Falls at the interface between geriatric and psychiatric patients: a critical review from a psychopharmacological perspective

Fabian Max Wedmann1, Andreas Conca1, Patrizia Di Gregorio2, vincenzo florio1, Marco Toscano3, Giancarlo Giupponi1

1Dipartimento di Psichiatria, Ospedale di Bolzano, Italia; 2Medicina Geriatrica, Ospedale di Bolzano, Italia; 3UO Psichiatria Ospedaliera e Territoriale ASST Rhodense, Garbagnate Milanese (Milano), Italia.

Summary. Falls in the elderly represent one of the major clinical problems as they are serious events that often result in high residual disability and mortality rates. Knowledge on the subject derives mainly from geriatric and gerontopsychiatric research. However, gerontopsychiatric patients differ from geriatric patients not only for the psychiatric and neurological comorbidities, which are often not sufficiently taken into account in the scientific context, but also for the intake of psychotropic drugs, notoriously described as one of the main risk factors for falls. Such drugs are widely prescribed in this group of patients, often even off-label. Clinicians therefore should pay particular attention to falls, since various comorbidities and polypharmacy as a prescribing issue can have important consequences for clinical management. Falls have not been sufficiently investigated yet in a purely psychiatric context.

Key words. Confounding, falls, gerontopsychiatry, psychiatry, psychotropic drugs.

Le cadute nei pazienti geriatrici e psichiatrici: una revisione critica dalla prospettiva psicofarmacologica.

Riassunto. Le cadute nel paziente anziano rappresentano un problema clinico di grande rilevanza poiché esitano spesso in disabilità e mortalità molto elevate. Le conoscenze sull’argomento sono prevalentemente derivanti dall’ambito geriatrico e psicogeriatrico. Tuttavia questo secondo gruppo di pazienti si differenzia dal primo per la comorbilità psichiatria e/o neurologica, che spesso non viene sufficientemente presa in considerazione nel contesto scientifico, e per l’assunzione di farmaci psicotropi, notoriamente descritti come uno dei principali fattori di rischio per le cadute. Tali farmaci vengono spesso prescritti nella categoria di pazienti in questione, talvolta anche off-label. Risulta pertanto evidente quanto sia fondamentale considerare adeguatamente le cadute nelle categorie di pazienti sopracitate, sia per le comorbilità sia per le polifarmacoterapie assunte da questi ultimi. A oggi le cadute non vengono adeguatamente approfondite in un contesto puramente psichiatrico. 

Parole chiave. Cadute, confounding, gerontopsichiatria, psichiatria, psicofarmaci.

Introduction

According to the literature, falls are a frequent and serious problem in the elderly population as they often lead to a deterioration in the quality of life and a reduction in the self-sufficiency of the elderly person1,2. 30% of people over 65 years of age and 50% of people over 80 years of age fall at least once; older people who have already fallen once have a 2-3 times greater likelihood of falling again within 12 months3,4.

60% of elderly persons fall at home, 30% in public places and the remaining 10% fall in a nursing home or hospital; in 10-25 % of cases falls lead to fractures or serious injuries.

In most studies, fall incidence rates vary between 1.6 and 17 falls per 1000 patient days (pd). In one of the largest studies conducted in the United States with 315 817 falls included, the total fall rate was 3.56 falls per 1000 pd5. In psychiatric wards, fall rates ranged from 4.1 to 6.4 falls per 1000 pd, which is higher than the average fall rate of 3.56 referring to hospitalized patients. The highest fall rates, from 9.1 to 17 falls per 1000 pd, were found in geriatric or psychogeriatric wards. The fall rate is up to three times higher in institutions such as hospitals or nursing homes than at home6-8.

Last but not least, falls are also an economic problem. Prolonged hospital stays of patients admitted for falls, increase the costs of treatment and constrain resources9,10. The costs of the treatment for fall injuries vary between 2,000 and 42,000 US dollars11.

Psychotropic drugs are often highlighted as a major cause of falls. Antipsychotics, antidepressants, benzodiazepines and Z-drugs increased the likelihood of falls in elderly patient groups12-14. Side effects of medication such as reduced cognitive ability, attention, visual acuity, sedation and orthostasis are often reported as causes of falls15-18. But also age by itself inevitably leads to a deterioration of cognitive and physical functions, so the task of finding risk factors for falls remains often multifactorial4.

As far as the current context of psychiatric research is concerned, the subject of falls has been barely studied and convincing data are still missing.

With increasing age of patients, there is often an overlap between geriatric and psychiatric clinical conditions. Thus, on the one hand, psychiatric comorbidities increase in geriatric patients and, on the other hand, we are confronted with the natural ageing process in the psychiatric patient population19. The relevance of geriatric syndromes, such as falls, in the context of the pressing polypharmacy prescribing issue is therefore gaining more and more importance6,8,20.

The aim of this review is to present the problem of falls in the intersection between geriatric and psychiatric conditions and to summarize the current literature on mostly pharmacological risk factors highlighting the multiple difficulties of prescribing in elderly patients.

Methods

While this article is by no means a complete review of fall studies, the goal is to familiarize the reader with the strengths and limitations of the types of research often used to examine falls and its risk factors in psychiatric and geriatric patients. Bias and confounding are common problems affecting fall studies. We therefore chose a quality criterion by which we selected only studies with a methodology that tried to reduce the effects of bias and confounding, such as multivariate logistic regression analysis. We performed a PubMed/MEDLINE, Scopus and PsycINFO search to identify all articles within the last 10 years until 2021. The following terms were cross-referenced with falls in the search: “polypharmacy”; “antidepressants”; “antipsychotics”; “anticonvulsants”; “benzodiazepines”; “non-benzodiazepines”; “Z-drugs”. The resulting reference list of the article was first auto-searched using Boolean operators (“AND”, “OR”) as well as filters. The resulting list was hand-checked to eliminate duplicates (figure 1).




249 articles were identified of which 57 met our inclusion criteria. We further classified the resulting medications based on high odds-ratios or relative risk scores in the primary research or review articles in high or low risk categories. To provide information on connected topics like “side effects”; “hyponatremia”; “cognitive function”; “aging”; “fractures”; “sarcopenia”, “pharmacokinetics”; “pharmacodynamics”; “pharmaco-interactions” and “confounding” we selected 80 key articles independently of publication date. All original articles found through the resulting literature search were read.

The following criteria were used to exclude articles:

■ studies/articles whose material is incomplete or whose content does not concern our research topic;

■ studies/articles that do not clearly demonstrate a link between pharmacy and falls;

■ studies that do not report for important confounders, report unclear methodology or reported results of univariate analysis only;

■ studies/articles published before 2010.

All resulting listed articles in English and German were reviewed.

Results

A total of 137 articles were included in our review. No case reports were found that specifically addressed the topic. There are 5 main reviews, which include almost all studies that examined fall risk factors up to 2018. Leipzig et al. were the first to include in their review 43 studies investigating risk factors in nursing homes, hospitals and home environment12-14,21,22. Other authors were supplementing these findings with more recent studies on classes of drugs that had not been studied so far. However, these studies mainly represent studies in nursing homes and in the home environment. Studies on fall risk factors in the inpatient setting are represented by Leipzig et al. with only 5 studies. This also applies to the other reviews. Some classes of medication were more frequently associated with an increased risk of falls in the elderly. The investigations focus in particular on certain groups of psychoactive substances (table 1)23-64.




 These include: benzodiazepines, antipsychotics, antidepressants, Z-drugs, anticonvulsants and polypharmacy.

Benzodiazepines

Many studies associate benzodiazepines with an increased risk of falls23-28. However, data regarding the risk of falls for various preparations with different elimination half-life are still inconsistent14,21,22,28. Preparations with long and short half-life have been both associated with falls14,23,25,28-30,65,66. Higher doses were more likely to be associated with falls than lower doses14,29,67. Seppala et al.14 in their meta-analysis found long acting benzodiazepines 1,81 OR (95%, CI 1.05-3.16) associated with a higher fall risk then short acting benzodiazepines 1,27 OR (95%, CI 1.04-1.56). These results were replicated also by other authors31.

As early as 1978, Reidenberg et al. were able to demonstrate that the plasma concentration depends not only on the administered dose, but also on the age of the patients68. The focus was mainly put on the cognitive effects, influenced by the γ-aminobutyric acid (GABA) transmission, which probably play a decisive role in the risk of falling69.

Attention, working memory, processing speed, visual construction, recent memory and expressive language deteriorate significantly with long-term use of benzodiazepines16. The onset of orthostatic hypotension has also been reported following the prescription of benzodiazepines70. Up to now, it has not been possible to fully clarify whether there is also an increased risk of developing dementia16,71-73.

Z-drugs

Z-drugs approved in the early 1990s, proclaimed as a safe alternative to benzodiazepines, have also been associated with falls and an increased risk of fractures23,32-36,74. Berry et al. conducted a study on the long-term use of Z-drugs and found an increased risk of fall-related hip fractures 1,66 OR (95% CI, 1.45-1.90) on zolpidem medication75. These results could subsequently be replicated by other authors33. Zolpidem and zopiclone have long been considered the drugs of choice for sleep disorders in old age due to their lower addictive potential compared to benzodiazepines and a lower impact on sleep architecture76. Like benzodiazepines, Z-drugs exert their effects through increased GABA transmission. Their pharmacokinetics are characterized by a rapid onset within 30 min and short half-life (1-7 h). However, it has been shown that the addictive potential is comparable to that of benzodiazepines77,78. Commonly neuropsychiatric adverse events like hallucinations, anmnesia and parasomnia have been described with Z-Drugs33,34. Especially the elderly were prone to elevated plasma concentrations in comparison to younger individuals which could explain the higher risk of falling79.

Antipsychotics

Data regarding antipsychotics and falls is controversial. Although typical and atypical antipsychotics have been associated with falls, there is also evidence that they might act as protective factor in psychiatric patients13,21,22,38,80.

Among the most important undesirable side effects are listed extrapyramidal motor disturbances that could provoke falls81. However, hyponatremia is also mentioned as an undesirable side effect, which is considered a separate risk factor for falls82-84.

Low potency antipsychotics are often used in elderly patients with sleep disorders, because of their favourable side effect profile39,85,86. However, attention needs to paid on their anticholinergic effects that could provoke falls.

Studies regarding the fall risk have been shown an increased risk of falls and fractures, especially in long-term prescriptions40,57,81,87-89. Epidemiolgical studies designed to investigate antipsychotic prescription are rare41,90.

Antidepressants

Different antidepressant classes (Tricyclic Antidepressants - TCA; Selective serotonin reuptake inhibitors - SSRI; Selective norepinephrine reuptake inhibitors - SNRI) were associated with falls in several studies44-48,57. The most frequently prescribed SSRI, considered as the drugs of choice in depressive and anxiety disorders, have been associated in many studies with an increased risk of falling. Above all, the risk of fracture appeared to be increased, which may be related to an increased likelihood of developing osteoporosis under treatment49-52. Wang et al. for instance found an adjusted OR of 3.05 (95% CI 2.73-3.42) for patients affected by osteoporosis and falls52. SNRIs, on the other hand, are still poorly studied with regards to their fall risk12,13,15,48. An association with the risk of developing orthostatic hypotension seems possible15. But even during treatment with SSRIs and SNRIs, a variety of unwanted side effects can occur. A new onset of sleep disorders and the frequent feeling of restlessness at the start of treatment could have contributed on increasing the risk of falls27,91-97.

As already described in the case of antipsychotics, hyponatremia in blood examination occurs relatively frequently during treatment with antidepressants and is considered an independent risk factor for both, falls and hospital admissions98-100. The risk appears to be increased with SSRIs and SNRIs, especially in patients suffering from an impaired renal function and dementia. TCAs have virtually disappeared from clinical practice, due to their anticholinergic effects, orthostatic hypotension and ECG changes, which more likely occur in the elderly101. Low-dose doxepin, on the other hand, is considered to be well tolerated and therefore occasionally prescribed by general practitioners to improve sleep quality102,103.

Sleep quality, as evidenced by polysomnography, was also improved by other antidepressants like mirtazapine and trazodone, which are recommended for elderly patients due to their good safety profile57,53,55,104,105. For the newer antidepressant vortioxetine, there are no studies to date that demonstrated an association with falls.

Anticonvulsants

Anticonvulsants are not only prescribed in the treatment of epilepsy but also in the psychiatric context for bipolar disorder, behavioral disorder, anxiety disorder and sleep disorder58. The therapeutic effects through various mechanisms of action, including regulation of ion channels, blocking glutamate-mediated stimulating neurotransmitter interaction, and enhancing the inhibitory GABA transmission are very heterogenous59-61. Common side effects include sedation, nausea, and headache. However, more adverse effects, such as auditory and visual problems, hyponatremia, liver dysfunction and kidney disorders may also contribute to their fall risk. A clear association, especially in elderly patients, was demonstrated by Haasum et al. in their systematic review with two studies demonstrating a stastical significant association62. For instance Masud et al. found ORs of 2.8 for falls and 2.6, respectively, for recurrent falls, but with relatively wide confidence intervals60.

Polypharmacy

In addition to the risk of falling posed by the individual drug, particular attention should be paid to polypharmacy106-112. Hand grip strength index is an important indicator of frailty in geriatric medicine and appeared significantly reduced under psychoactive polypharmacy, i.e., the simultaneous use of more than one psychoactive drug113,114.

From a pharmacokinetic point of view, the risk of drug-drug interactions at the level of the hepatic cytochrome was increased up to 80% when five or more drugs were prescribed at the same time, especially in the elderly63. In particular, the inhibition of CYP2D6 enzyme, involved in the metabolism of several antidepressant drugs, may lead to elevated drug levels. It seems obvious that elderly patients, frequently affected by various comorbidities, are particularly exposed to this phenomenon. There are few population studies highlighting the real role of metabolic drug interactions in association with adverse events, like falls64. In line with these findings a recent meta-analysis attempted to prove that a reduction in medication also would lead to a reduction of falls. Unfortunately, with discouraging results115,116.

Discussion

To date little is known about falls in psychiatric patients51. Literature on this subject, especially regarding younger patients, is lacking. A first case-control study on a general population sample aged between 25 and 60 years included 335 cases of patients who died or were hospitalized due to falls in the outpatient setting. The study revealed that falls also affected younger patients mainly subject to polypharmacy, thus bringing the fall event closer to a younger age group which is the host of psychiatric structures117.

Given the high rates of falls in psychiatric wards in epidemiological studies, future research is needed to extent the scientific knowledge of falls also on psychiatric patients.

Our review instead shows that falls are of great clinical relevance, especially in the geriatric and psychogeriatric context. Most of the studies examining falls are based on results obtained in the outpatient setting. The situation in the inpatient setting – quite different due to the presence of acute pathologies – is represented by Leipzig et al. with only five studies reviewed. In fact, in the other reviews the composition of studies is similar12-14,21,22.

Another limitation is the lack of randomized controlled trials in the selected study designs, which mainly consist of case-control and case-crossover studies, more prone to bias.

The research of risk factors for falls almost always leads to psychotropic drugs, on which we have focused in our research. Unfortunately, their use often occurs beyond approved psychiatric indications, such as the treatment of sleep disorders and psychomotor agitation. Therefore, the prescription of these drugs, developed mainly in the psychiatric field, can increase the risk of falls in elderly patients. In this case, it is often a “off-label” prescription, which may not be free of legal issues39,85,118-120.

In fact, the elderly patient often presents various comorbidities, which interfere with the natural changes in pharmacokinetics and pharmacodynamics related to the ageing process, which can favour cognitive and motor alterations, and consequently lead to falls71,107,121.

These changes lead to an increase in body-fat and a decrease in total body water. That is why water-soluble (hydrophilic) drugs have higher peak plasma levels in the elderly. Inversely, fat-soluble (lipophilic) drugs have a greater volume of distribution in the elderly121. Decreasing serum albumin concentration affect the protein binding potency of drugs. The age-related decrease in liver size lead to a reduced hepatic blood flow and cytochrome enzyme activity which compromise hepatic clearance of drugs. Decreased renal blood flow, decreased glomerular filtration (GFR) and tubular secretion have a considerable impact on the renal clearance of drugs122. In addition, the elderly suffer often of sarcopenia, which implies the loss of muscle strength with an increase in problems related to movement and therefore suggests a greater vulnerability to unwanted side effects123-125.

A correlation of the physiological changes of ageing, in particular regarding pharmacokinetics, with polypharmacy and falls has been documented in several studies. An often reported example regards the interactions based on the CYP2D6 enzyme, where the drugs fluoxetine, paroxetine and metoprolol are metabolized. Fluoxetine and paroxetine are considered potent inhibitors of the CYP2D6 enzyme, with the consequent risk of increased plasma levels of metoprolol when prescribed concurrently126-129. Therefore, as reported in a recent systematic review of the literature, in many studies, as expected, there is reported an increased risk of bradycardia and hypotension with the simultaneous prescription of metoprolol and paroxetine or fluoxetine128.

Approximately 30% of hospital admissions of patients aged 75 or older are caused by adverse drug reactions130. The prevalence of drug interactions based on hepatic cytochrome enzymes was 80% when 5 drugs or more were prescribed131. Due to the numerous possible interactions, it remains a difficult task to attribute the fall to a specific drug.

Based on these considerations, it seems difficult to justify that prescribing these drugs often continues after discharge. To date evidence-based strategies for discontinuation of prescriptions after symptom relief are still missing132,133.

In geriatric medicine, falls are considered as an independent syndrome which always requires a systematic approach to evaluate the specific variables involved4,134.

The association between falls and sedative drugs such as benzodiazepines is well known and reported in various studies12-14,22. Antidepressants and antipsychotics have also been associated with falls in many studies, but it seems likely that the results are subject to bias. Leipzig et al. have already shown that the use of antipsychotics reduces the number of falls in psychiatric patients21. Their results demonstrate the importance of subgroup analysis and the inclusion of diagnoses in the study design to avoid bias and confounding. Confounding is a problem in most study designs examining fall risk135. Especially during hospitalization, clinicians often face symptoms which on the one hand require the use of psychiatric drugs, but on the other hand are considered risk factors for falls, for example in case of delirium. Although there are statistical methods that take the possible risk of confounding into account, it remains still a difficult task to include all the variables involved in the multifactorial genesis of falls in a model.

For example, “Time” as a variable, to document a direct association of the drug intake with the fall event, should be considered within the applied study designs, which is why the importance of prospective study designs must be emphasized.

Especially SSRIs, which are often recommended in the elderly, have unexpectedly shown an increased risk of falls in many studies. Despite, the neurobiological mechanism of action does not suggest a direct correlation with falls.

Depressive symptoms are very common in the elderly, which can lead to a significant impairment in quality of life136. In fact, social withdrawal, reduced physical activity with consequent loss of muscle mass and increased morbidity and mortality are factors which contribute to an increased risk of falls in patients with untreated depressive disorders. Therefore, it is important to consider these aspects when evaluating the introduction of antidepressant therapy48,137. At the time of antidepressant choice, there is a greater tendency to prescribe SSRIs in this category of frail patients (selective prescribing) due to their higher tolerability and acceptability profile compared to other classes of antidepressants, such as TCA drugs. This could be a potential confounder within the literature regarding the prescription of SSRI and falls in the elderly.

Limitations

Our review is not a complete summary of the literature on falls. We have restricted our research to psychopharmacological risk factors and discussed them with regards to their pharmacodynamic and pharmacokinetic properties. Other important risk factors, such as environmental factors and comorbidities, were not considered. Neither we considered the setting (in-patient and out-patient), which could also influence the risk of falls under certain medications due to the presence of acute illnesses.

Considerations

Clinicians should always consider pharmacological risk factors in their prescribing, especially in the elderly with greater comorbidities involved. Prescribing psychoactive medications is challenging and, especially in the context of falls, even more emphasis should be placed on developing individualized treatment algorithms. Since so far, there are hardly any evidence-based algorithms available, prescribing tools should be used whenever possible to facilitate the clinician to take pharmacodynamic and pharmacokinetic aspects into account, when prescribing risk medications. Simultaneous prescribing of several drugs with the same pharmacodynamic properties should be avoided.

Conclusions

Scientific research on the causes of falls in psychiatric medicine is lacking despite the risk factors appear very similar to those in elderly patients. Due to their effect on cognition and mobility research on risk factors for falls in the elderly predominantly is focused on psychotropic drugs. The identification of risk factors for falls remains subject to a high likelihood of bias and confounding, because quality study designs such as RCT or prospective studies are missing. The fall event can be a problem of clinical and sometimes legal relevance even in the psychiatric field. Therefore, considering pharmacokinetic and pharmacodynamic properties when prescribing psychoactive medications seems crucial. Despite the tools and knowledge now available, the sensitivity to the fall syndrome in clinicians and psychiatric institutions is still low and little attention is paid to both the measurement and the reduction of risks.

Conflict of interests: the authors have no conflict of interests to declare.

References

1. Deandrea S, Bravi F, Turati F, Lucenteforte E, La Vecchia C, Negri E. Risk factors for falls in older people in nursing homes and hospitals. A systematic review and meta-analysis. Arch Gerontol Geriatr 2013; 56: 407-15.

2. Inacio MC, Moldovan M, Whitehead C, et al. The risk of fall-related hospitalisations at entry into permanent residential aged care. BMC Geriatr 2021; 21: 686.

3. Lahmann NA, Heinze C, Rommel A. Stürze in deutschen Krankenhäusern und Pflegeheimen 2006-2013: Häufigkeiten, Verletzungen, Risikoeinschätzung und durchgeführte Prävention. Bundesgesundheitsblatt - Gesundheitsforsch - Gesundheitsschutz 2014; 57: 650-9.

4. Pasquetti P, Apicella L, Mangone G. Pathogenesis and treatment of falls in elderly. Clin Cases Miner Bone Metab 2014; 11: 222-5.

5. Bouldin ELD, Andresen EM, Dunton NE, et al. Falls among adult patients hospitalized in the United States: prevalence and trends. J Patient Saf 2013; 9: 13-7.

6. Oepen D, Fleiner T, Oliva y Hausmann A, Zank S, Zijlstra W, Haeussermann P. Falls in hospitalized geriatric psychiatry patients: High incidence, but only a few fractures. Int Psychogeriatrics 2018; 30: 161-5.

7. Turner K, Bjarnadottir R, Jo A, et al. Patient falls and injuries in U.S. Psychiatric care: incidence and trends. Psychiatr Serv 2020; 71: 899-905.

8. Rao WW, Zeng LN, Zhang JW, et al. Worldwide prevalence of falls in older adults with psychiatric disorders: a meta-analysis of observational studies. Psychiatry Res 2019; 273: 114-20.

9. Stevens JA, Corso PS, Finkelstein EA, Miller TR. The costs of fatal and non-fatal falls among older adults. Inj Prev 2006; 12: 290-5.

10. Morello RT, Barker AL, Watts JJ, et al. The extra resource burden of in-hospital falls: a cost of falls study. Med J Aust 2015; 203: 367.

11. Heinrich S, Rapp K, Rissmann U, Becker C, König HH. Cost of falls in old age: a systematic review. Osteoporos Int 2010; 21: 891-902.

12. Park H, Satoh H, Miki A, Urushihara H, Sawada Y. Medications associated with falls in older people: systematic review of publications from a recent 5-year period. Eur J Clin Pharmacol 2015; 71: 1429-40.

13. Woolcott JC, Richardson KJ, Wiens MO, et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med 2009; 169: 1952-60.

14. Seppala LJ, Wermelink AMAT, de Vries M, et al. Fall-risk-increasing drugs: a systematic review and meta-analysis: II. Psychotropics. J Am Med Dir Assoc 2018; 19: 371.

15. Wathra R, Mulsant BH, Thomson L, et al. Hypertension and orthostatic hypotension with venlafaxine treatment in depressed older adults. J Psychopharmacol 2020; 34: 1112-88.

16. Crowe S, Stranks E. The residual medium and long-term cognitive effects of benzodiazepine use: an updated meta-analysis. Arch Clin Neuropsychol 2018; 33: 901-11.

17. Boettger S, Jenewein J, Breitbart W. Haloperidol, risperidone, olanzapine and aripiprazole in the management of delirium: a comparison of efficacy, safety, and side effects. Palliat Support Care 2015; 13: 1079-85.

18. Bet PM, Hugtenburg JG, Penninx BWJH, Hoogendijk WJG. Side effects of antidepressants during long-term use in a naturalistic setting. Eur Neuropsychopharmacol 2013; 23: 1443-51.

19. Nguyen TT, Eyler LT, Jeste DV. Systemic biomarkers of accelerated aging in schizophrenia: a critical review and future directions. Schizophr Bull 2018; 44: 398.

20. Fisher J, Teodorczuk A. Old age psychiatry and geriatric medicine: shared challenges, shared solutions? Br J Psychiatry 2017; 210: 91-3.

21. Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systematic review and meta-analysis: I. Psychotropic drugs. J Am Geriatr Soc 1999; 47: 30-9.

22. Hartikainen S, Lönnroos E, Louhivuori K. Medication as a risk factor for falls: critical systematic review [Internet]. Journals Gerontol - Ser A Biol Sci Med Sci 2007; 62: 1172-81.

23. Chang CM, Chen MJ, Tsai CY, et al. Medical conditions and medications as risk factors of falls in the inpatient older people: a case-control study. Int J Geriatr Psychiatry 2011; 26: 602-7.

24. O’Neil CA, Krauss MJ, Bettale J, et al. Medications and patient characteristics associated with falling in the hospital. J Patient Saf 2018; 14: 27-33.

25. Ham AC, Swart KMA, Enneman AW, et al. Medication-related fall incidents in an older, ambulant population: the B-PROOF study. Drugs Aging 2014; 31: 917-27.

26. Dyer AH, Murphy C, Lawlor B, et al. Cognitive outcomes of long-term Benzodiazepine and Related Drug (BDZR) use in people living with mild to moderate Alzheimer’s disease: results from NILVAD. J Am Med Dir Assoc 2020; 21: 194-200.

27. Thorell K, Ranstad K, Midlöv P, Borgquist L, Halling A. Is use of fall risk-increasing drugs in an elderly population associated with an increased risk of hip fracture, after adjustment for multimorbidity level: a cohort study. BMC Geriatr 2014; 14: 114-31.

28. Morishita C, Ichiki M, Shimura A, et al. Psychotropics use and occurrence of falls in hospitalized patients: a matched case-control study. Psychiatry Clin Neurosci 2022; 76: 71-6.

29. Blachman NL, Leipzig RM, Mazumdar M, Poeran J. High-Risk medications in hospitalized elderly adults: are we making it easy to do the wrong thing? J Am Geriatr Soc 2017; 65: 603-7.

30. Díaz-Gutiérrez MJ, Martínez-Cengotitabengoa M, Sáez de Adana E. Relationship between the use of benzodiazepines and falls in older adults: a systematic review. Maturitas 2017; 101: 17-22.

31. Ballokova A, Peel NM, Fialova D, et al. Use of benzodiazepines and association with falls in older people admitted to hospital: a prospective cohort study. Drugs Aging 2014; 31: 299-310.

32. Quach L, Yang FM, Berry SD, et al. Depression, antidepressants, and falls among community-dwelling elderly people: the MOBILIZE Boston study. J Gerontol A Biol Sci Med Sci 2013; 68: 1575-81.

33. Harbourt K, Nevo ON, Zhang R, Chan V, Croteau D. Association of eszopiclone, zaleplon, or zolpidem with complex sleep behaviors resulting in serious injuries, including death. Pharmacoepidemiol Drug Saf 2020; 29: 684-91.

34. Richardson K, Loke YK, Fox C, et al. Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study. BMC Med 2020; 18: 1-15.

35. Treves N, Perlman A, Geron LK, Asaly A, Matok I. Z-drugs and risk for falls and fractures in older adults-a systematic review and meta-analysis. Age Ageing 2018; 47: 201-8.

36. Westerlind B, Östgren CJ, Mölstad S, Midlöv P, Hägg S. Use of non-benzodiazepine hypnotics is associated with falls in nursing home residents: a longitudinal cohort study. Aging Clin Exp Res 2019; 31: 1087-95.

37. Drake CL, Durrence H, Cheng P, et al. Arousability and fall risk during forced awakenings from nocturnal sleep among healthy males following administration of Zolpidem 10 mg and Doxepin 6 mg: a randomized, placebo-controlled, four-way crossover trial. Sleep 2017; 40 (7).

38. Greenblatt DJ, Harmatz JS, Singh NN, et al. Pharmacokinetics of zolpidem from sublingual zolpidem tartrate tablets in healthy elderly versus non-elderly subjects. Drugs Aging 2014; 31: 731-6.

39. Hoorn EJ, Rivadeneira F, Van Meurs JBJ, et al. Mild hyponatremia as a risk factor for fractures: the Rotterdam Study. J Bone Miner Res 2011; 26: 1822-8.

40. Bozat-Emre S, Doupe M, Kozyrskyj AL, Grymonpre R, Mahmud SM. Atypical antipsychotic drug use and falls among nursing home residents in Winnipeg, Canada. Int J Geriatr Psychiatry 2015; 30: 842-50.

41. Oderda LH, Young JR, Asche CV, Pepper GA. Psychotropic-related hip fractures: meta-analysis of first-generation and second-generation antidepressant and antipsychotic drugs. Ann Pharmacother 2012; 46: 917-28.

42. Kalisch Ellett LM, Lim R. We need to do better: most people with dementia living in aged care facilities use antipsychotics for too long, for off-label indications and without documented consent. Int Psychogeriatrics 2020; 32: 299-302.

43. Stenhagen M, Ekström H, Nordell E, Elmståhl S. Falls in the general elderly population: a 3- and 6- year prospective study of risk factors using data from the longitudinal population study “Good ageing in Skane”. BMC Geriatr 2013; 13: 81.

44. Arnold I, Straube K, Himmel W, et al. High prevalence of prescription of psychotropic drugs for older patients in a general hospital. BMC Pharmacol Toxicol 2017; 18: 76.

45. Chiu MH, Lee HD, Hwang HF, Wang SC, Lin MR. Medication use and fall-risk assessment for falls in an acute care hospital. Geriatr Gerontol Int 2015; 15: 856-63.

46. Leach MJ, Pratt NL, Roughead EE. Risk of hip fracture in older people using selective serotonin reuptake inhibitors and other psychoactive medicines concurrently: a matched case-control study in Australia. Drugs Real World Outcomes 2017; 4: 87-96.

47. Coupland CAC, Dhiman P, Barton G, et al. A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database. Health Technol Assess 2011; 15: 215-8.

48. Pi HY, Gao Y, Wang J, Hu MM, Nie D, Peng PP. Risk factors for in-hospital complications of fall-related fractures among older Chinese: a retrospective study. Biomed Res 2016; 2016.8612143.

49. Wadhwa R, Kumar M, Talegaonkar S, Vohora D. Serotonin reuptake inhibitors and bone health: A review of clinical studies and plausible mechanisms. Osteoporos Sarcopenia 2017; 3: 75-81.

50. Macri JC, Iaboni A, Kirkham JG, et al. Association between antidepressants and fall-related injuries among long-term care residents. Am J Geriatr Psychiatry 2017; 25: 1326-36.

51. Chan CH, Gau SSF, Chan HY, et al. Risk factors for falling in psychiatric inpatients: a prospective, matched case-control study. J Psychiatr Res 2013; 47: 1088-94.

52. Wang CY, Fu SH, Wang CL, Chen PJ, Wu FLL, Hsiao FY. Serotonergic antidepressant use and the risk of fracture: a population-based nested case-control study. Osteoporos Int 2016; 27: 57-63.

53. Wedmann F, Himmel W, Nau R. Medication and medical diagnosis as risk factors for falls in older hospitalized patients. Eur J Clin Pharmacol 2019; 75; 1117-24.

54. Hutka P, Krivosova M, Muchova Z, et al. Association of sleep architecture and physiology with depressive disorder and antidepressants treatment. Int J Mol Sci 2021; 22: 1-17.

55. Tamblyn R, Bates DW, Buckeridge DL, et al. Multinational investigation of fracture risk with antidepressant use by class, drug, and indication. J Am Geriatr Soc 2020; 68: 1494-503.

56. Haddad YK, Luo F, Bergen G, Legha JK, Atherly A. Special report from the CDC: antidepressant subclass use and fall risk in community-dwelling older Americans. J Safety Res 2021; 76: 332-40.

57. Mehta S, Chen H, Johnson ML, Aparasu RR. Risk of falls and fractures in older adults using antipsychotic agents: a propensity-matched retrospective cohort study. Drugs Aging 2010; 27: 815-29.

58. Kaufman KR. Antiepileptic drugs in the treatment of psychiatric disorders. Epilepsy Behav 2011; 21: 1-11.

59. Maximos M, Chang F, Patel T. Risk of falls associated with antiepileptic drug use in ambulatory elderly populations: a systematic review. Can Pharm 2017; 150: 101-11.

60. Masud T, Frost M, Ryg J, et al. Central nervous system medications and falls risk in men aged 60-75 years: the Study on Male Osteoporosis and Aging (SOMA). Age Ageing 2013; 42: 121-4.

61. Akyüz E, Köklü B, Ozenen C et al. Elucidating the potential side effects of current anti-seizure drugs for epilepsy. Curr Neuropharmacol 2021; 19: 1865-83.

62. Haasum Y, Johnell K. Use of antiepileptic drugs and risk of falls in old age: a systematic review. Epilepsy Res 2017; 138: 98-104.

63. Doan J, Zakrzewski-Jakubiak H, Roy J, Turgeon J, Tannenbaum C. Prevalence and risk of potential cytochrome P450-mediated drug-drug interactions in older hospitalized patients with polypharmacy. Ann Pharmacother 2013; 47: 324-32.

64. Dahl ML, Leander K, Vikström M, et al. CYP2D6-inhibiting drugs and risk of fall injuries after newly initiated antidepressant and antipsychotic therapy in a Swedish, register-based case-crossover study. Sci Rep 2021; 11: 5796.

65. Yu NW, Chen PJ, Tsai HJ, et al. Association of benzodiazepine and Z-drug use with the risk of hospitalisation for fall-related injuries among older people: a nationwide nested case-control study in Taiwan. BMC Geriatr 2017; 17: 140.

66. Masudo C, Ogawa Y, Yamashita N, Mihara K. [Association between elimination half-life of benzodiazepines and falls in the elderly: a meta-analysis of observational studies]. Yakugaku Zasshi 2019; 139: 113-22.

67. Jamieson HA, Nishtala PS, Scrase R, et al. Drug burden and its association with falls among older adults in New Zealand: a national population cross-sectional study. Drugs Aging 2018; 35: 73-81.

68. Reidenberg MM, Levy M, Warner H, et al. Relationship between diazepam dose, plasma level, age, and central nervous system depression. Clin Pharmacol Ther 1978; 23: 371-4.

69. Amboni M, Barone P, Hausdorff JM. Cognitive contributions to gait and falls: evidence and implications. Mov Disord 2013; 28: 1520-33.

70. Rivasi G, Kenny RA, Ungar A, Romero-Ortuno R. Effects of benzodiazepines on orthostatic blood pressure in older people. J Hypertens 2021; 39: e370-371.

71. Nafti M, Sirois C, Kröger E, Carmichael PH, Laurin D. Is benzodiazepine use associated with the risk of dementia and cognitive impairment–not dementia in older persons? The Canadian Study of Health and Aging. Ann Pharmacother 2020; 54: 219-25.

72. Gray SL, Dublin S, Yu O, et al. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ 2016; 352: i90.

73. Picton JD, Brackett Marino A, Lovin Nealy K. Benzodiazepine use and cognitive decline in the elderly. Am J Heal Pharm 2018; 75: e6-12.

74. Cashin RP, Yang M. Medications prescribed and occurrence of falls in general medicine inpatients. Can J Hosp Pharm 2011; 64: 321-6.

75. Berry SD, Lee Y, Cai S, Dore DD. Nonbenzodiazepine sleep medication use and hip fractures in nursing home residents. JAMA Intern Med 2013; 173: 754-61.

76. Tom SE, Wickwire EM, Park Y, Albrecht JS. Nonbenzodiazepine sedative hypnotics and risk of fall-related injury. Sleep 2016; 39: 1009-14.

77. Nissen C, Frase L, Hajak G, Wetter TC. Hypnotika - Stand der forschung. Nervenarzt 2014; 85: 67-76.

78. Victorri-Vigneau C, Gérardin M, Rousselet M, Guerlais M, Grall-Bronnec M, Jolliet P. An update on zolpidem abuse and dependence. J Addict Dis 2014; 33: 15-23.

79. Touchard J, Sabatier P, Airagnes G, Berdot S, Sabatier B. Consequences of the new zolpidem prescription regulations: a cohort study from the French national healthcare database. Eur J Clin Pharmacol 2020; 76: 89-95.

80. Stenhagen M, Nordell E, Elmståhl S. Falls in elderly people: a multifactorial analysis of risk markers using data from the Swedish general population study “Good Ageing in Skåne.” Aging Clin Exp Res 2013; 25: 59-67.

81. Ramcharran D, Qiu H, Schuemie MJ, Ryan PB. Atypical antipsychotics and the risk of falls and fractures among older adults: an emulation analysis and an evaluation of additional confounding control strategies. J Clin Psychopharmacol 2017; 37: 162-8.

82. Lee SH, Hsu WT, Lai CC, et al. Use of antipsychotics increases the risk of fracture: a systematic review and meta-analysis. Osteoporos Int 2017; 28: 1167-8.

83. Ganguli A, Mascarenhas RC, Jamshed N, Tefera E, Veis JH. Hyponatremia: incidence, risk factors, and consequences in the elderly in a home-based primary care program. Clin Nephrol 2015; 84: 75-85.

84. Corona G, Norello D, Parenti G, Sforza A, Maggi M, Peri A. Hyponatremia, falls and bone fractures: a systematic review and meta-analysis. Clin Endocrinol 2018; 89: 505-13.

85. Carton L, Cottencin O, Lapeyre-Mestre M, et al. Off-label prescribing of antipsychotics in adults, children and elderly individuals: a systematic review of recent prescription trends. Curr Pharm Des 2015; 21: 3280-97.

86. Lücke C, Gschossmann JM, Grömer TW, et al. Off-label prescription of psychiatric drugs by non-psychiatrist physicians in three general hospitals in Germany. Ann Gen Psychiatry 2018; 17: 7.

87. Rigler SK, Shireman TI, Cook-Wiens GJ, et al. Fracture risk in nursing home residents initiating antipsychotic medications. J Am Geriatr Soc 2013; 61: 715-22.

88. Chatterjee S, Chen H, Johnson ML, Aparasu RR. Risk of falls and fractures in older adults using atypical antipsychotic agents: a propensity score-adjusted, retrospective cohort study. Am J Geriatr Pharmacother 2012; 10: 83-94.

89. Leach MJ, Pratt NL, Roughead EE. The risk of hip fracture due to mirtazapine exposure when switching antidepressants or using other antidepressants as add-on therapy. Drugs Real World Outcomes 2017; 4: 247-55.

90. Tamiya H, Yasunaga H, Matusi H, Fushimi K, Ogawa S, Akishita M. Hypnotics and the occurrence of bone fractures in hospitalized dementia patients: a matched case-control study using a national inpatient database. PLoS One 2015; 10: e0129366.

91. Lanteigne A, Sheu YH, Stürmer T, et al. Serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor use and risk of fractures: a new-user cohort study among us adults aged 50 years and older. CNS Drugs 2015; 29: 245-52.

92. Letmaier M, Painold A, Holl AK, et al. Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme. Int J Neuropsychopharmacol 2012; 15: 739-48.

93. Mandrioli R, Forti G, Raggi M. Fluoxetine metabolism and pharmacological interactions: the role of cytochrome P450. Curr Drug Metab 2006; 7: 127-33.

94. Sobieraj D, Martinez B, Hernandez A, et al. Adverse effects of pharmacologic treatments of major depression in older adults. J Am Geriatr Soc 2019; 67: 1571-81.

95. Sterke CS, Ziere G, van Beeck EF, Looman CWN, Van der Cammen TJM. Dose-response relationship between selective serotonin re-uptake inhibitors and injurious falls: a study in nursing home residents with dementia. Br J Clin Pharmacol 2012; 73: 812-20.

96. Coupland C, Hill T, Morriss R, Moore M, Arthur A, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in people aged 20-64 years: cohort study using a primary care database. BMC Med 2018; 16: 36.

97. Hankey GJ, Hackett ML, Almeida OP, et al. Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2020; 19: 651-60.

98. Farmand S, Lindh JD, Calissendorff J, et al. Differences in associations of antidepressants and hospitalization due to hyponatremia. Am J Med 2018; 131: 56-63.

99. Leth-Møller K, Hansen A, Torstensson M, et al. Antidepressants and the risk of hyponatremia: a Danish register-based population study. BMJ Open 2016; 6: e011200.

100. Ribeiro TB, De Melo DO, Maia FDOM, Ribeiro E. Medication-related inpatient falls: a critical review. Brazilian J Pharm Sci 2018; 54(1).

101. Sultana J, Spina E, Trifirò G. Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety. Expert Opin Drug Metab Toxicol 2015; 11: 883-92.

102. Krystal A, Durrence H, Scharf M, et al. Efficacy and safety of Doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient trial of elderly subjects with chronic primary insomnia. Sleep 2010; 33: 1553-61.

103. Everitt H, Baldwin DS, Stuart B, et al. Antidepressants for insomnia in adults. Cochrane Database Syst Rev 2018; 5: CD010753.

104. Goodarzi Z, Mele B, Guo S, et al. Guidelines for dementia or Parkinson’s disease with depression or anxiety: a systematic review. BMC Neurol 2016; 16: 244.

105. Wichniak A, Wierzbicka A, Wale˛cka M, Jernajczyk W. Effects of antidepressants on sleep. Curr Psychiatry Reports 2017; 19: 1-7.

106. Nobili A, Licata G, Salerno F, et al. Polypharmacy, length of hospital stay, and in-hospital mortality among elderly patients in internal medicine wards. The REPOSI study. Eur J Clin Pharmacol 2011; 67: 507-19.

107. Richardson K, Bennett K, Kenny RA. Polypharmacy including falls risk-increasing medications and subsequent falls in community-dwelling middle-aged and older adults. Age Ageing 2015; 44: 90-6.

108. Damián J, Pastor-Barriuso R, Valderrama-Gama E, de Pedro-Cuesta J. Factors associated with falls among older adults living in institutions. BMC Geriatr 2013; 13: 6.

109. Izza MAD, Lunt E, Gordon AL, Gladman JRF, Armstrong S, Logan P. Polypharmacy, benzodiazepines, and antidepressants, but not antipsychotics, are associated with increased falls risk in UK care home residents: a prospective multi-centre study. Eur Geriatr Med 2020; 11: 1043-50.

110. Ie K, Chou E, Boyce RD, Albert SM. Fall risk-increasing drugs, polypharmacy, and falls among low-income community-dwelling older adults. Innov Aging 2021; 5: 1-9.

111. Morin L, Larrañaga AC, Welmer AK, Rizzuto D, Wastesson JW, Johnell K. Polypharmacy and injurious falls in older adults: a nationwide nested case-control study. Clin Epidemiol 2019; 11: 483-93.

112. Seppala LJ, van de Glind EMM, Daams JG, et al. Fall-Risk-increasing drugs: a systematic review and meta-analysis: III. Others. J Am Med Dir Assoc 2018; 19: 372.e1-372.e8.

113. Sandvik MK, Watne LO, Brugård A, Wang-Hansen MS, Kersten H. Association between psychotropic drug use and handgrip strength in older hospitalized patients. Eur Geriatr Med 2021; 12: 1213-20.

114. Nurminen J, Puustinen J, Lähteenmäki R, et al. Handgrip strength and balance in older adults following withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotics. BMC Geriatr 2014; 14: 114-21.

115. Boyé NDA, van der Velde N, de Vries OJ, et al. Effectiveness of medication withdrawal in older fallers: results from the Improving Medication Prescribing to reduce Risk Of FALLs (IMPROveFALL) trial. Age Ageing 2017; 46: 142-6.

116. Lee J, Negm A, Peters R, Wong EKC, Holbrook A. Deprescribing fall-risk increasing drugs (FRIDs) for the prevention of falls and fall-related complications: a systematic review and meta-analysis. BMJ Open 2021; 11: e035978.

117. Kool B, Ameratunga S, Robinson E. Association between prescription medications and falls at home among young and middle-aged adults. Inj Prev 2012; 18: 200-3.

118. Abad VC, Guilleminault C. Insomnia in elderly patients: recommendations for pharmacological management. Drugs Aging 2018; 35: 791-817.

119. Mansbach W, Mace R, Clark K, Firth I, Breeden J. Predicting off-label antipsychotic medication use in a randomly selected nursing home sample based on resident and facility characteristics. Res Gerontol Nurs 2016; 9: 257-66.

120. Garriga M, Pacchiarotti I, Kasper S, et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016; 17: 86-128.

121. Airagnes G, Pelissolo A, Lavallée M, Flament M, Limosin F. Benzodiazepine misuse in the elderly: risk factors, consequences, and management. Curr Psychiatry Rep 2016; 18: 89.

122. Eldesoky ES. Pharmacokinetic-pharmacodynamic crisis in the elderly. Am J Ther 2007; 14: 488-98.

123. Landi F, Liperoti R, Russo A, et al. Sarcopenia as a risk factor for falls in elderly individuals: Results from the ilSIRENTE study. Clin Nutr 2012; 31: 652-8.

124. Nasimi N, Dabbaghmanesh MH, Sohrabi Z. Nutritional status and body fat mass: determinants of sarcopenia in community-dwelling older adults. Exp Gerontol 2019; 122: 67-73.

125. Kennedy WK, Jann MW, Kutscher EC. Clinically significant drug interactions with atypical antipsychotics. CNS Drugs 2013; 27: 1021-48.

126. Van Der Weide K, Van Der Weide J. The Influence of the CYP3A4*22 polymorphism and CYP2D6 polymorphisms on serum concentrations of aripiprazole, haloperidol, pimozide, and risperidone in psychiatric patients. J Clin Psychopharmacol 2015; 35: 228-36.

127. Hemeryck A, Lefebvre RA, De Vriendt C, Belpaire FM. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 2000; 67: 283-91.

128. Bahar MA, Kamp J, Borgsteede SD, Hak E, Wilffert B. The impact of CYP2D6 mediated drug-drug interaction: a systematic review on a combination of metoprolol and paroxetine/fluoxetine. Br J Clin Pharmacol 2018; 84: 2704-15.

129. Shin J, Hills NK, Finley PR. Combining antidepressants with β-blockers: evidence of a clinically significant CYP2D6 drug interaction. Pharmacotherapy 2020; 40: 507-16.

130. Runciman WB, Roughead EE, Semple SJ, Adams RJ. Adverse drug events and medication errors in Australia. Int J Qual Heal Care 2003; 15: 49-59.

131. Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lancet 2007; 370: 185-91.

132. Pourmand A, Lombardi K, Roberson J, Mazer-Amirshahi M. Patterns of benzodiazepine administration and prescribing to older adults in U.S. emergency departments. Aging Clin Exp Res 2020; 32: 2621-8.

133. Van Leeuwen E, Petrovic M, van Driel ML, et al. Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev 2018; 30: 2CD007726.

134. Smith E, Shah A. Screening for geriatric syndromes: falls, urinary/fecal incontinence, and osteoporosis. Clin Geriatr Med 2018; 34: 55-67.

135. Skelly A, Dettori J, Brodt E. Assessing bias: the importance of considering confounding. Evid Based Spine Care J 2012; 3: 9-12.

136. Kok RM, Reynolds CF. Management of depression in older adults: a review. JAMA 2017; 317: 2114-22.

137. Lyketsos CG, DelCampo L, Steinberg M, et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry 2003; 60: 737-46.