Introduction

Due to demographic change, the health care system will face a growing number of older, often multimorbid patients ≥ 65 years. Multimorbidity is often associated with polypharmacy [1]. Therefore, older patients who take multiple drugs are high-risk patients of developing adverse drug reactions (ADRs) [2], as polypharmacy increases the risk of pharmacokinetic and pharmacodynamic drug-drug and drug-disease interactions [3,4,5,6].

Because of age-related changes in pharmacokinetics and pharmacodynamics [7, 8], older patients, particularly people with frailty syndrome [9,10,11], are more prone to develop ADRs. Especially in gerontopsychiatry, physicians should consider the increased sensitivity to antipsychotic, e.g., anticholinergic, drugs (e.g., clozapine) [12,13,14,15,16], leading to peripheral and central anticholinergic ADRs, such as cognitive impairment and delirium [17,18,19].

Many psychotropic drugs are listed as potentially inappropriate medication (PIM) in older people [20,21,22,23]. Potentially inappropriate medication means that prescribing of those drugs in older patients may cause significant harm [17, 24, 25]. Therefore, PIM should be avoided or replaced by more tolerable alternative drugs [22, 26,27,28,29] in the older population. According to this, several lists of PIM have been published [21, 23, 30,31,32].

Lists of PIM in older patients, such as the PRISCUS list [20], have been developed to improve safety and tolerability of pharmacotherapy in older patients. The German PRISCUS list [33, 34] contains 83 drugs, arranged in 18 drug classes, with a high prevalence of psychotropic drugs.

Different studies have shown that PIM were more commonly associated with ADRs or medication errors, lower quality of life, hospitalizations, and higher health care costs than non-PIM in older patients [25, 35,36,37,38,39,40]. Based on German health insurance data, Schubert and coworkers [41] detected the highest PIM prevalence for antidepressants (6.5%), antihypertensive medication (3.8%), and antiarrhythmic drugs (3.5%). The most commonly prescribed PRISCUS-PIM observed by Amann, using claims data from three statutory health insurances in Germany [42], were amitriptyline (2.6%), acetyldigoxin (2.4%), tetrazepam (2.0%), and oxazepam (2.0%).

In particular, PIM-prescribing is common in psychiatric patients and potentially fatal [43]. Wucherer [44] conducted home medication reviews in a large sample of community-dwelling primary care patients in Germany and found that 22% of patients who were screened positive for dementia received at least one PRISCUS-PIM. In a study by Hefner, more than half (n = 89; 53.0%) of older psychiatric patients (inpatients and day hospital care) took at least 1 PRISCUS-PIM, whereas lorazepam > 2 mg/day (n = 31), zopiclone > 3.75 mg/day (n = 11), diazepam (n = 10), haloperidole > 2 mg/d (n = 8), amitriptyline (n = 7), clozapine (n = 7), and zolpidem > 5 mg/day (n = 7) were the most frequently prescribed PRISCUS-PIM [45].

Risk factors for using a PRISCUS-PIM were, e.g., older age, depression, polypharmacy, and female gender [41,42,43, 46, 47]. Interventions designed to considerably optimize medication may reduce the risk of ADRs in older adults [48].

This study aimed to determine the prevalence and sort of PIM-prescribing in psychiatric inpatients in a naturalistic psychiatric setting.

Methods

Study design

Since 2017, the Federal Joint Committee (G-BA, project executing organization, Deutsches Zentrum für Luft- und Raumfahrt, DLR) is funding health care research projects that aim to optimize quality of care for statutory insured persons in Germany. In this regard, the innovative study “Optimization of pharmacological treatment in hospitalized psychiatric patients” (OSA-PSY, study number 01VSF16009) is sponsored by the DLR. The present retrospective, longitudinal study used data from this large pharmacovigilance project. The study (ethical approval reference number FF 116/2017) is conducted in 10 psychiatric hospitals (Vitos corporation) in Germany. Data from 27,396 cases of treatment (24,118 inpatients and 3278 patients receiving day hospital care), assessed between October 2017 and September 2018, were retrospectively screened. Because of the longitudinal study design, medication patient data were screened on every day of hospital stay.

The project was started in October 2017. Pharmacovigilance is the primary focus of the study OSA-PSY, aiming to optimize psychopharmacotherapy by different interventions. In the first episode of the 3-year study, status quo of psychopharmacological treatment will be assessed. Based on detected discrepancies between clinical treatment and evidence-based recommendations and guidelines and in collaboration with an expert panel, parameters to optimize psychopharmacotherapy will be discussed. Based on these parameters, interventions to optimize psychopharmacotherapy will be developed. Afterwards, in the second episode, clinical utility and effectiveness of the new tools will be determined, based amongst others on quality indicators that have been implemented in all psychiatric Vitos hospitals by different indicators, e.g., CGI, GAF, and PANSS-8.

The study analyzed patient data stored electronically in the hospital information system, which has a computerized order entry system to prescribe all the drugs that are dispensed to the patient, and also includes “as needed” medications. Therefore, the data describes the present prescribing behavior in a real-world psychiatric setting.

Data from inpatients or day hospital care patients in adult psychiatry with a psychiatric disorder were included for analysis. Data from 4760 older patients ≥ 65 years were available. No further exclusion criteria were applied.

Clinical assessment

Medical records were screened for clinical data. Patient characteristics like age, gender, diagnosis (ICD-10), and medication were collected for analysis. The number and sort of PRISCUS-PIM were extracted by analyzing the patients’ medication profile. We included all drugs that fulfilled the criteria (dosage) of a potentially inappropriate medication for older patients, designated as PIM in the PRISCUS list [20].

Statistical analyses provided measures of central tendencies and dispersion for continuous data and number of observations and proportions for categorical variables. Differences between means, medians, and proportions were tested with Welch’s oneway, Kruskal-Wallis’s rank sum, and Pearson’s chi-squared tests, respectively. All statistical analyses were carried out in R (R Core Team. R; a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. 2019).

Results

In total, 4760 patient cases (59.2% female) with a mean (mean ± SD) age of 77.33 ± 7.77 years were included in the study (Table 1). Patient characteristics, such as hospital treatment, duration of hospital stay, and principal diagnosis, are shown in Table 1.

Table 1 Patient characteristics
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Altogether, 1615 patient cases (33.9%) received at least 1 and up to 4 PRISCUS-PIM at the same day (regular and as-needed medication included). They received an average number of 0.24 ± 0.45 PIM per day during their hospital stay (Table 1).

The most frequently prescribed PRISCUS-PIM (n = 2144, Table 2) were zopiclone > 3.75 mg/day (n = 310), lorazepam > 2 mg/day (n = 269), haloperidol > 2 mg/day (n = 252), and diazepam (n = 182). Patient cases with PRISCUS-PIM were younger (75.7 vs. 78.2 years, p < 0.001) and had a longer (26 vs. 22 days, p < 0.001) hospital length of stay (Table 3).

Table 2 Frequencies of potentially inappropriate medication (PIM), as defined by the PRISCUS list. Alternative drugs were stated in the PRISCUS list
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Table 3 Differences in patient characteristics of elderly patients who receive at least 1 potentially inappropriate medication (PIM), as defined by the PRISCUS list (n = 1617) and patients who receive no PIM (n = 3143)
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Figure 1 shows odds ratios calculated for the prescription of potentially inappropriate medication in relation to different factors, as length of hospital stay, number of comorbidities, and diagnoses. CGI at admission (clinical global impression score), length of stay, number of comorbidities, and F1-F3 diagnosis were positive influencing factors for the prescription of PRISCUS-PIM.

Fig. 1
figure 1

Odds ratios calculated for the prescription of potentially inappropriate medication in relation to different factors

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Discussion

The objective of this study was to analyze the prevalence and type of PIM prescription [20] in a naturalistic psychiatric setting.

Special feature of this study was the approach to analyze the electronic patient data in the hospital information system, reflecting the actual prescribing at psychiatric hospitals.

Altogether, this study revealed a high PRISCUS-PIM prevalence rate of 33.9% (regular and as-needed medication included) with the prescription of at least 1 PRISCUS-PIM during hospital stay (range 1–4, Table 1). Nearly 1% (45 patient cases) of the study group even received 3 or 4 PRISCUS-PIM simultaneously, which should be avoided to reduce the risk of ADRs and prescribing cascades.

This high PRISCUS-PIM prevalence rate in hospitalized older psychiatric patients can be explained by the fact of a large proportion of psychotropic drugs listed as potentially inappropriate in the PRISCUS list [20], e.g., benzodiazepines. After discharge, some of these drugs will not be prescribed anymore by the general practitioner, as observed by Siebert and coworkers [49]. In this study by Siebert and coworkers [49], 43% of the patients received a PRISCUS-PIM while hospitalized and 29% at discharge. While hospitalized, the mean number of administered PIM per patient was 0.5 based on the PRISCUS list [49]. In this study, patients received an average number of 0.24 ± 0.45 PIM per day during hospital stay. As this is a longitudinal study, these results are hardly comparable. Nevertheless, PIM prescriptions should be further decreased in the inpatient psychiatric setting, e.g., “as needed” benzodiazepines or first generation antihistamines.

CGI at admission (clinical global impression score), length of stay, and number of comorbidities, treated with multiple drugs (Table 1, Fig. 1), were positive influencing factors for the prescription of PRISCUS-PIM. This can be explained by the fact that with increasing number of ingested drugs because of comorbidities or a severe psychiatric illness, the possibility of PRISCUS-PIM prescription is increasing, too.

Patient cases with PRISCUS-PIM were younger (p < 0.001) and had a longer (p < 0.001) hospital length of stay (Table 3). The longer hospital stay could possibly be due to a reduced tolerability of the medication regime and a higher rate of ADRs [25, 35,36,37,38,39,40]. But it could also reflect that patients receiving PIM did not tolerate other drugs or more tolerable drugs were ineffective. Due to the need of tapering in and tapering out psychotropic drugs, the switch of medications prolongs the length of hospitalization.

The most frequently prescribed PRISCUS-PIM (n = 2144, Table 2) were zopiclone > 3.75 mg/day (n = 310), lorazepam > 2 mg/day (n = 269), haloperidol > 2 mg/day (n = 252), and diazepam (n = 182). In a study by Hefner, more than half (n = 89; 53.0%) of older psychiatric patients took at least 1 PRISCUS-PIM. Overall, lorazepam > 2 mg/day (n = 31), zopiclone > 3.75 mg/day (n = 11), diazepam (n = 10), and haloperidole > 2 mg/day (n = 8) were the most frequently prescribed PRISCUS-PIM [45], similar to this study. The higher prevalence rate of 53.0% in the study by Hefner, compared with the prevalence rate of 33.9% in this study, may be explained by the fact that the study was conducted much earlier, and therefore, the PRISCUS list was not that famous in clinical practice. Furthermore, the small sample size in the study by Hefner should be considered.

A significantly higher prevalence of PIM could be detected in female patients, compared with male patients, in concordance with previous studies [41, 42]. In the past, some studies reported female sex as an independent factor for PIM use [50,51,52,53,54]. Furthermore, benzodiazepines are a drug group of potentially inappropriate medication that is more frequently used by women than men [41].

The high rate of PIM prescription especially in patients with a diagnosis of dementia should be reduced, first of all the prescription of benzodiazepines which can increase the risk for, e.g., falls, delirium, or cognitive decline [55]. Hessmann also identified a high prevalence rate of benzodiazepines of 12.4% (n = 49) in 395 patients with a diagnosis of Alzheimer’s disease as well [56]. The inappropriate prescribing and use of benzodiazepines conflict with national and international guidelines and are a public health problem worldwide. Several major medical and psychiatric organizations, e.g., the American Geriatrics Society, advise not to use benzodiazepines in older adults. Despite these recommendations, benzodiazepines are still prescribed very often to a group of patients with the highest risk of serious adverse effects from these exact medications. Alternative medications for treating insomnia and anxiety in older adults should be preferably prescribed, e.g., sedative antidepressants as mirtazapine or selective serotonin reuptake inhibitors as escitalopram [55,56,57,58,59,60,61].

Due to age-related changes in pharmacokinetics and pharmacodynamics [7, 8], older people are more vulnerable to develop, e.g., anticholinergic ADRs [12,13,14,15,16,17,18,19].

Rational deprescribing especially of anticholinergics, benzodiazepines, and antipsychotics in older patients may be a key factor to diminish the risk of ADRs [26]. Clinical advice to reduce PRISCUS-PIM use is shown in Table 4. This table also includes the recommended upper limits of benzodiazepine dosage, given in the PRISCUS list. They should only be prescribed if the risk of ADRs outweighs the clinical benefit, in the recommended dose range per day. Alternative, more tolerable, medications in older adults should be preferably prescribed. According to indication, alternative drugs are prescribed in the PRISCUS list.

Table 4 Clinical advice to reduce the use of potentially inappropriate medications (PIM) in the elderly (PRISCUS list)
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Clinical advice to reduce PRISCUS-PIM use is presented in Table 4.

Replacing benzodiazepines and z-substances, haloperidol > 2 mg, tricyclic antidepressants, first generation antihistaminergic drugs, and clonidine by non-PIM could reduce 81.6% of PRISCUS-PIM prescription. Furthermore, replacing clozapine and olanzapine by non-PIM could avoid 8.1% of PIM prescription.

Study limitations

The interpretation of the study results is limited by the naturalistic and retrospective study design but represents a real-word setting for psychiatric patients. The presented results are explorative and do not prove any causal relationship. Lastly, a patient bias could have occurred when inpatients were registered more than one time during the study period or changed to day hospital care, respectively.

A prescribed medication is potentially inappropriate if the risk of ADRs outweighs the clinical benefit in an older patient. Therefore, medications in the PRISCUS list are not generally contraindicated in older patients. After an individual patient-based risk-benefit analysis, more tolerable alternatives not listed as PRISCUS-PIM are often available [20]. Nevertheless, in some cases, PRISCUS-PIM are not avoidable in older patients. This investigation had no information about possibly conducted risk-benefit analysis. The longer length of stay in patients with PIM could be due to the non-efficacy or ADRs of the first choice drugs in these patients required a switch of the drugs to PIM. Therefore, final conclusion can be drawn in respect of the overall prevalence of PIM-prescribing (PRISCUS list drugs), but not in respect of the overall prevalence of definitively inappropriate prescribing in existence of more tolerable alternative drugs.

Conclusions

The prevalence of PRISCUS-PIM in psychiatry is relatively high. More than one-third of older patients, especially with a diagnosis of dementia, received at least 1 PRISCUS-PIM at at least 1 day of their hospital stay in this study. PIM-prescribing should be markedly reduced in hospitalized psychiatric patients above 65 years old. PIM were more commonly associated with ADRs or medication errors, lower quality of life, hospitalizations, and higher health care costs than non-PIM in older patients. The inappropriate prescribing and use especially of benzodiazepines conflict with national and international guidelines and are a global public health problem. Alternative, more tolerable medications in older adults should be preferably prescribed [55,56,57]. The PRISCUS list should be integrated in a complex treatment model for geriatric psychopharmacotherapy. Rational deprescribing especially of inappropriate anticholinergics, benzodiazepines, and antipsychotics in older patients may play a key role to lower the risk of ADRs [26].