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Multifocal cognitive dysfunction in high-dose benzodiazepine users: a cross-sectional study
Abstract
Benzodiazepines (BZDs) are the most widely prescribed drug class in developed countries, but they have high potential for tolerance, dependence and abuse. Cognitive deficits in long-term BZD users have long been known, but previous results might have been biased by patients’ old age, coexisting neurological or psychiatric conditions or concurrent alcohol or psychotropic drug dependence. The study was aimed to explore the neuropsychological effect of high-dose BZD dependence, which represents an emerging addiction phenomenon. We recruited a group of high-dose BZD users with neither neurological or psychiatric comorbidity except anxiety or depression nor concurrent alcohol or psychotropic drug dependence. They underwent a battery of cognitive tests to explore verbal, visuospatial memory, working memory, attention, and executive functions. All the neuropsychological measures were significantly worse in patients than controls, and some of them were influenced by the BZD cumulative dose. The severity of depression and anxiety had a minimal influence on cognitive tests. Patients with high-dose BZD intake show profound changes in cognitive function. The impact of cognition should be considered in this population of patients, who may be involved in risky activities or have high work responsibilities.
... Country of the study Asia and Australia (n = 7) Harnod et al., 2015;Hata et al., 2018;Kim et al., 2017;Rintoul et al., 2013;Takeshima et al., 2016;Tien et al., 2020;Wen et al., 2014 Canada (n = 3) Egan et al., 2001;Sketris et al., 1985;Sullivan & Sellers, 1992 France (n = 2) Etchepare et al., 2016;Imbert et al., 2016 Germany (n = 4) Brinkers et al., 2016;Holzbach et al., 2010;Janhsen et al., 2015;Kaendler et al., 1996 BeNeLux (n = 2) Cloos et al., 2015;Voshaar et al., 2003 Mediterranean Europe (n = 12) Faccini et al., 2016Faccini et al., , 2019Federico et al., 2020Federico et al., , 2017Lekka et al., 1997Lekka et al., , 2002Lugoboni et al., 2020Lugoboni et al., , 2014Lugoboni et al., , 2018Martinez-Cano et al., 1996;Quaglio et al., 2012;Tamburin et al., 2017 Scandinavia (n = 12) Andenaes et al., 2016;Bajwah et al., 2018;Bjerrum et al., 1994;Fredheim et al., 2019Fredheim et al., , 2020Fride Tvete et al., 2015;Johansson et al., 2003;Neutel et al., 2012;Nordfjaern et al., 2014Nordfjaern et al., , 2013Sidorchuk et al., 2018;Vorma et al., 2003 South America (n = 1) Moreno-Gutíerrez et al., 2020 ...
... Switzerland (n = 4) Liebrenz, Schneider et al., 2015;Liebrenz et al., 2016aLiebrenz et al., , 2016b UK (n = 2) Perera & Jenner, 1987;Seivewright & Dougal, 1993 USA (n = 7) Conry et al., 2009;Ellinwood et al., 1990;Hanlon et al., 2009;Hermos et al., 2007Hermos et al., , 2005Kroll et al., 2016;Soumerai et al., 2003 Not applicable (n = 2) Alexander & Perry, 1991;Teboul & Chouinard, 1991 Type of study Systematic review (n = 5) Alexander & Perry, 1991;Brinkers et al., 2016;Janhsen et al., 2015;Kim et al., 2017;Teboul & Chouinard, 1991 Randomized controlled trial (n = 2) Conry et al., 2009;Ellinwood et al., 1990 Epidemiological study (n = 13) Andenaes et al., 2016;Bajwah et al., 2018;Egan et al., 2001;Etchepare et al., 2016;Federico et al., 2017;Hanlon et al., 2009;Harnod et al., 2015;Holzbach et al., 2010;Johansson et al., 2003;Nordfjaern et al., 2014Nordfjaern et al., , 2013Rintoul et al., 2013;Soumerai et al., 2003 National or large registry (n = 9) Cloos et al., 2015;Fredheim et al., 2019Fredheim et al., , 2020Fride Tvete et al., 2015;Moreno-Gutíerrez et al., 2020;Neutel et al., 2012;Sidorchuk et al., 2018;Takeshima et al., 2016;Wen et al., 2014 Local register (n = 8) Bjerrum et al., 1994;Faccini et al., 2016;Federico et al., 2020;Hata et al., 2018;Hermos et al., 2007;Lugoboni et al., 2020Lugoboni et al., , 2014Tamburin et al., 2017; Selected patients (n = 20) Faccini et al., 2019;Hermos et al., 2005;Imbert et al., 2016;Kaendler et al., 1996;Kroll et al., 2016;Lekka et al., 1997Lekka et al., , 2002Liebrenz, Schneider et al., 2015;Liebrenz et al., 2016aLiebrenz et al., , 2016bLugoboni et al., 2018;Martinez-Cano et al., 1996;Perera & Jenner, 1987;Quaglio et al., 2012;Seivewright & Dougal, 1993;Sullivan & Sellers, 1992;Tien et al., 2020;Vorma et al., 2003;Voshaar et al., 2003 Selected physicians (n = 1) Sketris et al., 1985 Length of follow-up Less than 3 months (n = 4) Andenaes et al., 2016;Bjerrum et al., 1994;Ellinwood et al., 1990;Etchepare et al., 2016 3 months to 1 year (n = 16) Conry et al., 2009;Egan et al., 2001;Faccini et al., 2016;Federico et al., 2017;Holzbach et al., 2010;Johansson et al., 2003;Quaglio et al., 2012;Seivewright & Dougal, 1993;Lekka et al., 1997;Lugoboni et al., 2014, Neutel et al., 2012Perera & Jenner, 1987;Sketris et al., 1985;Tamburin et al., 2017;Vorma et al., 2003;Wen et al., 2014 (Continues) CLOOS ET AL. ...
... Switzerland (n = 4) Liebrenz, Schneider et al., 2015;Liebrenz et al., 2016aLiebrenz et al., , 2016b UK (n = 2) Perera & Jenner, 1987;Seivewright & Dougal, 1993 USA (n = 7) Conry et al., 2009;Ellinwood et al., 1990;Hanlon et al., 2009;Hermos et al., 2007Hermos et al., , 2005Kroll et al., 2016;Soumerai et al., 2003 Not applicable (n = 2) Alexander & Perry, 1991;Teboul & Chouinard, 1991 Type of study Systematic review (n = 5) Alexander & Perry, 1991;Brinkers et al., 2016;Janhsen et al., 2015;Kim et al., 2017;Teboul & Chouinard, 1991 Randomized controlled trial (n = 2) Conry et al., 2009;Ellinwood et al., 1990 Epidemiological study (n = 13) Andenaes et al., 2016;Bajwah et al., 2018;Egan et al., 2001;Etchepare et al., 2016;Federico et al., 2017;Hanlon et al., 2009;Harnod et al., 2015;Holzbach et al., 2010;Johansson et al., 2003;Nordfjaern et al., 2014Nordfjaern et al., , 2013Rintoul et al., 2013;Soumerai et al., 2003 National or large registry (n = 9) Cloos et al., 2015;Fredheim et al., 2019Fredheim et al., , 2020Fride Tvete et al., 2015;Moreno-Gutíerrez et al., 2020;Neutel et al., 2012;Sidorchuk et al., 2018;Takeshima et al., 2016;Wen et al., 2014 Local register (n = 8) Bjerrum et al., 1994;Faccini et al., 2016;Federico et al., 2020;Hata et al., 2018;Hermos et al., 2007;Lugoboni et al., 2020Lugoboni et al., , 2014Tamburin et al., 2017; Selected patients (n = 20) Faccini et al., 2019;Hermos et al., 2005;Imbert et al., 2016;Kaendler et al., 1996;Kroll et al., 2016;Lekka et al., 1997Lekka et al., , 2002Liebrenz, Schneider et al., 2015;Liebrenz et al., 2016aLiebrenz et al., , 2016bLugoboni et al., 2018;Martinez-Cano et al., 1996;Perera & Jenner, 1987;Quaglio et al., 2012;Seivewright & Dougal, 1993;Sullivan & Sellers, 1992;Tien et al., 2020;Vorma et al., 2003;Voshaar et al., 2003 Selected physicians (n = 1) Sketris et al., 1985 Length of follow-up Less than 3 months (n = 4) Andenaes et al., 2016;Bjerrum et al., 1994;Ellinwood et al., 1990;Etchepare et al., 2016 3 months to 1 year (n = 16) Conry et al., 2009;Egan et al., 2001;Faccini et al., 2016;Federico et al., 2017;Holzbach et al., 2010;Johansson et al., 2003;Quaglio et al., 2012;Seivewright & Dougal, 1993;Lekka et al., 1997;Lugoboni et al., 2014, Neutel et al., 2012Perera & Jenner, 1987;Sketris et al., 1985;Tamburin et al., 2017;Vorma et al., 2003;Wen et al., 2014 (Continues) CLOOS ET AL. ...
Objectives
A clear definition of what we understand of high‐dose misuse or of a ‘markedly increased dose’ (as stated by the DSM‐5) is important and past definitions may be inadequate. The aim of this review is to describe the different definitions used and to test these definitions for their accuracy.
Methods
A narrative PubMed literature review was conducted based on articles published between 1 January 1990 and 31 December 2020 describing benzodiazepines (in MeSH Terms or MeSH Major Topic) and high‐dose (or high‐dosage). Specific definitions were applied to a population sample to show how definitions affect high‐dose benzodiazepine prevalence.
Results
Multiples of an equivalent‐diazepam dose or of the World Health Organization ‘defined daily dosage’ were used more frequently than the overstep of the recommended maximum therapeutic dosage as a cut‐off point.
Conclusion
High‐dose use is rare but the prevalence in the general population varies among studies, mainly due to different definitions, making both clinical and epidemiological comparisons between studies difficult. Defining a high‐dose user as a person who takes at least a higher dose than the maximum usual therapeutic dose over a defined period of time therefore appears to be clinically more consistent.
... The estimated prevalence of long-term use of BZDs and Z-drugs at high doses ranges from 0.06 to 0.16% of the population in Europe (Ohayon and Lader 2002;Petitjean et al. 2007). We have previously documented that high-dose BZD and Z-drug use (i.e., ≥ 5 times the recommended maximum daily dose; Liebrenz et al. 2015) is associated with worse quality of life (QoL; Tamburin et al. 2017b) and cognitive dysfunction involving multiple domains (Federico et al. 2017). ...
... The inclusion criteria were: (a) age > 18 years, (b) formal education ≥ 8 years, (c) Italian as mother language, (d) normal or corrected-to-normal vision, (e) no hearing loss, (f) no acute drug intoxication, (g) normal overall cognition documented by a Mini Mental State Examination score > 24/30, (h) no neurological diseases that might interfere with cognition, (i) no major psychiatric disorders, and (j) no concurrent alcohol use or other SUD (Federico et al. 2017). The diagnosis of psychiatric disorders was based on screening tests, diagnostic interviews, and previous psychiatric evaluations, when available. ...
... The Beck Depression Inventory II (BDI-II), a 21-item selfadministered questionnaire (score 0-3 for each item, cutoff for moderate to severe depression 28), was used to measure the severity of depressive symptoms during the previous 2 weeks (Federico et al. 2017). The State Trait Anxiety Inventory form Y (STAI-Y), which is composed of two 20-item self-applied questionnaires, was used to measure state and trait anxiety. ...
High-dose use of benzodiazepines (BZDs) and Z-drugs was found to be associated with adult attention deficit/hyperactivity disorder (ADHD) and multidomain cognitive deficits, but the interplay between these factors and its effect on quality of life (QoL) is unclear. We explored (a) whether cognitive dysfunction differs in high-dose BZD/Z-drug users with and without adult ADHD and (b) the impact of cognitive deficits and adult ADHD on QoL in this substance-use disorder (SUD). From January 2015 to December 2019, we recruited 207 high-dose BZD/Z-drug users seeking treatment. We assessed the presence of adult ADHD with a screening tool, which was validated in SUD patients, and collected demographic, clinical and QoL data from the 76 included patients. A neuropsychological battery explored five cognitive domains. We found that: (a) screening for adult ADHD was frequently positive; (b) Short Form-36 (SF-36), a self-administered QoL questionnaire, was worse than the general population and worse in patients positive (ADHD+) vs. those negative (ADHD−) to ADHD screening tool; (c) executive function was significantly worse in ADHD+ than ADHD− patients; (d) some SF-36 dimensions were negatively influenced by executive dysfunction; (e) multivariate analysis showed an interplay between adult ADHD and cognitive dysfunction in worsening QoL. We documented a complex interplay between adult ADHD, cognitive dysfunc-tion and QoL in high-dose BZD/Z-drug users. Assessing adult ADHD, neuropsychological measures and QoL may offer a full scenario of these patients, who are frequently impaired in everyday activities. Future research should explore whether pharmacological treatment might improve cognitive dysfunction and QoL in this SUD.
... High-dose dependence of BZDs or related Z-drugs (e.g., zolpidem, zopiclone, eszopiclone, zaleplon), i.e., daily intake ≥5 times the recommended maximum daily dosage (1) is an emerging substance use disorder estimated to affect 0.16% of the adult population in Switzerland (11), associated to poor quality of life (12), and cognitive dysfunction (13). Data on etizolam high-dose dependence are lacking. ...
... The remaining 1,282 patients used other BZD/Z-drugs highdoses [for further details see (12,13)]. ...
... Etizolam negatively influenced most of the cognitive domains in the patient who underwent neuropsychological testing, in particular working memory, visuospatial memory, and executive function, some of them being <2 SDs worse than normal values. This finding, despite being preliminary since stemming from a single patient, extends the notion that high doses of BZDs have an impact on cognition, even in younger patients (13,24). BZDs cognitive side effects have been suggested to be related to the function of the GABA-A receptor α1 (responsible for anterograde amnesia) and the α5 subunits, which are involved in cognition, learning and memory (25). ...
Introduction: The use of novel designer drugs has increased worldwide over the years. Etizolam is a designer benzodiazepine (BZD) that has raised concern because of its growing non-medical use, liability to tolerance and dependence, and related harms. Studies exploring the abuse liability and cognitive effects of etizolam outside the therapeutic doses are lacking.
Aims: To explore the abuse liability of etizolam and the characteristics of patients affected by etizolam high-dose dependence in a nationwide tertiary referral addiction unit. To document the cognitive changes to etizolam high-dose use.
Design and Methods: Sociodemographic and clinical data on subjects with etizolam high-dose use were retrospectively collected from a database of 1,293 patients consecutively admitted to the Addiction Medicine Unit, Verona University Hospital, Italy for detoxification from high-dose BZDs or Z-drugs dependence. Thorough neuropsychological testing explored the cognitive side effects of high-dose etizolam use.
Results: We found eleven etizolam high-dose users, of which eight used etizolam only, and three used etizolam with other BZDs/zolpidem. All the patients were prescribed etizolam for medical reasons, i.e., anxiety and/or insomnia. Neuropsychological evaluation showed deficits of working memory, visuospatial memory and executive function in a 27-year-old woman who used etizolam 15 mg daily.
Discussion: Our findings suggest that abuse and dependence liability of etizolam should be considered a public health and social problem. They offer preliminary evidence on the cognitive side effects of etizolam high-dose use.
Conclusions: This report offers new information on the potential harms of etizolam in patients who are prescribed this drug for medical reasons.
... High-dose BZD users offer a unique chance to explore the effect of BZD/Z on cognition, because of their relatively young age, and the absence of significant comorbidity in many of them (Federico et al., 2017). We have previously shown profound multidomain dysfunction involving all cognitive domains in a group of young adults (age 44.2 ± 9.7) with high-dose BZD/Z abuse, no neurological or psychiatric comorbidity, except depression and anxiety disorders, and no concurrent substance use disorders (Federico et al., 2017). ...
... High-dose BZD users offer a unique chance to explore the effect of BZD/Z on cognition, because of their relatively young age, and the absence of significant comorbidity in many of them (Federico et al., 2017). We have previously shown profound multidomain dysfunction involving all cognitive domains in a group of young adults (age 44.2 ± 9.7) with high-dose BZD/Z abuse, no neurological or psychiatric comorbidity, except depression and anxiety disorders, and no concurrent substance use disorders (Federico et al., 2017). Different treatments have been proposed for BZD detoxification (Kawasaki et al., 2012;Soyka, 2017). ...
... The inclusion criteria were: (a) age ≥18 years, (b) formal education ≥ 8 years, (c) Italian as mother language, (d) normal or corrected-to-normal vision, (e) no hearing loss, (f) no acute drug intoxication, (g) no neurological diseases that might interfere with cognition, (h) normal overall cognition documented by a Mini Mental State Examination score >24/30, (i) no psychiatric diseases except depression and/or anxiety disorders, and (j) no documented concurrent alcohol or other substance use disorder (Federico et al., 2017). ...
Purpose
High-dose benzodiazepines (BZDs) abuse has been documented to cause multidomain cognitive dysfunction. We explored whether cognitive abnormalities to high-dose BZD abuse might be reversed by detoxification with slow subcutaneous infusion of flumazenil.
Methods
We recruited 96 patients consecutively admitted to the Department of Internal Medicine, Addiction Medicine Unit, Verona University Hospital, Italy for detoxification from high-dose BZD dependence. After selection for inclusion and exclusion criteria, 50 patients (23 men, 27 women; age 42.7 ± 10.3 years) were included. They underwent a comprehensive neuropsychological battery to explore verbal memory, visuospatial memory, working memory, attention, and executive functions 28–30 days prior to admission for detoxification (T0) and at the end of detoxification, i.e., 7 days after admission (T1). A group of 50 healthy adults (24 men, 26 women; mean age 44.5 ± 12.8 years) matched for age, sex, and education served as controls.
Results
At T0, patients scored significantly worse than healthy controls in all the neuropsychological tests. Depression and anxiety scores were associated with impaired verbal memory at T0 in patients. T1–T0 comparison showed improved performances in all neuropsychological tests after the end of detoxification in patients.
Conclusion
We confirmed that all neuropsychological domains were significantly and profoundly impaired by high-dose BZD abuse and documented that cognitive abnormalities improved after detoxification with slow subcutaneous infusion of flumazenil.
... Benzodiazepines are related with significant adverse effects (especially in older adults) such as falls, motor vehicle crashes, respiratory failure, delirium, and activity limitations (Airagnes et al., 2016;Crome et al., 2015;Lader, 2011;Madhusoodanan & Bogunovic, 2004). Several impairments in attention, memory, and executive functions have been studied in research performed in older adults who use benzodiazepines (Federico et al., 2017;Mura et al., 2013;Tveito et al., 2014). Furthermore, benzodiazepines may cause acceleration of cognitive impairment and even dementia (Bierman et al., 2007;Billioti et al., 2014;Gallacher et al., 2012;Madhusoodanan & Bogunovic, 2004;Mura et al., 2013;Tannenbaum et al., 2012;Zhong et al., 2015). ...
... This visual memory alteration was specially related to a visuo-constructive impairment performance. These fi ndings are in line with previous research demonstrating immediate visual memory and visuomotor processing speed dysfunctions (Federico et al., 2017;Mura et al., 2013). As in other studies, attention, working memory, and executive functions (verbal fl uency, language comprehension, processing speed, solving problems, and planning and reasoning) were also impaired (Federico et al., 2017;Helmes & Østbye, 2015). ...
... These fi ndings are in line with previous research demonstrating immediate visual memory and visuomotor processing speed dysfunctions (Federico et al., 2017;Mura et al., 2013). As in other studies, attention, working memory, and executive functions (verbal fl uency, language comprehension, processing speed, solving problems, and planning and reasoning) were also impaired (Federico et al., 2017;Helmes & Østbye, 2015). However, other authors did not fi nd a direct influence between benzodiazepines misuse and cognitive decline (Lagnaoui et al., 2009) or detected a dysfunction after chronic benzodiazepines use only in women (Boeuf-Cazou et al., 2011). ...
Objective:
Adverse health effects including cognitive impairment have been described in older adults with benzodiazepine misuse, although the literature about this issue is scarce. The present study aimed to assess cognitive decline in older adults with benzodiazepine use disorder and changes in cognitive state at the 6-month follow-up, as well as whether patients achieved abstinence.
Method:
A 6-month follow-up longitudinal study was conducted in an outpatient drug center in Barcelona in a sample of older adults (≥65 years old) who had benzodiazepine use disorder. The sample was compared with an equivalent control group. A neuropsychological protocol was performed at baseline and after 6-month follow-up covering the most important cognitive domains.
Results:
The final sample comprised 33 patients with an average age of 73.5 years. At baseline, patients presented impairment in several domains compared with the control group: visual immediate recall (p < .001), visual delayed recall (p < .001), copy (p < .001), working memory (p < .003), immediate verbal learning (p < .002), total words learned (p < .009), set switching (p < .001), verbal fluency (p < .007), speed processing (p < .002), solving problems (p < .006), nonverbal fluency (p < .004), and sustained attention in all three areas omissions (p < .001), variability (p < .001), and perseverance (p < .005). At 6-month follow-up, patients achieving abstinence showed improvement compared with patients in active consumption in visual delayed recall (p < .006), total words learned (p < .010), and verbal fluency (p < .013).
Conclusions:
Benzodiazepine misuse in older adults may produce negative effects on cognitive skills. Recovery of some of these cognitive deficits may be possible with benzodiazepine abstinence.
... The prescription and use of BZDs has been under scrutiny for over 40 years [23] due to their many side effects [8,24,25]. In the short term, they increase daytime sleepiness and the risk of road accidents [26,27]. ...
... Tolerance to BZDs develops rapidly, followed by physical and psychological dependence, often creating conditions leading to doses being increased and their chronic use or abuse. Long-term use may result in altered sleep structure (reduced slow wave sleep), as well as cognitive dysfunction (especially with high doses: reduced attentional resources and impaired verbal and visuospatial memory, working memory, and executive functions) [25]. ...
Benzodiazepines have proven to be highly effective for treating insomnia and anxiety. Although considered safe when taken for a short period of time, a major risk–benefit dilemma arises in the context of long-term use, relating to addiction, withdrawal symptoms, and potential side effects. For these reasons, benzodiazepines are not recommended for treating chronic sleep disorders, anxiety disorders, nor for people over the age of 65, and withdrawal among long-term users is a public health issue. Indeed, only 5% of patients manage to discontinue using these drugs on their own. Even with the help of a general practitioner, this rate does not exceed 25 to 30% of patients, of which approximately 7% manage to remain drug-free in the long term. Cognitive Behavioral Therapies (CBT) offer a crucial solution to this problem, having been shown to increase abstinence success to 70–80%. This article examines traditional and novel CBT techniques in this regard, such as Acceptance and Commitment Therapy, which address both the underlying condition (insomnia/anxiety) and the substance-related disorder. The theoretical framework and evidence supporting the use of these approaches are reviewed. Finally, current research gaps are discussed, and key research perspectives are proposed.
... It was found that patients with dementia had a higher cumulative dose, a longer duration of BDZ exposure and a higher likelihood of long-term BDZ use [11]. Consistent with these findings, a prospective population-based study reported that new use of BDZs was associated with an increased risk of dementia [12]. Furthermore, dependence on high-dose BDZs was associated with poorer performance on cognitive aspects, while severity of anxiety and depression had minimal effect on cognitive tests. ...
... Benzodiazepines (BDZs) are medications commonly used in the treatment of anxiety and insomnia. Whilst effective in the short-term, BDZs are only indicated for up to four weeks as dependence can occur rapidly with regular use (Royal Australian College of General Practitioners, 2015) and limited evidence supports their efficacy long-term (Soyka, 2017) With prolonged use a range of harms, in addition to dependence, can come to outweigh the benefits of BDZs, including an increased risk of car accidents (Rudisill, Zhu, Kelley, Pilkerton, & Rudisill, 2016), cognitive and memory issues (Federico et al., 2017), worsening mood and sleep (Guina & Merrill, 2018), falls and fractures in older adults (Díaz-Gutiérrez et al., 2017), and dementia and premature mortality (Billioti de Gage et al., 2012). ...
Introduction
Benzodiazepines (BDZs) are often inappropriately prescribed to manage anxiety and insomnia for longer-term use, despite guidelines recommending short-term use (i.e., <4 weeks). A range of harms can occur rapidly with regular use, and dependence can make stopping BDZs challenging. Evidence shows that a combination of BDZ tapering and psychological support are effective interventions, yet are not widely accessible.
Methods
This was a one-group pilot trial of a 6-week fully automated self-help BDZ digital intervention (‘BDZ digital health’), providing guidance on how to safely taper BDZs as well as psychological support. The trial was undertaken with Australian adults considering a reduction and/or withdrawal from their BDZ (N = 43). Participants were assessed at pre-intervention (Week 0), during intervention (Week 3), post-intervention (Week 6), and at a 3- and 6-month follow-up (Week 18 and 30 respectively).
Results
Reductions in BDZ use and self-reported dependency were observed over the course of the intervention. Significant symptom reductions in anxiety, insomnia, depression, psychological distress, and emotional dysregulation, as well as improvements in mental wellbeing and quality of life were observed when looking across all timepoints. However, the specific assessment timepoint changes for depression and psychological distress did not reach significance from the pre- to post-intervention timepoint. The intervention acceptability ratings were in the moderately high to high range.
Discussion
The preliminary results of the pilot trial suggest that BDZ digital health is an acceptable and promising self-help digital intervention to assist adults reducing and withdrawing from their BDZs, and to improve their mental health and wellbeing.
Trial registration: ACTRN12617000574347 (24/04/2017).
... В ряде случаев это может привести к развитию дефицита холинергической активности с развитием центрального антихолинергического синдрома -специфического осложнения общей анестезии, проявляющегося нарушениями пробуждения в форме его замедления, резкого психомоторного возбуждения или выраженной мышечной дрожи, в патогенезе которого лежит острый дефицит центральной холинергической активности. Антихолинергические препараты, используемые в анестезиологии и интенсивной терапии, в большинстве своем проявляют избирательный антагонизм в отношении мускариновых рецепторов (атропин, скополамин), однако некоторые имеют смешанный механизм действия (антигистаминные препараты, антипсихотики, трициклические антидепрессанты), в то время как другие снижают секрецию ацетилхолина (опиаты, бензодиазепины, клонидин) [84,85]. ...
Impairment of higher mental functions can complicate the course of the postoperative period even after short and minimally invasive, including laparoscopic, surgical procedures. Postoperative cognitive dysfunction significantly challenges patients’ quality of life, negating real success of surgical intervention and anesthetic support. In some cases, early postoperative cognitive dysfunction may be one of the main predictors of persistent cognitive impairment.
The purpose of the review. To contemplate etiology, pathogenesis and the current perspective of postoperative cognitive dysfunction.
We analyzed 96 publications in various databases (PubMed, Medline, RSCI and others), including 67 papers published over the past 5 years.
The review provides an overview of current definitions and classification of postoperative cognitive dysfunction, data on the prevalence, polyethyology and risk factors, potential impact of the type of anesthesia and surgical intervention on the development of postoperative cognitive dysfunction. Various pathogenetic mechanisms of higher mental functions impairment alongside with available effective pharmacotherapies to correct them were considered.
C onclusion. Numerous adverse factors of the perioperative period, such as neurotoxic effects of general anesthetics, neuroinflammation in response to operational stress and surgical trauma, impaired autoregulation of the cerebral blood flow, imperfect oxygen homeostasis, interactions of neurotransmitter, etc., can potentially cause postoperative cognitive dysfunction. Further deeper insights into etiology and pathogenesis of early postoperative cognitive dysfunction are relevant and necessary to improve prevention strategies and identify most effective pharmacotherapies to correct such disorders.
... Only one study explored the neuropsychological effect of high-dose BDZ [42] on a population with mean daily diazepam equivalent dose similar to ours (253.5 ± 221.6 mg). This study involved a group of patients admitted to an Addiction Unit with an established diagnosis of BDZ use disorder lasting for more than 6 months and daily BDZ intake at least five times the maximum daily recommended dose (i.e., >50 mg diazepam/day), without neurological comorbidities, concurrent alcohol or psychotropic drug dependence. ...
Benzodiazepine (BDZ) misuse is a growing health problem, with 1–2% of patients under BDZ treatment meeting the criteria for use disorder or dependence. Although BDZ addiction potential has been known for decades, much remains unknown its effects on brain functions. The aim of this study was to assess the neuropsychological and neurophysiological profile of a group of chronic insomniacs taking long-term high doses of benzodiazepine. We recruited 17 consecutive patients admitted to our third-level Sleep Medicine Unit for drug discontinuation (7 males, mean age 49.2 ± 11.2 years, mean education 13.7 ± 3.9 years, mean daily diazepam-equivalent BDZ: 238.1±84.5 mg) and 17 gender/age-matched healthy controls (7 males, mean age 46.8 ± 14.1 years, mean education 13.5 ± 4.5 years). We performed a full neuropsychological evaluation of all subjects and recorded their scalp event-related potentials (Mismatch-Passive Oddball-Paradigm and Active Oddball P300 Paradigm). Patients with chronic insomnia and BDZ use disorder showed a profound frontal lobe executive dysfunction with significant impairment in the cognitive flexibility domain, in face of a preserved working, short and long-term memory. In patients, P300 amplitude tended to be smaller, mainly over the frontal regions, compared to controls. BDZ use disorder has a severe cognitive impact on chronic insomnia patients. Long-term high-dose BDZ intake should be carefully evaluated and managed by clinicians in this specific patient population, especially in relation to risky activities.
... In line with research conducted in Italy by Federico et al., benzos usage in this study adversely impacted executive functioning, particularly flexibility and problemsolving skills [48]. Despite the fact that studies conducted in Bangladesh by Chowdhury et al. [49] and Mexico by Contreras-González et al. [49], it indicated that benzodiazepines influence all domains of executive function. ...
Background
Substance abuse is a major health problem, associated with multiple clinical correlates. Cognitive dysfunctions were among the most relevant health problems associated with substance abuse among adolescents. The aim of the study is investigate the main cognitive domains affected in a sample of adolescents with substance use disorders. A case-control comparison was performed between 100 substance abusers versus 40 controls. The Mini-International Neuropsychiatric Interview v.5, Addiction Severity Index, Wisconsin Card Sorting Test, socioeconomic scale, and multiple historical variables investigated.
Results
Substance abusers showed higher mean than control as regard all other WCST domains. The difference between two groups was statistically significant. Cannabis substance mostly affects early conceptualization and problem-solving abilities, while inhalants affect predominantly sustained attention, and alcohol mostly affect cognitive flexibility. Polysubstance use is more harmful to most of the executive function domain than mono substance use.
Conclusions
The substance use disorders are a major health problem accompanied cognitive dysfunction among adolescents and associated with increased rates of executive dysfunction. Cognitive flexibility, sustained attention, problem-solving abilities, and early conceptualization are the most domains affected.
... Potentially confounding factors such as mood, co-morbidities, pain, and medications were not consistently measured or controlled for in all of the included studies. In many of the studies included, pwCD were also prescribed anticholinergics and benzodiazepines in addition to receiving BTX treatment for their symptoms, which have been shown to have an impact on cognitive function (Federico et al., 2017). Other potential confounding factors such as depression, anxiety or other common psychiatric co-morbidities were not adequately controlled for, which is an important consideration for future studies given the known impact of mood difficulties on cognition in addition to the effect of psychiatric medications (Prado et al., 2018). ...
Growing evidence points to a spectrum of non-motor symptoms, including cognitive difficulties that have a greater impact on functional outcomes and quality of life than motor symptoms in cervical dystonia (CD). Some cognitive impairments have been reported; however, findings are inconsistent, and described across mixed groups of dystonia. The current review aimed to examine the evidence for cognitive impairments in CD. MEDLINE, EMBASE, PsychINFO and Web of Science databases were searched. Studies were included if they met the following criteria (i) cross-sectional or longitudinal studies of adults with CD, (ii) where the results of standardised measures of cognitive or neuropsychological function in any form were assessed and reported, (iii) results compared to a control group or normative data, and (iv) were published in English. Results are presented in a narrative synthesis. Twenty studies were included. Subtle difficulties with general intellectual functioning, processing speed, verbal memory, visual memory, visuospatial function, executive function, and social cognition were identified while language, and attention and working memory appear to be relatively spared. Several methodological limitations were identified that should be considered when interpreting the evidence to describe a specific profile of cognitive impairment in CD. Clinical and research implications are discussed.
... The first group of factors is very diverse, and it is interesting that they exist even before the start of the operation. Among them, there are obvious ones, such as the administration of anticholinergic drugs or benzodiazepines for the purpose of premedication, which has long become by no means a positive tradition for many medical institutions [28,29]. A less obvious factor that is rarely paid attention to is the increased level of preoperative anxiety in the child, which significantly increases the risk of developing POD in the postoperative period [30,31]. ...
This chapter presents the current data on delirium in children in the postoperative period with the correction of congenital heart defects. The analysis of the causes of delirium, according to the literature data, pathophysiology, clinical signs, and methods of diagnosis of postoperative delirium, is shown. In addition, methods for the prevention of delirium in children during cardiac surgery are presented.
... Exposure to BZDs in BD individuals has been correlated with worse performance in measures of psychomotor speed, attention and executive functions; however, mean doses were higher than those in our study, and duration of exposure was not specified (Martino et al., 2008). In this sense, studies with BZD abusers found diffuse cognitive dysfunction, with deficits in verbal memory, working memory, visuospatial memory and attention (Federico et al., 2017). In our sample, higher BZD doses were significantly associated with worse performances in auditory memory domains and interference; however, cognitive performance in these areas was not significantly different between groups. ...
Objective
Neurocognitive dysfunction is a common feature of bipolar disorder even in euthymia, and psychopharmacological treatment could have an effect on cognition. Long-term prescription of benzodiazepines in bipolar disorder is a common practice, and their effect on neurocognition has not been well studied in this population. The aim of this study was to evaluate the impact of concomitant benzodiazepine long-term use on neurocognitive function in stable euthymic bipolar disorder patients.
Methods
Seventy-three euthymic bipolar disorder outpatients and 40 healthy individuals were assessed using a neurocognitive battery. Patients were classified in two groups according to the presence of benzodiazepines in their treatment: the benzodiazepine group ( n = 34) and the non- benzodiazepine group ( n = 39). Neurocognitive performance was compared between the groups using a multivariate analysis of covariance, considering age, number of depressive episodes, adjuvant antipsychotic drugs, Young Mania Rating Scale score and Hamilton Depression Rating Scale score as covariates.
Results
Both bipolar disorder groups (benzodiazepine and non-benzodiazepine) showed an impairment in memory domains (Immediate Visual Memory [ p = 0.013], Working Memory [ p < 0.001], and Letter-Number Sequence [ p < 0.001] from the Wechsler Memory Scale-Revised-III) and slower processing speed functions (Stroop Colour [ p < 0.001]) relative to the control group. Nevertheless, the benzodiazepine group showed a greater impairment in executive functions (Conceptual Level Responses [ p = 0.024] from the Wisconsin Card Sorting Test and Frontal Assessment Battery [ p = 0.042]).
Conclusion
Although memory and processing speed impairments were found in bipolar disorder, regardless of their benzodiazepine treatment, benzodiazepine users presented additional neurocognitive impairments in terms of executive functioning. These findings support restricted prescription of benzodiazepines in individuals with bipolar disorder.
... Consistent with previous systematic reviews, our meta-analysis suggests no impairment in global cognition among elderly BZD users (49,50). Interestingly, studies with young adults showed opposing results (51,52), suggesting BZD use significantly impairs participants' global cognitive functioning. One reason for these results may be the fact that the negative effect of various risk factors on global cognitive decline decreases with age (53). ...
Objective
Benzodiazepines (BZD) are one of the most frequently prescribed drugs worldwide. However, the cognitive effects of benzodiazepines in the elderly are highly debated. This systematic review and meta-analysis aims to explore the following two questions in the elderly population: (i) Do BZD lead to any impairments in cognitive functions in elderly users? and (ii) Which specific cognitive domains are most affected by BZD use and abuse?
Methods
First, we performed a literature search following the PRISMA guidelines. Electronic databases, including PubMed, PsycINFO, EMBASE, Cochrane Library, and Web of Science were searched until May 14th, 2020. After selecting the relevant articles, we integrated the results of the selected studies with a standardized cognitive classification method. Next, we performed meta-analyses with the random-effects model on the cognitive results. Finally, we specifically examined the cognitive impairments of BZD in the abuse subgroup.
Results
Of the included studies, eight of the thirteen had meta-analyzable data. Compared to the controls, elderly BZD users had significantly lower digital symbol test scores (n=253; SMD: -0.61, 95% CI: -0.91 to 0.31, I² = 0%, p < 0.0001). There was no significant difference in Mini-Mental State Examination, Auditory Verbal Learning Test, and Stroop Color and Word Test scores between BZD users and controls. According to the subgroup analyses, BZD abusers performed significantly worse than controls in Mini-Mental State Examination (n=7726; SMD: -0.23, 95% CI: -0.44 to -0.03, I² = 86%, p = 0.02), while there was no significant difference between the regular BZD users and the controls (n=1536; SMD: -0.05, 95% CI: -0.59 to 0.48, I² = 92%, p =0.85).
Conclusion
In the elderly population, the processing speed (digital symbol test scores) was significantly impaired in BZD users; global cognition (Mini-Mental State Examination scores) was significantly impaired in BZD abusers but not in BZD regular users. This study provides insight into the factors that interact with BZD cognitive effects, such as aging, testing tools, and abuse. Clinicians should be cautious when prescribing BZD for the elderly.
Systematic Review Registration
PROSPERO, identifier CRD42019124711.
... However, acute and chronic harms reported by Lombardi et al. [1] and us [2], respectively, represent the tip of the iceberg of BZD/ZD use and abuse, but other features, such as cognitive side effects, or the risk of cognitive decline, falls, and related fractures [4] should also be taken into account, especially in elderly people. This point is of great importance, because international guidelines currently recommend avoiding BZD and ZD use in the elderly, both in short-(<4 weeks) and long-term (≥4 weeks) treatments, but these drugs are frequently and inappropriately prescribed in older adults [1]. ...
... The estimated prevalence of higher-thanrecommended dose of anxiolytics and hypnotics was reported to be 0.14 and 0.06%, respectively, in Europe [7], and that of high-dose BZD use to be 0.16% in Switzerland [8]. We have previously found that high-dose BZD use is associated with worse quality of life (QoL) [9, 10] and multifocal cognitive dysfunction [11]. ...
Background:
Problematic high-dose benzodiazepine (BZD) and related Z-drug use for a long period is a substance use disorder previously found to be associated with adult attention-deficit/hyperactivity disorder (ADHD) and worse quality of life (QoL). Whether adult ADHD impacts QoL in high-dose BZD/Z-drug users has not been explored.
Aim:
The aim of the study was to explore the impact of adult ADHD on QoL in high-dose BZD and related Z-drug users.
Methods:
We recruited 393 patients (205 men and 188 women) consecutively admitted to the Department of Medicine, Addiction Medicine Unit, Verona University Hospital, Italy, from July 2016 to July 2019 for detoxification from high-dose BZD or Z-drug dependence. Demographic and clinical variables and QoL measures were recorded. The World Health Organization ADHD Self-Report Scale version 1.1 Symptom Checklist Part A was used to detect adult ADHD.
Results:
In our sample, 39.4% of patients were positive to adult ADHD testing (ADHD+), with some clinical features differing in comparison to patients negative to ADHD testing (ADHD-). QoL was worse in high-dose BZD/Z-drug users than the general population. The ADHD+ group showed significantly worse QoL measures than the ADHD- group. Multivariate analysis, including potential covariates showed adult ADHD and age to have the most robust and consistent positive effect for age (i.e., higher QoL) and negative effect for ADHD (i.e., lower QoL) on QoL measures.
Conclusions:
Adult ADHD is associated with worse QoL measures in high-dose BZD/Z-drug users. Future studies should explore whether appropriate BZD/Z-drug detoxification might improve QoL measures and whether the most appropriate detoxification protocol differs in ADHD+ versus ADHD- populations.
... According to the definition by Ruan and collaborators [33], reversible CF corresponds to SCD, a non-specific condition characterized by self-report of persistent decline in cognitive capacity in comparison with a previously normal status and unrelated to an acute event, without objective impairment detected by standardized neuropsychological tests [41]. SCD may result from multiple causes, such as normal aging, preclinical AD, other psychiatric and neurologic disorders, side effect of drugs and substance use disorders (SUD) [41,62,63]. Indeed, neurobehavioral changes should have a clearly defined recent onset, be persistent and not explained by life events [59]. ...
Background
The progressive aging of the population will dramatically increase the burden of dementia related to Alzheimer’s disease (AD) and other neurodegenerative disorders in the future. Because of the absence of drugs that can modify the neuropathological substrate of AD, research is focusing on the application of preemptive and disease-modifying strategies in the pre-symptomatic period of the disease. In this perspective, the identification of people with cognitive frailty (CF), i.e., those individuals with higher risk of developing dementia, on solid pathophysiological bases and with clear operational clinical criteria is of paramount importance.
Objective/Methods
This hypothesis paper reviews the current definitions of CF, presents and discusses some of their limitations, and proposes a framework for updating and improving the conceptual and operational definition of the CF construct.
Results
The potential for reversibility of CF should be supported by the assessment of amyloid, tau, and neuronal damage biomarkers, especially in younger patients. Physical and cognitive components of frailty should be considered as separate entities, instead of part of a single macro-phenotype. CF should not be limited to the geriatric population, because trajectories of amyloid accumulation are supposed to start earlier than 65 years in AD. Operational criteria are needed to standardize assessment of CF.
Conclusion
Based on the limitations of current CF definitions, we propose a revised one according to a multidimensional subtyping. This new definition might help stratifying CF patients for future trials to explore new lifestyle interventions or disease-modifying pharmacological strategies for AD and dementia.
... Weaker attentional ability is expected in individuals with epilepsy, as not only can seizure activity disrupt the cortical regions and circuits in the brain necessary to sustain attention but antiepileptic medications known to be effective in reducing abnormal brain activity (Glauser et al. 2016) also notoriously impact attentional capacity (Dunn and Kronenberger 2016). While overwhelming evidence suggests significant neuropsychological deficits in those with high-dose benzodiazepine use and those who develop dependence (Crowe and Stranks 2017;Federico et al. 2017), use in pediatric and otherwise healthy populations is also shown to negatively impact important cognitive functions ranging from attention to shortterm memory (Buffet-Jerrott et al. 2003). Clobazam is reported as a treatment option with reduced sedation potential due to high affinity for α2 of the GABA A receptor (Ochoa and Kilgo 2016) and improve quality of life assessed by parent reports (Weinstock et al. 2018), but still serves to depress the central nervous system. ...
Objective An 8-year-old, Caucasian, and right-handed female presented for a baseline neuropsychological evaluation due to diagnosis of electrical status epilepticus during sleep (ESES) preceded by postictal, late-night discovery of the patient on the floor and subsequent overnight electroencephalography. This first recognized seizure was tonic-clonic.
Method The patient was born at 39 weeks gestation weighing approximately 5 lb, subsequently spending 48 h in NICU due to low birth weight and hypoglycemia. Developmental milestones were recalled within normal limits (WNL). The patient is prescribed levetiracetam, clobazam, and acetazolamide and has undergone multiple EEGs since diagnosis. Remaining medical history unremarkable including absence of known head trauma. Family history is remarkable for anxiety and developmental disability.
Results Tests suggest global impairment, particularly in motor abilities and processing speed. Academic achievement is average across basic reading and writing, but verbal learning and memory are significantly diminished unless in story form. Evidence of impulsivity and inattention were present along with deficits in mathematics. Affect recognition was intact and tests of cognitive flexibility and planning were discontinued.
Conclusion ESES generally presents early and results in neuropsychological deficits that are dependent upon length of condition and frequency and intensity of seizures. While deficits may improve when ESES subsides in pre-pubescence, some may persist into adulthood with high outcome variability. Baseline and ongoing neuropsychological testing are critical to early, targeted interventions and ongoing care. When early baselines are not feasible, it is important to construct a detailed, data-driven conceptualization to accommodate potential factors involved in notable deficits.
... mg daily diazepam dose equivalent) BZD abusers of comparable demography (age 44.2 6 9.7 years, education 13.4 6 3.0 years), which showed very significant changes in all the neuropsychological domains (ie, verbal, visuospatial memory, working memory, attention, and executive function) that survived after adjustment for sex and age and were minimally influenced by depression and anxiety. 9 The discrepancy between the results from Saloner et al 1 and ours can be related to the presence of a BZD dose-effect curve, whereby BZD high-dose may cause more severe cognitive dysfunction. Alternatively, the small changes they reported might be related to the coexistence of psychiatric comorbidities (depression and anxiety), whose scores were significantly higher in PLWH reporting BZD use, or sleep disorders that were not recorded. ...
... Since that time evidence of broad-ranging harms resulting from long-term BDZ use has continued to grow, including cognitive deficits [8][9][10], reductions in quality of life [11][12][13], depression [14][15][16], risk of suicide [17], risk for road accidents [18,19], and specific to older adults-the risk of falls [20][21][22], developing dementia [23][24][25], and of mortality [26][27][28]. Short-term, paradoxical effects such as increased anxiety, agitation, disinhibition, and aggression have also been observed [29,30]. ...
: Internationally there is an escalation of prescription-related overdose deaths, particularly related to benzodiazepine use. As a result, many countries have implemented prescription monitoring programs (PMPs) to increase the regulation of benzodiazepine medications. PMPs centralize prescription data for prescribers and pharmacists and generate alerts to high-doses, risky combinations, or multiple prescribers with the aim to reduce inappropriate prescribing and subsequently the potential of patient harm. However, it has become clear that prescribers have been provided with minimal guidance and insufficient training to effectively integrate PMP information into their decision making around prescribing these medications. Accordingly, this paper discusses how PMPs have given rise to a range of unintended consequences in those who have been prescribed benzodiazepines (BDZs). Given that a gradual taper is generally required to mitigate withdrawal from BDZs, there are concerns that alerts from PMPs have resulted in BDZs being ceased abruptly, resulting in a range of unintended harms to patients. It is argued that best practice guidelines based upon a patient-centered framework of decision-making, need to be developed and implemented, in order to curtail the unintended consequences of PMPs. This paper outlines some key considerations when starting the conversation with patients about their BDZ use.
... However, this association remains less well understood, and symptoms that BZDs or z-hypnotics are indicated for may be the prodromal symptoms of dementia. The use of BZDs and zhypnotics may result in acute cognitive decline [15], but evidence regarding their long-term use and cognitive decline varies greatly [16][17][18][19][20][21]. Although some studies have suggested that BZDs and z-hypnotics may not have long-term effects [16,17], others have reported a potential association between the use of BZDs and z-hypnotics and the subsequent development of dementia or Alzheimer's disease [22,23]. ...
The utilization of benzodiazepines (BZDs) and z-hypnotics has substantially increased with the aging of the population, but the risk of BZDs and z-hypnotics in the development of dementia remains a strong concern. This cohort study aimed to evaluate the risk of BZDs and z-hypnotics for subsequent dementia development with a special consideration of their half-lives and the concomitant use of these medications. People aged 65 years and older who were newly prescribed oral BZDs or z-hypnotics between 2003 and 2012 were identified from Taiwan’s National Health Insurance Research Database. All BZDs were categorized as long-acting drugs (≥ 20 h) or short-acting drugs (< 20 h) for further comparisons, and data were collected on a quarterly basis, starting on the first date of drug prescription and ending on the date of death, occurrence of dementia, or end of the follow-up period (December 31, 2012), whichever came first. All dementia events except vascular dementia occurring during the follow-up period were identified. Among 260,502 eligible subjects, short-acting BZDs and z-hypnotics users were at greater risk of dementia than long-acting users [adjusted odds ratio (95% confidence interval) in short-acting BZD users, 1.98 (1.89–2.07); z-hypnotic users, 1.79 (1.68–1.91); and long-acting BZD users, 1.47 (1.37–1.58)]. In addition, subjects concomitantly using 2 or more BZDs or z-hypnotics had a higher risk of dementia than those who used 1 of these drugs (4.79 (3.95–5.81)). The use of BZDs and z-hypnotics was strongly associated with the risk of dementia development, especially the short-acting BZDs, z-hypnotics, and concomitant use of multiple agents. These findings deserve further interventional studies for clarification.
... Meta regression indicated that drug dose was not significantly related to the overall effect of corticosteroids on cognition. This finding is surprising, given that medications with cognitive side effects are frequently demonstrated to influence cognitive functioning in a dose-dependent manner (Federico et al., 2017;Mula, 2012;Newcomer et al., 1999;Warrington & Bostwick, 2006). This finding is also inconsistent with previous research which has demonstrated the dose-dependent effect of corticosteroids on a range of neuropsychiatric outcomes, including psychiatric symptoms (Brown & Chandler, 2001), working memory function (Lupien et al., 1999), associative learning (Brown, 2009) and memory (Beckwith et al., 1986). ...
A thorough understanding of the cognitive effects of corticosteroids is essential given their frequency of use. This meta-analysis was conducted to investigate the effects of corticosteroids on the various domains of cognitive functioning, grouped by duration of use. An electronic search of PsycInfo, Medline and Google Scholar was conducted for all journal articles published between January 1990 and May 2018. Twenty six studies were included enabling calculation of standardised mean difference (SMD) using a random effects model for the cognitive domains of divided attention, executive function, expressive language, immediate memory, processing speed, recent memory, sustained attention, very long term memory and working memory. Results revealed that corticosteroids had a modest, negative effect on executive function for acute users, recent memory for short term and chronic users, and very long term memory for acute users. Corticosteroids had a small, significant, positive effect on expressive language for short term users.
... High-dose BZD dependence is an emerging substance use disorder (SUD) [2,6] associated with poor quality of life [7,8] and multifocal cognitive dysfunction [9]. The prevalence of high-dose BZD dependence in Switzerland was estimated to be 0.16% of the adult population [10], but there are no data from other countries. ...
High-dose benzodiazepine (BZD) abuse is emerging as a substance use disorder (SUD). The aim of the study is to explore the impact of high-dose lormetazepam (LMZ) abuse and the characteristics of patients affected by this SUD in a tertiary referral addiction unit. We have retrospectively evaluated 1112 patients admitted to the Addiction Medicine Unit, Verona University Hospital, Italy for detoxification from high-dose BZD dependence. LMZ was the most common BZD, with an increasing prevalence from January 2003 to June 2018. Socio-demographic (more women; higher age and education) and clinical features (higher daily diazepam dosage equivalent, BZD abuse duration, age of first BZD intake; BZD prescribed more frequently for sleep disorders; less frequent history of other SUDs, previous/active alcohol, previous opioids abuse; more frequent overall major psychiatric diseases and major depression; less-frequent bipolar disorders and other psychoses, personality disorders, and more than one psychiatric disease) of LMZ vs. other BZD abusers significantly differed. 96.7% LMZ abusers took oral solution, while two-thirds of other BZD abusers took tablets. Oral solution, BZD abuse duration and prescription of BZD for sleep disorders increased, while history of other SUDs, previous/active alcohol and active cannabinoids SUD reduced the risk of high-dose LMZ vs. other BZDs abuse. The large prevalence of high-dose LMZ abusers in Italy may be strongly related to the availability and characteristics of oral formulation that may transform the innocuous Dr. Jekyll tablets into an evil Mr. Hyde. Restriction to the market of LMZ oral formulation might reduce the risk of high-dose abuse.
... From several electrophysiology studies, it has been speculated that dystonia arises from increased inhibition of both the STN and GPi by inputs from the globus pallidus externus, causing disinhibition of the thalamus and increased excitation to the cortex (132). Pathophysiology of cognitive modifications in dystonia after DBS is not concrete, but a few theories have been postulated to explain potential dysfunctions: anti-dystonic medications affecting memory (133,134), concurrent mood disorders (i.e., depression or anxiety) leading to impairments in executive function or other cognitive domains (135)(136)(137)(138), or severe motor impairments shadowing intact cognitive functioning (139,140). Altogether, evidence suggests that dystonia patients have intact global cognition, language and memory, while isolated incidents of impaired executive function and sustained attention may stem from fronto-striatal abnormalities (137,140,141). ...
Introduction: Although the benefit in motor symptoms for well-selected patients with deep brain stimulation (DBS) has been established, cognitive declines associated with DBS can produce suboptimal clinical responses. Small decrements in cognition can lead to profound effects on quality of life. The growth of indications, the expansion of surgical targets, the increasing complexity of devices, and recent changes in stimulation paradigms have all collectively drawn attention to the need for re-evaluation of DBS related cognitive outcomes.
Methods: To address the impact of cognitive changes following DBS, we performed a literature review using PubMed. We searched for articles focused on DBS and cognition. We extracted information about the disease, target, number of patients, assessment of time points, cognitive battery, and clinical outcomes. Diseases included were dystonia, Tourette syndrome (TS), essential tremor (ET), and Parkinson's disease (PD).
Results: DBS was associated with mild cognitive issues even when rigorous patient selection was employed. Dystonia studies reported stable or improved cognitive scores, however one study using reliable change indices indicated decrements in sustained attention. Additionally, DBS outcomes were convoluted with changes in medication dose, alleviation of motor symptoms, and learning effects. In the largest, prospective TS study, an improvement in attentional skills was noted, whereas smaller studies reported variable declines across several cognitive domains. Although, most studies reported stable cognitive outcomes. ET studies largely demonstrated deficits in verbal fluency, which had variable responses depending on stimulation setting. Recently, studies have focused beyond the ventral intermediate nucleus, including the post-subthalamic area and zona incerta. For PD, the cognitive results were heterogeneous, although deficits in verbal fluency were consistent and related to the micro-lesion effect.
Conclusion: Post-DBS cognitive issues can impact both motor and quality of life outcomes. The underlying pathophysiology of cognitive changes post-DBS and the identification of pathways underpinning declines will require further investigation. Future studies should employ careful methodological designs. Patient specific analyses will be helpful to differentiate the effects of medications, DBS and the underlying disease state, including disease progression. Disease progression is often an underappreciated factor that is important to post-DBS cognitive issues.
... Thus, it is plausible that subjective and objective illness severity has different effects on subjective cognitive impairment in patients with MDD. Furthermore, while objectively assessed cognitive impairment appears to be affected by the severity of depression, duration of illness, and medications used (Borkowska and Rybakowski, 2001;Federico et al., 2017;Gorenstein et al., 2006;Hasselbalch et al., 2011;Tourjman et al., 2018), it remains unclear which demographic and clinical factors affect subjective cognitive impairment. ...
Objective: The impact of subjective vs. objective illness severity on subjective cognitive impairment in patients with depression has not been addressed. Methods: This study is a post-hoc analysis of our cross-sectional study in Japanese outpatients with depressive disorder (ICD-10) (Ozawa et al., 2017). The participants received assessments with the Japanese version of the Perceived Deficits Questionnaire (J-PDQ), Quick Inventory of Depressive Symptomatology (QIDS), and Montgomery–Asberg Depression Rating Scale (MADRS). First, multiple regression analysis was conducted to examine the effects of demographic and clinical characteristics, including illness severity and medications (e.g., antidepressants and benzodiazepines), on the PDQ total score. Next, we categorized the participants into 4 groups based on the presence/absence of subjective and objective symptom remission (i.e., QIDS total score of ≤5 and MADRS total score of ≤9, respectively), and compared the differences in PDQ total scores between the QIDS- and MADRS-remitted group and the QIDS-non-remitted but MADRS-remitted group. Results: 102 participants were included (45 men; mean ± SD age, 50.5 ± 14.7 years). Higher QIDS and MADRS total scores were significantly associated with a greater PDQ total score (both p's < 0.001), while other factors did not exhibit any associations. The QIDS-non-remitted but MADRS-remitted group showed a significantly higher PDQ total score than that of the QIDS- and MADRS-remitted group (median 10.0 [8.0–12.0] vs. 3.0 [range: 2.0–4.0], p < 0.001). Conclusions: These findings suggest that objective remission in the absence of subjective remission may not be adequate to improve subjective cognitive functioning.
... One did not find any deficits on the Mini Mental State Examination or the Frontal Assessment Battery in either group (Dias et al, 2009) and the other study (Lange et al, 2016a) found deficits on a computerized WCST for the patients with blepharospasm but not those with hemifacial spasm, suggesting that these deficits were not simply due to symptom-related distraction. A second potential confounding factor is the anticholinergic and benzodiazepine medication that many patients are taking for the treatment of their dystonia, which could independent of the dystonia have a negative impact on cognitive function (Taylor et al, 1991); Britt and Day, 2016;Lampela et al, 2015;Federico et al, 2017). Third, as discussed below, depression and anxiety and obsessive compulsive disorder (OCD) are common psychiatric comorbidities in dystonia for which at least a proportion of the patients would have been taking psychoactive medication and these co-morbidites and their medical treatment could also independently influence cognition (Austin et al, 1992;Purcell et al, 1997;Vytal et al, 2013;Chamberlain e al, 2005). ...
Dystonia is a hyperkinetic movement disorder, characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Executive dysfunction is a feature of cognitive function in idiopathic and DYT1 dystonia. Psychiatric morbidity is increased in dystonia, and depression, anxiety, obsessive compulsive disorders are the most common disorders. Sleep problems and pain are also frequently experienced. Evidence suggest that mood and anxiety disorders are intrinsic to the neurobiology of dystonia, but also that psychiatric co-morbidity can be secondary to pain experience and the psychosocial functioning and quality of life of the patients. Medical treatment of dystonia with botulinum toxin injections into affected muscles or with deep brain stimulation surgery improves the symptoms as well as mood and the quality of the patients and does not produce any adverse effects on cognitive function. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]
... Benzodiazepines, Z-drugs, antidepressants and neuroleptics contribute to cognitive deficits in patients [13][14][15]. Chronic use of benzodiazepines is associated with a lower latent cognitive level [16]. Antidepressants or neuroleptics with strong anticholinergic side effects are more likely to induce cognitive decline than less anticholinergic drugs [17]. ...
Background
Many elderly patients receive psychotropic drugs. Treatment with psychotropic agents is associated with serious side effects including an increased risk of falls and fractures. Several psychotropic drugs are considered potentially inappropriate for treatment of the elderly.
Methods
A retrospective chart review was conducted covering all patients aged ≥ 65 years who were admitted to Evangelisches Krankenhaus Göttingen-Weende between 01/01/2013 and 03/31/2013. Psychotropic drugs reviewed for included benzodiazepines, Z-drugs, antidepressants and neuroleptics, but not drugs for sedation during artificial ventilation or pre-medication before surgery. Potentially inappropriate drugs were identified according to the PRISCUS list. To assess which factors were associated with the administration of psychotropic drugs, univariate and multivariable logistic regression analyses were performed.
Results
The charts of 2130 patients (1231 women) were analyzed. 53.9% of all patients received at least one psychotropic medication (29.5% benzodiazepines, 12.6% Z-drugs, 22.2% antidepressants, 11.9% neuroleptics). The mean number of psychotropic drugs prescribed per patient with at least one prescription was 1.6. Patients treated in the geriatric department most often received antidepressants (45.0%), neuroleptics (20.6%) and Z-drugs (27.5%). Benzodiazepines and Z-drugs were prescribed mostly as medication on demand (77.7% of benzodiazepines, 73.9% of Z-drugs). Surgical patients most frequently received benzodiazepines (37.1%). Nearly one-third of all patients ≥ 65 years was treated with at least one potentially inappropriate psychotropic medication. The mean number of potentially inappropriate psychotropic medications per patient with at least one psychotropic prescription was 0.69. The percentage of patients with potentially inappropriate psychotropic medication was highest in the surgical departments (74.1%). Female gender (adjusted OR 1.36; 95% CI 1.14 to 1.63), stay in the Department of Geriatrics (2.69; 2.01 to 3.60) or the interdisciplinary intensive care unit (1.87; 1.33 to 2.64) and age ≥ 85 years (1.33; 1.10 to 1.60) were associated with psychotropic drug treatment.
Conclusions
A high percentage of patients aged ≥ 65 years received psychotropic drugs. The chance that a potentially inappropriate psychotropic drug would be administered was highest in the surgical departments. Antidepressants, neuroleptics and Z-drugs were used surprisingly often in geriatric medicine. Educational strategies could reduce the use of psychotropic drugs and the prescription of potentially inappropriate medications.
Currently, cardiovascular diseases remain the leading ones in mortality among other causes. Increasingly, interventional methods are used in their treatment. In the postoperative period, complications in the form of somatogenic psychoses, including postoperative delirium, are not uncommon. The purpose of the review is to study the prevalence, pathophysiological hypotheses and mechanisms of delirium, as well as risk factors and outcomes associated with the development of this complication in cardiac surgery. Materials and methods. Information was searched in the PubMed database by Key words: delirium, postoperative period, cognitive dysfunction, cardiac surgery. The search yielded a total of 57 results. During the review of titles and abstracts, 47 articles were selected for detailed consideration. Results. There are three forms of postoperative delirium: hyperactive, hypoactive, mixed. The frequency of confused mental state development after heart surgery is 26-52%, and its hypoactive form dominates. Delirium is considered as an acutely developing, reversible nonspecific syndrome of multifactorial etiology, characterized by a combined disorder of consciousness and attention, perception, thinking, memory, sleep–wake rhythm, psychomotor disorders with alternating hypo- and hyperactivity. The factors influencing the onset of delirium include increased inflammatory response, changes in the concentration of neurotransmitters (especially acetylcholine), electrolyte and metabolic and hemodynamic disorders, and the presence of a genetic predisposition. There is a number of preoperative, intraoperative and postoperative risk factors for the development of delirium in patients after cardiac surgery. Delirium after cardiac surgery is associated with such adverse outcomes as increased mortality, stroke risk, sepsis development, more frequent repeated hospitalizations and persistent severe cognitive impairment during 1 year after the surgery. Differential diagnosis is carried out for depression, dementia, psychogenic psychoses and organic lesions of the central nervous system. Delirium treatment is aimed at eliminating the underlying cause; it includes supportive therapy, correction of agitation, elimination of water-electrolyte disorders and elimination of provoking factors (discontinuation of the causal drug), replenishment of nutritional deficiencies, vitamins B12 or B1 (thiamine) with adequate dietary regimen and fluid intake. Conclusions. Taking into consideration that delirium is a dangerous condition that develops in the postoperative period, the following main provisions are important: 1) eliminate correctable risk factors in every period of surgical intervention in outpatient and inpatient settings; 2) carry out drug prevention and, if necessary, delirium therapy; 3) increase alertness regarding the occurrence of confused mental state episodes in patients in the postoperative period; 4) conduct screening in patients over the age of 65 to assess the main risk factors of delirium, cognitive impairment development.
Objectives:
Neurocognitive complications significantly reduce long-term health-related quality of life in patients undergoing liver transplantation; however, few studies have focused on their perioperative cognitive status. The authors designed a prospective observational study to determine the incidence and risk factors of posttransplant cognitive dysfunction.
Methods:
This study included patients with end-stage liver disease who were on the liver transplantation waiting list. We performed an investigation with a neuropsychological battery before and 1 week after the successful transplant, analyzed the changes, and further explored the complicated perioperative factors that contribute to cognitive dysfunction.
Results:
A total of 132 patients completed all the investigations. Compared with healthy controls and preoperative cognitive performance, 54 patients experienced deterioration, 50 patients remained unchanged, and 28 patients showed rapid improvement. Logistic regression analysis showed that age [odds ratio (OR) = 1.15, 95% confidence interval (CI, 1.07-1.22), P < 0.001], the model for end-stage liver disease (MELD) score [OR = 1.07, 95% CI (1.03-1.13), P = 0.038], systemic circulation pressure [OR = 0.95, 95% CI (0.91-0.99), P = 0.026] within the first 30 min after portal vein opening, and total bilirubin concentration [OR = 1.02, 95% CI (1.01-1.03), P = 0.036] on the seventh day post-transplant were closely related to the deterioration of cognitive function.
Conclusion:
The incidences of deterioration, maintenance, and improvement in cognitive function were 40.9%, 37.9%, and 21.2%, respectively. Increasing age, higher MELD score, lower perfusion pressure in the early stage of the new liver, and higher total bilirubin concentration postoperatively may be independent pathogenic factors.
In the last years, only few studies in literature have focused on the use and abuse of benzodiazepines (BZDs) in sport. Benzodiazepine-related problems include misuse, addiction, driving impairments, and morbidity and mortality related to overdose and withdrawal. Two clinical cases regarding elite endurance athletes evidenced that they had started to use BZDs to counteract insomnia, to recover faster from training sessions and to manage muscle pain. One of the important points that emerged from their stories was that their sports doctors did not recognize the drugs’ addictive properties, and did not intervene to gradually reduce the dosage. Experts have previously provided recommendations for BZD therapy management in clinical practice. In this article, we would like to address sports medicine physicians specifically and provide guidelines to help them manage situations involving BZD prescription, the recognition of addiction, and intervention strategies.
Aim
This study investigated the bromazepam effects in male subjects during the time estimation performance and EEG alpha asymmetry in electrodes associated with the frontal and motor cortex.
Material and methods
This is a double-blind, crossover study with a sample of 32 healthy adults under control (placebo) vs. experimental (bromazepam) during visual time-estimation task in combination with electroencephalographic analysis.
Results
The results demonstrated that the bromazepam increased the relative error in the 4 s, 7 s, and 9 s intervals (p = 0.001). In addition, oral bromazepam modulated the EEG alpha asymmetry in cortical areas during the time judgment (p ≤ 0.025).
Conclusion
The bromazepam decreases the precision of time estimation judgments and modulates the EEG alpha asymmetry, with greater left hemispheric dominance during time perception. Our findings suggest that bromazepam influences internal clock synchronization via the modulation of GABAergic receptors, strongly relating to attention, conscious perception, and behavioral performance.
The issue of organ protection has always occupied a special position in cardiac surgery due to the use of cardiopulmonary bypass (CPB). CPB is a necessary part of most cardiac surgeries. However, perfusion also poses an advanced risk for the patient’s organs and systems. Brain is very sensitive to various pathological influences. Thus, on-pump surgery often results its damage and dis-ruption of normal function for a short or long period. The authors report such violations and their incidence. In addition, atten-tion is focused on pathophysiological mechanisms of cerebral damage under CPB considering the concept of neurovascular unit of the brain. These factors are cerebrovascular embolism, insufficient cerebral oxygenation, intraoperative transfusion and systemic inflammatory response as a multifactorial process. Etiology of this process includes all of the above-described factors, as well as ma-ny others mentioned in the article. The authors discuss the modern methods of monitoring and prevention of these complications.
Chronic use of benzodiazepines (BDZs) is a widespread phenomenon which can lead to side effects such as tolerance, dependence and cognitive impairment, as well as resulting in accidents at work. High-dose BDZ dependence (HD-BDZ) is little studied, and it is mainly attributed to major psychiatric disorders and polydrug abuse. To date, few studies have investigated HD-BDZ among active workers, with none among health-care professionals (HPs). Tapering from high doses of BDZs can cause severe withdrawal symptoms, including seizures. The Addiction Unit of the University Hospital in Verona uses a protocol based on flumazenil slow infusion (FLU-SI), the safest and most effective treatment for HD-BDZ. Since 2003, 1281 patients have been detoxified from long-term use of high doses of BDZ using FLU-SI. The sample includes 139 (10.8%) HPs. Mean daily doses were 336 mg diazepam equivalent among HPs and 365 mg diazepam equivalent among non-HPs (no statistically significant difference). HPs are at higher risk of sleep disorders and work-related stress. Most of these HPs experience difficulties at work due to cognitive impairment, but they are often afraid of the potential legal implications and too ashamed to ask for help. It is important to study the prevalence of HD-BDZ among HPs and to investigate the impact on their working skills and working eligibility.
The number of anesthetic managements is constantly increasing all over the world. However, there are always cases of postoperative delirium despite all modern technologies and drugs. In surgery of congenital heart diseases, the incidence of delirium is tra-ditionally high due to a large number of pathological factors of these operations. Most of them are due to cardiopulmonary by-pass. This review is devoted to etiology and epidemiology of delirium. We have analyzed the most significant articles and clinical recommendations on postoperative delirium and determined essential perioperative risk factors of this event. Pathophysiology of delirium and its clinical manifestations are described. Moreover, the diagnosis of delirium at the intensive care unit with vari-ous special scales was demonstrated.
Benzodiazepines are frequently prescribed on an ongoing basis to individuals with depression, mainly to alleviate anxiety or insomnia, despite current guideline recommendations that continuous use should not exceed 4 weeks. Currently, there are no efficacy trials published beyond 8 weeks. Several antidepressant trials demonstrate that the concomitant use of a benzodiazepine is associated with poorer depressive outcomes and functional status; however, it is unclear why this is the case. Patients with depression receiving a benzodiazepine may reflect a more ill or high anxiety group, although even within anxiety disorders, the use of a benzodiazepine is associated with poorer outcomes. The neuroadaptive consequences of long-term benzodiazepine use may be a factor underlying these findings. Chronic benzodiazepine use results in decreased gamma-aminobutyric acid and monoaminergic function, as well as interference with neurogenesis, which are all purported to play a role in antidepressant efficacy. This review will discuss the oppositional neuropharmacological interactions between chronic benzodiazepine use and antidepressant mechanism of action, which could result in reduced antidepressant efficacy and function in depression.
Background and Aims. Benzodiazepines have been widely used for long periods of time despite their adverse effects. The acute effects on cognition are well established. However, less is known about the long-term effects. This study critically reviewed existing evidence of the association between long-term exposure to benzodiazepines and risk of cognitive decline in adults. Methods. A systematic review with narrative synthesis was conducted. PubMed and PsycINFO databases were searched using combinations of keywords related to “benzodiazepines” and “cognitive function” from database inception to 12 February 2018 to identify prospective longitudinal studies. The records were evaluated for relevance according to the inclusion and exclusion criteria. Results. Fourteen studies involving 2145 long-term benzodiazepine users were included. Meta-analysis was not undertaken because the combined result would not be meaningful as the included studies differed in several key aspects such as frequency and duration of benzodiazepine use, follow-up periods, cognitive domains, cognitive tests, scoring systems, and statistical analysis. The definition of long-term benzodiazepine use was problematic in all the studies. The exposure was determined by measures which were assumed to represent the whole period in-between the follow-ups. Only 3 of the 14 studies provided support for an association between long-term benzodiazepine use and cognitive decline with a small to medium effect size. However, these three studies used different methods to assess the strength of this association. Global cognitive functioning, verbal memory, intelligence, psychomotor speed, and speed of processing were the cognitive domains affected which also varied across these three studies. Conclusions. Little evidence of an association between long-term benzodiazepine use and a higher risk of cognitive decline among the general adult population was found. However, discrepancies among the results and inconsistencies regarding the cognitive domains affected and methodological limitations prevent definite conclusions. Therefore, future research with prospective studies specially designed would be of great value.
1. Introduction
The prevalence of long-term use of benzodiazepine (BZD) worldwide, including the BZD related drugs called Z-drugs, is approximately 3% in the general population despite the repeated warnings over their safety and lack of evidence of long-term effectiveness [1–3]. The acute cognitive effects of BZDs are well established [3, 4]. However, the long-term impact on cognition is still an area of debate, despite epidemiological evidence which suggests that exposure to BZD might be a risk factor for cognitive impairment and cognitive decline [3, 5, 6]. Cognitive impairment refers to impairments in one or more cognitive functions according to a cognitive performance cutoff point and measured at a single time point whereas cognitive decline involves any deterioration in cognitive function over time according to change in cognitive performance between baseline and follow-up [7, 8]. Cognitive decline is more difficult to assess properly than cognitive impairment as its definition is sometimes arbitrary depending on the cognitive test and the statistical approach used [7]. For this reason, cognitive decline associated with long-term BZD use has been assessed by few prospective longitudinal studies.
Verdoux et al. [9] explored the association between long-term BZD use and cognitive decline through a literature review of prospective studies with unselected subjects from general population and concluded that there were many inconsistencies across the studies. Methodological issues such as differences in sampling method, nonspecification of parameters of BZD use, variation in the definition of BZD long-term exposure, cognitive assessment, follow-up characteristics, potential confounders, and statistical analyses might have compromised the comparability of findings [9, 10].
Also, a series of meta-analyses of the effects of long-term BZD use (≥1 year) on cognition were conducted by Barker et al. in 2004 [11, 12] and updated by Crowe and Stranks in 2018 [13]. Crowe and Stranks corroborated the findings of Barker et al. that there is an association between current [11] or previous [12] long-term BZD use and cognitive impairment. However, the findings might be difficult to generalise as most studies included in these meta-analyses were conducted on populations of problematic BZD users requiring specialised treatment, and thus the impairments measured could be related to the return of premorbid symptoms rather than reflecting the effects of chronic BZD treatment [9, 14]. In addition, these three meta-analyses address the concept of cognitive impairment indicating a cross-sectional deleterious effect of BZDs as opposed to the concept of cognitive decline which involves the longitudinal effects of BZDs on cognitive change with age [7].
Considering that the existing review [9] is somewhat out of date and no systematic review has been conducted on epidemiological studies that addressed the association between long-term BZD use and cognitive decline, the question remains open. Taken together, the potential burden of impaired cognitive functioning on society, the discrepancy of findings, and the methodological limitations of the studies, an updated review of prospective longitudinal studies addressing this issue is warranted. The aim of this review was to evaluate and integrate current data available by systematically reviewing studies that examined the association between cognitive decline and long-term exposure to BZDs in the general population.
2. Methods
This is a systematic literature review of prospective longitudinal studies that assessed the risk of cognitive decline in long-term BZD users compared with nonusers. It was conducted in line with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines (Supplementary Materials Appendix S1) [15].
2.1. Data Source
The target population was defined as the general population (adults aged 18 or older) with no restriction as to the setting. Studies involving individuals with schizophrenia or other psychotic disorder as well as those with a comorbid substance use disorder other than BZD use were excluded. These conditions have been associated with cognitive impairment and therefore might have affected the results and the generalisability of the findings [16, 17]. The exposure was long-term BZD use defined as the use of a BZD for six months or longer during a time period of one year regardless of whether the use was daily or infrequent [1]. For the purpose of this review, BZDs included the Z-drugs. The comparator (control) group consisted of individuals who were BZD nonusers. The primary outcome of interest investigated was cognitive decline assessed using cognitive function tests [11].
2.2. Inclusion and Exclusion Criteria
Inclusion criteria were as follows: (1) prospective longitudinal studies that investigated the effects of long-term BZD use on cognitive decline; (2) administration of cognitive tests at a minimum of two time points with no minimum period of follow-up required; (3) presence of a control group of BZD nonusers; (4) human studies with adults aged 18 years or over; (5) studies published in English in peer-reviewed journals.
The exclusion criteria were as follows: (1) retrospective or cross-sectional studies; (2) studies with children or adolescents (<18 years old); (3) studies involving participants with schizophrenia or other psychotic disorder; (4) studies involving participants with a substance use disorder other than BZD; (5) BZD use for less than six months or not specified; (6) studies that focused on the effects of withdrawing from BZD; (7) studies with dementia as the only outcome; (8) specific information about the cognitive tests utilized not included; (9) control group which included subjects with prior long-term use of BZD.
2.3. Data Selection
Electronic searches were conducted in the PubMed and PsycINFO databases (via APA PsycNET platform) to identify potential studies to be included in the review. The searches were carried out for scientific papers with no publication date restrictions. Searches were based on combinations of keywords related to “benzodiazepines” and “cognitive function,” with separate searches for Z-drugs (details are given in Supplementary Materials Appendices S2 and S3). The last searches in both databases were performed on 12 February 2018. The references of the selected articles were also screened for further relevant studies. The database searches yielded a total of 978 records, of which 693 were retrieved through PubMed search (680 in Search 1; 13 in Search 2) and 285 through PsycINFO search (282 in Search 1; 3 in Search 2). One-hundred twenty-five records were identified as duplicates and removed. The remaining 853 records were initially evaluated for relevance by review of the title or abstract. Eight-hundred and eleven records met exclusion criteria and were excluded. The full text of the remaining 42 articles and of the four additional articles obtained by hand searching references were assessed against the inclusion and exclusion criteria to determine eligibility. Fourteen studies that fulfilled inclusion criteria were included in the systematic review [7, 10, 18–29]. Figure 1 shows the PRISMA flow diagram used to summarize the study selection process [15]. The search strategy was determined by both reviewers. The screening of titles, abstracts, and full texts was conducted by reviewer D.N. and approved by reviewer L.G.
Exhaustive reference list of empirical studies (n=390) reporting on neuropsychological assessment of executive functions in substance dependence populations following a rigorous search strategy of MEDLINE, PubMed and PsycINFO. Blinded screening and selection was conducted by two reviewers independently.
[date range: articles published up until April 2019]
Background:
This study aimed to evaluate the effect of short-term use of benzodiazepines (BZDs) on cognitive function of major depressive disorder (MDD) patients being treated with antidepressants (ADs).
Methods:
This was a part of a multi-center, multi-stage and prospective study of "Objective Diagnostic Indicators and Individualized Drug Intervention of Major Depressive Disorder (OIMDD)". Three hundred and fifty-three patients treated with the selective serotonin reuptake inhibitors (SSRIs) alone (Group 1) and 49 patients treated with SSRIs combined with short-term use of BZDs (Group 2) during the acute treatment period were included in the analysis. Cognitive function and depressive and anxiety symptoms were assessed at baseline, weekend 8 and 48. A cognitive test battery included 5 domains: information processing speed assessed by the Animal Verbal Fluency Scale (AVFS), Digit Symbol Coding Test (DSCT) and Color Trial Test (CTT), verbal learning assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R), visual learning assessed by the Brief Visual Memory Test-Revised (BVMT-R), executive function assessed by the Stroop Color Word Test (SCWT), and attention or vigilance assessed by the Continuous Performance Test (CPT).
Results:
Significant differences were found in education level (χ2 = 5.442, p = 0.020), the severity of depressive (t = -1.982, p = 0.048) and anxiety symptoms (t = -2.629, p = 0.009) between Group 1 and 2 at baseline. There were no significant differences between G1 and G2 in cognitive functions at baseline. After Multiple correction, DSCT was better in patients treated with BZDs combined with ADs than in patients with ADs alone at weekend 8 without controlling education level, depressive and anxiety symptoms at baseline (F = -2.747, p = 0.042). After controlling these factors at baseline, the DSCT was still slightly high in patients treated with ADs combined with BZDs than in patients with ADs alone at weekend 8 (OR = 1.052, 95%CI:1.000-1.105). The repeated measurement analysis of variance showed that the DSCT could be improved by the treatment of BZDs combined with ADs at 1-year follow-up compared to baseline (F = 7.569, p = 0.006).
Conclusions:
The findings suggest that short-term use of BZDs does not impair cognitive function of MDD patients; conversely, it could improve the information processing speed after acute treatment and at 1 year follow up.
Background and aims:
Patients suffering from chronic nonmalignant pain constitute a heterogeneous population in terms of clinical presentation and treatment results. Few data are available about what distinguishes different groups in this huge population of patients with chronic persistent pain (CPP). A subgroup that is poorly studied, consists of the most severely impaired chronic pain patients. At the Uppsala University Hospital Pain Clinic, there is a specialized department accepting the most complex patients for rehabilitation. In the endeavour to improve and evaluate treatment for this subgroup, a better understanding of the complex nature of the illness is essential. This prospective study aimed to describe the characteristics of this subgroup of patients with CPP.
Methods:
Seventy-two consecutive patients enrolled in the Uppsala programme were evaluated. We collected data on demographics, type of pain and experienced symptoms other than pain using a checklist of 41 possible symptoms. Psychiatric comorbidity was assessed by a psychiatrist using a structured clinical interview. Quality of life (QoL), pain rating and medication/drug/alcohol usage were measured by validated questionnaires: SF-36, NRS, DUDIT and AUDIT. Concerning physical functioning and sick leave, a comparison was made with data from the Swedish Quality Register Registry for pain rehabilitation (SQRP).
Results:
The cohort consisted of 61% women and the average age was 45 (range 20-70) years. For this cohort, 74% reported being on sick leave or disability-pension. In the SQRP 59% were on sick leave at the time they entered the rehabilitation programmes [1]. On average, the study-population reported 22 symptoms other than pain, to be at a high rate of severity. Patients treated in conventional pain-rehabilitation programmes reported a mean of 10 symptoms in average. Symptoms reported with the highest frequency (>80%), were lethargy, tiredness, headache and difficulties concentrating. Seventy-six percent were diagnosed with a psychiatric disorder. Sixty-nine fulfilled the criteria for depression or depression/anxiety disorder despite that most (65%) were treated with psychotropic medication. Alcohol/drug abuse was minimal. Seventy-one percent were on opioids but the doses were moderate (<100mg) MEq. The pain rating was ≥7 (out of a maximum of 10) for 60% of the patients.
Conclusion:
This study describes what makes the subgroup of pain patients most affected by their pain special according to associated factors and comorbidity We found that they were distinguished by a high degree of psychiatric comorbidity, low physical functioning and extreme levels of symptom preoccupation/hypervigilance. Many severe symptoms additional to pain (e.g. depression/anxiety, tiredness, disturbed sleep, lack of concentration, constipation) were reported. The group seems hypervigilant, overwhelmed with a multitude of different symptoms on a high severity level.
Implications:
When treating this complex group, the expressions of the illness can act as obstacles to achieve successful treatment outcomes. The study provides evidence based information, for a better understanding of the needs concerning these pain patients. Our result indicates that parallel assessment and treatment of psychiatric comorbidities and sleep disorders combined with traditional rehabilitation, i.e. physical activation and cognitive reorganization are imperative for improved outcomes.
Prefrontal cortex executive functions, such as working memory (WM) interact with limbic processes to foster impulse control. Such an interaction is referred to in a growing body of publications by terms such as cognitive control, cognitive inhibition, affect regulation, self-regulation, top-down control, and cognitive–emotion interaction. The rising trend of research into cognitive control of impulsivity, using various related terms reflects the importance of research into impulse control, as failure to employ cognitions optimally may eventually result in mental disorder. Against this background, we take a novel approach using an impulse control spectrum model – where anorexia nervosa (AN) and substance use disorder (SUD) are at opposite extremes – to examine the role of WM for cognitive control. With this aim, we first summarize WM processes in the healthy brain in order to frame a systematic review of the neuropsychological, neural and genetic findings of AN and SUD. In our systematic review of WM/cognitive control, we found n = 15 studies of AN with a total of n = 582 AN and n = 365 HC participants; and n = 93 studies of SUD with n = 9106 SUD and n = 3028 HC participants. In particular, we consider how WM load/capacity may support the neural process of excessive epistemic foraging (cognitive sampling of the environment to test predictions about the world) in AN that reduces distraction from salient stimuli. We also consider the link between WM and cognitive control in people with SUD who are prone to ‘jumping to conclusions’ and reduced epistemic foraging. Finally, in light of our review, we consider WM training as a novel research tool and an adjunct to enhance treatment that improves cognitive control of impulsivity.
Dystonia is a common movement disorder. In this paper, we review the literature on cognitive function in idiopathic and DYT1 dystonia. In idiopathic or DYT1 dystonia, cognition is largely intact with only isolated executive dysfunction. Dystonia patients also have increased temporal and spatial discrimination thresholds, considered endophenotypes of the disorder because deficits are also shown by unaffected relatives and nonmanifesting carriers of the DYT1 mutation. Anticholinergic medication in high doses can be associated with memory impairment in dystonia. The successful treatment of dystonia with botulinum toxin injections or deep brain stimulation does not produce any major adverse effects on cognition. The aspects of cognition that require further investigation in future studies of dystonia include inhibitory control, decision making, and social cognition. © 2017 International Parkinson and Movement Disorder Society.
Importance:
The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications.
Objective:
To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS).
Design, setting, and participants:
The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC- participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015.
Main outcomes and measures:
Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC- participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression.
Results:
The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores on Weschler Memory Scale-Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC- participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC- participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC- participants; P = .04) than the 350 AC- participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC- participants.
Conclusions and relevance:
The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.
The Stroop color and word test (SCWT) is widely used to evaluate attention, information processing speed, selective attention, and cognitive flexibility. Normative values for the Italian population are available only for selected age groups, or for the short version of the test. The aim of this study was to provide updated normal values for the full version, balancing groups across gender, age decades, and education. Two kinds of indexes were derived from the performance of 192 normal subjects, divided by decade (from 20 to 90) and level of education (4 levels: 3–5; 6–8; 9–13; >13 years). They were (i) the correct answers achieved for each table in the first 30 s (word items, WI; color items, CI; color word items, CWI) and (ii) the total time required for reading the three tables (word time, WT; color time, CT; color word time, CWT). For each index, the regression model was evaluated using age, education, and gender as independent variables. The normative data were then computed following the equivalent scores method. In the regression model, age and education significantly influenced the performance in each of the 6 indexes, whereas gender had no significant effect. This study confirms the effect of age and education on the main indexes of the Stroop test and provides updated normative data for an Italian healthy population, well balanced across age, education, and gender. It will be useful to Italian researchers studying attentional functions in health and disease.
Background:
High-dose benzodiazepine (BZD) dependence is associated with a wide variety of negative health consequences. Affected individuals are reported to suffer from severe mental disorders and are often unable to achieve long-term abstinence via recommended discontinuation strategies. Although it is increasingly understood that treatment interventions should take subjective experiences and beliefs into account, the perceptions of this group of individuals remain under-investigated.
Methods:
We conducted an exploratory qualitative study with 41 adult subjects meeting criteria for (high-dose) BZD-dependence, as defined by ICD-10. One-on-one in-depth interviews allowed for an exploration of this group's views on the reasons behind their initial and then continued use of BZDs, as well as their procurement strategies. Mayring's qualitative content analysis was used to evaluate our data.
Results:
In this sample, all participants had developed explanatory models for why they began using BZDs. We identified a multitude of reasons that we grouped into four broad categories, as explaining continued BZD use: (1) to cope with symptoms of psychological distress or mental disorder other than substance use, (2) to manage symptoms of physical or psychological discomfort associated with somatic disorder, (3) to alleviate symptoms of substance-related disorders, and (4) for recreational purposes, that is, sensation-seeking and other social reasons. Subjects often considered BZDs less dangerous than other substances and associated their use more often with harm reduction than as recreational. Specific obtainment strategies varied widely: the majority of participants oscillated between legal and illegal methods, often relying on the black market when faced with treatment termination.
Conclusions:
Irrespective of comorbidity, participants expressed a clear preference for medically related explanatory models for their BZD use. We therefore suggest that clinicians consider patients' motives for long-term, high-dose BZD use when formulating treatment plans for this patient group, especially since it is known that individuals are more compliant with approaches they perceive to be manageable, tolerable, and effective.
Objectives To investigate the relation between the risk of Alzheimer’s disease and exposure to benzodiazepines started at least five years before, considering both the dose-response relation and prodromes (anxiety, depression, insomnia) possibly linked with treatment.
Design Case-control study.
Setting The Quebec health insurance program database (RAMQ).
Participants 1796 people with a first diagnosis of Alzheimer’s disease and followed up for at least six years before were matched with 7184 controls on sex, age group, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09.
Main outcome measure The association between Alzheimer’s disease and benzodiazepine use started at least five years before diagnosis was assessed by using multivariable conditional logistic regression. Ever exposure to benzodiazepines was first considered and then categorised according to the cumulative dose expressed as prescribed daily doses (1-90, 91-180, >180) and the drug elimination half life.
Results Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91-180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones).
Conclusion Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.
The Brief Repeatable Battery (BRB) of Neuropsychological Tests is one of the most widely used instruments to assess cognitive functioning in multiple sclerosis patients. However, to date, normative data for the Italian population are available only for the version A, which limits the use of the battery in longitudinal evaluations. We administered the BRB version B to 132 healthy subjects to obtain normative values taking into account the influences of demographic factors on the test scores and calculating corrections for these relevant factors (age, gender and education). Higher age and educational level were associated with better performance on all the tests. The World List Generation was also influenced by gender, since women performed better than men. Moreover, some tests of the version B seem to be easier than those of version A. Our data can improve the applicability of the BRB for both clinical and research purposes in longitudinal assessments.
The purpose of this study was to determine, in the context of a hospital addiction unit, which benzodiazepines were abused and to look for correlations with the characteristics of detoxified patients.
A retrospective study was carried out using the database of hospital admissions to the addiction unit for detoxification from 2003 to 2010.
Of 879 admissions to the addiction unit during the seven-year period, 281 were for benzodiazepines. The percentage of patients addicted only to benzodiazepines was higher among females than males. Benzodiazepine consumption had started as a drug addiction behavior in only 10% of cases. The main sources of prescription identified were general practitioners (52% of cases) or compliant pharmacists (25%). Overall, 15 different benzodiazepines were abused, with lormetazepam being the most commonly used (by 123 patients, 43.8% of the total).
Our data show that, outside the population of multidrug addicts, there is an underestimated group of chronic benzodiazepine consumers who are often not referred to medical institutions for treatment. Even in the group of patients addicted to one substance only, we observed an abnormal number of requests for detoxification from lormetazepam, which appears to be more "popular" than other benzodiazepines. This drug should be prescribed according to stricter criteria and submitted to closer control.
Introduction: While benzodiazepines are the most widely used psychotropic drugs, there are relatively few studies that have examined deficits in cognitive functioning after long-term use. The literature that is available is difficult to interpret due to conflicting results as well as a variety of methodological flaws.
Objective: To systematically evaluate and integrate the available research findings to determine the effect of long-term benzodiazepine use on cognitive functioning using meta-analytical techniques.
Methods: Thirteen research studies that employed neuropsychological tests to evaluate cognitive performance after long-term use of benzodiazepine medication met inclusion criteria. The neuropsychological tests employed in these 13 studies were each categorised as measuring one of 12 cognitive domains. Separate effect sizes were calculated for each of the 12 cognitive categories. Each study was only allowed to contribute one effect size to each cognitive category by averaging together the effect sizes from the same study if more than one type of test was used to measure a particular category. This strategy resulted in equal weight being given to each study per category, regardless of the number of tests in that category.
Results: The overall mean number of patients who were benzodiazepine users was 33.5 (SD ± 28.9) and the mean number of controls was 27.9 (SD ± 19.6). The duration of benzodiazepine use ranged from 1 to 34 (mean 9.9) years. Long-term benzodiazepine users were consistently more impaired than controls across all cognitive categories examined, with effect sizes ranging in magnitude from −1.30 to −0.42. The mean weighted effect size was −0.74 (SD ± 0.25). None of the effect sizes had 95% CIs that spanned zero and, therefore, all of these effects were significant and different to zero.
Conclusion: Moderate-to-large weighted effect sizes were found for all cognitive domains suggesting that long-term benzodiazepine users were significantly impaired, compared with controls, in all of the areas that were assessed. However, this study has several limitations, one being that it includes a relatively small number of studies. Further studies need to be conducted; ideally, well designed, controlled studies that thoroughly investigate certain areas of cognitive functioning and present data in such a way so as to be amenable to inclusion in a meta-analysis. Incorporating the information from these studies into a larger meta-analysis would allow for a more thorough and statistically sound investigation of the effects of moderator variables. The observation that long-term benzodiazepine use leads to a generalised effect on cognition has numerous implications for the informed and responsible prescription of these drugs.
To determine whether zolpidem is a safer alternative to benzodiazepines.
Retrospective cohort study.
Community based.
Health maintenance organization members with an initial prescription for zolpidem (n = 43,343), alprazolam (n = 103,790), lorazepam (n = 150,858), or diazepam (n = 93,618).
Zolpidem and benzodiazepine prescriptions were identified from pharmacy databases. Rates of nonvertebral fractures and hip fractures requiring hospitalization were compared before and after an initial prescription for each treatment, adjusting for confounders using doubly robust estimation.
In patients aged 65 and older, the rates of nonvertebral fractures and dislocations were similar in the pre- treatment intervals. The rate ratios (RRs) for the 90-day posttreatment interval relative to the pretreatment interval were 2.55 (95% confidence interval (CI) = 1.78-3.65; P < .001) for zolpidem, 1.14 (95% CI = 0.80-1.64; P = .42) for alprazolam, 1.53 (95% CI = 1.23-1.91; P < .001) for lorazepam, and 1.97 (95% CI = 1.22-3.18; P = .01) for diazepam. The ratio of RRs (RRR)-the RR in the posttreatment period adjusted for the corresponding RR in the pretreatment period-were 2.23 (95% CI = 1.36-3.66; P = .006) for zolpidem relative to alprazolam, 1.68 (95% CI = 1.12-2.53; P = .02) for zolpidem relative to lorazepam, and 1.29 (95% CI = 0.72-2.30; P = .32) for zolpidem relative to diazepam. The RRs decreased with time from the initial prescription (trend P < .001), as would be expected if the association is causal.
In older adults, the risk of injury with zolpidem exceeded that with alprazolam and lorazepam and was similar to that with diazepam. If the associations are causal, then the high incidence of these fractures implies that these treatment induce a substantial number of fractures and consequential costs. Further study of the association is imperative.
Results from a number of studies have suggested a relationship between cognitive alteration and benzodiazepine use in the elderly. The aim of this study was to determine the impact of benzodiazepine use on cognitive functions in a young adult population.
This study included 1,019 French salaried workers from the VISAT (Aging, Health and Work) cohort whose objective was to determine the long-term impact of working conditions on health and aging. Data were collected during interviews by occupational physicians in 1996, 2001 and 2006. Cognitive function was assessed using five cognitive tests (immediate free recall test, delayed free recall test, recognition test, Digit Symbol Substitution Subtest and visual search speed test). Cognitive scores obtained after a 10-year follow-up were investigated among three categories of benzodiazepine users, namely, non-users, occasional users and long-term users, using analysis of covariance models adjusted for several potential confounders in men and women separately.
In the course of the 10 year-follow-up, 3.9% of subjects were defined as occasional users of benzodiazepine and 7.5% as long-term users. The analysis revealed a significant alteration of long-term memory in women whereas there was no significant association in men.
Long-term use of benzodiazepine leads to specific impairment in long-term memory only in women.
Norms are provided for verbal and visuo-spatial immediate memory span, two tasks widely used in the clinical assessment of short-term memory and its neurological disorders. Data have been collected from 1355 male and female adult subjects, with various educational backgrounds and a 20-99 years age range. Span shows a major decrement after the late sixties and is affected by educational level. Male subjects score better on the spatial task. Data collected from 1112 male and female children, 4-to-10 year-old, show that span increases with age and boys score better on the spatial test.
This paper reviews the effects of benzodiazepines (BZs) on the performance of tasks measuring human cognitive abilities. The paper reviews the most common cognitive side effects of BZs: increased sedation, decreased attention, and anterograde amnesia. In particular, this paper focuses on recent findings regarding time course-related effects on BZ-induced deficits in explicit and implicit human memory performance. Specifically, we reviewed recent research indicating that both explicit memory and priming are impaired by BZs if the encoding task takes place near the time of the theoretical peak plasma concentrations of the drug. Although BZs also appear to increase objective and subjective sedation, as well as to impair attentional processing, these other cognitive impairments do not appear to fully account for the widespread memory deficits caused by BZ administration. The theoretical and clinical implications of benzodiazepine-induced memory impairments are discussed.
A double-blind, placebo-controlled, crossover design was employed to determine whether acute lorazepam (2mg orally) cognitive side effects would emerge in a differential age-dependent fashion in 15 young (mean age=22years) and 12 older (mean age=64years) subjects. Acute use of lorazepam is frequently the initial treatment choice for convulsive status epilepticus or repetitive seizure clusters. Cognitive assessment was performed during drug and placebo conditions using a computerized battery of cognitive tests. With the exception of performance on the reasoning composite score, significant drug effects were present on all primary cognitive domain measures. However, the only significant drug-by-age interaction effect was seen for dual-task performance. The relationship between test performance and plasma lorazepam concentrations was generally modest and non-significant, suggesting that individual differences in pharmacokinetics are not a major factor contributing to the emergence of cognitive side effects. Despite robust lorazepam effects on multiple measures of neurocognitive function, differential age effects are largely restricted to dual-task performance. These results indicate that with the exception of dual-task performance, older individuals in the age range of this study do not appear to be at increased risk for the emergence of cognitive side effects following a single 2-mg dose of lorazepam.
To re-examine various aspects of the benzodiazepines (BZDs), widely prescribed for 50 years, mainly to treat anxiety and insomnia. It is a descriptive review based on the Okey Lecture delivered at the Institute of Psychiatry, King's College London, in November 2010.
A search of the literature was carried out in the Medline, Embase and Cochrane Collaboration databases, using the codeword 'benzodiazepine(s)', alone and in conjunction with various terms such as 'dependence', 'abuse', etc. Further hand-searches were made based on the reference lists of key papers. As 60,000 references were found, this review is not exhaustive. It concentrates on the adverse effects, dependence and abuse.
Almost from their introduction the BZDs have been controversial, with polarized opinions, advocates pointing out their efficacy, tolerability and patient acceptability, opponents deprecating their adverse effects, dependence and abuse liability. More recently, the advent of alternative and usually safer medications has opened up the debate. The review noted a series of adverse effects that continued to cause concern, such as cognitive and psychomotor impairment. In addition, dependence and abuse remain as serious problems. Despite warnings and guidelines, usage of these drugs remains at a high level. The limitations in their use both as choice of therapy and with respect to conservative dosage and duration of use are highlighted. The distinction between low-dose 'iatrogenic' dependence and high-dose abuse/misuse is emphasized.
The practical problems with the benzodiazepines have persisted for 50 years, but have been ignored by many practitioners and almost all official bodies. The risk-benefit ratio of the benzodiazepines remains positive in most patients in the short term (2-4 weeks) but is unestablished beyond that time, due mainly to the difficulty in preventing short-term use from extending indefinitely with the risk of dependence. Other research issues include the possibility of long-term brain changes and evaluating the role of the benzodiazepine antagonist, flumazenil, in aiding withdrawal.
The associate learning subtest from the Wechsler Memory Scale; Benton's Visual Retention test and a Controlled Word Association Task (FAS) were administered to a random sample of normal, healthy individuals whose age ranged from 20 to 79 years, recruited within the Italian peninsula. The neuropsychological examination took place on a mobile unit and the tests were given by the same team of neuropsychologists to reduce variability among examiners. The Research Project was known as Progetto Memoria. Corrections to the scores of these tests were calculated for age, sex, and education. These corrected values will allow clinicians to screen for memory impairment with greater precision among normally aging individuals, thus improving differential diagnosis between physiologic and pathologic deterioration of cognitive functions.
Despite the widespread prescribing of benzodiazepines, uncertainty still surrounds the potential for cognitive impairment
following their long-term use. Furthermore, the degree of recovery that may take place after withdrawal or the level of residual
impairment, if any, that is maintained in long-term benzodiazepine users is also unclear. The current paper employed meta-analytic
techniques to address two questions: (1) Does the cognitive function of long-term benzodiazepine users improve following withdrawal?
(2) Are previous long-term benzodiazepine users still impaired at follow-up compared to controls or normative data? Results
of the meta-analyses indicated that long-term benzodiazepine users do show recovery of function in many areas after withdrawal.
However, there remains a significant impairment in most areas of cognition in comparison to controls or normative data. The
findings of this study highlight the problems associated with long-term benzodiazepine therapy and suggest that previous benzodiazepine
users would be likely to experience the benefit of improved cognitive functioning after withdrawal. However, the reviewed
data did not support full restitution of function, at least in the first 6 months following cessation and suggest that there
may be some permanent deficits or deficits that take longer than 6 months to completely recover.
Initially thought to be virtually free of negative effects, benzodiazepines are now known to carry risks of dependence, withdrawal, and negative side effects. Among the most controversial of these side effects are cognitive effects. Long-term treatment with benzodiazepines has been described as causing impairment in several cognitive domains, such as visuospatial ability, speed of processing, and verbal learning. Conversely, long-term benzodiazepine use has also been described as causing no chronic cognitive impairment, with any cognitive dysfunction in patients ascribed to sedation or inattention or considered temporary and associated with peak plasma levels. Complicating the issue are whether anxiety disorders themselves are associated with cognitive deficits and the extent to which patients are aware of their own cognitive problems. In an attempt to settle this debate, meta-analyses of peer-reviewed studies were conducted and found that cognitive dysfunction did in fact occur in patients treated long term with benzodiazepines, and although cognitive dysfunction improved after benzodiazepines were withdrawn, patients did not return to levels of functioning that matched benzodiazepine-free controls. Neuroimaging studies have found transient changes in the brain after benzodiazepine administration but no brain abnormalities in patients treated long term with benzodiazepines. Such findings suggest that patients should be advised of potential cognitive effects when treated long term with benzodiazepines, although they should also be informed that the impact of such effects may be insignificant in the daily functioning of most patients.
A major public health issue is to determine whether long-term benzodiazepine use may induce cognitive deficits persisting after withdrawal. The aim of the present review was to examine findings from prospective studies carried out in general population samples exploring whether exposure to benzodiazepines is associated with an increased risk of incident cognitive decline.
Using a MEDLINE search and a hand-search of related references in selected papers, we retrieved original studies published in peer-reviewed journals that explored in general population samples the association between benzodiazepine exposure and change in cognitive performance between baseline and follow-up assessment.
Six papers met the inclusion criteria. Two studies reported a lower risk of cognitive decline in former or ever users, two found no association whatever the category of user, and three found an increased risk of cognitive decline in benzodiazepine users.
The discrepant findings obtained by studies examining the link between benzodiazepine exposure and risk of cognitive decline may be due to methodological differences, especially regarding the definitions of exposure and cognitive outcome. As a large proportion of subjects are exposed to benzodiazepines, a small increase in the risk of cognitive decline may have marked deleterious consequences for the health of the general population. This issue needs to be explored further by pharmaco-epidemiological studies.
The purpose of the study was to assess prevalence of benzodiazepine use in the Swiss adult population and to assess on benzodiazepine prescription patterns of physicians in domiciliary practice.
A retrospective, population-based cross-sectional study with 520 000 patients covering a 6-month period.
We estimated the prevalence, amount and duration of benzodiazepine use using a pharmacy dispensing database.
Of all patients, 9.1% (n=45 309) received at least one benzodiazepine prescription in the 6-month period. Most persons receiving benzodiazepine prescriptions were women (67%), and half of all patients were aged 65 or older. Of 45 309 patients with benzodiazepine prescriptions, 44% (n=19 954) had one single prescription, mostly for a short period (<90 days) and in lower than the recommended dose range. Fifty-six percent (n=25 354) had repeated benzodiazepine prescriptions, mostly for a long time period (>90 days), and in lower than the recommended or within the recommended dose range. In patients with long-term use (n=25 354), however, 1.6% had benzodiazepine prescriptions in extremely high doses. The sample of patients with repeated prescriptions allowed an estimation of a benzodiazepine use of 43.3 daily defined doses per 1000 inhabitants in Switzerland.
Benzodiazepine prescriptions were appropriate for most patients and thus were prescribed in therapeutic doses, as indicated in the treatment guidelines. On the other hand, our survey showed that 1.6% of the patients had prescriptions for long time periods at very high doses, indicating an abuse or dependence on benzodiazepines in this subgroup.