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Antipsychotic Deprescription for Older Adults in Long-term Care: The HALT Study
JAMDA 19 (2018) 592e600
JAMDA journal homepage: www.jamda.com
Original Study
Antipsychotic Deprescription for Older Adults in Long-term Care: The HALT Study Henry Brodaty MD, DSc a, b, c, *, Liesbeth Aerts PhD a, Fleur Harrison BA, GDipSc (Psych) a, b, Tiffany Jessop PhD a, Monica Cations a, Lynn Chenoweth BA, MA Hons, MAdEd, PhD b, Allan Shell MB, BS a, Gordana C. Popovic BSc, BEd, PhD d, Megan Heffernan PhD a, b, Sarah Hilmer MBBS, PhD e, Perminder S. Sachdev MD, PhD b, f, Brian Draper MBBS, MD b, c a
Dementia Centre for Research Collaboration, School of Psychiatry, University of New South Wales Sydney, New South Wales, Australia Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Sydney, New South Wales, Australia c Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Randwick, New South Wales, Australia d Stats Central, Mark Wainwright Analytical Centre, University of New South Wales Sydney, New South Wales, Australia e Kolling Institute, Royal North Shore Hospital and University of Sydney, St Leonards, New South Wales, Australia f Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, New South Wales, Australia b
a b s t r a c t Keywords: Antipsychotic withdrawal dementia behavioral and psychological symptoms of dementia
Objectives: Despite limited efficacy and significant safety concerns, antipsychotic medications are frequently used to treat behavioral and psychological symptoms of dementia (BPSD) in long-term residential care. This study evaluates the sustained reduction of antipsychotic use for BPSD through a deprescribing intervention and education of health care professionals. Design: Repeated-measures, longitudinal, single-arm study. Setting: Long-term residential care of older adults. Participants: Nursing staff from 23 nursing homes recruited 139 residents taking regular antipsychotic medication for 3 months, without primary psychotic illness, such as schizophrenia or bipolar disorder, or severe BPSD. Intervention: An antipsychotic deprescribing protocol was established. Education of general practitioners, pharmacists, and residential care nurses focused on nonpharmacological prevention and management of BPSD. Measurements: The primary outcome was antipsychotic use over 12-month follow-up; secondary outcomes were BPSD (Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory, and social withdrawal) and adverse outcomes (falls, hospitalizations, and cognitive decline). Results: The number of older adults on regular antipsychotics over 12 months reduced by 81.7% (95% confidence interval: 72.4-89.0). Withdrawal was not accompanied by drug substitution or a significant increase in pro-renata antipsychotic or benzodiazepine administration. There was no change in BPSD or in adverse outcomes. Conclusion: In a selected sample of older adults living in long-term residential care, sustained reduction in regular antipsychotic use is feasible without an increase of BPSD. Ó 2018 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
This study was funded by the Australian Department of Health under the Aged Care Service Improvement and Healthy Ageing Grant Fund. The project is supported by the Centre for Research Collaboration, UNSW Sydney. Over the last 3 years, Henry Brodaty has been on the advisory board of Nutricia. He has been recipient of grants for research by the National Health and Medical Research Council and Australian Department of Health and Ageing. Monica Cations is currently employed to assist with data collection for drug trials by Janssen, https://doi.org/10.1016/j.jamda.2018.05.002 1525-8610/Ó 2018 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
Merck, and Paraxel. The other authors declare no competing interests reports and no financial relationships with commercial interests. * Address correspondence to Henry Brodaty, MD, DSc, Dementia Centre for Research Collaboration, AGSM Building, University of New South Wales Sydney, NSW 2052, Australia. E-mail address: [email protected] (H. Brodaty).
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Behavioral and psychological symptoms of dementia (BPSD) are prevalent in people living with dementia especially as the disease progresses.1 Although there is some evidence for the efficacy of antipsychotics in treating aggression and psychosis,2,3 they have significant side effects. Increased risks of cognitive decline, cerebrovascular adverse effects, and death have triggered warnings from international agencies against their use in people with dementia.4e7 Antipsychotics have been linked to socially withdrawn behavior and increased risk of falls and hospitalizations.8 Despite some reports indicating a decline in antipsychotic prescription,9 their use remains common in people with dementia in long-term care (LTC): 20% to 50% are prescribed antipsychotics.10e12 In Sydney, Australia, the setting for this study, more than a quarter are prescribed antipsychotics.13 Most have a long history of continuous antipsychotic use, although current guidelines stipulate review and withdrawal within 12 weeks.14,15 Reduction in antipsychotic prescribing is feasible with reemergence of behavioral symptoms in only a minority of participants.3,16e19 However, one key trial in people with Alzheimer’s disease (AD) living in the community or assisted-living residences found that BPSD increased after antipsychotic discontinuation.20 Although a systematic review of interventions to reduce inappropriate prescribing of antipsychotics in people with dementia in LTC concluded that 9 of 11 well-designed interventions were effective, only 4 studies evaluated long-term effects, at up to 9 months postintervention, and conclusions were mixed.21 In this trial, we aimed to achieve a reduction in inappropriate use of antipsychotic medications for at least 12 months, without an increase in BPSD or use of substitute psychotropic medications.22 Because successful withdrawal depends on the implementation of effective support strategies involving all relevant stakeholders, antipsychotic withdrawal was implemented by general practitioners (GPs), following specific training for nursing staff, GPs, and pharmacists, and awareness raising with family members. This concerted approach aimed to encourage a culture change in prescribing practices and in the prevention and management of BSPD. LTC nursing homes were approached and asked to recruit residents on antipsychotics for study participation. As the Australian Government “funding of initiatives to improve aged care service delivery” proscribed randomized controlled trials, we used repeated measures, including 2 preintervention assessments, to assess changes in medication use, BPSD, and adverse outcomes, including social withdrawal, cognition, falls, and hospitalizations. We hypothesized that antipsychotic withdrawal would not be associated with an increase in BPSD and would be beneficial in reducing adverse effects. Methods Study Design and Ethics The Halting Antipsychotic use in Long Term care (HALT) study was a single-arm longitudinal study in a convenience sample of 23 LTC residences (12 private, 10 charitable, and 1 community-based, each with >60 beds) in Sydney and surrounding areas conducted between April 2014 and October 2016. In Australia, LTC is government subsidized according to level of dependency, and residents can choose which GP they consult. No nursing home in this study had dedicated in-house doctors. Community pharmacists are rebated for undertaking medication reviews. The study was approved by the UNSW Ethics Committee (HC13203) and registered with the Australian New Zealand Clinical Trials Registry (no. 12614000309684). The study design has been described in detail.22 Briefly, prebaseline and baseline assessments
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were conducted approximately 1 month apart, before antipsychotic withdrawal was initiated, to control for changes over time in the absence of a control group. Follow-up assessments occurred after 3, 6, and 12 months (Figure 1). Participants Adults aged 60 or older, living in LTC for 1 month, and on regular antipsychotic medication for 3 months, without primary psychotic illness such as schizophrenia or bipolar disorder, were identified via an appointed registered nurse at each nursing home.22 After obtaining written consent from residents and/or their “person responsible” (proxy) and consent from their general practitioner (GP; because the deprescribing agreement was reliant on GP involvement), research psychologists determined eligibility via staff interviews and file audits. Residents with a terminal illness or very severe BPSD at baseline were excluded [nursing home version of the Neuropsychiatric Inventory (NPI-NH) score 50; domain scores of 12 for at least 2 of delusions, hallucinations, agitation/aggression, anxiety or disinhibition, and occupational disruptiveness score 4 for at least 2 of these domains]. This exclusion criterion was an ethical consideration based on previous findings of a significant worsening of symptoms on deprescribing among those with severe BPSD and based on contemporaneous Australian Department of Health rules for a severe behavior supplement.16,23 Dementia was not an inclusion criterion, as we relied on file audits and a dementia diagnoses are not always recorded. However, 137 participants (98.5%) were considered to have dementia based on documented diagnosis (n ¼ 130), or after review of all available data, including cognitive assessment (Psychogeriatric AssessmenteCognitive Impairment Scale [PAS-CIS]24) by an experienced old-age psychiatrist (H.B.) (n ¼ 7). Interventions The intervention comprised 2 components: (1) education/training of health care staff, and (2) deprescribing antipsychotic medication. The former included education and training opportunities for designated LTC staff (“Champions”), participants’ GPs, and pharmacists involved in the supply of medication services to participating nursing homes.22 Champions, usually 1 to 2 registered nurses from each home, attended a 3-day workshop on dementia, BPSD, and person-centered, nonpharmacologic approaches to BPSD prevention, reduction, and management. Champions were encouraged to implement training strategies at their respective nursing home to educate other staff members. Participants’ GPs were offered academic detailing involving a 30- to 60-minute peer education session, additional reading material on antipsychotic use, and an optional follow-up educational seminar and evaluation. Pharmacists were offered a continuing professional development module. Continuing education credits were awarded to GPs and nursing staff. The second component was an individualized deprescribing protocol, which followed Australian guidelines stipulating a dose reduction of 50% every 2 weeks and ceasing after 2 weeks on the minimum dose, withdrawing one antipsychotic at a time, with risperidone (if prescribed) to be withdrawn last.15 Study pharmacists developed a protocol for each participant that was provided to nursing staff at baseline (Supplemental Figure 2). GPs were instructed to commence the outlined medication change(s) within the next week. If GPs considered emergency medication may be required, consistent with current best practice guidelines,25 they were recommended if concerned about deprescribing antipsychotics to prescribe a short-acting benzodiazepine (oxazepam or lorazepam) pro-re-nata (PRN). GPs could restart antipsychotic therapy at any time if they determined it
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was indicated. If extra support was needed, Champions, GPs, and pharmacists could consult the study team. Assessment Procedures and Outcome Measures Antipsychotic and sedative prescription and administration Research psychologists audited participant medication charts to determine prescribed and administered dosage of regular and PRN antipsychotics, sedatives, and antidepressants. Doses of antipsychotics and benzodiazepines were converted to olanzapine and diazepam equivalents, respectively, for analysis (Supplemental Table 1).
BPSD and adverse outcomes Research psychologists interviewed participants (where possible) and nursing staff. Staff assessments comprised the nursing home version of the NPI (NPI-NH; range 0-144, higher scores indicating more frequent and/or severe BPSD; weighted k: 0.93), the CohenMansfield Agitation Inventory (CMAI; range 29-203, higher scores indicating more frequent manifestations of agitation; weighted k: 0.98; the item “trying to get to a different place” was erroneously excluded from the questionnaire package; therefore, the total score was pro-rated for all participants), and the Multidimensional Observation Scale for Elderly Subjectsdwithdrawn behavior subscale
Fig. 1. Consort diagram. Appointed nurses at each of the 24 nursing homes that agreed to participate recruited residents aged 60 or older, living in current nursing home for 1 month and on regular antipsychotic medication for 3 months. After obtaining written consent from the resident and/or their “person responsible” (proxy), research psychologists determined eligibility based on the absence of a primary psychotic illness and the severity of BPSD. Information on medication use, falls and hospitalizations was determined by file audit. BPSD, socially withdrawn behavior and cognition required (complete) assessment by research psychologists.
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(range 8-32, higher scores indicating more withdrawal, weighted k: 0.96).26e29 Cognition was assessed with the PAS-CIS (range 0-21, higher scores indicating worse performance; k: 0.84) or, for those from noneEnglish-speaking backgrounds, the Rowland Universal Dementia Assessment Scale (RUDAS; range 0-30, lower scores indicating worse performance).24,30 Both PAS-CIS and RUDAS evaluate multiple cognitive domains and are recommended by the Australian Department of Health to establish care needs. Total scores were pro-rated when up to 20% of items were missing. RUDAS scores were converted to the same scale as the PASCIS, using a score of 21 on RUDAS and 5 on PAS-CIS as equivalent cut-offs.24,30 For some participants, it was not possible to complete resident or staff interviews at designated follow-up time points (most often due to participant having deceased recently or lack of an interpreter) or at (pre-)baseline because GPs enthusiastically but erroneously commenced the deprescription protocol prior to study assessment). File audit data were included where possible (Figure 1).
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Residents’ records provided number of falls and hospitalizations prior to and during study follow-up. Information was gathered from incident reports and all progress notes. Frequencies in the 6 months prior to study commencement (or pro-rated for those in the nursing home for less than 6 months) and the last 6 months of the study were compared. Data on falls were analyzed taking into account mobility, defined as able to ambulate with or without assistance (ie, bedbound participants were not included in the analysis of falls).
Statistical Analysis SPSS version 22 and GraphPad Prism version 6.07 were used for analysis. Statistical significance was set at 0.05 and the HolmBonferroni or Bonferroni method were used to correct for multiple testing. Differences between 2 groups were evaluated via Fisher exact (categorical) or Student t test (continuous data).
Table 1 Baseline Characteristics of Completers Versus Noncompleters and of Successful vs Unsuccessful Deprescribing Noncompleters
Completers
Deprescribed Successfully symbol referring to the notes
Represcribed/ Not Deprescribed
46
93
69 (74.2)
24 (25.8)
51 (73.9) 83.8 7.4 (59.5-99.7)
10 (41.7) 83.3 6.9 (67.6-94.3)
2.3 1.7 (0.1-7.5)
2.4 2.0 (0.5-7.6)
n (%) Demographics Gender, n females (%) Age, y, mean SD (range) Time at facility, y, mean SD (range) Antipsychotic use Daily dose in olanzapine equivalents, mg, median; IQR Risperidone, n (%) Olanzapine, n (%) Quetiapine, n (%) Haloperidol, n (%) PRN prescribed, n (%)
31 (67.4) 61 (65.6) 88.2 ± 7.3 (71.2-101.8) 84.3 ± 7.3 (59.5-99.7) P [ .004; t [ 2.964; df [ 137 3.7 3.0 (0.5-15.3) 2.5 7.3 (0.1-7.6) 1.88; 2.5 27 (58.7) 7 (15.2) 7 (15.2) 5 (10.9) 17 (37.0)
1.88; 2.5 58 (62.4) 11 (11.8) 18 (19.4) 9 (9.7) 14 (15.1)
1.88; 2.6 38 (55.1) 9 (13.0) 16 (23.2) 8 (11.6) 10 (14.5)
3.75; 3.75 20 (83.3) 2 (8.3) 2 (8.3) 1 (4.2) 6 (25.0)
P [ .005 PRN administered, n (%) Time on antipsychotics, y, mean SD (range) BPSD NPI-NH total score median; IQR (n [%]) Presence of BPSD, n (%) Delusions Hallucinations Agitation/Aggression Depression
7 (15.2) 2.4 1.9 (0.4-8.1)
3 (3.2) 2.4 1.8 (0.1-8.1)
22.0; 22.0 (35 [76.1])
26.6; 24.8 (70 [75.3])
Anxiety Elation/Euphoria Apathy Disinhibition Irritability/lability Ab motor behavior Sleep and nighttime behavior disorders Appetite changes CMAI, median; IQR (n [%]) Adverse outcomes MOSES, median; IQR (n [%]) Falls,* n (%) None 1 fall
13/35 (37.1) 4/34 (11.8) 24/35 (68.6) 10/35 (28.6) 21/35 (60.0) 16/35 (45.7) 12/35 (34.3) 9/32 (28.1) 51.7; 28.8 (35 [76.1])
39/73 (53.4) 14/74 (18.9) 57/74 (77.0) 23/73 (31.5) 54/73 (74.0) 33/73 (45.2) 22/70 (31.4) 13/66 (19.7) 51.6; 24.9 (72 [77.4])
24.0; 9.0 (41 [89.1])
24.0; 10.25 (78 [83.9])
6/29 5/34 25/35 12/35
(20.7) (14.7) (71.4) (34.3)
27 (58.7) 19 (41.3)
17/63 9/74 65/73 32/72
(27.0) (12.2) (89.0) (44.4)
43 (46.2) 50 (53.8)
1 (1.4) 2.4 1.8 (0.1-8.1)
2 (8.3) 2.4 1.8 (0.4-7.0)
25.0; 22.0 (52 [75.4])
31.6; 23.6 (19 [79.2])
13/47 6/53 47/53 30/51
(27.7) (11.3) (88.7) (58.8)
4/16 3/21 18/20 2/21
(25.0) (14.3) (90.0) (9.5)
P < .001 31/53 (58.5) 8/20 (40.0) 8/53 (15.1) 6/21 (28.6) 40/53 (75.5) 17/21 (81.0) 13/52 (25.0) 10/21 (47.6) 38/53 (71.7) 16/20 (80.0) 21/52 (40.4) 12/21 (57.1) 13/52 (25.0) 9/18 (50.0) 9/46 (19.6) 4/20 (20.0) 48.7; 22.5 (52 [75.4]) 58.0; 28.0 (19 [79.2]) 24.0; 9.5 (52 [75.4])
26.0; 7.0 (19 [79.2])
37 (53.6) 32 (46.4)
6 (25.0) 18 (75.0) P [ .018
NPI-NH, Neuropsychiatric Inventory - Nursing Home27; CMAI, Cohen-Mansfield Agitation Inventory36; MOSES, Multidimensional Observation Scale for Elderly Subjects withdrawn behavior subscale.29 For 3 individuals who dropped out between baseline and prebaseline, prebaseline data were used instead of baseline data. Differences were tested via Fisher exact test or Student t test. Bold values indicate significant differences, adjusting for multiple testing within each column and set of characteristics (Demographics, Antipsychotic use, BPSD, and Adverse outcomes). There was no significant difference in attrition in the group that has their regular antipsychotic medication deprescribed, compared to that with regular antipsychotic medication never deprescribed or represcribed (Fisher exact test: P ¼ .83). Deprescribed and never represcribed; as indicated in Supplemental Figure 6. *Falls in the 6-month period prior to prebaseline.
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The primary outcome was reduction in antipsychotic use comparing pre- and postintervention. For all secondary outcomes except falls and hospitalizations, linear mixed models were used to assess whether changes occurred on deprescribing. Variables included in the models were age, sex, time, and regular antipsychotic medication use (fixed) and subject and nursing home (random). As such, the data of all participants could be included in the analysis, including that of participants who were represcribed or never deprescribed, and participants who dropped out during follow-up. Covariance between repeated measures was specified according to an autoregressive model of order 1. Where applicable, noninferiority for deprescription was evaluated (Supplemental Figure 3). Role of the Funding Source The study sponsor(s) played no role in study design (apart from funding rules precluding randomized controlled trials); in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The corresponding author had full access to all data in the study and takes final responsibility for the decision to submit for publication. Results Cohort Characteristics Participant flow is summarized in the Consort diagram (Figure 1). Twenty-four LTC nursing homes with 3447 beds were recruited; 149
residents consented to participate (range: 2-22 per nursing home). Of 139 eligible participants from 23 different nursing homes, 93 (66.9%) completed the study to 12-month follow-up. Reasons for attrition were death (n ¼ 36), consent revocation [n ¼ 5; 3 of which occurred prior to (completion of) intervention], relocation (n ¼ 3), terminal illness (n ¼ 1), and nursing home withdrawal (n ¼ 1). Three participants dropped out prior to the baseline assessment and 3 more shortly afterwards, meaning 133 participants provided at least some postintervention data and were included in analyses. Table 1 compares the baseline characteristics, including baseline antipsychotic use for participants who completed the study with those who dropped out at any point (noncompleters). Among the 93 completers, participants whose regular antipsychotics were sustainably deprescribed (ie, antipsychotics were ceased and were not represcribed) are compared to those whose antipsychotics were represcribed or never deprescribed (Table 1). Primary Outcome Deprescribing Of the 133 participants for whom postintervention data were available, regular antipsychotic medication was ceased for 126 (94.7%). Complete cessation of regular antipsychotics was achieved after 27 days on average (range: 0-78 days, plus 2 participants whose medication was ceased after >5 months; Supplemental Figure 1). At follow-ups, 86.2% participants were not on regular antipsychotics at 3 months, 79.1% at 6 months, and 81.7% at 12 months post intervention (Figure 2). When assessing dose reduction, 93.5%, 87.3%, and 90.3% of all participants were administered none, or less than half of
Fig. 2. Regular daily dose of antipsychotic medication, expressed in terms of olanzapine equivalents.
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their original dose of regular antipsychotic, at the 3-, 6-, and 12-month follow-ups, respectively. Antipsychotic dose was initially reduced but never ceased for 7 (6.3%) participants. Of these, 4 participants dropped out shortly after intervention and 3 completed the study but remained on regular antipsychotics throughout the entire 12 months (albeit with dose halved for 2). Represcribing Of the 126 residents whose medication was ceased, 28 (22.2%) were subsequently represcribed a regular antipsychotic
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(Supplemental Figure 6), on average 2.7 months after original cessation (range: 7 dayse8.4 months; Supplemental Figure 1); 20 (71.4%) were represcribed risperidone, 3 (10.7%) olanzapine, 1 quetiapine (3.6%), and 4 (14.3%) haloperidol (later supplemented with quetiapine for one participant). For 8 of these 28 participants, antipsychotics were deprescribed a second time, and for 1 they were subsequently represcribed again. Accordingly, 105 of the total sample of 133 participants (78.9%) with postintervention data were no longer taking regular antipsychotics at their last assessment.
Fig. 3. Scores for BPSD and adverse outcomes over time. (A) NPI-NH, (B) CMAI, (C) MOSES withdrawn behavior, and (D) PAS-CIS total scores for all participants at each assessment. Proportions of participants who (E) fell or (F) were hospitalized in the 6 months prior to the intervention and at the end of the study. Start of deprescription is indicated with a red dashed line. Blue lines and error bars indicate median and interquartile range. NPI-NH, Neuropsychiatric Inventory Nursing Home. CMAI, Cohen-Mansfield Agitation Inventory. MOSES, Multidimensional Observation Scale for Elderly Subjects.
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Sustainability of deprescribing The sustainability of deprescribing was assessed in the 93 participants that completed the full 12-month follow-up period; antipsychotics were deprescribed successfully for 69 of 93 completers (74.2%; ie, regular antipsychotic ceased and not represcribed during the study follow-up). They were not on regular antipsychotics for 11.5 months on average (range: 9.4-14.4 months, with 1 outlier at 4.3 months). Even when also considering the 29 noncompleters who were deprescribed antipsychotics (69 þ 29 ¼ 98 participants), the median length of cessation remained high at 11.1 months. Among the group of 28 participants who were represcribed a regular antipsychotic, the average total time postintervention not taking regular antipsychotics was 4.1 months (range: 7 dayse11 months); 16 (57.1%) remained free of regular antipsychotics for 3 months or more, and 12 (42.9%) were represcribed a lower dose than their initial dose of antipsychotics. Overall, there was a significant reduction in antipsychotic use after intervention: 81.7% (95% CI: 72.4-89.0) of participants (n ¼ 76/93) had their regular antipsychotics deprescribed at 12 months. Secondary Outcomes Substitution: PRN antipsychotics and sedatives Approximately 1 in 5 participants was prescribed a PRN antipsychotic prior to baseline (Supplemental Table 2). PRN antipsychotic administration was infrequent and occurred at a low dose. They were administered to only 5 participants after ceasing regular medication, 3 of whom received less than 2.5 mg olanzapine (or equivalent) on average monthly. Linear mixed model analysis of the data across the entire sample (n ¼ 139) showed there was no significant increase in PRN antipsychotic prescribing (b ¼ 0.3 mg/mo, P ¼ .33, 97.5% CI: 1.0 to 0.4, t ¼ 0.98, df ¼ 474) or administration (b ¼ 0.9 mg/mo, P ¼ .31, 97.5% CI: 3.0 to 1.1, t ¼ 1.03, df ¼ 110) on deprescribing of regular antipsychotics (Supplemental Figure 3). We checked whether the deprescribed regular antipsychotic medication was substituted with other psychotropic medications such as benzodiazepines. There was no increase in regular benzodiazepine use, but more participants were administered a PRN benzodiazepine, particularly lorazepam and oxazepam (Supplemental Table 3). The proportion of participants administered PRN benzodiazepines increased from 11.0% and 8.2% at prebaseline and baseline, respectively, to 23.1%, 25.4%, and 29.8% at 3, 6, and 12 months, respectively. However, PRN benzodiazepine administration occurred for less than a third of participants at any time point, and most received 10 mg diazepam equivalents on average per month or 0.3 mg/d (Supplemental Figure 4A). Moreover, this increase in benzodiazepine use was independent of regular antipsychotic deprescribing (b ¼ 0.47 mg/ mo, P ¼ .528, 95% CI: 0.99 to 1.92; t ¼ 0.63, df ¼ 396; Supplemental Figure 3). In other words, although PRN use of benzodiazepine increased throughout the study, this increase was very low and not linked to deprescription of regular antipsychotic medication. Antidepressant use remained stable throughout the entire study period (Supplemental Figure 4B). BPSD Participants in our sample showed no significant behavioral changes over the study period (Figure 3). There was no significant change in total NPI-NH score on deprescription (b ¼ 1.0 point; ie, total NPI score was 1 point lower when not on regular antipsychotics, P ¼ .58, 97.5% CI: 5.03 to 3.02, t ¼ 0.56, df ¼ 450; Figure 3A and Supplemental Figure 3). Agitation/aggression, as measured by total CMAI score, did not increase with deprescribing (b ¼ 1.7 point, ie, total CMAI was 1.7 points lower when not on regular antipsychotics, P ¼ .37, 97.5% CI: 5.77 to 2.47, t ¼ 0.90, df ¼ 435; Figure 3B and Supplemental Figure 3). Specific behaviors were analyzed based on individual NPI-NH domain scores (Supplemental Figure 5), but
antipsychotic deprescribing was not significantly associated with changes in any domain after correcting for multiple testing. There was no significant interaction effect between deprescribing and the administration of PRN antipsychotic or benzodiazepine medication on either NPI or CMAI total scores (data not shown). Social engagement We used the Multidimensional Observation Scale for Elderly Subjects to verify whether our deprescribing intervention reduced social withdrawal, but found no significant change (Figure 3C; b ¼ 0.27, ie, the Multidimensional Observation Scale for Elderly Subjects score was 0.27 points higher when not regular antipsychotics, P ¼ .52, 97.5% CI: 0.67 to 1.22, t ¼ 0.65, df ¼ 379; Supplemental Figure 3). There were strong floor effects on cognitive scores (Figure 3C), but there was no significant improvement in cognition associated with deprescribing [b ¼ 0.22, ie, (converted) PAS score was 0.22 points higher when not on regular antipsychotics, P ¼ .56, 97.5% CI: 0.67 to 1.12, t ¼ 0.56, df ¼ 245; Supplemental Figure 3]. Adverse outcomes Falls and hospitalizations were analyzed for the 6-month periods prior to the intervention (when participants were on regular antipsychotics) and at the end of the study (when most were either withdrawn or prescribed a lower dose of antipsychotics). When considering only participants who were mobile, 54.2% fell at least once in the 6 months prior to study enrolment (n ¼ 39/72 mobile participants; who fell 3.5 times on average, SD: 3.2, range: 1-12). This was not significantly different from the final 6 months of the study, when 44.7% fell at least once (n ¼ 22/47 mobile participants; who fell 3.2 times on average, SD: 3.1, range: 1-13; Figure 3E). There was no difference in attrition between mobile and immobile participants (Fisher exact test: P ¼ .45). Accordingly, there were no differences in falls pre- and postintervention for the mobile participants who completed the study and whose antipsychotics were deprescribed (56.3% prior to intervention vs 42.4% after; P ¼ .32). For hospitalizations, the proportion of participants hospitalized was 18.0% at preintervention (n ¼ 25, mean: 1.1 hospitalization, SD: 0.4, range: 1-3) and 12.9% (n ¼ 12, mean: 1.4, SD: 0.7, range: 1-3) post intervention, a nonsignificant decrease (Figure 3F). Among participants who completed the study and were successfully deprescribed, 18.8% were hospitalized at least once in the period before the intervention, compared to 8.8% at the end of the study; this decrease was not statistically significant (P ¼ .14). Baseline hospitalization rate was not linked to attrition (P ¼ .16). Discussion The Halting Antipsychotic use in Long-Term care (HALT) study demonstrated successful and sustainable reduction of antipsychotic use in a sample of older adults residing in LTC who were recruited by nursing staff, without an associated rise in BPSD (Figure 3A, B). Withdrawal was not accompanied by an increase in substitute regular or PRN antipsychotics. Although PRN benzodiazepines were prescribed for more participants, they were administered for a minority of participants, infrequently, at very low doses (<0.3 mg/d in diazepam equivalents), and independent of antipsychotic withdrawal (Supplemental Figure 4). There was no significant improvement in adverse outcomes, such as withdrawn behaviors, falls, hospitalizations, and cognitive decline. Four in 5 participants had their regular antipsychotic successfully deprescribed compared to about 1 in 5 in other studies.17,31 Although this high success rate may partially be driven by residence and resident selection (see limitations below), it is also in line with previous findings that active engagement of all involved stakeholders, as in this study, is linked to greater success.32 In contrast to most other studies,
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our intervention involved multiple components. Providing additional skills to nurses by nurses (via a train-the-trainer approach), to pharmacists by pharmacists, and to GPs by an academic GP was a truly multidisciplinary approach. Good leadership and focused training providing clear practical directions on pharmacologic and nonpharmacologic approaches for the prevention and management of BPSD. We hypothesize that the application of best practice principles of deprescribing in a clear, individualized way, which held both nursing staff and GPs accountable to enact within a specific time frame, was a key factor in the success of HALT. The use of PRN benzodiazepines increased slightly (most likely as a consequence of the HALT protocol allowing inclusion of a PRN prescription of oxazepam or lorazepam, if deemed necessary), but this increase was small in terms, <0.3 mg/d in diazepam equivalents, and independent of antipsychotic withdrawal. Participants who did or did not have their antipsychotics successfully deprescribed showed few differences at baseline (Table 1), and there were no significant effects on any of the secondary outcome measures on antipsychotic withdrawal. Interestingly, depression scores at baseline were significantly higher in the group that had their antipsychotic medication successfully deprescribed. This suggests that antipsychotics may have been administered, perhaps unsuccessfully, as an add-on to antidepressant medication (antidepressant medication use remained stable throughout the entire study). Overall, there was a large variation in BPSD over time and between participants. We found no relationship between use of antipsychotics and severity of BPSD over 12 months’ follow-up (Supplemental Figure 3). Devanand et al reported increased BPSD on antipsychotic withdrawal for AD patients who had previously responded to risperidone for agitation or psychosis treatment.20 Sampling differences could explain the differing outcomes, as we have no knowledge of the appropriateness of the original prescription or the treatment response for our sample. There was no statistically significant decrease in adverse events. The lack of improvement could have reflected the natural history of these outcomes over time (see limitations). Cognitive assessment was limited by floor effects, reduced power due to frequent lack of interpreters (31.7% of participants did not have English as a preferred language), and lack of assessment of specific cognitive domains. Our study was powered to measure decline in antipsychotic prescription rates (primary outcome), but was insufficiently powered for small effect sizes in secondary outcomes. Noninferiority analysis did indicate there was no increase in BPSD. A larger sample and more sensitive assessment measures, ideally in a randomized controlled trial, might confirm the beneficial effects found in earlier studies.33,34 The success of HALT should be interpreted with consideration of a number of limitations. First, in a single-arm trial it is difficult to tease out whether any of the observed changes are due to the intervention or another time-dependent change in the outcome. For example, as dementia severity increases, cognition and BPSD change over time (eg, aggression declines and apathy increases), which may mask positive effects of deprescribing. We attempted to control for time-dependent changes by including 2 preintervention assessments 1 month apart that did not demonstrate variability albeit over a limited time period (see Figure 2). Also, we cannot ascertain whether the antipsychotic was never or no longer indicated, or if other (nonspecific) aspects of the intervention, such as greater care and vigilance, obviated their need. Second, in common with most antipsychotic deprescribing interventions,21 HALT had multiple components, including multidisciplinary education and medication review. This precludes identification of component(s) or professional group(s) that were instrumental in achieving such a high rate of deprescribing. On the other hand, this multipronged strategy is a strength, and possibly the essential factor for sustainable reduction of antipsychotic use.34
599
A third limitation lies in nonrandom recruitment of nursing homes, of which 24/58 agreed to join the study (and one subsequently withdrew), and residents. Because of an ethical requirement for armslength recruitment, nurse champions were relied on to identify residents. Although they were instructed to approach families of every resident who met eligibility criteria, selective recruitment of participants who were stable and perceived to no longer need the medication is possible. We expected that a much larger proportion of residents from participating nursing homes would have been prescribed antipsychotic medication. Because we do not have access to this information, it is difficult to assess the representativeness of our sample. Based on the literature, we can estimate to have recruited between 15% and 20% of all potentially eligible residents in the participating nursing homes. Fourth, a third of our sample dropped out, most commonly because of death. Some outcomes may be skewed because of the loss of primarily older participants at more advanced stages of dementia (Table 1). However, our sensitivity analysis, conservatively allowing that all noncompleters would have been represcribed regular antipsychotics, shows that we would still achieve a high success rate (50% reduction in participants taking antipsychotics). We reiterate that there was no significant difference in attrition between participants whose antipsychotic medication was deprescribed or not. Fifth, neither staff nor assessors were blind to previous and current medication administration. Because we did not find significant differences in any of our secondary outcomes, reporting bias is unlikely to have affected our conclusions. Overall, our results highlight the feasibility and safety of withdrawing antipsychotics for at least a subgroup of people with dementia in LTC without (re)emergence of BPSD. Accepting the potential for selection bias, the results of this study suggest that many people with dementia in LTC who currently use antipsychotic medication stand to benefit from more active review practices. Further analysis might provide more insight into differences between groups who were represcribed antipsychotics and those who were not. In addition, qualitative data collected from participants, care staff and GPs will be used to explored the context of antipsychotic (re) prescribing. Even though health care policy and guidelines advise against antipsychotic use in people with dementia, our findings demonstrate that implementation of correct review and withdrawal practices is currently lacking in LTC nursing homes. Anecdotal information from the revocations for this study further reinforce that a conservative approach to care, rather than actual symptom management, may underlie the continued prescription of antipsychotic medication in older nursing home residents. Further research should focus on the specific strengths of the different components of the multifaceted intervention implemented in this study. A comprehensive strategy involving all stakeholders in the care process likely improves its success rate, but cost and feasibility are important limitations for its application in routine practice. Previous studies have demonstrated the cost-effectiveness of implementing training in person-centered dementia care.35 The results of this trial should encourage antipsychotic withdrawal in people with dementia living in LTC, following existing guidelines, and the implemented measures could serve as a blueprint for wider integration into dementia care practices. Acknowledgments We thank all participating residents, their families, GPs, pharmacists, and nursing staff. We thank the members of the steering committee, Jacqui Close, Juanita Westbury, Lee-Fay Low, Aine Heaney, Marie Alford, Stacy Wake, Janet Mitchell, Millie Marinkovich, and Jenny Blennerhassett. Linda Nattrass, Anne-Nicole Casey, Emily Trigge,
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and Tiffany Chau are thanked for their assistance with administration and data entry. References 1. Brodaty H, Draper B, Saab D, et al. Psychosis, depression and behavioural disturbances in Sydney nursing home residents: prevalence and predictors. Int J Geriatr Psychiatry 2001;16:504e512. 2. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. J Clin Psychiatry 1999;60:107e115. 3. Ballard C, Corbett A, Chitramohan R, Aarsland D. Management of agitation and aggression associated with Alzheimerʼs disease: controversies and possible solutions. Curr Opin Psychiatry 2009;22:532e540. 4. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934e1943. 5. Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: Meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 2006;14:191e210. 6. Rochon PA, Normand S-L, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med 2008;168:1090e1096. 7. Vigen CLP, Mack WJ, Keefe RSE, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: Outcomes from CATIE-AD. Am J Psychiatry 2011;168:831e839. 8. Declercq T, Petrovic M, Azermai M, et al. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. In: Declercq T, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2013. p. CD007726. 9. Gallini A, Andrieu S, Donohue JM, et al. Trends in use of antipsychotics in elderly patients with dementia: Impact of national safety warnings. Eur Neuropsychopharmacol 2014;24:95e104. 10. Briesacher BA, Tjia J, Field T, et al. Antipsychotic use among nursing home residents. JAMA 2013;309:440. 11. Stock KJ, Amuah JE, Lapane KL, et al. Prevalence of, and resident and facility characteristics associated with, antipsychotic use in assisted living vs. longterm care facilities: A cross-sectional analysis from Alberta. Canada. Drugs Aging 2017;34:39e53. 12. Janus SIM, van Manen JG, IJzerman MJ, Zuidema SU. Psychotropic drug prescriptions in Western European nursing homes. Int Psychogeriatr 2016;28: 1775e1790. 13. Snowdon J, Galanos D, Vaswani D. Patterns of psychotropic medication use in nursing homes: Surveys in Sydney, allowing comparisons over time and between countries. Int Psychogeriatr 2011;23:1520e1525. 14. Ballard C, Hanney ML, Theodoulou M, et al. DART-AD Investigators. The Dementia Antipsychotic Withdrawal Trial (DART-AD): Long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol 2009;8:151e157. 15. Royal Australian and New Zealand College of Psychiatrists. The Use of Antipsychotics in Residential Aged Care. Clinical Recommendations; 2011. 16. Ballard C, Lana MM, Theodoulou M, et al. A randomised, blinded, placebocontrolled trial in dementia patients continuing or stopping neuroleptics (The DART-AD Trial). PLoS Med 2008;5:0587e0599. 17. Fossey J, Ballard C, Juszczak E, et al. Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: Cluster randomised trial. BMJ 2006;332:756e761.
18. van Reekum R, Clarke D, Conn D, et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Int Psychogeriatr 2002;14:197e210. 19. Ruths S, Straand J, Nygaard HA, et al. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: A randomized, placebo-controlled, double-blinded study the Bergen District Nursing Home Study. J Am Geriatr Soc 2004;52:1737e1743. 20. Devanand DP, Mintzer J, Schultz SK, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s disease. N Engl J Med 2012;367:1497e1507. 21. Thompson Coon J, Abbott R, Rogers M, et al. Interventions to reduce inappropriate prescribing of antipsychotic medications in people with dementia resident in care homes: A systematic review. J Am Med Dir Assoc 2014;15: 706e718. 22. Jessop T, Harrison F, Cations M, et al. Halting Antipsychotic Use in Long-Term care (HALT): A single-arm longitudinal study aiming to reduce inappropriate antipsychotic use in long-term care residents with behavioral and psychological symptoms of dementia. Int Psychogeriatr; 2017:1e13. 23. Australian Department of Health. Dementia and Severe Behaviours Supplement. Canberra, AU: Australian Government; 2013. 24. Jorm A, Mackinnon AJ, Henderson AS, et al. The Psychogeriatric Assessment Scales: A multi-dimensional alternative to categorical diagnoses of dementia and depression in the elderly. Psychol Med 1995;25:447e460. 25. The Royal Australian & New Zealand College of Pyschiatrists. Assessment and Management of People with Behavioural and Psychological Symptoms of Dementia (BPSD)dA Handbook for NSW Health Clinicians; 2013. 26. Mandrekar JN. Measures of interrater agreement. J Thorac Oncol 2011;6:6e7. 27. Wood S, Cummings JL, Hsu MA, et al. The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 2000;8:75e83. 28. Cohen-Mansfield J, Billig N. Agitated behaviors in the elderly. I. A conceptual review. J Am Geriatr Soc 1986;34:711e721. 29. Pruchno RA, Kleban MH, Resch NL. Psychometric assessment of the Multidimensional Observation Scale for Elderly Subjects (MOSES). J Gerontol 1988;43: P164eP169. 30. Storey JE, Rowland JTJ, Basic D, et al. The Rowland Universal Dementia Assessment Scale (RUDAS): A multicultural cognitive assessment scale. Int Psychogeriatr 2004;16:13e31. 31. Patterson SM, Hughes CM, Crealey G, et al. An evaluation of an adapted U.S. model of pharmaceutical care to improve psychoactive prescribing for nursing home residents in Northern Ireland (Fleetwood Northern Ireland Study). J Am Geriatr Soc 2010;58:44e53. 32. Lawrence V, Fossey J, Ballard C, et al. Improving quality of life for people with dementia in care homes: Making psychosocial interventions work. Br J Psychiatry 2012;201:344e351. 33. Declercq T, Petrovic M, Azermai M, et al. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev 2013;3:1e80. 34. Ballard C, Orrell M, Psych FRC, et al. Impact of antipsychotic review and nonpharmacological intervention on antipsychotic use, neuropsychiatric symptoms, and mortality in people with dementia living in nursing homes: A factorial cluster-randomized controlled trial by the Well-Being and Health for People With Dementia (WHELD) Program. Am J Psychiatry 2016;173: 252e262. 35. Chenoweth L, King MT, Jeon YH, et al. Caring for Aged Dementia Care Resident Study (CADRES) of person-centred care, dementia-care mapping, and usual care in dementia: A cluster-randomised trial. Lancet Neurol 2009;8: 317e325.
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Appendix
Supplemental Table 1 Equivalents for Antipsychotic Medications and Benzodiazepines1e4 Antipsychotics (Eq to 1 mg Olanzapine)
Benzodiazepines (Eq to 10 mg Diazepam)
Haloperidol Risperidone Quetiapine
Alprazolam Clobazam Clonazepam Lorazepam Midazolam Nitrazepam Oxazepam Temazepam Triazolam
0.533 mg 0.267 mg 20 mg
0.75 mg 15 mg 0.5 mg 1.5 mg 8.75 mg 10 mg 30 mg 20 mg 0.5 mg
Supplemental Table 2 PRN Antipsychotic Prescriptions and Administrations Olanzapine Equivalents
Prescribed
None
0 < x ≤ 2.5 mg
2.5 < x ≤ 5 mg
> 7.5 mg
Administered
N/A None 0 < x ≤ 2.5 mg
2.5 < x ≤ 5 mg
> 7.5 mg
Unknownc
Preintervention, n (%)
Postintervention, n (%)
Prebaseline (n ¼ 139)
Baseline (n ¼ 136)
3 mo (n ¼ 124)
6 mo (n ¼ 110)
12 mo (n ¼ 93)
105 (75.5)
104 (76.5)
98 (79.0)
94 (85.5)
74 (79.6)
28 (20.1)
26 (19.1)
23 (18.5)
12 (10.9)
14 (15.1)
4 (2.9)
5 (3.7)
1 (0.8)
2 (1.8)
4 (4.3)
0
0
0
0
0
2 (1.4)
1 (0.7)
2 (1.6)
2 (1.8)
1 (1.4)
103 (74.1)*
103 (75.7)y
98 (79.0)
93 (84.5)y
73 (78.5)y
18 (12.9)
25 (18.4)
18 (14.5)
10 (9.1)
7 (5.0)
4 (2.9)
5 (4.0) [1 no reg AP]
0
8 (8.6) [3 no reg AP]
5 (3.6)
1 (0.7)
3 (2.4) [1 no reg AP]
2 (1.8)
3 (3.2) [1 no reg AP]
0
0
0
3 (2.2)
2 (1.5)
0
3 (2.2)
1 (0.7)
3 (2.7) [2 no reg AP]
1 (0.9)
9 (9.7)
0
0
1 (0.9)
Note: Time frame for administration: amount of olanzapine (in milligrams) administered in one month [monthly average over last 3 months (for prebaseline) or in the time period since the previous assessment (for all other assessments)]. [“X” no reg AP] ¼ individuals who were not prescribed regular antipsychotic medication at the current time of assessment. *Three participants were administered PRN antipsychotics even though not prescribed. y One person was administered PRN antipsychotics even though not prescribed.
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Supplemental Table 3 Benzodiazepine Use: Participants on Regular and PRN Benzodiazepines (and Frequency of PRN Administration) Preintervention, n (%)
Regular Diazepam Lorazepam Oxazepam Temazepam PRN administered Diazepam
Postintervention, n (%)
Prebaseline (n ¼ 139)
Baseline (n ¼ 136)
3 mo (n ¼ 124)
6 mo (n ¼ 110)
12 mo (n ¼ 93)
1 1 3 21
1 1 3 19
1 1 6 17
0 1 (0.9) 2 (1.8) 17 (15.5)
1 2 3 16
2 (1.8) 1 < monthly 1 < weekly 5 (4.5) 3 < monthly 1 < weekly 1 once/week 16 (14.5) 5 < monthly 6 < weekly 5 once/week 8 (7.3) 4 < monthly 1 < weekly 3 once/week
3 (3.2) All < weekly
(0.7) (0.7) (2.2) (15.1)
(0.7) (0.7) (2.2) (14.0)
3 (2.2) 2 < weekly 1 once/week 1 (0.7) < monthly
2 (1.5) 1 < monthly 1 once/week 1 (0.7) < weekly
Oxazepam
1 (0.7) < monthly
1 (0.7) < weekly
Temazepam
9 (6.5) 6 monthly 3 once/week
7 (5.1) 2 < monthly 2 < weekly 3 once/week
Lorazepam
(0.8) (0.8) (4.8) (13.7)
3 (2.4) All monthly 4 (3.2) All < monthly
17 (13.7) 6 < monthly 3 < weekly 8 once/week 8 (6.5) 3 < monthly 4 < weekly 1 once/week
(1.1) (2.2) (3.2) (17.2)
5 (5.4) 1 < monthly 3 < weekly 1 once/week 13 (14.0) 6 < monthly 4 < weekly 2 once/week 9 (9.7) 3 < monthly 6 < weekly
Other sedatives such as midazolam, nitrazepam, triazolam, clobazam, clonazepam, and melatonin were administered to less than 2% of the sample population at any time point (and there were no significant differences across the different timepoints). These data are not included in the table.
Supplemental. Fig. 1. Time profile of participants’ de- and represcription. Time from baseline to complete cessation of all regular antipsychotic medication (solid line; % of total n ¼ 133, ie, all participants with postbaseline data; see text for details) and the time between baseline and (first) represcription of a regular antipsychotic (dashed line, % of total n ¼ 126 participants who had ceased after intervention).
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Supplemental Fig. 2. Example of participant deprescribing protocol.
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Supplemental Fig. 3. Sample confidence intervals and inference for trials assessing superiority or noninferiority of regular antipsychotic prescription and deprescription. Prespecified noninferiority d0 s for deprescription of regular antipsychotics are as follows: for PRN medication prescription (olanzapine or diazepam equivalents for antipsychotics and benzodiazepines, respectively), 5 mg/mo; for NPI-NH total score, 4 points; and for CMAI total score, 6 points. Confidence intervals indicated are 97.5% to correct for multiple testing, except for benzodiazepine PRN administration, which is 95%. Antipsychotic withdrawal was not inferior to regular antipsychotic administration in terms of PRN administration of antipsychotics or benzodiazepines, or in terms of NPI-NH and CMAI total scores. There was no significant change in MOSES withdrawn behavior or PAS-CIS total scores on withdrawal.
Supplemental Fig. 4. Substitution: (A) PRN benzodiazepine administration, expressed in terms of diazepam equivalents; (B) antidepressant use.
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Supplemental Fig. 5. NPI domain scores. Domain scores (severity by frequency score) for the NPI-NH at 5 assessments. Blue lines and error bars indicate median and interquartile range, respectively.
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Supplemental Fig. 5. continued
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Supplemental Fig. 6. Sankey diagram of regular antipsychotic prescription patterns and attrition. Participant flow in terms of participant inclusion for intervention and at 12month follow-up is indicated and patterns of de- and represcription of regular antipsychotic medication are indicated (irrespective of at which time point during the study deor represcription occurred).
Supplemental References 1. Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose equivalents for second-generation antipsychotics: The minimum effective dose method. Schizophr Bull 2014;40:314e326. 2. Cooper AJ. Benzodiazepines: towards more logical use. Scott Med J 1982;27:297e304.
3. Goodman LS, Gilman A, Brunton LL. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. New York: McGraw-Hill Medical; 2008. 4. Ruiz P, Strain EC, Lowinson JH. Lowinson and Ruiz’s Substance Abuse: A Comprehensive Textbook. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.
JAMDA journal homepage: www.jamda.com
Original Study
Antipsychotic Deprescription for Older Adults in Long-term Care: The HALT Study Henry Brodaty MD, DSc a, b, c, *, Liesbeth Aerts PhD a, Fleur Harrison BA, GDipSc (Psych) a, b, Tiffany Jessop PhD a, Monica Cations a, Lynn Chenoweth BA, MA Hons, MAdEd, PhD b, Allan Shell MB, BS a, Gordana C. Popovic BSc, BEd, PhD d, Megan Heffernan PhD a, b, Sarah Hilmer MBBS, PhD e, Perminder S. Sachdev MD, PhD b, f, Brian Draper MBBS, MD b, c a
Dementia Centre for Research Collaboration, School of Psychiatry, University of New South Wales Sydney, New South Wales, Australia Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Sydney, New South Wales, Australia c Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Randwick, New South Wales, Australia d Stats Central, Mark Wainwright Analytical Centre, University of New South Wales Sydney, New South Wales, Australia e Kolling Institute, Royal North Shore Hospital and University of Sydney, St Leonards, New South Wales, Australia f Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, New South Wales, Australia b
a b s t r a c t Keywords: Antipsychotic withdrawal dementia behavioral and psychological symptoms of dementia
Objectives: Despite limited efficacy and significant safety concerns, antipsychotic medications are frequently used to treat behavioral and psychological symptoms of dementia (BPSD) in long-term residential care. This study evaluates the sustained reduction of antipsychotic use for BPSD through a deprescribing intervention and education of health care professionals. Design: Repeated-measures, longitudinal, single-arm study. Setting: Long-term residential care of older adults. Participants: Nursing staff from 23 nursing homes recruited 139 residents taking regular antipsychotic medication for 3 months, without primary psychotic illness, such as schizophrenia or bipolar disorder, or severe BPSD. Intervention: An antipsychotic deprescribing protocol was established. Education of general practitioners, pharmacists, and residential care nurses focused on nonpharmacological prevention and management of BPSD. Measurements: The primary outcome was antipsychotic use over 12-month follow-up; secondary outcomes were BPSD (Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory, and social withdrawal) and adverse outcomes (falls, hospitalizations, and cognitive decline). Results: The number of older adults on regular antipsychotics over 12 months reduced by 81.7% (95% confidence interval: 72.4-89.0). Withdrawal was not accompanied by drug substitution or a significant increase in pro-renata antipsychotic or benzodiazepine administration. There was no change in BPSD or in adverse outcomes. Conclusion: In a selected sample of older adults living in long-term residential care, sustained reduction in regular antipsychotic use is feasible without an increase of BPSD. Ó 2018 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
This study was funded by the Australian Department of Health under the Aged Care Service Improvement and Healthy Ageing Grant Fund. The project is supported by the Centre for Research Collaboration, UNSW Sydney. Over the last 3 years, Henry Brodaty has been on the advisory board of Nutricia. He has been recipient of grants for research by the National Health and Medical Research Council and Australian Department of Health and Ageing. Monica Cations is currently employed to assist with data collection for drug trials by Janssen, https://doi.org/10.1016/j.jamda.2018.05.002 1525-8610/Ó 2018 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
Merck, and Paraxel. The other authors declare no competing interests reports and no financial relationships with commercial interests. * Address correspondence to Henry Brodaty, MD, DSc, Dementia Centre for Research Collaboration, AGSM Building, University of New South Wales Sydney, NSW 2052, Australia. E-mail address: [email protected] (H. Brodaty).
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Behavioral and psychological symptoms of dementia (BPSD) are prevalent in people living with dementia especially as the disease progresses.1 Although there is some evidence for the efficacy of antipsychotics in treating aggression and psychosis,2,3 they have significant side effects. Increased risks of cognitive decline, cerebrovascular adverse effects, and death have triggered warnings from international agencies against their use in people with dementia.4e7 Antipsychotics have been linked to socially withdrawn behavior and increased risk of falls and hospitalizations.8 Despite some reports indicating a decline in antipsychotic prescription,9 their use remains common in people with dementia in long-term care (LTC): 20% to 50% are prescribed antipsychotics.10e12 In Sydney, Australia, the setting for this study, more than a quarter are prescribed antipsychotics.13 Most have a long history of continuous antipsychotic use, although current guidelines stipulate review and withdrawal within 12 weeks.14,15 Reduction in antipsychotic prescribing is feasible with reemergence of behavioral symptoms in only a minority of participants.3,16e19 However, one key trial in people with Alzheimer’s disease (AD) living in the community or assisted-living residences found that BPSD increased after antipsychotic discontinuation.20 Although a systematic review of interventions to reduce inappropriate prescribing of antipsychotics in people with dementia in LTC concluded that 9 of 11 well-designed interventions were effective, only 4 studies evaluated long-term effects, at up to 9 months postintervention, and conclusions were mixed.21 In this trial, we aimed to achieve a reduction in inappropriate use of antipsychotic medications for at least 12 months, without an increase in BPSD or use of substitute psychotropic medications.22 Because successful withdrawal depends on the implementation of effective support strategies involving all relevant stakeholders, antipsychotic withdrawal was implemented by general practitioners (GPs), following specific training for nursing staff, GPs, and pharmacists, and awareness raising with family members. This concerted approach aimed to encourage a culture change in prescribing practices and in the prevention and management of BSPD. LTC nursing homes were approached and asked to recruit residents on antipsychotics for study participation. As the Australian Government “funding of initiatives to improve aged care service delivery” proscribed randomized controlled trials, we used repeated measures, including 2 preintervention assessments, to assess changes in medication use, BPSD, and adverse outcomes, including social withdrawal, cognition, falls, and hospitalizations. We hypothesized that antipsychotic withdrawal would not be associated with an increase in BPSD and would be beneficial in reducing adverse effects. Methods Study Design and Ethics The Halting Antipsychotic use in Long Term care (HALT) study was a single-arm longitudinal study in a convenience sample of 23 LTC residences (12 private, 10 charitable, and 1 community-based, each with >60 beds) in Sydney and surrounding areas conducted between April 2014 and October 2016. In Australia, LTC is government subsidized according to level of dependency, and residents can choose which GP they consult. No nursing home in this study had dedicated in-house doctors. Community pharmacists are rebated for undertaking medication reviews. The study was approved by the UNSW Ethics Committee (HC13203) and registered with the Australian New Zealand Clinical Trials Registry (no. 12614000309684). The study design has been described in detail.22 Briefly, prebaseline and baseline assessments
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were conducted approximately 1 month apart, before antipsychotic withdrawal was initiated, to control for changes over time in the absence of a control group. Follow-up assessments occurred after 3, 6, and 12 months (Figure 1). Participants Adults aged 60 or older, living in LTC for 1 month, and on regular antipsychotic medication for 3 months, without primary psychotic illness such as schizophrenia or bipolar disorder, were identified via an appointed registered nurse at each nursing home.22 After obtaining written consent from residents and/or their “person responsible” (proxy) and consent from their general practitioner (GP; because the deprescribing agreement was reliant on GP involvement), research psychologists determined eligibility via staff interviews and file audits. Residents with a terminal illness or very severe BPSD at baseline were excluded [nursing home version of the Neuropsychiatric Inventory (NPI-NH) score 50; domain scores of 12 for at least 2 of delusions, hallucinations, agitation/aggression, anxiety or disinhibition, and occupational disruptiveness score 4 for at least 2 of these domains]. This exclusion criterion was an ethical consideration based on previous findings of a significant worsening of symptoms on deprescribing among those with severe BPSD and based on contemporaneous Australian Department of Health rules for a severe behavior supplement.16,23 Dementia was not an inclusion criterion, as we relied on file audits and a dementia diagnoses are not always recorded. However, 137 participants (98.5%) were considered to have dementia based on documented diagnosis (n ¼ 130), or after review of all available data, including cognitive assessment (Psychogeriatric AssessmenteCognitive Impairment Scale [PAS-CIS]24) by an experienced old-age psychiatrist (H.B.) (n ¼ 7). Interventions The intervention comprised 2 components: (1) education/training of health care staff, and (2) deprescribing antipsychotic medication. The former included education and training opportunities for designated LTC staff (“Champions”), participants’ GPs, and pharmacists involved in the supply of medication services to participating nursing homes.22 Champions, usually 1 to 2 registered nurses from each home, attended a 3-day workshop on dementia, BPSD, and person-centered, nonpharmacologic approaches to BPSD prevention, reduction, and management. Champions were encouraged to implement training strategies at their respective nursing home to educate other staff members. Participants’ GPs were offered academic detailing involving a 30- to 60-minute peer education session, additional reading material on antipsychotic use, and an optional follow-up educational seminar and evaluation. Pharmacists were offered a continuing professional development module. Continuing education credits were awarded to GPs and nursing staff. The second component was an individualized deprescribing protocol, which followed Australian guidelines stipulating a dose reduction of 50% every 2 weeks and ceasing after 2 weeks on the minimum dose, withdrawing one antipsychotic at a time, with risperidone (if prescribed) to be withdrawn last.15 Study pharmacists developed a protocol for each participant that was provided to nursing staff at baseline (Supplemental Figure 2). GPs were instructed to commence the outlined medication change(s) within the next week. If GPs considered emergency medication may be required, consistent with current best practice guidelines,25 they were recommended if concerned about deprescribing antipsychotics to prescribe a short-acting benzodiazepine (oxazepam or lorazepam) pro-re-nata (PRN). GPs could restart antipsychotic therapy at any time if they determined it
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was indicated. If extra support was needed, Champions, GPs, and pharmacists could consult the study team. Assessment Procedures and Outcome Measures Antipsychotic and sedative prescription and administration Research psychologists audited participant medication charts to determine prescribed and administered dosage of regular and PRN antipsychotics, sedatives, and antidepressants. Doses of antipsychotics and benzodiazepines were converted to olanzapine and diazepam equivalents, respectively, for analysis (Supplemental Table 1).
BPSD and adverse outcomes Research psychologists interviewed participants (where possible) and nursing staff. Staff assessments comprised the nursing home version of the NPI (NPI-NH; range 0-144, higher scores indicating more frequent and/or severe BPSD; weighted k: 0.93), the CohenMansfield Agitation Inventory (CMAI; range 29-203, higher scores indicating more frequent manifestations of agitation; weighted k: 0.98; the item “trying to get to a different place” was erroneously excluded from the questionnaire package; therefore, the total score was pro-rated for all participants), and the Multidimensional Observation Scale for Elderly Subjectsdwithdrawn behavior subscale
Fig. 1. Consort diagram. Appointed nurses at each of the 24 nursing homes that agreed to participate recruited residents aged 60 or older, living in current nursing home for 1 month and on regular antipsychotic medication for 3 months. After obtaining written consent from the resident and/or their “person responsible” (proxy), research psychologists determined eligibility based on the absence of a primary psychotic illness and the severity of BPSD. Information on medication use, falls and hospitalizations was determined by file audit. BPSD, socially withdrawn behavior and cognition required (complete) assessment by research psychologists.
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(range 8-32, higher scores indicating more withdrawal, weighted k: 0.96).26e29 Cognition was assessed with the PAS-CIS (range 0-21, higher scores indicating worse performance; k: 0.84) or, for those from noneEnglish-speaking backgrounds, the Rowland Universal Dementia Assessment Scale (RUDAS; range 0-30, lower scores indicating worse performance).24,30 Both PAS-CIS and RUDAS evaluate multiple cognitive domains and are recommended by the Australian Department of Health to establish care needs. Total scores were pro-rated when up to 20% of items were missing. RUDAS scores were converted to the same scale as the PASCIS, using a score of 21 on RUDAS and 5 on PAS-CIS as equivalent cut-offs.24,30 For some participants, it was not possible to complete resident or staff interviews at designated follow-up time points (most often due to participant having deceased recently or lack of an interpreter) or at (pre-)baseline because GPs enthusiastically but erroneously commenced the deprescription protocol prior to study assessment). File audit data were included where possible (Figure 1).
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Residents’ records provided number of falls and hospitalizations prior to and during study follow-up. Information was gathered from incident reports and all progress notes. Frequencies in the 6 months prior to study commencement (or pro-rated for those in the nursing home for less than 6 months) and the last 6 months of the study were compared. Data on falls were analyzed taking into account mobility, defined as able to ambulate with or without assistance (ie, bedbound participants were not included in the analysis of falls).
Statistical Analysis SPSS version 22 and GraphPad Prism version 6.07 were used for analysis. Statistical significance was set at 0.05 and the HolmBonferroni or Bonferroni method were used to correct for multiple testing. Differences between 2 groups were evaluated via Fisher exact (categorical) or Student t test (continuous data).
Table 1 Baseline Characteristics of Completers Versus Noncompleters and of Successful vs Unsuccessful Deprescribing Noncompleters
Completers
Deprescribed Successfully symbol referring to the notes
Represcribed/ Not Deprescribed
46
93
69 (74.2)
24 (25.8)
51 (73.9) 83.8 7.4 (59.5-99.7)
10 (41.7) 83.3 6.9 (67.6-94.3)
2.3 1.7 (0.1-7.5)
2.4 2.0 (0.5-7.6)
n (%) Demographics Gender, n females (%) Age, y, mean SD (range) Time at facility, y, mean SD (range) Antipsychotic use Daily dose in olanzapine equivalents, mg, median; IQR Risperidone, n (%) Olanzapine, n (%) Quetiapine, n (%) Haloperidol, n (%) PRN prescribed, n (%)
31 (67.4) 61 (65.6) 88.2 ± 7.3 (71.2-101.8) 84.3 ± 7.3 (59.5-99.7) P [ .004; t [ 2.964; df [ 137 3.7 3.0 (0.5-15.3) 2.5 7.3 (0.1-7.6) 1.88; 2.5 27 (58.7) 7 (15.2) 7 (15.2) 5 (10.9) 17 (37.0)
1.88; 2.5 58 (62.4) 11 (11.8) 18 (19.4) 9 (9.7) 14 (15.1)
1.88; 2.6 38 (55.1) 9 (13.0) 16 (23.2) 8 (11.6) 10 (14.5)
3.75; 3.75 20 (83.3) 2 (8.3) 2 (8.3) 1 (4.2) 6 (25.0)
P [ .005 PRN administered, n (%) Time on antipsychotics, y, mean SD (range) BPSD NPI-NH total score median; IQR (n [%]) Presence of BPSD, n (%) Delusions Hallucinations Agitation/Aggression Depression
7 (15.2) 2.4 1.9 (0.4-8.1)
3 (3.2) 2.4 1.8 (0.1-8.1)
22.0; 22.0 (35 [76.1])
26.6; 24.8 (70 [75.3])
Anxiety Elation/Euphoria Apathy Disinhibition Irritability/lability Ab motor behavior Sleep and nighttime behavior disorders Appetite changes CMAI, median; IQR (n [%]) Adverse outcomes MOSES, median; IQR (n [%]) Falls,* n (%) None 1 fall
13/35 (37.1) 4/34 (11.8) 24/35 (68.6) 10/35 (28.6) 21/35 (60.0) 16/35 (45.7) 12/35 (34.3) 9/32 (28.1) 51.7; 28.8 (35 [76.1])
39/73 (53.4) 14/74 (18.9) 57/74 (77.0) 23/73 (31.5) 54/73 (74.0) 33/73 (45.2) 22/70 (31.4) 13/66 (19.7) 51.6; 24.9 (72 [77.4])
24.0; 9.0 (41 [89.1])
24.0; 10.25 (78 [83.9])
6/29 5/34 25/35 12/35
(20.7) (14.7) (71.4) (34.3)
27 (58.7) 19 (41.3)
17/63 9/74 65/73 32/72
(27.0) (12.2) (89.0) (44.4)
43 (46.2) 50 (53.8)
1 (1.4) 2.4 1.8 (0.1-8.1)
2 (8.3) 2.4 1.8 (0.4-7.0)
25.0; 22.0 (52 [75.4])
31.6; 23.6 (19 [79.2])
13/47 6/53 47/53 30/51
(27.7) (11.3) (88.7) (58.8)
4/16 3/21 18/20 2/21
(25.0) (14.3) (90.0) (9.5)
P < .001 31/53 (58.5) 8/20 (40.0) 8/53 (15.1) 6/21 (28.6) 40/53 (75.5) 17/21 (81.0) 13/52 (25.0) 10/21 (47.6) 38/53 (71.7) 16/20 (80.0) 21/52 (40.4) 12/21 (57.1) 13/52 (25.0) 9/18 (50.0) 9/46 (19.6) 4/20 (20.0) 48.7; 22.5 (52 [75.4]) 58.0; 28.0 (19 [79.2]) 24.0; 9.5 (52 [75.4])
26.0; 7.0 (19 [79.2])
37 (53.6) 32 (46.4)
6 (25.0) 18 (75.0) P [ .018
NPI-NH, Neuropsychiatric Inventory - Nursing Home27; CMAI, Cohen-Mansfield Agitation Inventory36; MOSES, Multidimensional Observation Scale for Elderly Subjects withdrawn behavior subscale.29 For 3 individuals who dropped out between baseline and prebaseline, prebaseline data were used instead of baseline data. Differences were tested via Fisher exact test or Student t test. Bold values indicate significant differences, adjusting for multiple testing within each column and set of characteristics (Demographics, Antipsychotic use, BPSD, and Adverse outcomes). There was no significant difference in attrition in the group that has their regular antipsychotic medication deprescribed, compared to that with regular antipsychotic medication never deprescribed or represcribed (Fisher exact test: P ¼ .83). Deprescribed and never represcribed; as indicated in Supplemental Figure 6. *Falls in the 6-month period prior to prebaseline.
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The primary outcome was reduction in antipsychotic use comparing pre- and postintervention. For all secondary outcomes except falls and hospitalizations, linear mixed models were used to assess whether changes occurred on deprescribing. Variables included in the models were age, sex, time, and regular antipsychotic medication use (fixed) and subject and nursing home (random). As such, the data of all participants could be included in the analysis, including that of participants who were represcribed or never deprescribed, and participants who dropped out during follow-up. Covariance between repeated measures was specified according to an autoregressive model of order 1. Where applicable, noninferiority for deprescription was evaluated (Supplemental Figure 3). Role of the Funding Source The study sponsor(s) played no role in study design (apart from funding rules precluding randomized controlled trials); in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The corresponding author had full access to all data in the study and takes final responsibility for the decision to submit for publication. Results Cohort Characteristics Participant flow is summarized in the Consort diagram (Figure 1). Twenty-four LTC nursing homes with 3447 beds were recruited; 149
residents consented to participate (range: 2-22 per nursing home). Of 139 eligible participants from 23 different nursing homes, 93 (66.9%) completed the study to 12-month follow-up. Reasons for attrition were death (n ¼ 36), consent revocation [n ¼ 5; 3 of which occurred prior to (completion of) intervention], relocation (n ¼ 3), terminal illness (n ¼ 1), and nursing home withdrawal (n ¼ 1). Three participants dropped out prior to the baseline assessment and 3 more shortly afterwards, meaning 133 participants provided at least some postintervention data and were included in analyses. Table 1 compares the baseline characteristics, including baseline antipsychotic use for participants who completed the study with those who dropped out at any point (noncompleters). Among the 93 completers, participants whose regular antipsychotics were sustainably deprescribed (ie, antipsychotics were ceased and were not represcribed) are compared to those whose antipsychotics were represcribed or never deprescribed (Table 1). Primary Outcome Deprescribing Of the 133 participants for whom postintervention data were available, regular antipsychotic medication was ceased for 126 (94.7%). Complete cessation of regular antipsychotics was achieved after 27 days on average (range: 0-78 days, plus 2 participants whose medication was ceased after >5 months; Supplemental Figure 1). At follow-ups, 86.2% participants were not on regular antipsychotics at 3 months, 79.1% at 6 months, and 81.7% at 12 months post intervention (Figure 2). When assessing dose reduction, 93.5%, 87.3%, and 90.3% of all participants were administered none, or less than half of
Fig. 2. Regular daily dose of antipsychotic medication, expressed in terms of olanzapine equivalents.
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their original dose of regular antipsychotic, at the 3-, 6-, and 12-month follow-ups, respectively. Antipsychotic dose was initially reduced but never ceased for 7 (6.3%) participants. Of these, 4 participants dropped out shortly after intervention and 3 completed the study but remained on regular antipsychotics throughout the entire 12 months (albeit with dose halved for 2). Represcribing Of the 126 residents whose medication was ceased, 28 (22.2%) were subsequently represcribed a regular antipsychotic
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(Supplemental Figure 6), on average 2.7 months after original cessation (range: 7 dayse8.4 months; Supplemental Figure 1); 20 (71.4%) were represcribed risperidone, 3 (10.7%) olanzapine, 1 quetiapine (3.6%), and 4 (14.3%) haloperidol (later supplemented with quetiapine for one participant). For 8 of these 28 participants, antipsychotics were deprescribed a second time, and for 1 they were subsequently represcribed again. Accordingly, 105 of the total sample of 133 participants (78.9%) with postintervention data were no longer taking regular antipsychotics at their last assessment.
Fig. 3. Scores for BPSD and adverse outcomes over time. (A) NPI-NH, (B) CMAI, (C) MOSES withdrawn behavior, and (D) PAS-CIS total scores for all participants at each assessment. Proportions of participants who (E) fell or (F) were hospitalized in the 6 months prior to the intervention and at the end of the study. Start of deprescription is indicated with a red dashed line. Blue lines and error bars indicate median and interquartile range. NPI-NH, Neuropsychiatric Inventory Nursing Home. CMAI, Cohen-Mansfield Agitation Inventory. MOSES, Multidimensional Observation Scale for Elderly Subjects.
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Sustainability of deprescribing The sustainability of deprescribing was assessed in the 93 participants that completed the full 12-month follow-up period; antipsychotics were deprescribed successfully for 69 of 93 completers (74.2%; ie, regular antipsychotic ceased and not represcribed during the study follow-up). They were not on regular antipsychotics for 11.5 months on average (range: 9.4-14.4 months, with 1 outlier at 4.3 months). Even when also considering the 29 noncompleters who were deprescribed antipsychotics (69 þ 29 ¼ 98 participants), the median length of cessation remained high at 11.1 months. Among the group of 28 participants who were represcribed a regular antipsychotic, the average total time postintervention not taking regular antipsychotics was 4.1 months (range: 7 dayse11 months); 16 (57.1%) remained free of regular antipsychotics for 3 months or more, and 12 (42.9%) were represcribed a lower dose than their initial dose of antipsychotics. Overall, there was a significant reduction in antipsychotic use after intervention: 81.7% (95% CI: 72.4-89.0) of participants (n ¼ 76/93) had their regular antipsychotics deprescribed at 12 months. Secondary Outcomes Substitution: PRN antipsychotics and sedatives Approximately 1 in 5 participants was prescribed a PRN antipsychotic prior to baseline (Supplemental Table 2). PRN antipsychotic administration was infrequent and occurred at a low dose. They were administered to only 5 participants after ceasing regular medication, 3 of whom received less than 2.5 mg olanzapine (or equivalent) on average monthly. Linear mixed model analysis of the data across the entire sample (n ¼ 139) showed there was no significant increase in PRN antipsychotic prescribing (b ¼ 0.3 mg/mo, P ¼ .33, 97.5% CI: 1.0 to 0.4, t ¼ 0.98, df ¼ 474) or administration (b ¼ 0.9 mg/mo, P ¼ .31, 97.5% CI: 3.0 to 1.1, t ¼ 1.03, df ¼ 110) on deprescribing of regular antipsychotics (Supplemental Figure 3). We checked whether the deprescribed regular antipsychotic medication was substituted with other psychotropic medications such as benzodiazepines. There was no increase in regular benzodiazepine use, but more participants were administered a PRN benzodiazepine, particularly lorazepam and oxazepam (Supplemental Table 3). The proportion of participants administered PRN benzodiazepines increased from 11.0% and 8.2% at prebaseline and baseline, respectively, to 23.1%, 25.4%, and 29.8% at 3, 6, and 12 months, respectively. However, PRN benzodiazepine administration occurred for less than a third of participants at any time point, and most received 10 mg diazepam equivalents on average per month or 0.3 mg/d (Supplemental Figure 4A). Moreover, this increase in benzodiazepine use was independent of regular antipsychotic deprescribing (b ¼ 0.47 mg/ mo, P ¼ .528, 95% CI: 0.99 to 1.92; t ¼ 0.63, df ¼ 396; Supplemental Figure 3). In other words, although PRN use of benzodiazepine increased throughout the study, this increase was very low and not linked to deprescription of regular antipsychotic medication. Antidepressant use remained stable throughout the entire study period (Supplemental Figure 4B). BPSD Participants in our sample showed no significant behavioral changes over the study period (Figure 3). There was no significant change in total NPI-NH score on deprescription (b ¼ 1.0 point; ie, total NPI score was 1 point lower when not on regular antipsychotics, P ¼ .58, 97.5% CI: 5.03 to 3.02, t ¼ 0.56, df ¼ 450; Figure 3A and Supplemental Figure 3). Agitation/aggression, as measured by total CMAI score, did not increase with deprescribing (b ¼ 1.7 point, ie, total CMAI was 1.7 points lower when not on regular antipsychotics, P ¼ .37, 97.5% CI: 5.77 to 2.47, t ¼ 0.90, df ¼ 435; Figure 3B and Supplemental Figure 3). Specific behaviors were analyzed based on individual NPI-NH domain scores (Supplemental Figure 5), but
antipsychotic deprescribing was not significantly associated with changes in any domain after correcting for multiple testing. There was no significant interaction effect between deprescribing and the administration of PRN antipsychotic or benzodiazepine medication on either NPI or CMAI total scores (data not shown). Social engagement We used the Multidimensional Observation Scale for Elderly Subjects to verify whether our deprescribing intervention reduced social withdrawal, but found no significant change (Figure 3C; b ¼ 0.27, ie, the Multidimensional Observation Scale for Elderly Subjects score was 0.27 points higher when not regular antipsychotics, P ¼ .52, 97.5% CI: 0.67 to 1.22, t ¼ 0.65, df ¼ 379; Supplemental Figure 3). There were strong floor effects on cognitive scores (Figure 3C), but there was no significant improvement in cognition associated with deprescribing [b ¼ 0.22, ie, (converted) PAS score was 0.22 points higher when not on regular antipsychotics, P ¼ .56, 97.5% CI: 0.67 to 1.12, t ¼ 0.56, df ¼ 245; Supplemental Figure 3]. Adverse outcomes Falls and hospitalizations were analyzed for the 6-month periods prior to the intervention (when participants were on regular antipsychotics) and at the end of the study (when most were either withdrawn or prescribed a lower dose of antipsychotics). When considering only participants who were mobile, 54.2% fell at least once in the 6 months prior to study enrolment (n ¼ 39/72 mobile participants; who fell 3.5 times on average, SD: 3.2, range: 1-12). This was not significantly different from the final 6 months of the study, when 44.7% fell at least once (n ¼ 22/47 mobile participants; who fell 3.2 times on average, SD: 3.1, range: 1-13; Figure 3E). There was no difference in attrition between mobile and immobile participants (Fisher exact test: P ¼ .45). Accordingly, there were no differences in falls pre- and postintervention for the mobile participants who completed the study and whose antipsychotics were deprescribed (56.3% prior to intervention vs 42.4% after; P ¼ .32). For hospitalizations, the proportion of participants hospitalized was 18.0% at preintervention (n ¼ 25, mean: 1.1 hospitalization, SD: 0.4, range: 1-3) and 12.9% (n ¼ 12, mean: 1.4, SD: 0.7, range: 1-3) post intervention, a nonsignificant decrease (Figure 3F). Among participants who completed the study and were successfully deprescribed, 18.8% were hospitalized at least once in the period before the intervention, compared to 8.8% at the end of the study; this decrease was not statistically significant (P ¼ .14). Baseline hospitalization rate was not linked to attrition (P ¼ .16). Discussion The Halting Antipsychotic use in Long-Term care (HALT) study demonstrated successful and sustainable reduction of antipsychotic use in a sample of older adults residing in LTC who were recruited by nursing staff, without an associated rise in BPSD (Figure 3A, B). Withdrawal was not accompanied by an increase in substitute regular or PRN antipsychotics. Although PRN benzodiazepines were prescribed for more participants, they were administered for a minority of participants, infrequently, at very low doses (<0.3 mg/d in diazepam equivalents), and independent of antipsychotic withdrawal (Supplemental Figure 4). There was no significant improvement in adverse outcomes, such as withdrawn behaviors, falls, hospitalizations, and cognitive decline. Four in 5 participants had their regular antipsychotic successfully deprescribed compared to about 1 in 5 in other studies.17,31 Although this high success rate may partially be driven by residence and resident selection (see limitations below), it is also in line with previous findings that active engagement of all involved stakeholders, as in this study, is linked to greater success.32 In contrast to most other studies,
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our intervention involved multiple components. Providing additional skills to nurses by nurses (via a train-the-trainer approach), to pharmacists by pharmacists, and to GPs by an academic GP was a truly multidisciplinary approach. Good leadership and focused training providing clear practical directions on pharmacologic and nonpharmacologic approaches for the prevention and management of BPSD. We hypothesize that the application of best practice principles of deprescribing in a clear, individualized way, which held both nursing staff and GPs accountable to enact within a specific time frame, was a key factor in the success of HALT. The use of PRN benzodiazepines increased slightly (most likely as a consequence of the HALT protocol allowing inclusion of a PRN prescription of oxazepam or lorazepam, if deemed necessary), but this increase was small in terms, <0.3 mg/d in diazepam equivalents, and independent of antipsychotic withdrawal. Participants who did or did not have their antipsychotics successfully deprescribed showed few differences at baseline (Table 1), and there were no significant effects on any of the secondary outcome measures on antipsychotic withdrawal. Interestingly, depression scores at baseline were significantly higher in the group that had their antipsychotic medication successfully deprescribed. This suggests that antipsychotics may have been administered, perhaps unsuccessfully, as an add-on to antidepressant medication (antidepressant medication use remained stable throughout the entire study). Overall, there was a large variation in BPSD over time and between participants. We found no relationship between use of antipsychotics and severity of BPSD over 12 months’ follow-up (Supplemental Figure 3). Devanand et al reported increased BPSD on antipsychotic withdrawal for AD patients who had previously responded to risperidone for agitation or psychosis treatment.20 Sampling differences could explain the differing outcomes, as we have no knowledge of the appropriateness of the original prescription or the treatment response for our sample. There was no statistically significant decrease in adverse events. The lack of improvement could have reflected the natural history of these outcomes over time (see limitations). Cognitive assessment was limited by floor effects, reduced power due to frequent lack of interpreters (31.7% of participants did not have English as a preferred language), and lack of assessment of specific cognitive domains. Our study was powered to measure decline in antipsychotic prescription rates (primary outcome), but was insufficiently powered for small effect sizes in secondary outcomes. Noninferiority analysis did indicate there was no increase in BPSD. A larger sample and more sensitive assessment measures, ideally in a randomized controlled trial, might confirm the beneficial effects found in earlier studies.33,34 The success of HALT should be interpreted with consideration of a number of limitations. First, in a single-arm trial it is difficult to tease out whether any of the observed changes are due to the intervention or another time-dependent change in the outcome. For example, as dementia severity increases, cognition and BPSD change over time (eg, aggression declines and apathy increases), which may mask positive effects of deprescribing. We attempted to control for time-dependent changes by including 2 preintervention assessments 1 month apart that did not demonstrate variability albeit over a limited time period (see Figure 2). Also, we cannot ascertain whether the antipsychotic was never or no longer indicated, or if other (nonspecific) aspects of the intervention, such as greater care and vigilance, obviated their need. Second, in common with most antipsychotic deprescribing interventions,21 HALT had multiple components, including multidisciplinary education and medication review. This precludes identification of component(s) or professional group(s) that were instrumental in achieving such a high rate of deprescribing. On the other hand, this multipronged strategy is a strength, and possibly the essential factor for sustainable reduction of antipsychotic use.34
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A third limitation lies in nonrandom recruitment of nursing homes, of which 24/58 agreed to join the study (and one subsequently withdrew), and residents. Because of an ethical requirement for armslength recruitment, nurse champions were relied on to identify residents. Although they were instructed to approach families of every resident who met eligibility criteria, selective recruitment of participants who were stable and perceived to no longer need the medication is possible. We expected that a much larger proportion of residents from participating nursing homes would have been prescribed antipsychotic medication. Because we do not have access to this information, it is difficult to assess the representativeness of our sample. Based on the literature, we can estimate to have recruited between 15% and 20% of all potentially eligible residents in the participating nursing homes. Fourth, a third of our sample dropped out, most commonly because of death. Some outcomes may be skewed because of the loss of primarily older participants at more advanced stages of dementia (Table 1). However, our sensitivity analysis, conservatively allowing that all noncompleters would have been represcribed regular antipsychotics, shows that we would still achieve a high success rate (50% reduction in participants taking antipsychotics). We reiterate that there was no significant difference in attrition between participants whose antipsychotic medication was deprescribed or not. Fifth, neither staff nor assessors were blind to previous and current medication administration. Because we did not find significant differences in any of our secondary outcomes, reporting bias is unlikely to have affected our conclusions. Overall, our results highlight the feasibility and safety of withdrawing antipsychotics for at least a subgroup of people with dementia in LTC without (re)emergence of BPSD. Accepting the potential for selection bias, the results of this study suggest that many people with dementia in LTC who currently use antipsychotic medication stand to benefit from more active review practices. Further analysis might provide more insight into differences between groups who were represcribed antipsychotics and those who were not. In addition, qualitative data collected from participants, care staff and GPs will be used to explored the context of antipsychotic (re) prescribing. Even though health care policy and guidelines advise against antipsychotic use in people with dementia, our findings demonstrate that implementation of correct review and withdrawal practices is currently lacking in LTC nursing homes. Anecdotal information from the revocations for this study further reinforce that a conservative approach to care, rather than actual symptom management, may underlie the continued prescription of antipsychotic medication in older nursing home residents. Further research should focus on the specific strengths of the different components of the multifaceted intervention implemented in this study. A comprehensive strategy involving all stakeholders in the care process likely improves its success rate, but cost and feasibility are important limitations for its application in routine practice. Previous studies have demonstrated the cost-effectiveness of implementing training in person-centered dementia care.35 The results of this trial should encourage antipsychotic withdrawal in people with dementia living in LTC, following existing guidelines, and the implemented measures could serve as a blueprint for wider integration into dementia care practices. Acknowledgments We thank all participating residents, their families, GPs, pharmacists, and nursing staff. We thank the members of the steering committee, Jacqui Close, Juanita Westbury, Lee-Fay Low, Aine Heaney, Marie Alford, Stacy Wake, Janet Mitchell, Millie Marinkovich, and Jenny Blennerhassett. Linda Nattrass, Anne-Nicole Casey, Emily Trigge,
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and Tiffany Chau are thanked for their assistance with administration and data entry. References 1. Brodaty H, Draper B, Saab D, et al. Psychosis, depression and behavioural disturbances in Sydney nursing home residents: prevalence and predictors. Int J Geriatr Psychiatry 2001;16:504e512. 2. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. J Clin Psychiatry 1999;60:107e115. 3. Ballard C, Corbett A, Chitramohan R, Aarsland D. Management of agitation and aggression associated with Alzheimerʼs disease: controversies and possible solutions. Curr Opin Psychiatry 2009;22:532e540. 4. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934e1943. 5. Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: Meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 2006;14:191e210. 6. Rochon PA, Normand S-L, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med 2008;168:1090e1096. 7. Vigen CLP, Mack WJ, Keefe RSE, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: Outcomes from CATIE-AD. Am J Psychiatry 2011;168:831e839. 8. Declercq T, Petrovic M, Azermai M, et al. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. In: Declercq T, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2013. p. CD007726. 9. Gallini A, Andrieu S, Donohue JM, et al. Trends in use of antipsychotics in elderly patients with dementia: Impact of national safety warnings. Eur Neuropsychopharmacol 2014;24:95e104. 10. Briesacher BA, Tjia J, Field T, et al. Antipsychotic use among nursing home residents. JAMA 2013;309:440. 11. Stock KJ, Amuah JE, Lapane KL, et al. Prevalence of, and resident and facility characteristics associated with, antipsychotic use in assisted living vs. longterm care facilities: A cross-sectional analysis from Alberta. Canada. Drugs Aging 2017;34:39e53. 12. Janus SIM, van Manen JG, IJzerman MJ, Zuidema SU. Psychotropic drug prescriptions in Western European nursing homes. Int Psychogeriatr 2016;28: 1775e1790. 13. Snowdon J, Galanos D, Vaswani D. Patterns of psychotropic medication use in nursing homes: Surveys in Sydney, allowing comparisons over time and between countries. Int Psychogeriatr 2011;23:1520e1525. 14. Ballard C, Hanney ML, Theodoulou M, et al. DART-AD Investigators. The Dementia Antipsychotic Withdrawal Trial (DART-AD): Long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol 2009;8:151e157. 15. Royal Australian and New Zealand College of Psychiatrists. The Use of Antipsychotics in Residential Aged Care. Clinical Recommendations; 2011. 16. Ballard C, Lana MM, Theodoulou M, et al. A randomised, blinded, placebocontrolled trial in dementia patients continuing or stopping neuroleptics (The DART-AD Trial). PLoS Med 2008;5:0587e0599. 17. Fossey J, Ballard C, Juszczak E, et al. Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: Cluster randomised trial. BMJ 2006;332:756e761.
18. van Reekum R, Clarke D, Conn D, et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Int Psychogeriatr 2002;14:197e210. 19. Ruths S, Straand J, Nygaard HA, et al. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: A randomized, placebo-controlled, double-blinded study the Bergen District Nursing Home Study. J Am Geriatr Soc 2004;52:1737e1743. 20. Devanand DP, Mintzer J, Schultz SK, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s disease. N Engl J Med 2012;367:1497e1507. 21. Thompson Coon J, Abbott R, Rogers M, et al. Interventions to reduce inappropriate prescribing of antipsychotic medications in people with dementia resident in care homes: A systematic review. J Am Med Dir Assoc 2014;15: 706e718. 22. Jessop T, Harrison F, Cations M, et al. Halting Antipsychotic Use in Long-Term care (HALT): A single-arm longitudinal study aiming to reduce inappropriate antipsychotic use in long-term care residents with behavioral and psychological symptoms of dementia. Int Psychogeriatr; 2017:1e13. 23. Australian Department of Health. Dementia and Severe Behaviours Supplement. Canberra, AU: Australian Government; 2013. 24. Jorm A, Mackinnon AJ, Henderson AS, et al. The Psychogeriatric Assessment Scales: A multi-dimensional alternative to categorical diagnoses of dementia and depression in the elderly. Psychol Med 1995;25:447e460. 25. The Royal Australian & New Zealand College of Pyschiatrists. Assessment and Management of People with Behavioural and Psychological Symptoms of Dementia (BPSD)dA Handbook for NSW Health Clinicians; 2013. 26. Mandrekar JN. Measures of interrater agreement. J Thorac Oncol 2011;6:6e7. 27. Wood S, Cummings JL, Hsu MA, et al. The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 2000;8:75e83. 28. Cohen-Mansfield J, Billig N. Agitated behaviors in the elderly. I. A conceptual review. J Am Geriatr Soc 1986;34:711e721. 29. Pruchno RA, Kleban MH, Resch NL. Psychometric assessment of the Multidimensional Observation Scale for Elderly Subjects (MOSES). J Gerontol 1988;43: P164eP169. 30. Storey JE, Rowland JTJ, Basic D, et al. The Rowland Universal Dementia Assessment Scale (RUDAS): A multicultural cognitive assessment scale. Int Psychogeriatr 2004;16:13e31. 31. Patterson SM, Hughes CM, Crealey G, et al. An evaluation of an adapted U.S. model of pharmaceutical care to improve psychoactive prescribing for nursing home residents in Northern Ireland (Fleetwood Northern Ireland Study). J Am Geriatr Soc 2010;58:44e53. 32. Lawrence V, Fossey J, Ballard C, et al. Improving quality of life for people with dementia in care homes: Making psychosocial interventions work. Br J Psychiatry 2012;201:344e351. 33. Declercq T, Petrovic M, Azermai M, et al. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev 2013;3:1e80. 34. Ballard C, Orrell M, Psych FRC, et al. Impact of antipsychotic review and nonpharmacological intervention on antipsychotic use, neuropsychiatric symptoms, and mortality in people with dementia living in nursing homes: A factorial cluster-randomized controlled trial by the Well-Being and Health for People With Dementia (WHELD) Program. Am J Psychiatry 2016;173: 252e262. 35. Chenoweth L, King MT, Jeon YH, et al. Caring for Aged Dementia Care Resident Study (CADRES) of person-centred care, dementia-care mapping, and usual care in dementia: A cluster-randomised trial. Lancet Neurol 2009;8: 317e325.
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Appendix
Supplemental Table 1 Equivalents for Antipsychotic Medications and Benzodiazepines1e4 Antipsychotics (Eq to 1 mg Olanzapine)
Benzodiazepines (Eq to 10 mg Diazepam)
Haloperidol Risperidone Quetiapine
Alprazolam Clobazam Clonazepam Lorazepam Midazolam Nitrazepam Oxazepam Temazepam Triazolam
0.533 mg 0.267 mg 20 mg
0.75 mg 15 mg 0.5 mg 1.5 mg 8.75 mg 10 mg 30 mg 20 mg 0.5 mg
Supplemental Table 2 PRN Antipsychotic Prescriptions and Administrations Olanzapine Equivalents
Prescribed
None
0 < x ≤ 2.5 mg
2.5 < x ≤ 5 mg
> 7.5 mg
Administered
N/A None 0 < x ≤ 2.5 mg
2.5 < x ≤ 5 mg
> 7.5 mg
Unknownc
Preintervention, n (%)
Postintervention, n (%)
Prebaseline (n ¼ 139)
Baseline (n ¼ 136)
3 mo (n ¼ 124)
6 mo (n ¼ 110)
12 mo (n ¼ 93)
105 (75.5)
104 (76.5)
98 (79.0)
94 (85.5)
74 (79.6)
28 (20.1)
26 (19.1)
23 (18.5)
12 (10.9)
14 (15.1)
4 (2.9)
5 (3.7)
1 (0.8)
2 (1.8)
4 (4.3)
0
0
0
0
0
2 (1.4)
1 (0.7)
2 (1.6)
2 (1.8)
1 (1.4)
103 (74.1)*
103 (75.7)y
98 (79.0)
93 (84.5)y
73 (78.5)y
18 (12.9)
25 (18.4)
18 (14.5)
10 (9.1)
7 (5.0)
4 (2.9)
5 (4.0) [1 no reg AP]
0
8 (8.6) [3 no reg AP]
5 (3.6)
1 (0.7)
3 (2.4) [1 no reg AP]
2 (1.8)
3 (3.2) [1 no reg AP]
0
0
0
3 (2.2)
2 (1.5)
0
3 (2.2)
1 (0.7)
3 (2.7) [2 no reg AP]
1 (0.9)
9 (9.7)
0
0
1 (0.9)
Note: Time frame for administration: amount of olanzapine (in milligrams) administered in one month [monthly average over last 3 months (for prebaseline) or in the time period since the previous assessment (for all other assessments)]. [“X” no reg AP] ¼ individuals who were not prescribed regular antipsychotic medication at the current time of assessment. *Three participants were administered PRN antipsychotics even though not prescribed. y One person was administered PRN antipsychotics even though not prescribed.
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Supplemental Table 3 Benzodiazepine Use: Participants on Regular and PRN Benzodiazepines (and Frequency of PRN Administration) Preintervention, n (%)
Regular Diazepam Lorazepam Oxazepam Temazepam PRN administered Diazepam
Postintervention, n (%)
Prebaseline (n ¼ 139)
Baseline (n ¼ 136)
3 mo (n ¼ 124)
6 mo (n ¼ 110)
12 mo (n ¼ 93)
1 1 3 21
1 1 3 19
1 1 6 17
0 1 (0.9) 2 (1.8) 17 (15.5)
1 2 3 16
2 (1.8) 1 < monthly 1 < weekly 5 (4.5) 3 < monthly 1 < weekly 1 once/week 16 (14.5) 5 < monthly 6 < weekly 5 once/week 8 (7.3) 4 < monthly 1 < weekly 3 once/week
3 (3.2) All < weekly
(0.7) (0.7) (2.2) (15.1)
(0.7) (0.7) (2.2) (14.0)
3 (2.2) 2 < weekly 1 once/week 1 (0.7) < monthly
2 (1.5) 1 < monthly 1 once/week 1 (0.7) < weekly
Oxazepam
1 (0.7) < monthly
1 (0.7) < weekly
Temazepam
9 (6.5) 6 monthly 3 once/week
7 (5.1) 2 < monthly 2 < weekly 3 once/week
Lorazepam
(0.8) (0.8) (4.8) (13.7)
3 (2.4) All monthly 4 (3.2) All < monthly
17 (13.7) 6 < monthly 3 < weekly 8 once/week 8 (6.5) 3 < monthly 4 < weekly 1 once/week
(1.1) (2.2) (3.2) (17.2)
5 (5.4) 1 < monthly 3 < weekly 1 once/week 13 (14.0) 6 < monthly 4 < weekly 2 once/week 9 (9.7) 3 < monthly 6 < weekly
Other sedatives such as midazolam, nitrazepam, triazolam, clobazam, clonazepam, and melatonin were administered to less than 2% of the sample population at any time point (and there were no significant differences across the different timepoints). These data are not included in the table.
Supplemental. Fig. 1. Time profile of participants’ de- and represcription. Time from baseline to complete cessation of all regular antipsychotic medication (solid line; % of total n ¼ 133, ie, all participants with postbaseline data; see text for details) and the time between baseline and (first) represcription of a regular antipsychotic (dashed line, % of total n ¼ 126 participants who had ceased after intervention).
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Supplemental Fig. 2. Example of participant deprescribing protocol.
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Supplemental Fig. 3. Sample confidence intervals and inference for trials assessing superiority or noninferiority of regular antipsychotic prescription and deprescription. Prespecified noninferiority d0 s for deprescription of regular antipsychotics are as follows: for PRN medication prescription (olanzapine or diazepam equivalents for antipsychotics and benzodiazepines, respectively), 5 mg/mo; for NPI-NH total score, 4 points; and for CMAI total score, 6 points. Confidence intervals indicated are 97.5% to correct for multiple testing, except for benzodiazepine PRN administration, which is 95%. Antipsychotic withdrawal was not inferior to regular antipsychotic administration in terms of PRN administration of antipsychotics or benzodiazepines, or in terms of NPI-NH and CMAI total scores. There was no significant change in MOSES withdrawn behavior or PAS-CIS total scores on withdrawal.
Supplemental Fig. 4. Substitution: (A) PRN benzodiazepine administration, expressed in terms of diazepam equivalents; (B) antidepressant use.
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Supplemental Fig. 5. NPI domain scores. Domain scores (severity by frequency score) for the NPI-NH at 5 assessments. Blue lines and error bars indicate median and interquartile range, respectively.
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Supplemental Fig. 5. continued
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Supplemental Fig. 6. Sankey diagram of regular antipsychotic prescription patterns and attrition. Participant flow in terms of participant inclusion for intervention and at 12month follow-up is indicated and patterns of de- and represcription of regular antipsychotic medication are indicated (irrespective of at which time point during the study deor represcription occurred).
Supplemental References 1. Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose equivalents for second-generation antipsychotics: The minimum effective dose method. Schizophr Bull 2014;40:314e326. 2. Cooper AJ. Benzodiazepines: towards more logical use. Scott Med J 1982;27:297e304.
3. Goodman LS, Gilman A, Brunton LL. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. New York: McGraw-Hill Medical; 2008. 4. Ruiz P, Strain EC, Lowinson JH. Lowinson and Ruiz’s Substance Abuse: A Comprehensive Textbook. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.