Select a psychoactive drug that is of pharmacological interest to you, but not one you will review as part of your Critical Review. For this paper, you may choose drugs of abuse; however, the paper mu

The acute cognitive effects of zopiclone, zolpidem, zaleplon, and eszopiclone: A systematic review and meta-analysis Elizabeth K. Stranks and Simon F. Crowe School of Psychological Science, La Trobe University, Bundoora, VIC, Australia (Received 3 September 2013; accepted 21 May 2014 ) The “z-drugs ”zopiclone, zolpidem, eszopiclone, and zaleplon were introduced in the 1980s for the treatment of insomnia, as it was observed that the side effect profile associated with these medications were more benign than those related to the benzodiazepines. This meta-analysis set out to ascertain which domains of cognitive function, if any, were affected by the ingestion of these medications. A total of 20 studies met the study inclusion criteria.

Results revealed medium effect sizes for zopiclone and zolpidem on measures of verbal memory. An additional medium effect size was observed for zolpidem on attention. Finally, smaller effect sizes were observed for zolpidem speed of processing and for zopiclone on working memory. It is clear from these data that the use of a single dose of the z-drugs in healthy adults as measured in the morning following the exposure does produce a specific rather than a generalized negative effect on cognitive function. However, there were only enough studies to evaluate the individual cognitive effects of the zolpidem and zopiclone medications; the specific effects of zaleplon and eszopiclone cannot be ascertained because only one study met the inclusion and exclusion criteria for the review.

Keywords: Meta-analysis; Cognitive effects; Zopiclone; Zolpidem; Eszopiclone; Zaleplon. The 1995 Australian National Health Survey indi- cated that almost 4% of the population had recently used a tranquillizer, sedative, or sleeping medications. The proportion of people using these types of medications increases with age, from less than 1% of those under 25 to 10% of those aged 65 or older. Women are also more likely to use these medications than men. Despite the increase in the long-term use of benzodiazepine medications in the elderly (Cotroneo et al., 2007 ; Hollingworth & Siskind, 2010 ), there has been a reduction in the prescription of benzodiazepine hypnotics in favor of the z-drugs in response to safety concerns regarding the benzodiazepines (Ebert, Wafford, & Deacon, 2006 ; Siriwardena, Qureshi, Gibson, Collier, & Latham, 2006 ). The z-drugs are now the most commonly prescribed hypnotic agents worldwide (Huedo-Medina, Kirsch, Middlemass, Klonizakis, & Siriwardena, 2011 ), with prescrip- tion costs of $US285m in the United States (Chilcott & Shapiro, 1996 ) and £25m in the UK (Dündar et al., 2004 ). A number of studies have demonstrated the importance of adequate sleep in the consolidation of memory (Diekelmann & Born, 2010 ; Mednick et al., 2013 ). Indeed, recent evi- dence has indicated that healthy adults with phar- macologically modified sleep may experience memory improvement through the enhancement of sleep spindles, electrophysiological markers of nonrapid eye movement (NREM) sleep, which have been shown to play a critical role in human hippocampal memory performance (Mednick et al., 2013 ). Thus, the negative consequences of insomnia, coupled with the potential benefits of The authors would like to thank Professor Geoff Cumming for his advice regarding some of the statistical techniques that were used in the preparation of this manuscript.No direct sources of funding were used to assist in the preparation of this manuscript.The authors have no conflicts of interest that are relevant to the content of this manuscript. Address correspondence to: Simon F. Crowe, School of Psychological Science, La Trobe University, Bundoora, VIC 3086, Australia (E-mail: [email protected]) . Journal of Clinical and Experimental Neuropsychology , 2014 Vol. 36, No. 7, 691 –700, http://dx.doi.org/10.1080/13803395.2014.928268 © 2014 Taylor & Francis adequate sleep on important cognitive functions such as memory, underline the importance of effec- tive pharmacological treatment for insomnia.

There remains, however, persisting concerns regarding the acute effects of z-drugs on cognition.

It is often perceived that these drugs are cognitively safer agents in the treatment of insomnia (Hoffmann, 2013 ). However, research has indicated that standard doses of zolpidem (i.e., 10 mg) can induce statistically significant negative effects on psychomotor speed, speed of processing, and verbal memory abilities for up to 5 hours following nocturnal administration, with the shorter the interval between the dose admin- istration and evaluation, the greater the impact upon functioning (Danjou et al., 1999 ; Leufkens, Lund, & Vermeeren, 2009 ; Roehrs, Merlotti, Zorick, & Roth, 1994 ). However, a wealth of studies have also demonstrated that zolpidem does not induce signifi- cant next-day adverse effects on cognitive function in healthy individuals (Bensimon et al., 1990 ; Blin, Micallef, Audebert, & Legangneux, 2006 ;Gieschke, Cluydts, Dingemanse, De Roeck, & De Cock, 1994 ; Hindmarch, Legangneux, Stanley, Emegbo, & Dawson, 2006 ; Sicard, Trocherie, Moreau, Vieillefond, & Court, 1993 ). With regard to the cognitive effects of zopiclone, previous findings have indicated that performance on tests of attention, speed of processing, memory, and psychomotor function remained impaired approximately 9 hours after ingestion (Bensimon et al., 1990 ; Harrison, Subhan, & Hindmarch, 1984 ; Leufkens & Vermeeren, 2009 ;Metsetal., 2011 ; Uchiumi, Isawa, Suzuki, & Murasaki, 2000 ; Warot, Bensimon, Danjou, & Puech, 1987 ). However, there has also been contention about the residual cognitive effects of zopiclone. Minimal resi- dual impairment in speed of processing and psycho- motor and memory functions has been found after ingestion of standard doses of zopiclone for both healthy participants and insomnia patients (Allain, Bentue-Ferrer, Tarral, & Gandon, 2003 ;Hemmeter, Muller, Bischof, Annen, & Holsboer-Trachsler, 2000 ). Eszopiclone, an isomer of zopiclone, does not appear as of yet to impair performance on tests of neurocognition on the basis of the relatively small volume of data available.

A study conducted by Boyle and colleagues (Boyle, Trick, Johnsen, Roach, & Rubens, 2008 ) found zaleplon ingestion to minimally impair per- formance on tests of speed of processing, psycho- motor speed, or working memory. Numerous clinical studies have also suggested there are mini- mal residual effects of zaleplon on tests of neuro- cognition (Doghramji, 2001 ; Stone et al., 2002 ; Terzano, Rossi, Palomba, Smerieri, & Parrino, 2003 ; Vermeeren et al., 2002 ). In summary, it is evident that there have been inconsistent findings in the literature with regard to the neurocognitive effects of the z-drugs. This inconsistency may be attributable to a lack of effect altogether or due to the possibility that the actual effect may be small, culminating in the mixed findings noted. A powerful means to distin- guish between these possibilities arises from the use of more systematic reviews such as meta-analyses.

Thus the current study serves to fill the gap identi- fied in this literature by investigating the cognitive effects of another class of sleep-inducing agents. It is essential that we develop a clear picture of what the nature of these effects are, as the level of pre- scription of these agents is growing rapidly as they are being substituted as “safer ”alternatives to the benzodiazepines (National Institute for Clinical Excellence, 2004 ). METHOD Literature search and inclusion criteria A comprehensive search of the computerized data- bases Medline and PsycINFO was conducted to identify studies that assessed the cognitive effects of z-drug usage published between 1 January 1980 and 3 November 2013 (date of last update). This particular time frame was employed as the z-drugs were initially introduced in the 1980s; therefore, any investigations into the cognitive effects of these medications would have begun to be pub- lished around this time. In addition to appropriate Boolean search terms being used to identify rele- vant articles, advanced MESH headings specific to each database were also employed. The Boolean search terms and MESH headings in addition to limits imposed on the searches for each database are presented in Table 1 . For a study to be included in the meta-analysis, it was necessary for the following criteria to be met. The studies had to: (a) be published in a peer-reviewed journal between 1980 and 2013; (b) be written in the English language; (c) be either a randomized trial that included a control or placebo group and a treatment group or be a randomized crossover trial; (d) include healthy adults with no preexisting sleep disorders, mental health, substance abuse, or other disorder that may affect cognition; (e) incorporate objective neuropsychological and cognitive tests that were widely used and for which norms were published (it was decided that studies that employed objec- tive assessments developed by individual researchers or research teams, such as driving 692 STRANKS AND CROWE tests, would not be included in the meta-analysis due to the problems with comparability of these across settings); (f) involve nocturnal administra- tion of a z-drug followed by neuropsychological testing the next morning; and (g) report results that were sufficient to allow the calculation of effect sizes.

Coded variables For all included studies in the current analysis, a number of variables were coded; these were further divided into three categories: participant variables, test information, and outcome measures: ● Participant variables: (a) study N; (b) age; (c) gender; (d) method of participant recruitment; (e) type of z-drug; (f) dosage of z-drug; (g) time between z-drug ingestion and neuropsychological testing; (h) method of participant recruitment; (i)customary alcohol and drug use; (j) smokingstatus; and (k) customary caffeine consumption. ● Test information: (a) neuropsychological testused; and (b) cognitive domain assessed. ● Outcome variables: (a) means and standard deviations; and (b) results of statistical analyses. Statistical analyses A random effects model was employed for the pre- sent meta-analysis, as the distribution of effect sizes was often heterogeneous due to the use of different participants, designs, and cognitive measures (Harvey & Taylor, 2010 ). Cohen ’sd effect sizes were calculated for each cognitive domain and were used as the principal summary measure. In the context of the current research, effect sizes ( d) of 0.2, 0.4, and above 0.6 were considered small, medium, and large in magnitude, respectively.

The values were calculated in a multistage pro- cess. The first stage involved calculating effect sizes for each score of every test used by each individual study. The effect sizes were calculated according to the methods outlined by Rosenthal ( 1995 ). These represent the difference between the treatment group and control group data divided by the pooled standard deviation. Thus a positive effect size generally indicated better performance of the treatment group, and a negative effect size indi- cated that the control group performed better than the treatment group. However, in cases where a higher score indicated greater impairment TABLE 1 Boolean search terms and MESH headings employed for electronic databases used Search terms PsycINFO Medline MESH headings Cognitive impairment Cognition (subheading: drug effects) Executive function Psychomotor performance (subheading: drug effects) Cognitive ability Motor performance Keywords relating to cognition Cogniti a Cogniti a Neuropsych a Neuropsych a “Cognitive impairment ”“ Psychomotor performance ” “Executive function ” “Cognitive ability ” “Motor performance ” Drug terms Zopiclone Zopiclone Imovane Imovane Zimovane Zimovane Zolpidem Zolpidem Ambien Ambien Stilnox Stilnox Eszopiclone Eszopiclone Lunesta Lunesta Estorra Estorra Zaleplon Zaleplon Sonata Sonata Starnoc Starnoc Andante Andante Other terms Deficit a Deficit a Effect a Effect a Limits Human studies Human studies Published in English language Published in English language Note .aSearch term and its derivatives were used (e.g., cognition, cognitive, neuropsychology, neuropsychological, deficits, effects). COGNITIVE EFFECTS OF THE Z-DRUGS 693 than a lower score (e.g., errors and reaction time), the direction of the effect sizes for these scores was transformed so that a negative effect size still indi- cated greater impairment in the treatment group.

The majority of the studies included in the cur- rent meta-analysis used multiple outcome mea- sures. As with other meta-analyses (Anderson- Hanley, Sherman, Riggs, Agocha, & Compas, 2003 ; Harvey & Taylor, 2010 ; Hutchinson & Mathias, 2007 ; Stewart, Bielajew, Collins, Parkinson, & Tomiak, 2006 ), effect sizes were aver- aged for measures of the same cognitive domain to produce a single effect size per study for each cognitive domain.

Analyses of homogeneity, publication bias, and moderator analysis were also undertaken. In order to comprehensively examine the extent of homo- geneity, Q statistics were calculated for each effect size obtained for each cognitive domain measured in order to assess whether the variance exhibited by the effect sizes for each study was due to sampling error alone (Cooper, 2010 ). Statistically significant values indicate that the variation in effect sizes is too great to be explained by sampling error alone; that is, some other factor is likely to be contribut- ing to the variance in effect sizes (Cooper, 2010 ). Publication bias was assessed through the calcula- tion of fail-safe Ns, which indicate the number of unpublished studies with nonsignificant results that would be required to exist to call the significant findings into question. The formula developed by Orwin (1983, cited in Lipsey & Wilson, 2001 ) was used to calculate these values. As different tests were used with varying frequency, it was deter- mined that the fail-safe Ns should be greater than the number of published studies that had used the test (Hutchinson & Mathias, 2007 ). Finally, a moderator analysis using Pearson ’s correlations investigated the relationships between certain coded study characteristics and effect sizes for each study. The study variables included in this moderator analysis were: age, z-drug dosage, and time between dosing and testing. RESULTS A total of 284 studies were selected for possible inclusion in the meta-analysis and were evaluated as to whether they met the aforementioned criteria.

This process culminated in 18 independent studies (Allain et al., 2003 ; Bensimon et al., 1990 ; Blin et al., 2006 ; Boyle et al., 2008 ; Dingemanse, Bury, Bock, & Joubert, 1995 ; Fairweather, Kerr, & Hindmarch, 1992 ; Gieschke et al., 1994 ; Harrison et al., 1984 ; Hemmeter et al., 2000 ; Leufkens & Vermeeren, 2009 ; Mattila, Aranko, & Paakkari, 1994 ; Mattila & Mattila-Evenden, 1997 ; Melendez et al., 2005 ; Mets et al., 2011 ; Morgan, Kehne, Sprenger, & Malison, 2010 ; Quera-Salva et al., 1994 ; Roehrs et al., 1994 ; Silva et al., 2003 ; Tafti, Besset, & Billiard, 1992 ; Uchiumi et al., 2000 ; Vermeeren et al., 2002 ) being selected for inclusion. The reference lists of these studies were carefully scanned to check for additional papers, and two additional papers were located using this method (Harrison et al., 1984 ; Silva et al., 2003 ), bringing the total number of papers included in the meta-analysis to 20.

Each neuropsychological test was grouped into one of five categories corresponding to the broad cognitive ability each test was considered to tap into according to two standard neuropsychology textbooks (Lezak, Howieson, Bigler, & Tranel, 2012 ; Strauss, Sherman, & Spreen, 2006 ). In order for the results for each drug to be relatively comparable, only those cognitive domains that were investigated following the ingestion of each of the four z-drugs were included. The cognitive domains assessed and the specific neuropsycholo- gical tests employed in each study are listed in Table 2 along with the mean age of the partici- pants, the drug and dosage administered, and the number of hours between nocturnal dose adminis- tration and next-day cognitive testing. Table 3 includes the summary statistics for all studies.

Table 4 reveals a medium effect size for the association between zopiclone ingestion and verbal memory, indicating that next-day cognitive perfor- mance was impaired in the morning following night-time ingestion. Further, medium effect sizes were observed for zolpidem administration and performance on measures of attention and verbal memory, as shown in Table 5 . A small effect size was observed with regard to zolpidem ingestion and psychomotor speed. The analysis did not yield any significant effect sizes following the ingestion of eszopiclone and zaleplon.

An analysis of homogeneity was undertaken to test the assumption that sampling error alone could account for the variation between the study effect sizes. Q was used as the measure of the extent of heterogeneity, or variability between study effect sizes. As can be seen in Tables 4 and 5, all Q-statistics associated with the calculations of the effect sizes for zopiclone and zolpidem were statistically significant, indicating that the varia- tion in effect sizes was not due to sampling error alone. As the fail-safe N values for most cognitive domains were for the most part greater than the number of studies that measured a particular cog- nitive domain, it was determined that relative 694 STRANKS AND CROWE TABLE 2 The cognitive domains assessed and the neuropsychological measures employed in the analyzed studies Study Overall meanage (SD) Number ofparticipants(% male) Drug (dosageadministered, mg) Placebo or activecontrol used Comparability of baselinesinvestigated Number of hoursbetween dose and testing Cognitive domains assessed Neuropsychological tests used Allain et al. ( 2003 ) NS 48 (44) Zolpidem (5) Zopiclone (3.75) Both NS 9 Speed of processing Sternberg MemoryScanning Test (MRT) Bensimon et al. ( 1990 ) 23.6 (NS) 20 (100) Zolpidem (20) Both NS 10 Speed of processing CFF (Hz) CRT (ms) Verbal memory Word pairs recall (number correct) Working memory DSST (number correct) Blin et al. ( 2006 ) 26.3 (4.6) 18 (56) Zolpidem (12.5) Both NS 8.5 Speed of processing CFF (Hz) CRT (ms) CTT Verbal memory Immediate and delayed recall (number correct) Working memory DSST (number correct) Boyle et al. ( 2008 ) 27 (NS) 32 (53) Eszopiclone (3) Placebo control NS 9.75 Speed of processing CFF (Hz) CRT (ms) CTTSternberg Memory Scanning Test (MRT) Working memory DSST (number correct) Dingemanse et al. ( 1995 ) NS 12 (100) Zolpidem (10) Both NS 8 Verbal memory Long-term memory test (number correct) Gieschke et al. ( 1994 ) NS 12 (58) Zolpidem (10) Both NS 9.25 Speed of processing CRT (ms) Working memory SDMT (number correct) Harrison et al. ( 1984 ) 34 (NS) 10 (0) Zopiclone (7.5) Both NS 10 Speed of processing CFF (Hz) CRT (ms)Sternberg MemoryScanning Test (MRT) Hemmeter et al. ( 2000) 65.9 (3.6) 12 (50) Zopiclone (7.5) Both NS 9 Attention Simple attention d2 Trail Making Test Speed ofprocessing CFF (Hz) CRT (ms) Verbal memory Immediate recall Rivermead Behavioural Memory Test (Prose Recall subtest) Leufkens and Vermeeren(2009 ) 64.3 (4.2) 18 (44) Zopiclone (7.5) Both NS 9 Attention Speed ofprocessing DAT Critical Tracking Task Verbal memory Word Learning Test Mattila et al. ( 1994 ) NS 12 (NS) Zopiclone (7.5) Both NS 6 Working memory DSST (number correct) (Continued ) COGNITIVE EFFECTS OF THE Z-DRUGS 695 TABLE 2(Continued) Study Overall meanage (SD) Number ofparticipants(% male) Drug (dosageadministered, mg) Placebo or activecontrol used Comparability of baselinesinvestigated Number of hoursbetween dose and testing Cognitive domains assessed Neuropsychological tests used Mattila and Mattila-Evenden ( 1997 ) NS 12 (58) Zopiclone (7.5) Both NS 5 Working memory DSST (number correct) Melendez et al. ( 2005 ) NS 43 (47) Zolpidem (10) Both NS 10 Verbal memory Word recall (words and nonwords) Working memory Digit Span (backward) DSST (number correct) Mets et al. ( 2011 ) 25.9 (6.5) 15 (50) Zopiclone (7.5) Both NS 8.5 Attention DAT Speed ofprocessing Sternberg MemoryScanning Test (RT) Verbal memory Word Learning Test Working memory Sternberg Memory Scanning Test (% correctDSST (number correct) Morgan et al. ( 2010 ) 39 (10.4) 12 (100) Zolpidem (10) Both NS 8.45 Attention CPT Speed ofprocessing Motor Sequence Task Quera-Salva et al. ( 1994 ) 42 (NS) 10 (NS) Zolpidem (10) Placebo control NS 10.75 Speed of processing CFF CRT Working memory DSST (number correct) Roehrs et al. ( 1994 ) 26.8 (1) 23 (74) Zolpidem (10) Both NS 8 Attention CPT Speed ofprocessing CRT Working memory Digit Span (backward)Verbal memory Buschke Selective Reminding Test Silva et al. ( 2003 ) NS 8 (50) Zopiclone (7.5) Both NS 12 Verbal memory Word list free recall Working memory DSST (number correct) Tafti et al. ( 1992 ) NS 8 (100) Zopiclone (7.5) Placebo control NS 8 Speed of processing CRT CFF Uchiumi et al. ( 2000 ) 36.3 (5.2) 12 (100) Zopiclone (7.5) Both NS 13.5 Speed of processing CFF LCT Vermeeren et al. ( 2002 ) 31.6 (6.9) 30 (50) Zopiclone (7.5) Zaleplon (10) Yes NS 8.75 Attention Speed ofprocessing DATCTT Verbal memory Word Learning Test Note.

RT = reaction time; MRT = mean reaction time; NS = not specified; CFF = critical flicker fusion; CRT = choice reaction time; CTT = critical/compensatory tracking task; DSST = Digit Symbol Substitution Test; SDMT = Symbol Digit Modalities Test; CPT = Continuous Performance Task; DAT = Divided Attention Task; SDST = Symbol Digit Su bstitution Test; LCT = Letter Cancellation Task. 696 STRANKS AND CROWE confidence could be placed in the results obtained.

Finally, the moderator analysis revealed no signif- icant correlations between the effect sizes obtained for each study and participant age, z-drug dosage, and time between dosing and subsequent neurop- sychological testing. DISCUSSION Overall, the results of the current meta-analysis indi- cate that next-day cognition is adversely affected by the ingestion of zopiclone the previous night.

However, the deleterious effect is limited to tasks that tap into the domain of verbal memory. This indicates that the deleterious cognitive effects of zopi- clone are domain-specific rather than having a gen- eralized effect. In contrast, the effect sizes calculated for each domain of cognitive functioning based on data of participants who ingested zolpidem prior to bedtime revealed that performance on attention, per- formance on verbal memory, and performance on psychomotor speed were each impaired as compared to that of controls, with attention and verbal memory both found to be moderately impaired. Overall, this pattern of results indicates that the use of zopiclone has fewer deleterious effects on cognition in healthy adults than does zolpidem, which has additional spe- cific adverse effects on attention and processing speed. Based on this finding, the use of z-drugs in healthy adults produces more specific rather than generalized negative effects on cognitive function, which is the case with the use of benzodiazepine medications (Barker, Greenwood, Jackson, & Crowe, 2004 ; Barker, Jackson, Greenwood, & Crowe, 2003 ). Only one study investigated the cognitive effects of both eszopiclone and zaleplon. Whilst the results of the current meta-analysis indicate no significant adverse effect on cognition following the ingestion of these medications, caution should be taken in interpreting these results, as it is possible that these results may be different if more studies that inves- tigated the cognitive effects of these medications were included in the meta-analysis.

The moderator analysis revealed no statistically significant correlations between the effect sizes obtained for each study and participant age, z-drug dosage, and time between dosing or subsequent TABLE 3 Summary statistics for all studies (regardless of medication) Demographic variable N Studies Mean (SD) Range Sample size 20 18.35 (11.42) 8 –48 Age (Years) 12 36.89 (14.36) 23.6 –65.9 NMale 18 11.88 (5.28) 4 –21 Hours between drugingestion and cognitive testing 20 9.07 (1.85) 5 –13.5 Note. All studies included, regardless of medication. TABLE 5 Summary statistics for the effects of zolpidem on each domain of cognitive functioning Cognitive domain N studies Cohen ’sd 95% CI Q Nfs Lower Upper Attention 2 –0.56* –0.93 –0.18 40.5* 8 Verbal memory 5 –0.46* –0.66 –0.25 262.6* 16 Speed of processing 7 –0.15 –0.31 0.02 58.4* 13 Working memory 3 –0.01 –0.17 0.16 20.94* 3 Notes. Effects of zolpidem listed in order of decreasing weighted negative effect size. CI = confidence interval; Nfs = fail-safe N value.*Significance at the .05 level. TABLE 4 Summary statistics for the effects of zopiclone on each domain of cognitive functioning Cognitive domain Nstudies Cohen ’sd 95% CI Q Nfs Lower Upper Verbal memory 5 –0.42* –0.57 –0.26 613.3* 15 Working memory 4 –0.14 –0.39 0.09 7.8* 5 Speed of processing 6 –0.04 –0.17 0.09 3.2* 6 Attention 4 0.07 –0.14 0.29 28.4* 3 Notes. Effects of zopiclone listed in order of decreasing weighted negative effect size. CI = confidence interval; Nfs = fail-safe N value.*Significance at the .05 level. COGNITIVE EFFECTS OF THE Z-DRUGS 697 neuropsychological testing. However, it must be noted that there were a small number of studies that met the inclusion criteria for this analysis; thus it may be the case that some or all of these factors may significantly impact effect size magnitude but were undetectable given the relatively small number of studies included in the analysis.

The results of this meta-analysis must be inter- preted with a consideration of several important lim- itations. After careful scrutiny of the studies that met the inclusion criteria as outlined in the Method sec- tion, only 20 studies were included. The authors recognize that this limits the ability of the study to evaluate potential covariates such as dosage, time of administration, participant demographics, and any comorbid diagnoses. Further, as can be seen in Table 2 , there are many studies in which important information such as the use of concomitant medica- tion use was allowed, whether study participants were affected by current or past drug use was not ascer- tained, and, in every study, the comparability of base- lines was not reported. These are important quality assurance features for studies with crossover designs.

These omissions limit the confidence in the results obtained in the current meta-analysis to some extent, as these studies may be relatively weak due to the inadvertent presence of important confounding vari- ables. It is also noted that many of the studies did not perform comprehensive neuropsychological exami- nations; rather, the majority of the studies used neu- ropsychological tests that tapped into only a limited number of cognitive domains. Finally, there were many studies that could not be included in the analy- sis as they did not report sufficient data for effect sizes to be calculated. This indicates the need to ensure that such information is included in future research inves- tigating the cognitive effects of the z-drugs so these studies can be included in future meta-analyses.

The results of this meta-analysis provide direc- tion for future research. There is a need for the continued and more thorough investigation into the effects of the z-drugs on cognition. The current meta-analytic review was focused on the next-day residual cognitive effects of z-drugs following noc- turnal administration. Different results may be obtained if cognition was tested following the ingestion of z-drugs later in the course of the night or during the daytime when pharmacokinetic and pharmacodynamics factors may differentially impact the rate of absorption of these drugs and by extension their residual cognitive effects. Further, the cognitive effects of these medications in insom- nia patients need to be investigated. It is clear that insomnia patients suffer from adverse cognitive effects associated with sleep deprivation, which has been shown to reduce performance in more complex tasks involving working memory, verbal fluency and speech articulation, language, logical reasoning, flexible thinking and planning, decision making, and judgment (Thomas et al., 2008 ). Therefore, it is plausible that investigation of the cognitive effects of z-drugs in insomnia patients might yield different results with respect to which domains of cognitive functioning are most affected by the consumption of these medications and which specific z-drugs (if any) yield the most adverse effects on cognition. Finally, in addition to the acute effect of the z-drugs on the cognitive performance of insomnia patients, there is a need to further investigate and assess the residual cogni- tive effects as well as the cumulative effects of the chronic administration of these agents and the effects of more extended periods of time following withdrawal in this patient group.

The potential for adverse cognitive affects as a result of the ingestion of the z-drugs is of interest and importance to researchers and clinicians alike.

Due to the cost of chronic insomnia for individuals and society, effective treatments for this potentially debilitating condition are required. Indeed, the z- drugs have been heralded as a new frontier in the pharmacological treatments available for insomnia patients due to the adverse and deleterious effects associated with long-term benzodiazepine use.

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