Beiträge zum Themenschwerpunkt Z Gerontol Geriat 2014 · [jvn]:[afp]–[alp] DOI 10.1007/s00391-014-0654-5 Published online: 5 June 2014 © Springer-Verlag Berlin Heidelberg 2014
M. Gogol1 · H. Hartmann1 · S. Wustmann1 · A. Simm2 1 Department of Geriatrics, Lindenbrunn Hospital, Coppenbrügge 2 Interdisciplinary Centre for Ageing Halle (IZAH), Martin-Luther-Universität Halle-Wittenberg, Halle
Influence of central nervous system-acting drugs on results of cognitive testing in geriatric inpatients Cognitive decline in the elderly is a common feature, with the Mini Mental State Examination (MMSE) as the most accepted clinical assessment worldwide [1]. The use of central nervous system-acting drugs (CNSADs)—e.g., central-acting analgesics, antidepressants, sedatives, hypnotics—and other drug classes (e.g., antiepileptics) is common despite the wellknown potential side effects and adverse drug reactions (ADRs). Pain is one of the most described symptoms in the elderly [2]. In the United States, approximately 68 million people suffer from acute pain syndromes every year and 25% are 65 years of age or older [3]. In nursing homes, up to 40% of residents have had pain syndromes of varying severity, while 38–50% have chronic pain and of these, 14% have had severe chronic pain [4]. In the UK, 50% of people aged 65 years and 60% of individuals aged 75 years or older reported pain syndromes [5]. Central-acting analgesics have increasingly become a treatment option, even for patients in advanced age and without malignancy-associated pain, because other analgesic classes such as nonsteroidal antiinflammatory drugs and metamizole may have serious side effects [6, 7, 8, 9]. Few data have been published on the pharmacokinetics and pharmacodynamics of opioids in the elderly [10, 11]. Recent studies showed an increase in ADRs of opioid analgesics [12, 13, 14, 15]; side effects due to overdosing [16, 17, 18]; admissions to emergency rooms [19, 20, 21] and hospi-
talization [22]; falls, injuries, and road accidents [23, 24, 25, 26, 27, 28]; and mortality [29, 30, 31, 32, 33, 34]. The risk for hospitalization and mortality increases with the dose, the number of prescribers, and the number of pharmacists [35, 36]. Besides central-acting analgesics, the use of psychotropic drugs in the elderly is high as well and Simoni-Wastila and Yang reported their use in 25% of the US population [37]. In nursing homes, up to 46.8% of residents received psychotropic drugs with antidepressants (31.2%) being the leading drug class [38]. In a memory clinic, 22% of patients used CNSADs, with a potential negative impact on cognition [39]. Rikala et al. [40] described 38% of community-dwelling seniors taking CNSADs. The risk of cognitive decline associated with the use of drugs with anticholinergic properties has been reported [41, 42]. This occurred even in Alzheimer’s patients over various (short- and longterm) follow-up periods [43, 44]. In the Health, Aging and Body Composition Study, the use of CNSADs was not associated with the incidence but with the progress of cognitive decline [45]. Puustinen et al. [46] reported a high risk of cognitive decline associated with combinations of opioids and other CNSADs. Maust et al. [47] found that in the US most CNSADs were prescribed by nonpsychiatrists. Furthermore, Rossi and colleagues reported the use of more than one unnecessary drug, and 41.4% of drugs showed a lack of effectiveness [48].
Research question Do CNSADs have an influence on the results of cognitive testing using a standard instrument (MMSE) in geriatric inpatients?
Methods We analyzed the combined data from two prospective, single-center study cohorts from our department for acute, subacute, and rehabilitative geriatric medicine at a tertiary hospital, which were performed in 2011 and 2012. Both studies have the same design for the cognitive assessment; the measurements were done on day 2 or 3 after hospital admission by a trained research nurse. The first study compared MMSE with different short cognition tests (Prospective Comparison of Psychometric instruments, PROPSYC). The second study analyzed the influence of advanced glycation end products, a biomarker of aging, and functional outcome (AGE OUT). Statistical analysis was done with Statistica 10.0, Statsoft. Both studies were approved by the ethics committee of the Lower Saxony Physician Board.
Results Overall, 395 patients were included, 144 male (M) and 251 female (F); 166 patients were from the PROPSYC and 229 patients were from the AGE OUT study. The mean age was 80.0±8.4 years (M
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Beiträge zum Themenschwerpunkt Tab. 1 Patients and CNS-acting drugs Number Age BI admission BI discharge GDS 10 EBI MMSE hpNL lpNL NL all Amitriptyline TCA other TCA all SSRI NaSSA SSNRI AD new Oxazepam, Diazepam Lorazepam BD all Zopiclone Antiepilepticsa Othersb Opioids lpc Opioids td Opioids oral Opioids all
Patients 395 80.035±8.400 46.628±19.786 71.213±23.129 3.128±2.647 66.589±23.942 22.876±4.915 1 13 14 24 8 32 26 3 5 34 8 18 26 11 34 4 60 21 36 57
Men 144 76.772±9.103 44.375±20.164 70.657±24.918 2.888±2.603 67.920±23.992 23.285±4.657 1 5 6 9 2 11 9 1 1 11 5 7 12 5 14 1 18 6 9 51
Women 251 81.907±7.359 47.932±19.485 71.534±22.082 3.265±2.667 65.824±23.930 22.641±5.052 0 8 8 15 6 21 17 2 4 23 3 11 14 6 20 3 42 15 27 42
p 0.000000 0.085979 0.724268 0.175032 0.414997 0.211012
AD antidepressants, BD benzodiazepines, BI Barthel index, CNS central nervous system, EBI extended Barthel index, GDS 10 Geriatric Depression Scale 10-item, hpNL high-potency neuroleptics (haloperidol, risperidone), MMSE Mini Mental Status Examination, lpNL low-potency neuroleptics (melperone, promethazine), NaSSA noradrenergic and specific serotonergic antidepressants, NL neuroleptics, SSNRI selective serotonergic noradrenalin reuptake inhibitors, SSRI selective serotonin reuptake inhibitors, TCA tricyclic antidepressants, td transdermalaGabapentin, pregabalin, levetiracetambClomethiazole, lithiumclp Low-potency (tramadol, tilidine)
76.8±9.1, F 81.9±7.4, p=0.0000). The mean MMSE points were 22.9±4.9 (M 23.3±4.7, F 22.6±5.0, p=0.211). . Tab. 1 shows the patients’ basic data and frequency of CNSADs use. Analgesics with central activity were given to 117 of 395 patients (29.6%). Low-potency opioids (tramadole hydrochloride, tilidine) were identified in 60 patients (M 18, F 42, age 80.9±7.7 years); high-potency opioids in 57 patients (M 15, F 42, age 78.3±9.5 years). Transdermal patches were only found in 21 (M 6, F 15) and oral drugs in 36 patient (M 9, F 27). Antidepressants were used in 66 patients, benzodiazepines in 26, and hypnotics in 11, while 38 patients received other CNSADs. In total, 258 patients (65.3%) used drugs with potential adverse cognitive properties. Significant correlations with the results of cognitive testing
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were only found for sedatives (diazepam and oxazepam), but not for lorazepam (. Tab. 2). In the subset of the AGE OUT patients, we also correlated the total number of drugs for all patients and different groups of cognitive decline (. Tab. 3). A weak but significant correlation was identified for all patients; the group with severe cognitive impairment (MMSE ≤9) showed a high but nonsignificant correlation, possibly due to the small (n=3) number of patients in this group.
Discussion Antidepressants In an analysis of nursing homes of the US Veterans Administration, Hanlon et al. reported that 57.5% of antidepressive drugs
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showed the risk for drug–drug and drug– disease interactions. In 25.4% of the residents, they found an underuse of antidepressants and only in 17.6% of the residents was the use of antidepressants judged as appropriate [49]. Citalopram reduced agitation in Alzheimer’s disease (AD) patients but affected cognition negatively over 9 weeks [50]. In contrast to this finding, Caballero et al. [51] found no difference in AD patients treated with antidepressants for depressive symptoms. Moreover, Savaskan et al. [52] described better cognitive performances in patients with depression and specific drug treatment, and Rozzini et al. [53] reported that selective serotonin reuptake inhibitors in AD patients with depression resulted in better cognitive performance. For tricyclic antidepressants, an association with cognitive decline was not observed [54]. Potvin et al. [55] linked anxiety and depression to cognitive decline and vice versa, so that the rationale behind the hypothesis—antidepressants are able to reverse or stop cognitive decline—will be valid for some patients. Despite these heterogeneous findings, in our analysis we did not see an influence of antidepressants, even tricyclics or newer ones, on cognitive performance measured with the MMSE.
Neuroleptics Vigen et al. [43] found that neuroleptics given over 36 weeks worsened the cognition performance of AD patients, and Rosenberg et al. [44] confirm these results for long-term use of over 3.7 years. By contrast, Caballero et al. [56] found no influence on cognition. In our analysis we had only one patient treated with high-potency neuroleptics, but 13 treated with low-potency neuroleptics. In total we found no association between the results of cognitive testing and neuroleptic drug use.
Sedatives and hypnotics In a prospective cohort study of inpatients, the use of sedatives was associated with cognitive decline [57]. In their study in Finland on 781 patients, Desplenter et al. [58] found no difference in the cognitive abilities in users and non-users of sed-
Abstract · Zusammenfassung atives over 3 years. No influence was stated by Puustinen et al. [59], while another group identified a risk for cognitive decline related to sedatives in inpatients [57]. Our data identified users of diazepam and oxazepam with a significantly lower cognitive performance, while users of lorazepam and zopiclone showed no decline. It is noteworthy that the small numbers of patients (n=8) in our cohort may have had an effect on the results.
Opioids While pain prevalence [60] and pain therapy varied widely [61, 62], there are data that confirm the thesis that opioids are able to worsen cognition [63, 64, 65, 66], but one study with transdermal buprenorphine shows no influence. In our patients (57 with low-potency and 60 with highpotency opioids) we identified no association between cognition and drug use. For other CNSADs, e.g., antiepileptics, we found no correlation to cognitive testing results. Overall, we identified a weak, but significant association for the number of drugs given and cognitive performance. The weakness of the study may be the cognitive assessment instruments used. Sjogren et al. [65] discussed the fact that the MMSE may not be sensitive enough in detecting adverse effects on cognition. Taipale et al. [66] compared four methods for assessing cumulative effects of drugs and identified no method that worked ideally. Additionally, the number of CNSADs in different drug classes varied so that this may influence our results. Moreover, empirical and clinical data show a clear relationship between the number and dosage of CNSADs for mobility limitations [67], falls [68, 69, 70], and fractures [71, 72]; however, we found no effect within ADRs measured with the Barthel index (BI). The BI at admission showed a modest correlation with the MMSE, with a Pearson’s correlation of 0.39 at admission and of 0.45 at discharge (both p=0.05). Only for diazepam and oxazepam was there a high correlation for the BI, with 0.74 at admission (p=0.05) and 0.70 (nonsignificant) at discharge. However, the sensitivity of the BI is possibly not high enough to address this ques-
Z Gerontol Geriat 2014 · [jvn]:[afp]–[alp] DOI 10.1007/s00391-014-0654-5 © Springer-Verlag Berlin Heidelberg 2014 M. Gogol · H. Hartmann · S. Wustmann · A. Simm
Influence of central nervous system-acting drugs on results of cognitive testing in geriatric inpatients Abstract Introduction. Growing evidence shows a high correlation between extensive use of central nervous system-acting drugs (CNSADs) in elderly patients and adverse drug reactions (ADRs) such as falls, fractures, and mortality. Research question. Are results of cognitive testing with the Mini Mental Status Examination (MMSE) influenced by use of CNSADs? Setting. Geriatric inpatient service for acute, subacute, and rehabilitation care. Methods. Secondary combined analysis of two prospective, single-center study cohorts (PROPSYC, 2011 and AGE OUT, 2012) with identical procedure for the MMSE at a tertiary hospital. Results. Overall, 395 patients were included, 144 male (M) and 251 female (F). Mean age was 80.0±8.4 years (M 76.7±9.1, F 81.9±7.3, p=0.0000). Mean MMSE points were 22.9±4.8 (M 23.2±4.6, F 22.6±5.0, p=0.211). In total, 258 patients (65.3%) used drugs with poten-
tial adverse cognitive properties. Analgesics with central activity were given to 117 of 395 patients (29.6%). Low-potency opioids (tramadol hydrochloride, tilidine) were identified in 60 patients and high-potency opioids in 57 patients. Antidepressants were used in 66 patients, benzodiazepines in 26, and hypnotics in 11, while 38 patients received other CNSADs. We only found significant correlations with the results of cognitive testing for sedatives (diazepam and oxazepam, Pearson’s r −0.79, p=0.05), but not for lorazepam. Conclusion. Our analysis shows an influence of sedatives (diazepam and oxazepam, but not lorazepam) on cognitive testing with the MMSE in users of CNSADs. Keywords Cognition · Central nervous system-acting drugs (CNSADs) · MMSE · Elderly patients · Adverse drug reactions (ADRs)
Einfluss von zentralnervös wirkenden Medikamenten auf die kognitive Testung von geriatrischen Patienten im Krankenhaus Zusammenfassung Hintergrund. Eine zunehmende Evidenz zeigt bei älteren Menschen eine häufige Anwendung von Medikamenten mit zentralnervöser Wirkung („central nervous systemacting drugs“, CNSADs) und mit einer hohen Nebenwirkungsrate („adverse drug reactions“, ADRs) wie Stürze, Frakturen und erhöhter Mortalität. Fragestellung. Sind die Ergebnisse der kognitiven Tests mit dem Mini-Mental-StateTest (MMSE) von der CNSAD-Einnahme beeinflusst? Setting. Die Untersuchung erfolgte in einer geriatrischen Klinik mit Akut-, Frührehabilitations- und weiterführenden Rehabilitationsbereich. Methode. Mithilfe einer Sekundäranalyse wurden kombiniert Daten aus zwei prospektiven Kohortenstudien (PROPSYC, 2011 und AGE OUT, 2012) mit gleichem Design des kognitiven Assessments untersucht. Ergebnisse. Die Analyse umfasste 395 Patienten, davon waren 144 Männer (M) und 251 Frauen (F). Das mittlere Alter betrug
80,0±8,4 Jahre (M 76,7±9,1, F 81,9±7,3, p=0,0000). Der mittlere MMSE lag bei 22,8±4,8 Punkten (M 23,2±4,6, F 22,6±5,0, p=0,211). Insgesamt 258 Patienten (65,3%) erhielten CNSAD. Zentral wirksame Analgetika bekamen 117 Patienten (29,6%). Niedrigpotente Analgetika wurden in 57 und hochpotente in 60 Fällen gegeben. 60 Patienten erhielten Antidepressiva, 26 Sedativa und 11 Hypnotika. Andere CNSAD erhielten 38 Patienten. Signifikante Korrelationen mit den kognitiven Tests fanden wir nur für Sedativa (Diazepam und Oxazepam, Pearson r −0,79, p=0,05), aber nicht für Lorazepam. Zusammenfassung. In unserer Analyse fanden wir nur für Sedativa (Diazepam und Oxazepam, aber nicht für Lorazepam) eine signifikante Korrelation mit dem Ergebnis der kognitiven Tests. Schlüsselwörter Kognition · ZNS-aktive Medikamente · MMSE · Geriatrische Krankenhauspatientenen · Neben- und Wechselwirkungen
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Beiträge zum Themenschwerpunkt
Men
Women
vide an objective assessment of the brain and brain biomarkers [90] to evaluate patients with more or fewer vulnerabilities.
na 0.513889
na 0.123916
Conclusion
−0.140345 −1.000000 −0.162598 0.160779 na na 0.131243
−0.087436 −0.614256 −0.193894 −0.350798 1.000000 0.895184 0.099900
−0.954233* −0.131060 −0.265613
na −0.189748 −0.103874
−0.342217
0.086694
0.113523 na
0.187874 0.602881
0.336505 −0.712748 0.381128 0.288271
0.003318 0.032887 0.280475 0.088744
Tab. 2 Pearson correlation for MMSE and CNS-acting drugs All Neuroleptics hpNL na lpNL 0.392631 Antidepressants Amitriptyline −0.099636 TCA other −0.431857 TCA all −0.167213 SSRI −0.171247 NaSSA 0.671932 SSNRI 0.613122 AD new 0.133122 Sedatives Oxazepam, diazepam −0.794297* Lorazepam −0.165369 BD all −0.105447 Hypnotics Zopiclone −0.114537 Other CNS-acting drugs Antiepilepticsa 0.138968 Othersb 0.631122 Opioids Opioids lpc 0.044566 Opioids td −0.196472 Opioids oral 0.269694 Opioids all 0.174190
AD antidepressants, BD benzodiazepines, hpNL high-potency neuroleptics (haloperidol, risperidone), lpNL low-potency neuroleptics (melperone, promethazine), NaSSA noradrenergic and specific serotonergic antidepressants, NL neuroleptics, na not applicable, SSNRI selective serotonergic noradrenalin reuptake inhibitors, SSRI selective serotonin reuptake inhibitors, TCA tricyclic antidepressants, td transdermal*Indicating p=0.05aGabapentin, pregabalin, levetiracetambClomethiazole, lithiumclp Low-potency (tramadol, tilidine)
Tab. 3 Total number of drugs and CNS-acting drugs given and correlation to MMSE
Number of patients (men/ women)
All patients MMSE ≤9 MMSE 10–19 MMSE 20–26 MMSE ≥27
229 (87/142) 3 (1/2) 50 (16/34) 119 (46/73) 57 (24/33)
Mean number of drugs (number of CNS-acting drugs) 8.25 (1.95) 8.66 (2.00) 8.92 (1.98) 7.92 (1.94) 8.35 (1.92)
Pearson’s r for number of drugs vs. MMSE −0.0755 0.9607 0.0095 −0.0245 −0.1438
Pearson’s r for number of drugs vs. CNSacting drugs 0.5343* −0.9607 0.4733* 0.6048* 0.4146*
MMSE Mini Mental Status Examination, CNS central nervous system*p=0.05
tion, because it does not measure the quality and quantity of mobility. Furthermore, other factors have to be taken into account. For example, sleep problems may affect cognition seriously. Different groups described daily sleepiness as a risk factor for cognitive decline [73, 74, 75, 76], while reducing daily sleepiness was able to reduce cognitive impairment over a period of 6 months [77].
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Lifestyle factors are also associated with healthy or unhealthy aging (e.g., activity, nutrition, smoking, alcohol use) and some of them may have short- and midterm effects on cognition and may be able to influence or to mask potential effects of CNSADs [78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89]. Future research should examine the time of drug use and the possible adaptation to this drug and should pro-
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Our analysis identified diazepam and oxazepam as playing a role in worsening cognition, while other drugs showed no significant correlation. These results may be biased by the assessment instrument used and, in part, by the small number of patients using CNSADs. A significant negative effect on cognition was found for polypharmacy including CNSADs.
Corresponding address M. Gogol Department of Geriatrics, Lindenbrunn Hospital Lindenbrunn 1, 31863 Coppenbrügge Germany [email protected]
Compliance with ethical guidelines Conflict of interest. M. Gogol, H. Hartmann, S. Wustmann, and A. Simm state that there are no conflicts of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 (in its most recently amended version). Informed consent was obtained from all patients included in the study.
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M. Gogol1 · H. Hartmann1 · S. Wustmann1 · A. Simm2 1 Department of Geriatrics, Lindenbrunn Hospital, Coppenbrügge 2 Interdisciplinary Centre for Ageing Halle (IZAH), Martin-Luther-Universität Halle-Wittenberg, Halle
Influence of central nervous system-acting drugs on results of cognitive testing in geriatric inpatients Cognitive decline in the elderly is a common feature, with the Mini Mental State Examination (MMSE) as the most accepted clinical assessment worldwide [1]. The use of central nervous system-acting drugs (CNSADs)—e.g., central-acting analgesics, antidepressants, sedatives, hypnotics—and other drug classes (e.g., antiepileptics) is common despite the wellknown potential side effects and adverse drug reactions (ADRs). Pain is one of the most described symptoms in the elderly [2]. In the United States, approximately 68 million people suffer from acute pain syndromes every year and 25% are 65 years of age or older [3]. In nursing homes, up to 40% of residents have had pain syndromes of varying severity, while 38–50% have chronic pain and of these, 14% have had severe chronic pain [4]. In the UK, 50% of people aged 65 years and 60% of individuals aged 75 years or older reported pain syndromes [5]. Central-acting analgesics have increasingly become a treatment option, even for patients in advanced age and without malignancy-associated pain, because other analgesic classes such as nonsteroidal antiinflammatory drugs and metamizole may have serious side effects [6, 7, 8, 9]. Few data have been published on the pharmacokinetics and pharmacodynamics of opioids in the elderly [10, 11]. Recent studies showed an increase in ADRs of opioid analgesics [12, 13, 14, 15]; side effects due to overdosing [16, 17, 18]; admissions to emergency rooms [19, 20, 21] and hospi-
talization [22]; falls, injuries, and road accidents [23, 24, 25, 26, 27, 28]; and mortality [29, 30, 31, 32, 33, 34]. The risk for hospitalization and mortality increases with the dose, the number of prescribers, and the number of pharmacists [35, 36]. Besides central-acting analgesics, the use of psychotropic drugs in the elderly is high as well and Simoni-Wastila and Yang reported their use in 25% of the US population [37]. In nursing homes, up to 46.8% of residents received psychotropic drugs with antidepressants (31.2%) being the leading drug class [38]. In a memory clinic, 22% of patients used CNSADs, with a potential negative impact on cognition [39]. Rikala et al. [40] described 38% of community-dwelling seniors taking CNSADs. The risk of cognitive decline associated with the use of drugs with anticholinergic properties has been reported [41, 42]. This occurred even in Alzheimer’s patients over various (short- and longterm) follow-up periods [43, 44]. In the Health, Aging and Body Composition Study, the use of CNSADs was not associated with the incidence but with the progress of cognitive decline [45]. Puustinen et al. [46] reported a high risk of cognitive decline associated with combinations of opioids and other CNSADs. Maust et al. [47] found that in the US most CNSADs were prescribed by nonpsychiatrists. Furthermore, Rossi and colleagues reported the use of more than one unnecessary drug, and 41.4% of drugs showed a lack of effectiveness [48].
Research question Do CNSADs have an influence on the results of cognitive testing using a standard instrument (MMSE) in geriatric inpatients?
Methods We analyzed the combined data from two prospective, single-center study cohorts from our department for acute, subacute, and rehabilitative geriatric medicine at a tertiary hospital, which were performed in 2011 and 2012. Both studies have the same design for the cognitive assessment; the measurements were done on day 2 or 3 after hospital admission by a trained research nurse. The first study compared MMSE with different short cognition tests (Prospective Comparison of Psychometric instruments, PROPSYC). The second study analyzed the influence of advanced glycation end products, a biomarker of aging, and functional outcome (AGE OUT). Statistical analysis was done with Statistica 10.0, Statsoft. Both studies were approved by the ethics committee of the Lower Saxony Physician Board.
Results Overall, 395 patients were included, 144 male (M) and 251 female (F); 166 patients were from the PROPSYC and 229 patients were from the AGE OUT study. The mean age was 80.0±8.4 years (M
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Beiträge zum Themenschwerpunkt Tab. 1 Patients and CNS-acting drugs Number Age BI admission BI discharge GDS 10 EBI MMSE hpNL lpNL NL all Amitriptyline TCA other TCA all SSRI NaSSA SSNRI AD new Oxazepam, Diazepam Lorazepam BD all Zopiclone Antiepilepticsa Othersb Opioids lpc Opioids td Opioids oral Opioids all
Patients 395 80.035±8.400 46.628±19.786 71.213±23.129 3.128±2.647 66.589±23.942 22.876±4.915 1 13 14 24 8 32 26 3 5 34 8 18 26 11 34 4 60 21 36 57
Men 144 76.772±9.103 44.375±20.164 70.657±24.918 2.888±2.603 67.920±23.992 23.285±4.657 1 5 6 9 2 11 9 1 1 11 5 7 12 5 14 1 18 6 9 51
Women 251 81.907±7.359 47.932±19.485 71.534±22.082 3.265±2.667 65.824±23.930 22.641±5.052 0 8 8 15 6 21 17 2 4 23 3 11 14 6 20 3 42 15 27 42
p 0.000000 0.085979 0.724268 0.175032 0.414997 0.211012
AD antidepressants, BD benzodiazepines, BI Barthel index, CNS central nervous system, EBI extended Barthel index, GDS 10 Geriatric Depression Scale 10-item, hpNL high-potency neuroleptics (haloperidol, risperidone), MMSE Mini Mental Status Examination, lpNL low-potency neuroleptics (melperone, promethazine), NaSSA noradrenergic and specific serotonergic antidepressants, NL neuroleptics, SSNRI selective serotonergic noradrenalin reuptake inhibitors, SSRI selective serotonin reuptake inhibitors, TCA tricyclic antidepressants, td transdermalaGabapentin, pregabalin, levetiracetambClomethiazole, lithiumclp Low-potency (tramadol, tilidine)
76.8±9.1, F 81.9±7.4, p=0.0000). The mean MMSE points were 22.9±4.9 (M 23.3±4.7, F 22.6±5.0, p=0.211). . Tab. 1 shows the patients’ basic data and frequency of CNSADs use. Analgesics with central activity were given to 117 of 395 patients (29.6%). Low-potency opioids (tramadole hydrochloride, tilidine) were identified in 60 patients (M 18, F 42, age 80.9±7.7 years); high-potency opioids in 57 patients (M 15, F 42, age 78.3±9.5 years). Transdermal patches were only found in 21 (M 6, F 15) and oral drugs in 36 patient (M 9, F 27). Antidepressants were used in 66 patients, benzodiazepines in 26, and hypnotics in 11, while 38 patients received other CNSADs. In total, 258 patients (65.3%) used drugs with potential adverse cognitive properties. Significant correlations with the results of cognitive testing
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were only found for sedatives (diazepam and oxazepam), but not for lorazepam (. Tab. 2). In the subset of the AGE OUT patients, we also correlated the total number of drugs for all patients and different groups of cognitive decline (. Tab. 3). A weak but significant correlation was identified for all patients; the group with severe cognitive impairment (MMSE ≤9) showed a high but nonsignificant correlation, possibly due to the small (n=3) number of patients in this group.
Discussion Antidepressants In an analysis of nursing homes of the US Veterans Administration, Hanlon et al. reported that 57.5% of antidepressive drugs
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showed the risk for drug–drug and drug– disease interactions. In 25.4% of the residents, they found an underuse of antidepressants and only in 17.6% of the residents was the use of antidepressants judged as appropriate [49]. Citalopram reduced agitation in Alzheimer’s disease (AD) patients but affected cognition negatively over 9 weeks [50]. In contrast to this finding, Caballero et al. [51] found no difference in AD patients treated with antidepressants for depressive symptoms. Moreover, Savaskan et al. [52] described better cognitive performances in patients with depression and specific drug treatment, and Rozzini et al. [53] reported that selective serotonin reuptake inhibitors in AD patients with depression resulted in better cognitive performance. For tricyclic antidepressants, an association with cognitive decline was not observed [54]. Potvin et al. [55] linked anxiety and depression to cognitive decline and vice versa, so that the rationale behind the hypothesis—antidepressants are able to reverse or stop cognitive decline—will be valid for some patients. Despite these heterogeneous findings, in our analysis we did not see an influence of antidepressants, even tricyclics or newer ones, on cognitive performance measured with the MMSE.
Neuroleptics Vigen et al. [43] found that neuroleptics given over 36 weeks worsened the cognition performance of AD patients, and Rosenberg et al. [44] confirm these results for long-term use of over 3.7 years. By contrast, Caballero et al. [56] found no influence on cognition. In our analysis we had only one patient treated with high-potency neuroleptics, but 13 treated with low-potency neuroleptics. In total we found no association between the results of cognitive testing and neuroleptic drug use.
Sedatives and hypnotics In a prospective cohort study of inpatients, the use of sedatives was associated with cognitive decline [57]. In their study in Finland on 781 patients, Desplenter et al. [58] found no difference in the cognitive abilities in users and non-users of sed-
Abstract · Zusammenfassung atives over 3 years. No influence was stated by Puustinen et al. [59], while another group identified a risk for cognitive decline related to sedatives in inpatients [57]. Our data identified users of diazepam and oxazepam with a significantly lower cognitive performance, while users of lorazepam and zopiclone showed no decline. It is noteworthy that the small numbers of patients (n=8) in our cohort may have had an effect on the results.
Opioids While pain prevalence [60] and pain therapy varied widely [61, 62], there are data that confirm the thesis that opioids are able to worsen cognition [63, 64, 65, 66], but one study with transdermal buprenorphine shows no influence. In our patients (57 with low-potency and 60 with highpotency opioids) we identified no association between cognition and drug use. For other CNSADs, e.g., antiepileptics, we found no correlation to cognitive testing results. Overall, we identified a weak, but significant association for the number of drugs given and cognitive performance. The weakness of the study may be the cognitive assessment instruments used. Sjogren et al. [65] discussed the fact that the MMSE may not be sensitive enough in detecting adverse effects on cognition. Taipale et al. [66] compared four methods for assessing cumulative effects of drugs and identified no method that worked ideally. Additionally, the number of CNSADs in different drug classes varied so that this may influence our results. Moreover, empirical and clinical data show a clear relationship between the number and dosage of CNSADs for mobility limitations [67], falls [68, 69, 70], and fractures [71, 72]; however, we found no effect within ADRs measured with the Barthel index (BI). The BI at admission showed a modest correlation with the MMSE, with a Pearson’s correlation of 0.39 at admission and of 0.45 at discharge (both p=0.05). Only for diazepam and oxazepam was there a high correlation for the BI, with 0.74 at admission (p=0.05) and 0.70 (nonsignificant) at discharge. However, the sensitivity of the BI is possibly not high enough to address this ques-
Z Gerontol Geriat 2014 · [jvn]:[afp]–[alp] DOI 10.1007/s00391-014-0654-5 © Springer-Verlag Berlin Heidelberg 2014 M. Gogol · H. Hartmann · S. Wustmann · A. Simm
Influence of central nervous system-acting drugs on results of cognitive testing in geriatric inpatients Abstract Introduction. Growing evidence shows a high correlation between extensive use of central nervous system-acting drugs (CNSADs) in elderly patients and adverse drug reactions (ADRs) such as falls, fractures, and mortality. Research question. Are results of cognitive testing with the Mini Mental Status Examination (MMSE) influenced by use of CNSADs? Setting. Geriatric inpatient service for acute, subacute, and rehabilitation care. Methods. Secondary combined analysis of two prospective, single-center study cohorts (PROPSYC, 2011 and AGE OUT, 2012) with identical procedure for the MMSE at a tertiary hospital. Results. Overall, 395 patients were included, 144 male (M) and 251 female (F). Mean age was 80.0±8.4 years (M 76.7±9.1, F 81.9±7.3, p=0.0000). Mean MMSE points were 22.9±4.8 (M 23.2±4.6, F 22.6±5.0, p=0.211). In total, 258 patients (65.3%) used drugs with poten-
tial adverse cognitive properties. Analgesics with central activity were given to 117 of 395 patients (29.6%). Low-potency opioids (tramadol hydrochloride, tilidine) were identified in 60 patients and high-potency opioids in 57 patients. Antidepressants were used in 66 patients, benzodiazepines in 26, and hypnotics in 11, while 38 patients received other CNSADs. We only found significant correlations with the results of cognitive testing for sedatives (diazepam and oxazepam, Pearson’s r −0.79, p=0.05), but not for lorazepam. Conclusion. Our analysis shows an influence of sedatives (diazepam and oxazepam, but not lorazepam) on cognitive testing with the MMSE in users of CNSADs. Keywords Cognition · Central nervous system-acting drugs (CNSADs) · MMSE · Elderly patients · Adverse drug reactions (ADRs)
Einfluss von zentralnervös wirkenden Medikamenten auf die kognitive Testung von geriatrischen Patienten im Krankenhaus Zusammenfassung Hintergrund. Eine zunehmende Evidenz zeigt bei älteren Menschen eine häufige Anwendung von Medikamenten mit zentralnervöser Wirkung („central nervous systemacting drugs“, CNSADs) und mit einer hohen Nebenwirkungsrate („adverse drug reactions“, ADRs) wie Stürze, Frakturen und erhöhter Mortalität. Fragestellung. Sind die Ergebnisse der kognitiven Tests mit dem Mini-Mental-StateTest (MMSE) von der CNSAD-Einnahme beeinflusst? Setting. Die Untersuchung erfolgte in einer geriatrischen Klinik mit Akut-, Frührehabilitations- und weiterführenden Rehabilitationsbereich. Methode. Mithilfe einer Sekundäranalyse wurden kombiniert Daten aus zwei prospektiven Kohortenstudien (PROPSYC, 2011 und AGE OUT, 2012) mit gleichem Design des kognitiven Assessments untersucht. Ergebnisse. Die Analyse umfasste 395 Patienten, davon waren 144 Männer (M) und 251 Frauen (F). Das mittlere Alter betrug
80,0±8,4 Jahre (M 76,7±9,1, F 81,9±7,3, p=0,0000). Der mittlere MMSE lag bei 22,8±4,8 Punkten (M 23,2±4,6, F 22,6±5,0, p=0,211). Insgesamt 258 Patienten (65,3%) erhielten CNSAD. Zentral wirksame Analgetika bekamen 117 Patienten (29,6%). Niedrigpotente Analgetika wurden in 57 und hochpotente in 60 Fällen gegeben. 60 Patienten erhielten Antidepressiva, 26 Sedativa und 11 Hypnotika. Andere CNSAD erhielten 38 Patienten. Signifikante Korrelationen mit den kognitiven Tests fanden wir nur für Sedativa (Diazepam und Oxazepam, Pearson r −0,79, p=0,05), aber nicht für Lorazepam. Zusammenfassung. In unserer Analyse fanden wir nur für Sedativa (Diazepam und Oxazepam, aber nicht für Lorazepam) eine signifikante Korrelation mit dem Ergebnis der kognitiven Tests. Schlüsselwörter Kognition · ZNS-aktive Medikamente · MMSE · Geriatrische Krankenhauspatientenen · Neben- und Wechselwirkungen
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Beiträge zum Themenschwerpunkt
Men
Women
vide an objective assessment of the brain and brain biomarkers [90] to evaluate patients with more or fewer vulnerabilities.
na 0.513889
na 0.123916
Conclusion
−0.140345 −1.000000 −0.162598 0.160779 na na 0.131243
−0.087436 −0.614256 −0.193894 −0.350798 1.000000 0.895184 0.099900
−0.954233* −0.131060 −0.265613
na −0.189748 −0.103874
−0.342217
0.086694
0.113523 na
0.187874 0.602881
0.336505 −0.712748 0.381128 0.288271
0.003318 0.032887 0.280475 0.088744
Tab. 2 Pearson correlation for MMSE and CNS-acting drugs All Neuroleptics hpNL na lpNL 0.392631 Antidepressants Amitriptyline −0.099636 TCA other −0.431857 TCA all −0.167213 SSRI −0.171247 NaSSA 0.671932 SSNRI 0.613122 AD new 0.133122 Sedatives Oxazepam, diazepam −0.794297* Lorazepam −0.165369 BD all −0.105447 Hypnotics Zopiclone −0.114537 Other CNS-acting drugs Antiepilepticsa 0.138968 Othersb 0.631122 Opioids Opioids lpc 0.044566 Opioids td −0.196472 Opioids oral 0.269694 Opioids all 0.174190
AD antidepressants, BD benzodiazepines, hpNL high-potency neuroleptics (haloperidol, risperidone), lpNL low-potency neuroleptics (melperone, promethazine), NaSSA noradrenergic and specific serotonergic antidepressants, NL neuroleptics, na not applicable, SSNRI selective serotonergic noradrenalin reuptake inhibitors, SSRI selective serotonin reuptake inhibitors, TCA tricyclic antidepressants, td transdermal*Indicating p=0.05aGabapentin, pregabalin, levetiracetambClomethiazole, lithiumclp Low-potency (tramadol, tilidine)
Tab. 3 Total number of drugs and CNS-acting drugs given and correlation to MMSE
Number of patients (men/ women)
All patients MMSE ≤9 MMSE 10–19 MMSE 20–26 MMSE ≥27
229 (87/142) 3 (1/2) 50 (16/34) 119 (46/73) 57 (24/33)
Mean number of drugs (number of CNS-acting drugs) 8.25 (1.95) 8.66 (2.00) 8.92 (1.98) 7.92 (1.94) 8.35 (1.92)
Pearson’s r for number of drugs vs. MMSE −0.0755 0.9607 0.0095 −0.0245 −0.1438
Pearson’s r for number of drugs vs. CNSacting drugs 0.5343* −0.9607 0.4733* 0.6048* 0.4146*
MMSE Mini Mental Status Examination, CNS central nervous system*p=0.05
tion, because it does not measure the quality and quantity of mobility. Furthermore, other factors have to be taken into account. For example, sleep problems may affect cognition seriously. Different groups described daily sleepiness as a risk factor for cognitive decline [73, 74, 75, 76], while reducing daily sleepiness was able to reduce cognitive impairment over a period of 6 months [77].
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Lifestyle factors are also associated with healthy or unhealthy aging (e.g., activity, nutrition, smoking, alcohol use) and some of them may have short- and midterm effects on cognition and may be able to influence or to mask potential effects of CNSADs [78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89]. Future research should examine the time of drug use and the possible adaptation to this drug and should pro-
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Our analysis identified diazepam and oxazepam as playing a role in worsening cognition, while other drugs showed no significant correlation. These results may be biased by the assessment instrument used and, in part, by the small number of patients using CNSADs. A significant negative effect on cognition was found for polypharmacy including CNSADs.
Corresponding address M. Gogol Department of Geriatrics, Lindenbrunn Hospital Lindenbrunn 1, 31863 Coppenbrügge Germany [email protected]
Compliance with ethical guidelines Conflict of interest. M. Gogol, H. Hartmann, S. Wustmann, and A. Simm state that there are no conflicts of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 (in its most recently amended version). Informed consent was obtained from all patients included in the study.
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