinical trials (n = 9), and crossover studies (n = 5). Only 11 studies had more than 10 participants. Effects of zolpidem were wide ranging (eg, improvement on the JFK Coma Recovery Scale-Revised, the Unified Parkinson Disease Rating Scale, and the Burke-Fahn-Marsden Dystonia Rating Scale) and generally lasted 1 to 4 hours before the participant returned to baseline. Sedation was the most common adverse effect. Conclusions and Relevance:Zolpidem has been observed to transiently treat a large variety of neurologic disorders, most often related to movement disorders and disorders of consciousness. Much of what is known comes from case reports and small interventional trials. These findings may represent a new treatment mechanism for these disorders.
Pharmacodynamic effects of suvorexant and zolpidem on EEG during sleep in healthy subjects.
Struyk Arie,Gargano Cynthia,Drexel Melissa,Stoch S Aubrey,Svetnik Vladimir,Ma Junshui,Mayleben David
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
The objective of this study was to evaluate sleep electrophysiology in healthy subjects after bedtime administration of therapeutic doses of two insomnia treatments - the orexin receptor antagonist suvorexant or the GABAergic agonist zolpidem. Eighteen healthy men received single bedtime doses of suvorexant 20mg, zolpidem 10mg, or placebo in a double-blinded, randomized, balanced 3-period crossover study. EEG power spectral densities during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep were recorded in a polysomnography (PSG) laboratory using a 19-lead EEG recording array. Spectral density was analyzed for each lead for frequencies between 1-32Hz. During NREM and REM sleep, zolpidem treatment reduced spectral density across theta and alpha frequency bands in all leads. In contrast, suvorexant had no significant effects on spectral density in any frequency band during NREM sleep, and modestly increased spectral density in the theta frequency band during REM sleep. Although the study was not designed to detect effects on PSG sleep endpoints in healthy subjects, both suvorexant and zolpidem increased mean total sleep time and sleep efficiency. Zolpidem reduced latency to persistent sleep whereas suvorexant did not. Suvorexant decreased wake after sleep onset, whereas zolpidem did not. These findings suggest that EEG power spectral density profile after administration of suvorexant in healthy subjects more closely approximates placebo sleep physiology than after zolpidem treatment.
Zolpidem use and risk of fractures: a systematic review and meta-analysis.
Park S M,Ryu J,Lee D R,Shin D,Yun J M,Lee J
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
UNLABELLED:Zolpidem is a representative of non-benzodiazepine hypnotics. Recent epidemiologic studies have reported increased fracture risk in patients taking zolpidem, but the results have been inconsistent. The present meta-analysis shows that the use of zolpidem is associated with an increased risk of fractures. PURPOSE:Previous studies have reported inconsistent findings regarding the association between the use of zolpidem and the risk of fractures. We performed a systematic literature review and meta-analysis to assess the association. METHODS:We identified relevant studies by searching MEDLINE, EMBASE, Cochrane Library, and PsycINFO without language restrictions (until August 2014). Methodological quality was assessed based on the Newcastle-Ottawa Scale (NOS). RESULTS:A total of 1,092,925 participants (129,148 fracture cases) were included from 9 studies (4 cohort, 4 case-control, and 1 case-crossover study). Overall, the use of zolpidem was associated with an increased risk of fracture (relative risk [RR] 1.92, 95 % CI 1.65-2.24; I (2) = 50.9 %). High-quality subgroups (cohort studies, high NOS score, adjusted for any confounder, or adjusted for osteoporosis) had higher RRs than the corresponding low-quality subgroups (high quality, 1.94-2.76; low quality, 1.55-1.79). Of note, the risk for hip fracture was higher than that for fracture at any site (hip fracture, RR 2.80, 95 % CI 2.19-3.58; fracture at any site, RR 1.84, 95 % CI 1.67-2.03; P < 0.001). CONCLUSIONS:The use of zolpidem may increase the risk of fractures. Clinicians should be cautious when prescribing zolpidem for patients at high risk of fracture.
Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons.
Uygun David S,Ye Zhiwen,Zecharia Anna Y,Harding Edward C,Yu Xiao,Yustos Raquel,Vyssotski Alexei L,Brickley Stephen G,Franks Nicholas P,Wisden William
The Journal of neuroscience : the official journal of the Society for Neuroscience
Zolpidem, a GABA receptor-positive modulator, is the gold-standard drug for treating insomnia. Zolpidem prolongs IPSCs to decrease sleep latency and increase sleep time, effects that depend on α2 and/or α3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on α1 subunit-containing receptors, and which may make zolpidem-induced sleep less optimal. In this paper, we investigate whether zolpidem needs to potentiate only particular GABAergic pathways to induce sleep without reducing EEG power. Mice with a knock-in F77I mutation in the GABA receptor γ2 subunit gene are zolpidem-insensitive. Using these mice, GABA receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of γ2I77 mice were made selectively sensitive to zolpidem by genetically swapping the γ2I77 subunits with γ2F77 subunits. When histamine neurons were made selectively zolpidem-sensitive, systemic administration of zolpidem shortened sleep latency and increased sleep time. But in contrast to the effect of zolpidem on wild-type mice, the power in the EEG spectra of NREM sleep was not decreased, suggesting that these EEG power-reducing effects of zolpidem do not depend on reduced histamine release. Selective potentiation of GABA receptors in the frontal cortex by systemic zolpidem administration also reduced sleep latency, but less so than for histamine neurons. These results could help with the design of new sedatives that induce a more natural sleep. SIGNIFICANCE STATEMENT:Many people who find it hard to get to sleep take sedatives. Zolpidem (Ambien) is the most widely prescribed "sleeping pill." It makes the inhibitory neurotransmitter GABA work better at its receptors throughout the brain. The sleep induced by zolpidem does not resemble natural sleep because it produces a lower power in the brain waves that occur while we are sleeping. We show using mouse genetics that zolpidem only needs to work on specific parts and cell types of the brain, including histamine neurons in the hypothalamus, to induce sleep but without reducing the power of the sleep. This knowledge could help in the design of sleeping pills that induce a more natural sleep.
Therapeutic efficacy of zolpidem combined with cognitive-behavioral therapy on primary insomnia.
Song Ying,Liang Bing
BACKGROUND:In this study, we intend to assess the efficacy of zolpidem combined with cognitive-behavioral therapy (CBT) for patients with primary insomnia (PI). METHODS:A predefined search strategy will be used to search for associated literature from inception to the July 1, 2019: PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, Google Scholar, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure with no language limitation. In addition, we will also retrieve reference lists of included studies and relevant reviews, as well as the conference proceedings. All randomized controlled trials related to the zolpidem and CBT for PI will be included. Two authors will perform study selection, data collection, and study quality, respectively. We will also apply RevMan 5.3 software for statistical analysis. RESULTS:This study will provide a comprehensive overview of the available evidence of the benefits and safety of zolpidem and CBT for PI. Primary outcomes are sleep quality and severity of sleep disorders. Secondary outcomes consist of sleep-onset latency, total sleep duration, sleep efficiency, and frequency and adverse events. CONCLUSION:The results of this study will inform clinical and policy decisions regarding the benefits and harm of zolpidem and CBT for patients with PI. PROSPERO REGISTRATION NUMBER:PROSPERO CRD42019142796.
Potential benefits of zolpidem in disorders of consciousness.
Noormandi Afsaneh,Shahrokhi Maryam,Khalili Hossein
Expert review of clinical pharmacology
INTRODUCTION:It has been suggested that zolpidem may arouse patients with decreased level of consciousness. Zolpidem may partially or even completely reverse abnormal cell metabolism following brain damage. In this article, available evidences regarding effects of zolpidem on disorders of consciousness were reviewed. Areas covered: A literature review was conducted using PubMed, Scopus, Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Google Scholar as online databases. Search Keywords were 'vegetative state', 'minimally conscious state', 'semi-comatose', 'arousal', 'zolpidem', 'wakefulness', 'awareness', and 'loss of consciousness'. All English language studies that evaluated the effects of zolpidem on disorders of consciousness as a main surrogate endpoint were included. Finally 21 articles within this subject were included. Expert commentary: Zolpidem showed positive effects in several conditions with decreased level of consciousness. However, benefits of zolpidem were not detected in all patients with disorders of consciousness. Patients with post-anoxic encephalopathy or traumatic brain injury did not experience benefits of zolpidem. Available evidences support positive effects of zolpidem on brain functions in patients with non-brain stem injuries.
Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem.
Carberry Jayne C,Fisher Lauren P,Grunstein Ronald R,Gandevia Simon C,McKenzie David K,Butler Jane E,Eckert Danny J
The European respiratory journal
Hypnotics are contraindicated in obstructive sleep apnoea (OSA) because of concerns of pharyngeal muscle relaxation and delayed arousal worsening hypoxaemia. However, human data are lacking. This study aimed to determine the effects of three common hypnotics on the respiratory arousal threshold, genioglossus muscle responsiveness and upper airway collapsibility during sleep.21 individuals with and without OSA (18-65 years) completed 84 detailed sleep studies after receiving temazepam (10 mg), zolpidem (10 mg), zopiclone (7.5 mg) and placebo on four occasions in a randomised, double-blind, placebo-controlled, crossover trial (ACTRN12612001004853).The arousal threshold increased with zolpidem and zopiclone placebo (mean±sd -18.3±10 and -19.1±9 -14.6±7 cmHO; p=0.02 and p<0.001) but not with temazepam (-16.8±9 cmHO; p=0.17). Genioglossus muscle activity during stable non-REM sleep and responsiveness during airway narrowing was not different with temazepam and zopiclone placebo but, paradoxically, zolpidem increased median muscle responsiveness three-fold during airway narrowing (median -0.15 (interquartile range -1.01 to -0.04) -0.05 (-0.29 to -0.03)% maximum EMG per cmHO epiglottic pressure; p=0.03). The upper airway critical closing pressure did not change with any of the hypnotics.These doses of common hypnotics have differential effects on the respiratory arousal threshold but do not reduce upper airway muscle activity or alter airway collapsibility during sleep. Rather, muscle activity increases during airway narrowing with zolpidem.
Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects.
Kajiwara Ayami,Yamamura Masato,Murase Motoji,Koda Haruo,Hirota Seisuke,Ishizuka Tadao,Morita Kazunori,Oniki Kentaro,Saruwatari Junji,Nakagawa Kazuko
Aging & mental health
OBJECTIVES:Prescriptions of non-benzodiazepine sedative hypnotics, e.g. zolpidem, for insomnia in elderly subjects 80 years of age or older have markedly increased in the USA. However, a meta-analysis of the risks and benefits of hypnotics in older people reported the benefits associated with hypnotics use are outweighed by the risks. This study aimed to investigate the safety of zolpidem administration in extremely old elderly. METHODS:The prevalence of adverse reactions to zolpidem was investigated in a subpopulation of participants in the Drug Event Monitoring project of the Japan Pharmaceutical Association. A total of 1011 (316 males and 695 females) zolpidem users, including 261 (25.8%) subjects 80 years of age or older without cognitive or mental complications, were eligible for the analysis. RESULTS:The elderly and female patients were prescribed significantly lower doses of zolpidem than their counterparts. Adverse symptoms after the last prescription were reported by 60 (5.9%) subjects. The most common symptoms were impaired balance and/or falls (1.8%) and morning drowsiness (1.3%). The multiple logistic regression analyses showed that subjects 80 years of age or older were at lower risk of adverse symptoms (odds ratio 0.39, 95% confidence intervals: 0.17-0.88). CONCLUSION:Our findings in a real-world clinical setting suggest that low-dose zolpidem can be safely prescribed to subjects 80 years of age or older without cognitive or mental complications.
Zolpidem use and motor vehicle collisions in older drivers.
Booth John N,Behring Michael,Cantor Ryan S,Colantonio Lisandro D,Davidson Sherri,Donnelly John P,Johnson Erica,Jordan Kelsey,Singleton Chelsea,Xie Fenglong,McGwin Gerald
OBJECTIVE:Prescription sleep medication use is most prevalent among women and older adults. Morning drowsiness and impaired coordination are side effects of sleep medications that may affect driving safety. The association between current use of zolpidem-containing medications and motor vehicle collisions (MVCs) was evaluated among drivers of advanced age. METHODS:Participants were current drivers aged ≥70 years residing in north-central Alabama, spoke English, had a valid driver's license, and had driven within the past three months (n = 2000). Current zolpidem use was determined by pill bottle review. The participant's five-year MVC history was determined from Alabama Department of Public Safety accident reports. The five-year MVC and at-fault MVC rate ratios (RR) were estimated comparing zolpidem users with nonusers in the overall sample and a priori-defined age and sex subgroups. RESULTS:The unadjusted RR (95% confidence interval [CI]) of MVCs comparing zolpidem users with nonusers was attenuated after adjustment (1.46 [1.02-2.08] and 1.38 [0.97-1.98], respectively). Among women, the unadjusted and adjusted RRs (95% CI) were 1.65 (1.03-2.66) and 1.61 (1.00-2.60), respectively. The unadjusted and adjusted RRs (95% CI) among those aged 80 years or more were 2.24 (1.19-4.57) and 2.35 (1.20-4.61), respectively. There were no statistically significant associations among men or participants less than 80 years old. Similar patterns were present for at-fault MVCs. CONCLUSION:Current zolpidem users, specifically women and individuals aged 80 years or more, had higher MVC rates than nonusers. Practitioners should consider behavioral treatment before initiating low doses of zolpidem and increasing it as needed to achieve restorative sleep in women and individuals aged 80 years or more to reduce the risk of zolpidem-associated MVCs.
Zolpidem efficacy and safety in disorders of consciousness.
Machado Calixto,Estévez Mario,Rodriguez-Rojas Rafael
Sutton and Clauss presented a detailed review about the effectiveness of zolpidem, discussing recoveries from brain damage due to strokes, trauma and hypoxia. A significant finding has been the unexpected and paradoxical increment of brain activity in vegetative state/unresponsive wakefulness syndrome (VS/UWS). On the contrary, zolpidem is considered one of the best sleep inducers in normal subjects. We have studied series of VS/UWS cases after zolpidem intake. We have demonstrated EEG activation, increment of BOLD signal in different brain regions, and an autonomic influence, mainly characterized by a vagolytic chronotropic effect without a significant increment of the vasomotor sympathetic tone. As this autonomic imbalance might induce cardio- circulatory complications, which we didn't find in any of our patients, we suggest developing future trials under control of physiological indices by bedside monitoring. However, considering that the paradoxical arousing zolpidem effect might be certainly related to brain function improvement, we agree with Sutton and Clauss that future multicentre and multinational clinical trials should be developed, but under control of physiological indices.
Zolpidem ameliorates motor impairments in the unilaterally 6-hydroxydopamine-lesioned rat.
Assini Robert,Abercrombie Elizabeth D
The European journal of neuroscience
Nuclei within the basal ganglia-such as the globus pallidus external segment, subthalamic nucleus, and substantia nigra pars reticulata-have been shown to exhibit synchronous bursting activity entrained to excessive cortical beta oscillations following dopamine depletion. Zolpidem binds to GABA receptors with selectivity for those expressing the α subunit, potentiating inhibitory postsynaptic currents and increasing the time decay of channel opening. Interestingly, zolpidem-sensitive nuclei within the basal ganglia circuitry are also those that have been shown to exhibit hyperexcitation in a dopamine-depleted state. We hypothesized that a drug with selectivity for these nuclei may improve motor impairments associated with Parkinson's disease. In order to determine the threshold dose at which zolpidem might encumber motor behavior, a dose-response experiment was performed in intact rats using rotarod. Next, we tested whether subthreshold doses (0.1, 0.25, 0.5 mg/kg; i.p.) of zolpidem improved volitional motor behavior/coordination using the rotarod balance beam and cylinder/paw preference tests in unilaterally 6-hydroxydopamine-lesioned rats. It was found that 0.1 mg/kg zolpidem significantly improved rotarod performance and significantly reduced forelimb use asymmetry compared to undrugged post-lesion conditions. Here, we present the first translational evidence for a role of zolpidem-sensitive GABA receptors in the treatment of PD motor symptoms. Our data show that zolpidem improves both motor coordination and volitional forelimb use in the unilateral 6-hydroxydopamine lesion model of PD, and thus suggest that zolpidem-sensitive GABA receptors may represent a novel therapeutic target for the treatment of motor symptoms of Parkinson's disease.
The effect of zolpidem on cognitive function and postural control at high altitude.
Bouzat Pierre,Séchaud Guillaume,Banco Pierre,Davranche Karen,Casini Laurence,Baillieul Sébastien,Manhes Pauline,Botrè Fancesco,Mazzarino Monica,De la Torre Xavier,Robach Paul,Verges Samuel
Study Objectives:Sleep is altered at high altitude leading many mountaineers to use hypnotics in order to improve sleep efficiency. While after a full night at altitude the short-acting hypnotic zolpidem does not appear to alter cognitive function, residual adverse effects should be considered following early waking-up as performed by mountaineers. We hypothesized that zolpidem intake at high altitude would alter cognitive function 4 hours after drug intake. Methods:In a randomized double-blind controlled cross-over study, 22 participants were evaluated during two nights at sea level and two nights at 3800 m, 4 hours after zolpidem (10 mg) or placebo intake at 10:00 pm. Polygraphic recording was performed until waking-up at 01:30 am. Sleep quality, sleepiness and symptoms of acute mountain sickness were assessed by questionnaires. Two cognitive tasks (Simon task and duration-production task) were performed at rest and during exercise and postural control was evaluated. Results:Zolpidem increased reaction time in all conditions (zolpidem 407 ± 9 ms vs. placebo 380 ± 11 ms; p < 0.001) and error rate in incongruent trials only (10.2 ± 1.1% vs. 7.8 ± 0.8%; p < 0.01) in the Simon task and increased time perception variability (p < 0.001). Zolpidem also altered postural parameters (e.g. center of pressure area, zolpidem 236 ± 171.5 mm2 vs. placebo 119.6 ± 59 mm2; p < 0.001). Zolpidem did not affect apnea-hypopnea index and mean arterial oxygen saturation (p > 0.05) but increased sleep quality (p < 0.001). Zolpidem increased symptoms of acute mountain sickness and sleepiness (p < 0.05). Conclusions:Acute zolpidem intake at high altitude alters cognitive functions and postural control during early wakening which may be deleterious for safety and performances of climbers.
Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the PI3K/Akt pathway and inhibited by PK11195.
Jazvinšćak Jembrek Maja,Radovanović Vedrana,Vlainić Josipa,Vuković Lidija,Hanžić Nikolina
Excitotoxicity is a pathological process in which neuronal dysfunction and death are induced by excessive glutamate stimulation, the major fast excitatory neurotransmitter in the mammalian brain. Excitotoxicity-induced neurodegeneration is a contributing factor in ischemia-induced brain damage, traumatic brain injury, and various neurodegenerative diseases. It is triggered by calcium overload due to prolonged over-activation of ionotropic N-methyl-d-aspartate (NMDA) receptors. Enhanced Ca release results in neuronal vulnerability through several intertwined mechanisms, including activation of proteolytic enzymes, increased production of reactive oxygen species (ROS), mitochondrial dysfunction and modulation of intracellular signalling pathways. We investigated the neuroprotective effect of hypnotic zolpidem, a drug that exerts its central effects at the GABA receptor complex, against glutamate-induced toxicity in P19 neurons. Zolpidem prevented death of P19 neurons exposed to glutamate, and abolished the glutamate-induced increase in ROS production, p53 and Bax expression, and caspase-3/7 activity. Zolpidem effects were mediated by marked over-activation of Akt kinase. The pro-survival effect, as well as the pAkt induction, were prevented in the presence of wortmannin, an inhibitor of phosphatidylinositol-3-kinase (PI3K) that functions upstream of Akt. The beneficial effect of zolpidem on neuronal survival was not prevented by flumazenil, a GABA receptor antagonist. PK11195, a drug that modulates the mitochondrial translocator protein 18 kDa (TSPO) and FF-ATPase, prevented the beneficial effect of zolpidem, indicating that the mechanism of zolpidem action involves preservation of mitochondrial function and integrity. Zolpidem effects were further mediated by prevention of glutamate-induced increase in the expression of the NR2B subunit of NMDA receptor. The obtained results suggest the promising therapeutic potential of zolpidem against excitotoxic insults and highlight the importance of mitochondria and the Akt pathway as valuable targets for therapeutic interventions in glutamate-mediated neuropathological conditions.
Effect of zolpidem on functional recovery in a rat model of ischemic stroke.
Oh Min-Kyun,Yoon Kyung Jae,Lee Yong-Taek,Chae Seoung Wan,Choi Hye Young,Shin Hee Suk,Park Yun Hee,Chun Se-Woong,Park Young Sook
The Journal of international medical research
Objective To evaluate the effects of zolpidem on functional recovery in a rat model of acute ischemic stroke. Methods Following ischemic stroke procedures, 42 rats (six in each group) were randomly assigned to receive zolpidem (0.1, 0.25, 0.5, 1.0, 2.0 or 4.0 mg/kg) or normal saline administer intraperitoneally once daily for two weeks. Motor behavioural index (MBI) scores, radial 8-arm maze (RAM) test times and brain MRI scans were obtained 24 hours (Day 1) and two weeks (Day 14) post-procedure. Immunohistochemistry was performed on Day 14. Results By comparison with the normal saline group, the 0.5 and 1.0 mg/kg zolpidem groups showed statistically significant improvements in MBI scores and increased numbers of brain-derived neurotrophic factor (BDNF) stained cells over the two week dosing period. By contrast, the 4.0 mg/kg zolpidem group had statistically significantly impaired MBI scores compared with the control group. No differences among groups were found in RAM times or infarction volumes. Conclusions This study in a rat model showed that 0.5-1.0 mg/kg of zolpidem had beneficial effects on behavioural recovery by enhancing neural plasticity without causing any memory impairment in acute ischemic stroke.