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Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis
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European Neuropsychopharmacology (2018) 000, 1–11
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Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis Marc Krause a,c,∗, Maximilian Huhn a, Johannes Schneider-Thoma a, Philipp Rothe a, Robert C Smith b, Stefan Leucht a a
Department of Psychiatry and Psychotherapy, Technical University of Munich, Klinikum rechts der Isar, Ismaningerstraße 22, 81675 Munich, Germany b New York University Medical School, Department Of Psychiatry, and Nathan Kline Institute for Psychiatric Research, New York, USA c Ludwig-Maximilians Universität München, Germany Received 17 May 2018; accepted 5 September 2018 Available online xxx
KEYWORDS Elderly; Schizophrenia; Antipsychotics; Meta-analysis
Abstract Elderly patients with schizophrenia are a particularly vulnerable group often excluded from clinical trials. Currently there is no evidence-synthesis about the efficacy and safety of antipsychotics in this subgroup. We reviewed all randomized-controlled-trials, about antipsychotics in elderly schizophrenics (last search Dec 12, 2017). Pairwise meta-analyses were conducted. The primary outcome was overall symptoms. Secondary outcomes included positive symptoms, negative symptoms, response, dropouts, quality of life, social functioning and side-effects. We included 29 references from 18 unique randomized-controlled-trials with 1225 participants published from 1958 to 2009. The definition of “elderly” was very heterogeneous across the studies (minimum age 46–65, mean age 57–73). There were evidence gaps for most drugs in many outcomes. In terms of efficacy paliperidone was associated with fewer dropouts due to inefficacy than placebo in the only placebo-controlled-trial. Olanzapine was superior to haloperidol in overall symptoms, negative symptoms and response, and it was associated with fewer dropouts than risperidone. Risperidone and haloperidol produced more prolactin increase than olanzapine, and olanzapine was associated with less use of antiparkinson medication than haloperidol.
∗ Corresponding author at: Department of Psychiatry and Psychotherapy, Technical University of Munich. Klinikum rechts der Isar, Ismaningerstraße 22, 81675 Munich, Germany. E-mail address: [email protected] (M. Krause). https://doi.org/10.1016/j.euroneuro.2018.09.007 0924-977X/© 2018 Elsevier B.V. and ECNP. All rights reserved.
Please cite this article as: M. Krause et al., Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.09.007
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M. Krause et al. Although we found no marked differences of the effects of these drugs in the elderly, the evidence presented was based on very few usually small studies. To examine specifically whether there are differences in efficacy and side-effects in elderly, which differs in meaningful ways from the general population, studies in patients who are defined by critiera as truly geriatric, which incorporates older age together with multimorbidity and fraility dimensions, may be more informative. © 2018 Elsevier B.V. and ECNP. All rights reserved.
1.
Introduction
Aging is a global trend, according to studies by the United Nations Population Department (United Nations, Department of Economic and Social Affairs, Population Division, 2015), and demographic trends show an increase in the old and very old in many countries. The life morbidity risk for schizophrenia is approximately 1% (mean/median 11/7 per 1000), the median point prevalence per 1000 is 4.6 (10, 90 percent quantiles 1.9, 10.0), and the median yearly incidence per 100.000 is 15.2 (10, 90 percent quantiles 7.7, 43.0) (McGrath et al., 2008). Schizophrenia first appears in adolescence but continues throughout the life cycle. The life-time prevalence of schizophrenia in old age fluctuates between 0.5 and 1% (Andreas et al., 2017). Treatment with antipsychotic drugs is the primary therapy for patients with schizophrenia (Leucht et al., 2012) and they are widely used in older patients (Colenda et al., 2002). However, the efficacy and sideeffects of antipsychotic drugs for treatment of schizophrenia in older patients has not been systematically evaluated. Side-effects of antipsychotic drugs which can include weight gain, glucose-lipid abnormalities and hormonal changes can be especially important because they can increase cardiovascular and other risk factors which are more important in the elderly population. A systematic evaluation is important to provide a database to facilitate evidence-based decisions for selecting the best individual treatment for elderly patients with schizophrenia. However most of the clinical studies have excluded these patients, because their inclusion criteria were often restricted to patients up to an age of sixty-five years. This also applies to systematic reviews and meta-analyses, which deliberately exclude the few available studies that examine the subgroup of the old patients with schizophrenia (Leucht et al., 2013). Although older schizophrenics are often treated with antipsychotics, the available evidence is insufficient to provide data on which evidencebased clinical recommendations can be made. There is only one Cochrane Review about the antipsychotic treatment of patients with late onset schizophrenia, but nothing about elderly patients with schizophrenia in general, independent of the age of onset (Essali and Ali, 2012). However, the elderly may be more sensitive to antipsychotic drug side effects and may be less responsive to antipsychotic treatment in some conditions. This background provides a rationale for doing a separate meta-analysis of the efficacy and sideeffects of antipsychotics in the elderly. We, therefore, conducted a systematic review and meta-analysis on the effects of antipsychotics in elderly patients with schizophrenia. The aims were to determine which antipsychotics are more ef-
ficacious than placebo, and whether there are differences between specific antipsychotics in efficacy and side-effects.
2.
Methods
An a priori written study protocol was registered at PROSPERO under the registration number: CRD42016052060.
2.1.
Participants and interventions
We included all randomized controlled trials (RCTs) in elderly patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder (as defined by any diagnostic criteria). The interventions were 34 antipsychotic drugs which comprised all second-generation antipsychotics available in the US and/or Europe, and a selection of first-generation antipsychotics, licensed in at least one country, which were considered important based on a survey of international schizophrenia experts (Leucht et al., 2016) (amisulpride, aripiprazole, asenapine, benperidol, brexpiprazole, cariprazine, chlorpromazine, clopenthixol, clozapine, flupenthixol, fluphenazine, fluspirilene, haloperidol, iloperidone, levomepromazine, loxapine, lurasidone, molindone, olanzapine, paliperidone, penfluridol, perazine, perphenazine, pimozide, quetiapine, risperidone, sertindole, sulpiride, thioridazine, thiothixene, trifluoperazine, ziprasidone, zotepine, zuclopenthixol). We included these drugs at any dose and in any form of administration when compared with another antipsychotic or placebo, and used as monotherapy. Drugs that failed to obtain FDA/EMA approval or which had not yet been licensed were not considered.
2.2.
Search strategy and selection criteria
We conducted a comprehensive, systematic literature search in MEDLINE, EMBASE, PsycINFO, Cochrane Library, PubMed, Biosis, and ClinicalTrials.gov up to Nov 17, 2016 (eAppendix 2 in the Supplement) and a final PubMed search until Dec 12, 2017. The search terms included the generic names of 34 antipsychotics listed above. The minimum duration of the RCTs was set at three weeks. We also inspected the reference lists of the included studies and of previous systematic reviews (Fusar-Poli et al., 2015; Leucht et al., 2002) and a narrative review (Remington et al., 2016). Citations were screened independently by at least two reviewers (MK, MH, YZ) at both the title/abstract and fulltext stages. In the case of crossover studies, we only used
Please cite this article as: M. Krause et al., Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.09.007
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Antipsychotic drugs for elderly patients with schizophrenia the first crossover phase to avoid the problem of carryover effects (Elbourne et al., 2002). We excluded clusterrandomized trials (Divine et al., 1992). Studies that demonstrated a high risk of bias for sequence generation or allocation concealment were excluded (Higgins, 2011). If a trial was described as double-blind but randomization was not explicitly mentioned, we assumed that study participants were randomized, but we excluded the trial in a sensitivity analysis. We excluded studies from mainland China to avoid a systematic bias because many of these studies do not use appropriate randomization procedures, do not report their methods, and have been reported to often be not reliable (Bian et al., 2006; Wu et al., 2009).
2.3.
Outcome measures and data extraction
The primary outcome was the mean change from baseline to endpoint in overall symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987), the Brief Psychiatric Rating Scale (Overall, 1962), or any other validated scale for the overall assessment of schizophrenia symptoms, especially adapted versions of BPRS and PANSS for elderly. If change data were not available, we used the mean score at study end point of these scales. Intention-to-treat data sets were used whenever available. Secondary outcomes were clinically important responses to treatment defined by the authors, the mean change in positive, negative and depressive symptoms of schizophrenia, dropouts owing to any reason (all-cause discontinuation), dropouts owing to inefficacy of treatment and due to adverse events, the occurrence of important adverse effects (weight gain, at least one extrapyramidal symptom, sedation, akathisia, prolactin prolongation), antiparkinsonian medication used at least once as a proxy for extrapyramidal symptoms, quality of life, and social functioning. We used the Cochrane Collaboration’s risk-of-bias tool for the assessment of potential bias in terms of randomization, allocation concealment, blinding, missing outcomes, selective reporting and other biases (Higgins, 2011). Data extraction and assessment of study quality were performed independently by at least two reviewers (MK, MH, JS, PR, HR, SB, LB, MS, TA, LR and NP). Disagreement was resolved by discussion. If disagreement could not be resolved, we discussed with the team leader (SL). We sent emails to the first and corresponding authors of all included studies to request missing data. Missing SDs were estimated from test statistics or substituted by the mean SD of the other included studies using the same scale (Furukawa et al., 2006)
2.4.
3 dardized mean differences (SMDs) according to Hedges’s g (Cohen, 2013). For binary outcomes, the effect sizes were calculated as odds ratios (ORs) according to Mantel– Haenszel. Both types of effect sizes were presented along with their 95% confidence intervals (CIs). We applied the random-effects model by DerSimonian and Laird (1986) to all outcomes. Heterogeneity was assessed with the I² statistic (Higgins, 2011) and a chi²-square test for homogeneity. Small trial effects were explored by funnel-plots if at least ten studies were available (Higgins, 2011). As the method is based on symmetry, funnel-plots based on fewer trials are not meaningful (Higgins, 2011). P-values lower than 0.05 were considered to be statistically significant.
3. 3.1.
Results Description of included studies
We identified 29 references from 18 unique RCTs with 1225 unique participants published from 1958 to 2009. The PRISMA flowchart is shown in Fig. 2. Details of all included studies are presented in Table 1. Of 718 patients for whom gender was indicated, 445 were women (62%). The mean age of participants was 66.09 years (range 56.9–72.2 years). The median trial duration was 10 weeks (range 3–72 weeks). The assessment for risk of bias is presented in eAppendix 4 in the Supplement. Nearly all included studies reported insufficient information concerning random sequence generation (17 of 18 studies) and allocation concealment (17 of 18 studies). The blinding of patients and personnel showed a high risk of bias in five studies and low risk in 3 studies. The risk of bias for blinding of outcome assessment was similar with 4 studies at low risk and 3 at high risk. The number of studies with high risk of bias for missing outcomes and selective reporting were 5 and 6 respectively, and in both categories six studies showed low risk of bias. Fig. 1 shows the network of eligible comparisons for the primary outcome. The identified studies included the drugs amisulpride, carphenazine, chlorpromazine, clozapine, fluphenazine, haloperidol, olanzapine, paliperidone, placebo, quetiapine, risperidone, thioridazine, trifluoperazine. Two studies reported combined treatment groups (typical neuroleptic, conventional). The drug involved in most comparisons was risperidone (9 of 18 trials) followed by haloperidol (7 of 18 trials) olanzapine (6 of 18 trials) and clozapine (3 of 18 trials), whereas just single trials were available for other drugs: amisulpride, carphenazine, chlorpromazine, fluphenazine, paliperidone, placebo, quetiapine, thioridazine, trifluoperazine, typical neuroleptic/conventional.
Statistical analysis
We originally planned to conduct a network meta-analysis. However, the network plot was very poorly connected as there were only a few eligible studies (see Fig. 1). Also, there were neither triangular nor quadratic loops of direct comparisons. Therefore, we decided to calculate pairwise, random-effects meta-analyses using Review Manager 5.3. This decision had been foreseen in our protocol. For continuous outcomes, the effect sizes were calculated as stan-
3.2.
Overall symptoms
Nine studies reported usable outcome data for mean change in overall symptoms (see Fig. 3). There was only one placebo controlled study which showed no significant difference compared to paliperidone (N = 1, SMD −0.32, CI −0.71–0.08). Concerning head-tohead comparisons between different antipsychotics, only
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Fig. 1 Plot of direct comparisons – overall symptoms. The figure shows the direct comparisons of included studies. The thickness of the line corresponds to the inverse variance of the direct comparisons The size of the nodes corresponds to the number of trials that study the treatments.
olanzapine was significantly superior compared to haloperidol (N = 2, SMD 0.47, CI 0.10–0.84). There were no significant differences between amisulpride and risperidone (N = 1, SMD, −0.03, CI −0.90–0.84], chlorpromazine and clozapine (N = 1, SMD, 0.15, CI −0.58–0.88), olanzapine and risperidone (N = 3, SMD −0.51, CI −1.32–0.30] nor between quetiapine and risperidone (N = 1, SMD, 0.16, CI −0.29– 0.60).
3.3.
Response (authors’ definition)
Five studies reported usable outcome data for the outcome response (see eFig. 4). Concerning head-to-head comparisons between different antipsychotics, only olanzapine was significantly superior compared to haloperidol (N = 1 OR 2.63, CI 1.04–6.69). There were no significant differences between amisulpride and risperidone (N = 1 OR 0.94, CI 0.24–3.71), olanzapine and risperidone (N = 2 OR 0.59, CI 0.14–2.46) nor between quetiapine and risperidone (N = 1, OR 0.38, CI 0.13–1.06).
3.4.
Positive symptoms
Six studies reported usable outcome data for mean change of positive symptoms (see eFig. 3). There was no placebocontrolled trial which reported usable outcome data for positive symptoms. Concerning head-to-head comparisons between different antipsychotics, there were no significant differences between amisulpride and risperidone (N = 1, SMD 0.60, CI −0.29–1.49), chlorpromazine and clozapine (N = 1, SMD 0.09, CI −0.64–0.82), haloperidol and olanzapine (N = 2, SMD 0.10 CI −0.26–0.47) nor between olanzapine and risperidone (N = 2 SMD −0.11, CI −0.38–0.16].
3.5.
Negative symptoms
Seven studies reported usable outcome data for mean change of negative symptoms (see eFig. 4). There was no placebo-controlled trial which reported usable outcome data for negative symptoms. Concerning head-to-head comparisons between different antipsychotics, only olanzapine was significantly superior compared to haloperidol (N = 2 SMD 0.50, CI 0.02–0.99). There were no significant differences between amisulpride and risperidone (N = 1 SMD, −0.71, CI −1.61–0.18], chlorpromazine and clozapine (N = 1 SMD 0.11, CI −0.62–0.84], nor between olanzapine and risperidone (N = 3 SMD, −0.88 CI, −2.27–0.52].
3.6.
Depressive symptoms
Only four studies reported usable outcome data for mean change of depressive symptoms (see eFig. 5). There was no placebo-controlled trial which reported usable outcome data for depressive symptoms. Concerning head-to-head comparisons between different antipsychotics, there were no significant differences between amisulpride and risperidone (N = 1 SMD −0.44, CI −1.33–0.44), haloperidol and olanzapine (N = 1 SMD 0.35, CI −0.05–0.75) nor between olanzapine versus risperidone (N = 2 SMD 0.10, CI −0.15– 0.36).
3.7.
Quality of life
Only two studies reported usable outcome data for the improvement in quality of life (see eFig. 7). There was just one placebo controlled study which showed no significant difference compared to paliperidone (N = 1, SMD, −0.20
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Fig. 2 Flow-chart of study selection. The diagram illustrates the process of review and exclusion of studies.
CI −0.59–0.20). Concerning head-to-head comparisons between different antipsychotics there was only no significant difference between olanzapine and haloperidol.
3.8.
Social functioning
Only two studies reported usable outcome data for the improvement in social functioning (see eFig. 8). There was just one placebo controlled study which showed virtually no difference compared to paliperidone (N = 1 SMD −0.01, CI −0.41–0.39). Concerning head-to-head comparisons between different antipsychotics there was no significant difference for haloperidol compared to olanzapine.
3.9.
Prolactin increase
Only two studies reported usable outcome data for the outcome prolactin increase (see eFig. 11). Concerning head-tohead comparisons between different antipsychotics, olanzapine showed significantly lower prolactin increase compared to haloperidol (N = 1 SMD −0.66 CI −1.07–−0.25) and risperidone (N = 1 SMD −1.38 CI −1.80–−0.97).
3.10.
Weight gain
Five studies reported usable outcome data for the outcome weight gain (see eFig. 9). There was just one placebo controlled study which showed no difference compared
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Table 1
M. Krause et al.
Characteristics of included studies.
Study
Study groups
Number of participants
Trial Mean Minimum Mean Duration Year Blinding duration antipsychotic age age ill (years) (weeks) doses (mg/days)
Andia et al. (1998) Andia et al. (1998) Barak et al. (2000) Barak et al. (2000) Barak et al. (2002) Barak et al. (2002) Berman et al. (1995) Berman et al. (1995) Bora (1968) Bora (1968) Branchey et al. (1978) Branchey et al. (1978) Feldman et al. (2003) Feldman et al. (2003) Howanitz et al. (1999) Howanitz et al. (1999) Jeste et al. (2003) Jeste et al. (2003) Kennedy et al. (2003) Kennedy et al. (2003) Kinon et al. (2003) Kinon et al. (2003) Lacro (2001) Lacro (2001) Mintzer et al. (2004) Mintzer et al. (2004) Riedel et al. (2009) Riedel et al. (2009) Ritchie et al. (2003) Ritchie et al. (2003) Salganik et al. (1998) Salganik et al. (1998) Tzimos et al. (2008) Tzimos et al. (2008)
Clozapine Haloperidol Risperidone Typical neuroleptic Haloperidol Olanzapine Haloperidol Risperidone Carphenazine Trifluoperazine Fluphenazine Thioridazine Olanzapine Risperidone Chlorpromazine Clozapine Olanzapine Risperidone Haloperidol Olanzapine Conventional Olanzapine Haloperidol Risperidone Quetiapine Risperidone Amisulpride Risperidone Olanzapine Risperidone Clozapine Haloperidol Paliperidone Placebo
13 13 26 25 10 10 10 10 15 15 15 15 20 19 18 24 89 87 34 83 143 150 15 12 65 27 25 13 34 32 17 N.a. 76 38
3 72 N.a. N.a. 26 8 28 12 8 6 52 12 16 6 4 10 6
150 6 N.a. N.a. 7.2 13.1 N.a. N.a N.a. N.a N.a. N.a 18.8 8.9 600 300 11.1 1.9 9.4 11.9 N.a. N.a 3.4 1.8 237 3.3 198 1.9 9.9 1.7 N.a. N.a 8.4 0
46 65 63 57 50 60 50 55 60 60 N.a. N.a. 60 65 58 60 65
68,4 N.a. N.a. N.a. 30 N.a. 30 69,2 31,4 69,2 39,2 67,4 N.a. 67,4 N.a. N.a. N.a. N.a. N.a. 67 N.a. 67 N.a. 56,9 N.a. 57,2 N.a. 68,5 40 65 38 71,4 38 70,9 34,9 65,8 N.a. 66 N.a. N.a. N.a. N.a. N.a. 58 N.a. 58 N.a. 66 N.a. 67 N.a. 72,7 N.a. 72,7 N.a. 69,5 N.a. 69,7 N.a. 66,6 N.a. 66,6 N.a. 70 36 69 31
1998
OL-RCT
2000
N.a.
2002
OL-RCT
1995
DB-RCT
1968
N.a.
1978
DB-RCT
2003
DB-RCT
1999
DB-RCT
2003
DB-RCT
2003
DB-RCT
2003
N.a.
2001
DB-RCT
2004
OL-RCT
2009
DB-RCT
2003
OL-RCT
1998
DB-RCT
2008
DB-RCT
DB-RCT double blind randomized controlled trial; OL-RCT open label randomized controlled trial; N.a. not available.
to paliperidone (N = SMD 0.00, CI −0.40–0.40). Concerning head-to-head comparisons between different antipsychotics, there were no significant differences between haloperidol and olanzapine (N = 2 SMD −0.98, CI −2.21– 0.25) nor between olanzapine and risperidone (N = 2 SMD 0.42, CI −0.06–0.90).
3.11. Use of at least one antiparkinson medication Four studies reported usable outcome data for the outcome use of at least one antiparkinson medication (see eFig. 12). There was just one placebo controlled study which showed no significant difference compared to paliperidone (N = 1 OR 0.58, CI 0.23–1.47). Concerning head-to-head comparisons between different antipsychotics only olanzapine was significantly superior compared to haloperidol (N = 2 OR 4.81 CI 2.11–10.95). Finally risperidone showed no
significant difference compared to olanzapine (N = 1 OR 1.18 CI 0.50–2.80).
3.12.
Dropouts due to any reason
Eight studies reported usable outcome data for the outcome dropouts due to any reason (see Fig. 4). There was just one placebo controlled study which showed a nonsignificant superiority for paliperidone (N = 1, OR 0.41, CI 0.16– 1.02). Concerning head-to-head comparisons between different antipsychotics, olanzapine was significantly better accepted compared to risperidone (N = 3, OR 0.54, CI 0.31– 0.93). There were no significant differences between chlorpromazine and clozapine (N = 1, OR 1.38, CI 0.17–10.82, haloperidol and olanzapine (N = 1, OR 1.00, CI 0.17–5.98), haloperidol and risperidone (N = 1, OR 7.00, CI 0.33–150.06) nor between quetiapine versus risperidone (N = 1, OR 0.98, CI 0.37–2.62).
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Fig. 3 Meta-analysis - change of overall symptoms. CI, confidence interval; SMDs were obtained from a random-effects model assuming a common heterogeneity across all drugs. A negative value means that the first mentioned drug is favored and vice versa.
3.13.
Dropouts due to inefficacy
Five studies reported usable outcome data for the outcome dropouts due to inefficacy (see eFig. 14). There was just one placebo controlled study which showed significantly less dropouts due to inefficacy for paliperidone (N = 1 OR 0.22, CI 0.05–0.93). Concerning head-to-head comparisons between different antipsychotics, fairly there were no significant differences between haloperidol and olanzapine (N = 1 OR 0.26 0.02–3.06) nor between olanzapine and risperidone (N = 3 OR 0.84, CI 0.26–2.74).
3.15. bias
We did not detect significant heterogeneity in any outcome. As there were very few studies for most of the comparisons, heterogeneity might not be well estimated. Funnel plots to detect small trial/publication bias were not meaningful, because the maximum number of trials available for a comparison was three, not enough to determine asymmetry of the plots.
4. 3.14.
Assessment of heterogeneity and small trial
Discussion
Dropouts due to adverse events
Five studies reported usable outcome data for the outcome dropouts due to adverse events (see eFig. 13).There was no significant difference for this outcome.
To the best of our knowledge this is the first systematic review and meta-analysis regarding the effects of antipsychotics in elderly patients with schizophrenia. The main findings were that olanzapine was significantly more
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Fig. 4 Meta-analysis - dropouts due to any reason (acceptability). OR, odds ratio; CI, confidence interval; ORs were obtained from a random-effects model assuming a common heterogeneity across all drugs. A value < 1 means that the first mentioned drug is favored and vice versa.
efficacious compared to haloperidol, based on two trials, of which one showed no significant effects due to small sample size (N = 20). Moreover, olanzapine showed significant superiority compared to haloperidol for the reduction of negative symptoms. It also showed significantly higher response rates, lower prolactin increase, and less use of antiparkinson medication compared to haloperidol. While the only placebo-controlled study evaluating paliperidone showed no significant effect for any symptoms of schizophrenia, the number of dropouts due to inefficacy was significantly lower in the paliperidone group. We did not examine differences between secondgeneration and first-generation antipsychotics as classes, because this classification has been replaced with “Neuroscience Based Nomenclature (NbN)” by societies such as the European and the American Colleges of Neuropsychopharmacology (Zohar et al., 2014).
4.1.
Comparison to other meta-analyses
How do these results in differential efficacy and side effects of antipsychotics compare to findings from previous meta-analytic studies in the general population which often excluded elderly patients? Compared to a large network meta-analysis (NMA), do antipsychotics in treatment of schizophrenia (Leucht et al., 2013) which included 212 RCT’s with data for 43,049 patients in the general population (mean age 38.4), the direction of effects were generally similar, although the effect sizes differed and although most of our findings were not statistically significant. As the previous NMA which reported a small superiority for olanzapine compared to haloperidol (SMD –0.14 CI, –0.21 to –0.08), we also found a moderate effect favoring olanzapine in our meta-analysis about elderly patients (SMD −0.47, CI −0.84 to −0.10). In terms of prolactin increase we found
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Antipsychotic drugs for elderly patients with schizophrenia significant differences favoring olanzapine compared to risperidone (SMD − 1.38, CI − 1.80 to − 0.97] and to haloperidol (SMD −0.66, CI −1.07 to −0.25). However the effect sizes for the earlier NMA in the general population were again smaller: olanzapine vs. risperidone (SMD –1.09, CI –1.28 to –0.90) and olanzapine vs. haloperidol (SMD –0.56, CI –0.73 to –0.40). Except of these trend differences in a few comparisons, the insufficient evidence of the subgroup was not able to reveal clear differences in the effects of antipsychotic treatment in elderly patients compared to the earlier meta-analyses using mostly younger patients. In particular for those comparisons and outcomes for which no evidence was available, clinicians therefore need to rely on the results in the “general” people with schizophrenia, keeping the specific characteristics of elderly people such as higher side-effect vulnerability and reduced metabolism into account.
4.2.
General limitations
The present meta-analysis is not without limitations. For many comparisons only one study was available. This is not, however, a reason to not systematically present and review their effect sizes which primarily depend on sample size and not on number of studies. We systematically reviewed all the relevant studies available and presented results graphically using standardized statistical procedures utilized in modern meta-analysis. But it is possible that some comparisons which showed non-significant trends might show significant effects if statistical power was increased if a larger number of subjects and/or studies were available for that comparison. The lack of data is particularly important for some of the side-effect evaluations. In the supplement eFigs. 10–12 show that data on important side effects like QTC prolongation, prolactin increase or use of at least one antiparkinson medication were often not reported in the original studies. A reason for the low frequency of reporting for these outcomes may be due to the fact that most of the included publications from which we extracted our data were only subgroup analysis of larger studies, and some were presented only in abstracts. This is also an important reason for the high frequency of unclear risk of bias ratings and small sample sizes.
4.3.
Elderly vs geriatric patients
Another important issue is that the included studies used very heterogeneous definitions of “elderly”. The minimum age ranged from 46 up to 65 and the mean age from around 57 up to nearly 73. Only three out of eighteen included studies included patients with a minimum age of sixty-five. However, in a sample with more uniformly older age patients, all above age 60 or 65, it is quite possible we might still not find significant differences in efficacy or side effects of antipsychotic drugs, in elderly patients with schizophrenia. Many patients these days in their 60’s are in fairly good health and do not differ in important ways from patients 10 or even 20 years younger. Age itself may not be the most important differentiating factor. In order to explore whether there are
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9 meaningful differences we might have to focus more particularly on patients who would be classified as geriatric by recent definitions. The German Society of Geriatrics (DGG), the German Society of Gerontology and Geriatrics (DGGG), and the German Group of Geriatric Institutions (BAG) developed a definition of the geriatric patient (Sieber, 2007) including mainly an age of over 70 and a high multimorbidity. There are not sufficient trials with antipsychotic drugs in patients with schizophrenia or related psychosis who meet this more specific geriatric classification, but, as the population ages, more patients will be falling into this group. More studies of antipsychotics in patients with schizophrenia or related psychosis are needed, in patients who meet inclusion criteria for being truly geriatric as described above (Sieber, 2007), in order to determine whether there are important differences in efficacy or side effects in this geriatric group who are treated with antipsychotics for these illness.
Contributors The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SL and MK designed this study. MK, MH, JS, PR, HR, SB, LB, MS, TA, LR and NP extracted the data. MK and RS analyzed data. MK and SL wrote the first draft of the manuscript and RS revised it. All authors contributed to and have approved the final manuscript.
Declaration of interests SL has received honoraria for consulting from LB Pharma, Lundbeck, Otsuka, TEVA, Geodon Richter, Recordati, LTS Lohmann, and Boehringer Ingelheim; and for lectures from Janssen, Lilly, Lundbeck, Otsuka, SanofiAventis, and Servier. MH has received speaker’s honoraria from Janssen and Lundbeck. Robert Smith is a consultant for Abbot on the development of a new medication. The other authors declare no competing interests.
Acknowledgments This work was supported by a grant from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF, Grant no. FKZ 01KG1508). We thank Samantha Roberts for help in the literature search and Leonie Reichelt, Hannah Röder, Susanne Bächer, Lio Bäckers, Myrto Samara, Thomas Arndt and Natalie Peter for help in data extraction. We thank all authors of the included studies, particularly those who sent us additional information about their trials.
Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.euroneuro. 2018.09.007.
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References Andia, I., Zumarraga, M., Zabalo, M.J., Bulbena, A., Davila, R., 1998. Differential effect of haloperidol and clozapine on plasma homovanillic acid in elderly schizophrenic patients with or without tardive dyskinesia. Biol Psychiatry 43 (1), 20–23. Andreas, S., Schulz, H., Volkert, J., Dehoust, M., Sehner, S., Suling, A., Ausín, B., Canuto, A., Crawford, M., Da Ronch, C., Grassi, L., Hershkovitz, Y., Muñoz, M., Quirk, A., Rotenstein, O., Santos-Olmo, A.B., Shalev, A., Strehle, J., Weber, K., Wegscheider, K., Wittchen, H.-U., Härter, M., 2017. Prevalence of mental disorders in elderly people: the European MentDis_ICF65+ study. Brit. J. Psychiatry J. Ment. Sci. 210 (2), 125–131. doi:10. 1192/bjp.bp.115.180463. Barak, Y., Shamir, E., Weizman, R., 2000. Risperidone compared with typical neuroleptic treatment in elderly schizophrenic patients. Int. J. Neuropsychopharmacol. 3, S122 (Abstracts of the XXIInd CINP Congress, Brussels, Belgium, July 9-13, 2000). Barak, Y., Shamir, E., Zemishlani, H., Mirecki, I., Toren, P., Weizman, R., 2002. Olanzapine vs. haloperidol in the treatment of elderly chronic schizophrenia patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 26 (6), 1199–1202. Berman, I., Merson, A., Allan, E., Alexis, C., Losonczy, M., 1995. Effect of risperidone on cognitive performance in elderly schizophrenic patients: a double-blind comparison study with haloperidol. Psychopharmacol. Bull. 31 (3), 552. Bian, Z.X., Li, Y.P., Moher, D., Dagenais, S., Liu, L., Wu, T.X., Miao, J.X., Kwan, A.K., Song, L., 2006. Improving the quality of randomized controlled trials in Chinese herbal medicine, part I: clinical trial design and methodology. Zhong xi yi jie he xue bao. J. Chin. Integr. Med. 4 (2), 120–129. Bora, G., 1968. Comparison of dosage ranges of carphenazine and trifluoperazine in elderly chronic schizophrenics. Dis. Nerv. Syst. 29 (10), 695–697. Branchey, M.H., Lee, J.H., Amin, R., Simpson, G.M., 1978. Highand low-potency neuroleptics in elderly psychiatric patients. JAMA 239 (18), 1860–1862. Cohen, J., 2013. Statistical Power Analysis for the Behavioral Sciences. Elsevier Science, Burlington, p. 459. Colenda, C.C., Mickus, M.A., Marcus, S.C., Tanielian, T.L., Pincus, H.A., 2002. Comparison of adult and geriatric psychiatric practice patterns: findings from the American Psychiatric Association’s Practice Research Network. Am. J. Geriatric Psychiatry Off. J. Am. Assoc. Geriatric Psychiatry 10 (5), 609–617. DerSimonian, R., Laird, N., 1986. Meta-analysis in clinical trials. Controll. Clin. Trials 7 (3), 177–188. doi:10.1016/0197-2456(86) 90046-2. Divine, G.W., Brown, J.T., Frazier, L.M., 1992. The unit of analysis error in studies about physicians’ patient care behavior. J. General Internal Med. 7 (6), 623–629. Elbourne, D.R., Altman, D.G., Higgins, J.P.T., Curtin, F., Worthington, H.V., Vail, A., 2002. Meta-analyses involving cross-over trials: methodological issues. Int. J. Epidemiol. 31 (1), 140–149. Essali, A., Ali, G., 2012. Antipsychotic drug treatment for elderly people with late-onset schizophrenia. Cochrane Database Syst. Rev. 2, CD004162. doi:10.1002/14651858.CD004162.pub2. Feldman, P.D., Kaiser, C.J., Kennedy, J.S., Sutton, V.K., Tran, P.V., Tollefson, G.D., Zhang, F., Breier, A., 2003. Comparison of risperidone and olanzapine in the control of negative symptoms of chronic schizophrenia and related psychotic disorders in patients aged 50 to 65 years. J. Clin. Psychiatry 64 (9), 998–1004. Furukawa, T.A., Barbui, C., Cipriani, A., Brambilla, P., Watanabe, N., 2006. Imputing missing standard deviations in metaanalyses can provide accurate results. J. Clin. Epidemiol. 59 (1), 7–10. doi:10.1016/j.jclinepi.2005.06.006.
[m6+;September 19, 2018;17:35]
M. Krause et al. Fusar-Poli, P., Papanastasiou, E., Stahl, D., Rocchetti, M., Carpenter, W., Shergill, S., McGuire, P., 2015. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr. Bull. 41 (4), 892–899. doi:10.1093/schbul/sbu170. Higgins, JPT, 2011. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Wiley and Sons, Chichester, UK [updated March 2011]. Howanitz, E., Pardo, M., Smelson, D.A., Engelhart, C., Eisenstein, N., Losonczy, M.F., 1999. The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia. Erratum. J. Clin. Psychiatry 60 (5), 341. Jeste, D.V., Barak, Y., Madhusoodanan, S., Grossman, F., Gharabawi, G., 2003. International multisite double-blind trial of the atypical antipsychotics risperidone and olanzapine in 175 elderly patients with chronic schizophrenia. [Erratum appears in Am J Geriatr Psychiatry. 2004 Jan-Feb;12(1): 49]. Am. J. Geriatr. Psychiatry 11 (6), 638–647. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13 (2), 261–276. Kennedy, J.S., Jeste, D., Kaiser, C.J., Golshan, S., Maguire, G.A., Tollefson, G., Sanger, T., Bymaster, F.P., Kinon, B.J., Dossenbach, M., Gilmore, J.A., Breier, A., 2003. Olanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial. Int. J. Geriatr. Psychiatry 18 (11), 1013–1020. Kinon, B.J., Stauffer, V.L., Kaiser, C., Kollack-Walker, S., 2003. Incidence of presumptive tardive dyskinesia in elderly patients treated with olanzapine or conventional antipsychotics. In: Proceedings of the 156th Annual Meeting of the American Psychiatric Association. San Francisco CA Nr55. Lacro, J., 2001. Antipsychotic Treatment in Late Life Schizophrenia. CRISP Database. Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., Samara, M., Barbui, C., Engel, R.R., Geddes, J.R., Kissling, W., Stapf, M.P., Lässig, B., Salanti, G., Davis, J.M., 2013. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet 382 (9896), 951–962. Leucht, S., Förstl, H., Bäuml, J., 2012. Kurzlehrbuch Psychiatrie und Psychotherapie [+ campus.thieme.de]. Thieme, Stuttgart, p. 87 chapter 4, ISBN-10: 3131483814. Leucht, S., Pitschel-Walz, G., Engel, R.R., Kissling, W., 2002. Amisulpride, an unusual “atypical” antipsychotic: a metaanalysis of randomized controlled trials. Am. J. Psychiatry 159 (2), 180–190. doi:10.1176/appi.ajp.159.2.180. McGrath, J., Saha, S., Chant, D., Welham, J., 2008. Schizophrenia: A concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 30, 67–76. doi:10.1093/epirev/mxn001. Mintzer, J.E., Mullen, J.A., Sweitzer, D.E., 2004. A comparison of extrapyramidal symptoms in older outpatients treated with quetiapine or risperidone. Curr. Med. Res. Opin. 20 (9), 1483–1491. Overall, J.E., 1962. The brief psychiatric rating scale. PR 10 (3), 799. doi:10.2466/PR0.10.3.799-812. Remington, G., Foussias, G., Fervaha, G., Agid, O., Takeuchi, H., Lee, J., Hahn, M., 2016. Treating negative symptoms in schizophrenia: an update. Curr. Treat. Options Psychiatry 3, 133– 150. doi:10.1007/s40501- 016- 0075- 8. Riedel, M., Eich, F.X., Moller, H.J., 2009. A pilot study of the safety and efficacy of amisulpride and risperidone in elderly psychotic patients. Eur. Psychiatry 24 (3), 149–153. doi:10.1016/j.eurpsy. 2008.10.005. Ritchie, C.W., Chiu, E., Harrigan, S., Hall, K., Hassett, A., Macfarlane, S., Mastwyk, M., O’Connor, D.W., Opie, J., Ames, D., 2003. The impact upon extra-pyramidal side effects, clinical
Please cite this article as: M. Krause et al., Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.09.007
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ARTICLE IN PRESS
Antipsychotic drugs for elderly patients with schizophrenia symptoms and quality of life of a switch from conventional to atypical antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia. Int. J. Geriatr. Psychiatry 18 (5), 432–440. Salganik, I., Modai, I., Bercovici, B.R., Kutzuk, D., Weizman, A., 1998. Clozapine vs haloperidol therapy in elderly chronic schizophrenic inpatients - Preliminary results. A double-blind, cross-over randomized study. Int. J. Geriatr. Psychopharmacol. 1 (4), 185–187. Sieber, C.C., 2007. Der ältere Patient–wer ist das? Der. Internist 48 (11), 1192–1194. doi:10.1007/s00108- 007- 1945- 3, 1190. Leucht, S., Huhn, M., Rothe, P., Schneider, J., Zhu, Y, 2016. Which are the most important first-generation antipsychotic drugs? Survey of international schizophrenia experts. In: Abstracts from the 5th Biennial SIRS Conference - Poster Abstracts. NPJ Schizophrenia 25.
[m6+;September 19, 2018;17:35]
11 Tzimos, A., Samokhvalov, V., Kramer, M., Ford, L., GassmannMayer, C., Lim, P., Eerdekens, M., 2008. Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension. Am. J. Geriatr. Psychiatry 16 (1), 31–43. doi:10.1097/JGP.0b013e31815a3e7a. United Nations, Department of Economic and Social Affairs, Population Division, 2015. World population ageing, 2015. United Nations, New York, 1 online resource (164). Wu, T., Li, Y., Bian, Z., Liu, G., Moher, D., 2009. Randomized trials published in some Chinese journals: how many are randomized? Trials 10, 46. doi:10.1186/1745- 6215- 10- 46. Zohar, J., Nutt, D.J., Kupfer, D.J., Moller, H.-J., Yamawaki, S., Spedding, M., Stahl, S.M., 2014. A proposal for an updated neuropsychopharmacological nomenclature. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 24 (7), 1005–1014. doi:10.1016/j.euroneuro.2013.08.004.
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European Neuropsychopharmacology (2018) 000, 1–11
www.elsevier.com/locate/euroneuro
Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis Marc Krause a,c,∗, Maximilian Huhn a, Johannes Schneider-Thoma a, Philipp Rothe a, Robert C Smith b, Stefan Leucht a a
Department of Psychiatry and Psychotherapy, Technical University of Munich, Klinikum rechts der Isar, Ismaningerstraße 22, 81675 Munich, Germany b New York University Medical School, Department Of Psychiatry, and Nathan Kline Institute for Psychiatric Research, New York, USA c Ludwig-Maximilians Universität München, Germany Received 17 May 2018; accepted 5 September 2018 Available online xxx
KEYWORDS Elderly; Schizophrenia; Antipsychotics; Meta-analysis
Abstract Elderly patients with schizophrenia are a particularly vulnerable group often excluded from clinical trials. Currently there is no evidence-synthesis about the efficacy and safety of antipsychotics in this subgroup. We reviewed all randomized-controlled-trials, about antipsychotics in elderly schizophrenics (last search Dec 12, 2017). Pairwise meta-analyses were conducted. The primary outcome was overall symptoms. Secondary outcomes included positive symptoms, negative symptoms, response, dropouts, quality of life, social functioning and side-effects. We included 29 references from 18 unique randomized-controlled-trials with 1225 participants published from 1958 to 2009. The definition of “elderly” was very heterogeneous across the studies (minimum age 46–65, mean age 57–73). There were evidence gaps for most drugs in many outcomes. In terms of efficacy paliperidone was associated with fewer dropouts due to inefficacy than placebo in the only placebo-controlled-trial. Olanzapine was superior to haloperidol in overall symptoms, negative symptoms and response, and it was associated with fewer dropouts than risperidone. Risperidone and haloperidol produced more prolactin increase than olanzapine, and olanzapine was associated with less use of antiparkinson medication than haloperidol.
∗ Corresponding author at: Department of Psychiatry and Psychotherapy, Technical University of Munich. Klinikum rechts der Isar, Ismaningerstraße 22, 81675 Munich, Germany. E-mail address: [email protected] (M. Krause). https://doi.org/10.1016/j.euroneuro.2018.09.007 0924-977X/© 2018 Elsevier B.V. and ECNP. All rights reserved.
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2
M. Krause et al. Although we found no marked differences of the effects of these drugs in the elderly, the evidence presented was based on very few usually small studies. To examine specifically whether there are differences in efficacy and side-effects in elderly, which differs in meaningful ways from the general population, studies in patients who are defined by critiera as truly geriatric, which incorporates older age together with multimorbidity and fraility dimensions, may be more informative. © 2018 Elsevier B.V. and ECNP. All rights reserved.
1.
Introduction
Aging is a global trend, according to studies by the United Nations Population Department (United Nations, Department of Economic and Social Affairs, Population Division, 2015), and demographic trends show an increase in the old and very old in many countries. The life morbidity risk for schizophrenia is approximately 1% (mean/median 11/7 per 1000), the median point prevalence per 1000 is 4.6 (10, 90 percent quantiles 1.9, 10.0), and the median yearly incidence per 100.000 is 15.2 (10, 90 percent quantiles 7.7, 43.0) (McGrath et al., 2008). Schizophrenia first appears in adolescence but continues throughout the life cycle. The life-time prevalence of schizophrenia in old age fluctuates between 0.5 and 1% (Andreas et al., 2017). Treatment with antipsychotic drugs is the primary therapy for patients with schizophrenia (Leucht et al., 2012) and they are widely used in older patients (Colenda et al., 2002). However, the efficacy and sideeffects of antipsychotic drugs for treatment of schizophrenia in older patients has not been systematically evaluated. Side-effects of antipsychotic drugs which can include weight gain, glucose-lipid abnormalities and hormonal changes can be especially important because they can increase cardiovascular and other risk factors which are more important in the elderly population. A systematic evaluation is important to provide a database to facilitate evidence-based decisions for selecting the best individual treatment for elderly patients with schizophrenia. However most of the clinical studies have excluded these patients, because their inclusion criteria were often restricted to patients up to an age of sixty-five years. This also applies to systematic reviews and meta-analyses, which deliberately exclude the few available studies that examine the subgroup of the old patients with schizophrenia (Leucht et al., 2013). Although older schizophrenics are often treated with antipsychotics, the available evidence is insufficient to provide data on which evidencebased clinical recommendations can be made. There is only one Cochrane Review about the antipsychotic treatment of patients with late onset schizophrenia, but nothing about elderly patients with schizophrenia in general, independent of the age of onset (Essali and Ali, 2012). However, the elderly may be more sensitive to antipsychotic drug side effects and may be less responsive to antipsychotic treatment in some conditions. This background provides a rationale for doing a separate meta-analysis of the efficacy and sideeffects of antipsychotics in the elderly. We, therefore, conducted a systematic review and meta-analysis on the effects of antipsychotics in elderly patients with schizophrenia. The aims were to determine which antipsychotics are more ef-
ficacious than placebo, and whether there are differences between specific antipsychotics in efficacy and side-effects.
2.
Methods
An a priori written study protocol was registered at PROSPERO under the registration number: CRD42016052060.
2.1.
Participants and interventions
We included all randomized controlled trials (RCTs) in elderly patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder (as defined by any diagnostic criteria). The interventions were 34 antipsychotic drugs which comprised all second-generation antipsychotics available in the US and/or Europe, and a selection of first-generation antipsychotics, licensed in at least one country, which were considered important based on a survey of international schizophrenia experts (Leucht et al., 2016) (amisulpride, aripiprazole, asenapine, benperidol, brexpiprazole, cariprazine, chlorpromazine, clopenthixol, clozapine, flupenthixol, fluphenazine, fluspirilene, haloperidol, iloperidone, levomepromazine, loxapine, lurasidone, molindone, olanzapine, paliperidone, penfluridol, perazine, perphenazine, pimozide, quetiapine, risperidone, sertindole, sulpiride, thioridazine, thiothixene, trifluoperazine, ziprasidone, zotepine, zuclopenthixol). We included these drugs at any dose and in any form of administration when compared with another antipsychotic or placebo, and used as monotherapy. Drugs that failed to obtain FDA/EMA approval or which had not yet been licensed were not considered.
2.2.
Search strategy and selection criteria
We conducted a comprehensive, systematic literature search in MEDLINE, EMBASE, PsycINFO, Cochrane Library, PubMed, Biosis, and ClinicalTrials.gov up to Nov 17, 2016 (eAppendix 2 in the Supplement) and a final PubMed search until Dec 12, 2017. The search terms included the generic names of 34 antipsychotics listed above. The minimum duration of the RCTs was set at three weeks. We also inspected the reference lists of the included studies and of previous systematic reviews (Fusar-Poli et al., 2015; Leucht et al., 2002) and a narrative review (Remington et al., 2016). Citations were screened independently by at least two reviewers (MK, MH, YZ) at both the title/abstract and fulltext stages. In the case of crossover studies, we only used
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Antipsychotic drugs for elderly patients with schizophrenia the first crossover phase to avoid the problem of carryover effects (Elbourne et al., 2002). We excluded clusterrandomized trials (Divine et al., 1992). Studies that demonstrated a high risk of bias for sequence generation or allocation concealment were excluded (Higgins, 2011). If a trial was described as double-blind but randomization was not explicitly mentioned, we assumed that study participants were randomized, but we excluded the trial in a sensitivity analysis. We excluded studies from mainland China to avoid a systematic bias because many of these studies do not use appropriate randomization procedures, do not report their methods, and have been reported to often be not reliable (Bian et al., 2006; Wu et al., 2009).
2.3.
Outcome measures and data extraction
The primary outcome was the mean change from baseline to endpoint in overall symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987), the Brief Psychiatric Rating Scale (Overall, 1962), or any other validated scale for the overall assessment of schizophrenia symptoms, especially adapted versions of BPRS and PANSS for elderly. If change data were not available, we used the mean score at study end point of these scales. Intention-to-treat data sets were used whenever available. Secondary outcomes were clinically important responses to treatment defined by the authors, the mean change in positive, negative and depressive symptoms of schizophrenia, dropouts owing to any reason (all-cause discontinuation), dropouts owing to inefficacy of treatment and due to adverse events, the occurrence of important adverse effects (weight gain, at least one extrapyramidal symptom, sedation, akathisia, prolactin prolongation), antiparkinsonian medication used at least once as a proxy for extrapyramidal symptoms, quality of life, and social functioning. We used the Cochrane Collaboration’s risk-of-bias tool for the assessment of potential bias in terms of randomization, allocation concealment, blinding, missing outcomes, selective reporting and other biases (Higgins, 2011). Data extraction and assessment of study quality were performed independently by at least two reviewers (MK, MH, JS, PR, HR, SB, LB, MS, TA, LR and NP). Disagreement was resolved by discussion. If disagreement could not be resolved, we discussed with the team leader (SL). We sent emails to the first and corresponding authors of all included studies to request missing data. Missing SDs were estimated from test statistics or substituted by the mean SD of the other included studies using the same scale (Furukawa et al., 2006)
2.4.
3 dardized mean differences (SMDs) according to Hedges’s g (Cohen, 2013). For binary outcomes, the effect sizes were calculated as odds ratios (ORs) according to Mantel– Haenszel. Both types of effect sizes were presented along with their 95% confidence intervals (CIs). We applied the random-effects model by DerSimonian and Laird (1986) to all outcomes. Heterogeneity was assessed with the I² statistic (Higgins, 2011) and a chi²-square test for homogeneity. Small trial effects were explored by funnel-plots if at least ten studies were available (Higgins, 2011). As the method is based on symmetry, funnel-plots based on fewer trials are not meaningful (Higgins, 2011). P-values lower than 0.05 were considered to be statistically significant.
3. 3.1.
Results Description of included studies
We identified 29 references from 18 unique RCTs with 1225 unique participants published from 1958 to 2009. The PRISMA flowchart is shown in Fig. 2. Details of all included studies are presented in Table 1. Of 718 patients for whom gender was indicated, 445 were women (62%). The mean age of participants was 66.09 years (range 56.9–72.2 years). The median trial duration was 10 weeks (range 3–72 weeks). The assessment for risk of bias is presented in eAppendix 4 in the Supplement. Nearly all included studies reported insufficient information concerning random sequence generation (17 of 18 studies) and allocation concealment (17 of 18 studies). The blinding of patients and personnel showed a high risk of bias in five studies and low risk in 3 studies. The risk of bias for blinding of outcome assessment was similar with 4 studies at low risk and 3 at high risk. The number of studies with high risk of bias for missing outcomes and selective reporting were 5 and 6 respectively, and in both categories six studies showed low risk of bias. Fig. 1 shows the network of eligible comparisons for the primary outcome. The identified studies included the drugs amisulpride, carphenazine, chlorpromazine, clozapine, fluphenazine, haloperidol, olanzapine, paliperidone, placebo, quetiapine, risperidone, thioridazine, trifluoperazine. Two studies reported combined treatment groups (typical neuroleptic, conventional). The drug involved in most comparisons was risperidone (9 of 18 trials) followed by haloperidol (7 of 18 trials) olanzapine (6 of 18 trials) and clozapine (3 of 18 trials), whereas just single trials were available for other drugs: amisulpride, carphenazine, chlorpromazine, fluphenazine, paliperidone, placebo, quetiapine, thioridazine, trifluoperazine, typical neuroleptic/conventional.
Statistical analysis
We originally planned to conduct a network meta-analysis. However, the network plot was very poorly connected as there were only a few eligible studies (see Fig. 1). Also, there were neither triangular nor quadratic loops of direct comparisons. Therefore, we decided to calculate pairwise, random-effects meta-analyses using Review Manager 5.3. This decision had been foreseen in our protocol. For continuous outcomes, the effect sizes were calculated as stan-
3.2.
Overall symptoms
Nine studies reported usable outcome data for mean change in overall symptoms (see Fig. 3). There was only one placebo controlled study which showed no significant difference compared to paliperidone (N = 1, SMD −0.32, CI −0.71–0.08). Concerning head-tohead comparisons between different antipsychotics, only
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Fig. 1 Plot of direct comparisons – overall symptoms. The figure shows the direct comparisons of included studies. The thickness of the line corresponds to the inverse variance of the direct comparisons The size of the nodes corresponds to the number of trials that study the treatments.
olanzapine was significantly superior compared to haloperidol (N = 2, SMD 0.47, CI 0.10–0.84). There were no significant differences between amisulpride and risperidone (N = 1, SMD, −0.03, CI −0.90–0.84], chlorpromazine and clozapine (N = 1, SMD, 0.15, CI −0.58–0.88), olanzapine and risperidone (N = 3, SMD −0.51, CI −1.32–0.30] nor between quetiapine and risperidone (N = 1, SMD, 0.16, CI −0.29– 0.60).
3.3.
Response (authors’ definition)
Five studies reported usable outcome data for the outcome response (see eFig. 4). Concerning head-to-head comparisons between different antipsychotics, only olanzapine was significantly superior compared to haloperidol (N = 1 OR 2.63, CI 1.04–6.69). There were no significant differences between amisulpride and risperidone (N = 1 OR 0.94, CI 0.24–3.71), olanzapine and risperidone (N = 2 OR 0.59, CI 0.14–2.46) nor between quetiapine and risperidone (N = 1, OR 0.38, CI 0.13–1.06).
3.4.
Positive symptoms
Six studies reported usable outcome data for mean change of positive symptoms (see eFig. 3). There was no placebocontrolled trial which reported usable outcome data for positive symptoms. Concerning head-to-head comparisons between different antipsychotics, there were no significant differences between amisulpride and risperidone (N = 1, SMD 0.60, CI −0.29–1.49), chlorpromazine and clozapine (N = 1, SMD 0.09, CI −0.64–0.82), haloperidol and olanzapine (N = 2, SMD 0.10 CI −0.26–0.47) nor between olanzapine and risperidone (N = 2 SMD −0.11, CI −0.38–0.16].
3.5.
Negative symptoms
Seven studies reported usable outcome data for mean change of negative symptoms (see eFig. 4). There was no placebo-controlled trial which reported usable outcome data for negative symptoms. Concerning head-to-head comparisons between different antipsychotics, only olanzapine was significantly superior compared to haloperidol (N = 2 SMD 0.50, CI 0.02–0.99). There were no significant differences between amisulpride and risperidone (N = 1 SMD, −0.71, CI −1.61–0.18], chlorpromazine and clozapine (N = 1 SMD 0.11, CI −0.62–0.84], nor between olanzapine and risperidone (N = 3 SMD, −0.88 CI, −2.27–0.52].
3.6.
Depressive symptoms
Only four studies reported usable outcome data for mean change of depressive symptoms (see eFig. 5). There was no placebo-controlled trial which reported usable outcome data for depressive symptoms. Concerning head-to-head comparisons between different antipsychotics, there were no significant differences between amisulpride and risperidone (N = 1 SMD −0.44, CI −1.33–0.44), haloperidol and olanzapine (N = 1 SMD 0.35, CI −0.05–0.75) nor between olanzapine versus risperidone (N = 2 SMD 0.10, CI −0.15– 0.36).
3.7.
Quality of life
Only two studies reported usable outcome data for the improvement in quality of life (see eFig. 7). There was just one placebo controlled study which showed no significant difference compared to paliperidone (N = 1, SMD, −0.20
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Fig. 2 Flow-chart of study selection. The diagram illustrates the process of review and exclusion of studies.
CI −0.59–0.20). Concerning head-to-head comparisons between different antipsychotics there was only no significant difference between olanzapine and haloperidol.
3.8.
Social functioning
Only two studies reported usable outcome data for the improvement in social functioning (see eFig. 8). There was just one placebo controlled study which showed virtually no difference compared to paliperidone (N = 1 SMD −0.01, CI −0.41–0.39). Concerning head-to-head comparisons between different antipsychotics there was no significant difference for haloperidol compared to olanzapine.
3.9.
Prolactin increase
Only two studies reported usable outcome data for the outcome prolactin increase (see eFig. 11). Concerning head-tohead comparisons between different antipsychotics, olanzapine showed significantly lower prolactin increase compared to haloperidol (N = 1 SMD −0.66 CI −1.07–−0.25) and risperidone (N = 1 SMD −1.38 CI −1.80–−0.97).
3.10.
Weight gain
Five studies reported usable outcome data for the outcome weight gain (see eFig. 9). There was just one placebo controlled study which showed no difference compared
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Table 1
M. Krause et al.
Characteristics of included studies.
Study
Study groups
Number of participants
Trial Mean Minimum Mean Duration Year Blinding duration antipsychotic age age ill (years) (weeks) doses (mg/days)
Andia et al. (1998) Andia et al. (1998) Barak et al. (2000) Barak et al. (2000) Barak et al. (2002) Barak et al. (2002) Berman et al. (1995) Berman et al. (1995) Bora (1968) Bora (1968) Branchey et al. (1978) Branchey et al. (1978) Feldman et al. (2003) Feldman et al. (2003) Howanitz et al. (1999) Howanitz et al. (1999) Jeste et al. (2003) Jeste et al. (2003) Kennedy et al. (2003) Kennedy et al. (2003) Kinon et al. (2003) Kinon et al. (2003) Lacro (2001) Lacro (2001) Mintzer et al. (2004) Mintzer et al. (2004) Riedel et al. (2009) Riedel et al. (2009) Ritchie et al. (2003) Ritchie et al. (2003) Salganik et al. (1998) Salganik et al. (1998) Tzimos et al. (2008) Tzimos et al. (2008)
Clozapine Haloperidol Risperidone Typical neuroleptic Haloperidol Olanzapine Haloperidol Risperidone Carphenazine Trifluoperazine Fluphenazine Thioridazine Olanzapine Risperidone Chlorpromazine Clozapine Olanzapine Risperidone Haloperidol Olanzapine Conventional Olanzapine Haloperidol Risperidone Quetiapine Risperidone Amisulpride Risperidone Olanzapine Risperidone Clozapine Haloperidol Paliperidone Placebo
13 13 26 25 10 10 10 10 15 15 15 15 20 19 18 24 89 87 34 83 143 150 15 12 65 27 25 13 34 32 17 N.a. 76 38
3 72 N.a. N.a. 26 8 28 12 8 6 52 12 16 6 4 10 6
150 6 N.a. N.a. 7.2 13.1 N.a. N.a N.a. N.a N.a. N.a 18.8 8.9 600 300 11.1 1.9 9.4 11.9 N.a. N.a 3.4 1.8 237 3.3 198 1.9 9.9 1.7 N.a. N.a 8.4 0
46 65 63 57 50 60 50 55 60 60 N.a. N.a. 60 65 58 60 65
68,4 N.a. N.a. N.a. 30 N.a. 30 69,2 31,4 69,2 39,2 67,4 N.a. 67,4 N.a. N.a. N.a. N.a. N.a. 67 N.a. 67 N.a. 56,9 N.a. 57,2 N.a. 68,5 40 65 38 71,4 38 70,9 34,9 65,8 N.a. 66 N.a. N.a. N.a. N.a. N.a. 58 N.a. 58 N.a. 66 N.a. 67 N.a. 72,7 N.a. 72,7 N.a. 69,5 N.a. 69,7 N.a. 66,6 N.a. 66,6 N.a. 70 36 69 31
1998
OL-RCT
2000
N.a.
2002
OL-RCT
1995
DB-RCT
1968
N.a.
1978
DB-RCT
2003
DB-RCT
1999
DB-RCT
2003
DB-RCT
2003
DB-RCT
2003
N.a.
2001
DB-RCT
2004
OL-RCT
2009
DB-RCT
2003
OL-RCT
1998
DB-RCT
2008
DB-RCT
DB-RCT double blind randomized controlled trial; OL-RCT open label randomized controlled trial; N.a. not available.
to paliperidone (N = SMD 0.00, CI −0.40–0.40). Concerning head-to-head comparisons between different antipsychotics, there were no significant differences between haloperidol and olanzapine (N = 2 SMD −0.98, CI −2.21– 0.25) nor between olanzapine and risperidone (N = 2 SMD 0.42, CI −0.06–0.90).
3.11. Use of at least one antiparkinson medication Four studies reported usable outcome data for the outcome use of at least one antiparkinson medication (see eFig. 12). There was just one placebo controlled study which showed no significant difference compared to paliperidone (N = 1 OR 0.58, CI 0.23–1.47). Concerning head-to-head comparisons between different antipsychotics only olanzapine was significantly superior compared to haloperidol (N = 2 OR 4.81 CI 2.11–10.95). Finally risperidone showed no
significant difference compared to olanzapine (N = 1 OR 1.18 CI 0.50–2.80).
3.12.
Dropouts due to any reason
Eight studies reported usable outcome data for the outcome dropouts due to any reason (see Fig. 4). There was just one placebo controlled study which showed a nonsignificant superiority for paliperidone (N = 1, OR 0.41, CI 0.16– 1.02). Concerning head-to-head comparisons between different antipsychotics, olanzapine was significantly better accepted compared to risperidone (N = 3, OR 0.54, CI 0.31– 0.93). There were no significant differences between chlorpromazine and clozapine (N = 1, OR 1.38, CI 0.17–10.82, haloperidol and olanzapine (N = 1, OR 1.00, CI 0.17–5.98), haloperidol and risperidone (N = 1, OR 7.00, CI 0.33–150.06) nor between quetiapine versus risperidone (N = 1, OR 0.98, CI 0.37–2.62).
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Fig. 3 Meta-analysis - change of overall symptoms. CI, confidence interval; SMDs were obtained from a random-effects model assuming a common heterogeneity across all drugs. A negative value means that the first mentioned drug is favored and vice versa.
3.13.
Dropouts due to inefficacy
Five studies reported usable outcome data for the outcome dropouts due to inefficacy (see eFig. 14). There was just one placebo controlled study which showed significantly less dropouts due to inefficacy for paliperidone (N = 1 OR 0.22, CI 0.05–0.93). Concerning head-to-head comparisons between different antipsychotics, fairly there were no significant differences between haloperidol and olanzapine (N = 1 OR 0.26 0.02–3.06) nor between olanzapine and risperidone (N = 3 OR 0.84, CI 0.26–2.74).
3.15. bias
We did not detect significant heterogeneity in any outcome. As there were very few studies for most of the comparisons, heterogeneity might not be well estimated. Funnel plots to detect small trial/publication bias were not meaningful, because the maximum number of trials available for a comparison was three, not enough to determine asymmetry of the plots.
4. 3.14.
Assessment of heterogeneity and small trial
Discussion
Dropouts due to adverse events
Five studies reported usable outcome data for the outcome dropouts due to adverse events (see eFig. 13).There was no significant difference for this outcome.
To the best of our knowledge this is the first systematic review and meta-analysis regarding the effects of antipsychotics in elderly patients with schizophrenia. The main findings were that olanzapine was significantly more
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Fig. 4 Meta-analysis - dropouts due to any reason (acceptability). OR, odds ratio; CI, confidence interval; ORs were obtained from a random-effects model assuming a common heterogeneity across all drugs. A value < 1 means that the first mentioned drug is favored and vice versa.
efficacious compared to haloperidol, based on two trials, of which one showed no significant effects due to small sample size (N = 20). Moreover, olanzapine showed significant superiority compared to haloperidol for the reduction of negative symptoms. It also showed significantly higher response rates, lower prolactin increase, and less use of antiparkinson medication compared to haloperidol. While the only placebo-controlled study evaluating paliperidone showed no significant effect for any symptoms of schizophrenia, the number of dropouts due to inefficacy was significantly lower in the paliperidone group. We did not examine differences between secondgeneration and first-generation antipsychotics as classes, because this classification has been replaced with “Neuroscience Based Nomenclature (NbN)” by societies such as the European and the American Colleges of Neuropsychopharmacology (Zohar et al., 2014).
4.1.
Comparison to other meta-analyses
How do these results in differential efficacy and side effects of antipsychotics compare to findings from previous meta-analytic studies in the general population which often excluded elderly patients? Compared to a large network meta-analysis (NMA), do antipsychotics in treatment of schizophrenia (Leucht et al., 2013) which included 212 RCT’s with data for 43,049 patients in the general population (mean age 38.4), the direction of effects were generally similar, although the effect sizes differed and although most of our findings were not statistically significant. As the previous NMA which reported a small superiority for olanzapine compared to haloperidol (SMD –0.14 CI, –0.21 to –0.08), we also found a moderate effect favoring olanzapine in our meta-analysis about elderly patients (SMD −0.47, CI −0.84 to −0.10). In terms of prolactin increase we found
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Antipsychotic drugs for elderly patients with schizophrenia significant differences favoring olanzapine compared to risperidone (SMD − 1.38, CI − 1.80 to − 0.97] and to haloperidol (SMD −0.66, CI −1.07 to −0.25). However the effect sizes for the earlier NMA in the general population were again smaller: olanzapine vs. risperidone (SMD –1.09, CI –1.28 to –0.90) and olanzapine vs. haloperidol (SMD –0.56, CI –0.73 to –0.40). Except of these trend differences in a few comparisons, the insufficient evidence of the subgroup was not able to reveal clear differences in the effects of antipsychotic treatment in elderly patients compared to the earlier meta-analyses using mostly younger patients. In particular for those comparisons and outcomes for which no evidence was available, clinicians therefore need to rely on the results in the “general” people with schizophrenia, keeping the specific characteristics of elderly people such as higher side-effect vulnerability and reduced metabolism into account.
4.2.
General limitations
The present meta-analysis is not without limitations. For many comparisons only one study was available. This is not, however, a reason to not systematically present and review their effect sizes which primarily depend on sample size and not on number of studies. We systematically reviewed all the relevant studies available and presented results graphically using standardized statistical procedures utilized in modern meta-analysis. But it is possible that some comparisons which showed non-significant trends might show significant effects if statistical power was increased if a larger number of subjects and/or studies were available for that comparison. The lack of data is particularly important for some of the side-effect evaluations. In the supplement eFigs. 10–12 show that data on important side effects like QTC prolongation, prolactin increase or use of at least one antiparkinson medication were often not reported in the original studies. A reason for the low frequency of reporting for these outcomes may be due to the fact that most of the included publications from which we extracted our data were only subgroup analysis of larger studies, and some were presented only in abstracts. This is also an important reason for the high frequency of unclear risk of bias ratings and small sample sizes.
4.3.
Elderly vs geriatric patients
Another important issue is that the included studies used very heterogeneous definitions of “elderly”. The minimum age ranged from 46 up to 65 and the mean age from around 57 up to nearly 73. Only three out of eighteen included studies included patients with a minimum age of sixty-five. However, in a sample with more uniformly older age patients, all above age 60 or 65, it is quite possible we might still not find significant differences in efficacy or side effects of antipsychotic drugs, in elderly patients with schizophrenia. Many patients these days in their 60’s are in fairly good health and do not differ in important ways from patients 10 or even 20 years younger. Age itself may not be the most important differentiating factor. In order to explore whether there are
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9 meaningful differences we might have to focus more particularly on patients who would be classified as geriatric by recent definitions. The German Society of Geriatrics (DGG), the German Society of Gerontology and Geriatrics (DGGG), and the German Group of Geriatric Institutions (BAG) developed a definition of the geriatric patient (Sieber, 2007) including mainly an age of over 70 and a high multimorbidity. There are not sufficient trials with antipsychotic drugs in patients with schizophrenia or related psychosis who meet this more specific geriatric classification, but, as the population ages, more patients will be falling into this group. More studies of antipsychotics in patients with schizophrenia or related psychosis are needed, in patients who meet inclusion criteria for being truly geriatric as described above (Sieber, 2007), in order to determine whether there are important differences in efficacy or side effects in this geriatric group who are treated with antipsychotics for these illness.
Contributors The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SL and MK designed this study. MK, MH, JS, PR, HR, SB, LB, MS, TA, LR and NP extracted the data. MK and RS analyzed data. MK and SL wrote the first draft of the manuscript and RS revised it. All authors contributed to and have approved the final manuscript.
Declaration of interests SL has received honoraria for consulting from LB Pharma, Lundbeck, Otsuka, TEVA, Geodon Richter, Recordati, LTS Lohmann, and Boehringer Ingelheim; and for lectures from Janssen, Lilly, Lundbeck, Otsuka, SanofiAventis, and Servier. MH has received speaker’s honoraria from Janssen and Lundbeck. Robert Smith is a consultant for Abbot on the development of a new medication. The other authors declare no competing interests.
Acknowledgments This work was supported by a grant from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF, Grant no. FKZ 01KG1508). We thank Samantha Roberts for help in the literature search and Leonie Reichelt, Hannah Röder, Susanne Bächer, Lio Bäckers, Myrto Samara, Thomas Arndt and Natalie Peter for help in data extraction. We thank all authors of the included studies, particularly those who sent us additional information about their trials.
Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.euroneuro. 2018.09.007.
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References Andia, I., Zumarraga, M., Zabalo, M.J., Bulbena, A., Davila, R., 1998. Differential effect of haloperidol and clozapine on plasma homovanillic acid in elderly schizophrenic patients with or without tardive dyskinesia. Biol Psychiatry 43 (1), 20–23. Andreas, S., Schulz, H., Volkert, J., Dehoust, M., Sehner, S., Suling, A., Ausín, B., Canuto, A., Crawford, M., Da Ronch, C., Grassi, L., Hershkovitz, Y., Muñoz, M., Quirk, A., Rotenstein, O., Santos-Olmo, A.B., Shalev, A., Strehle, J., Weber, K., Wegscheider, K., Wittchen, H.-U., Härter, M., 2017. Prevalence of mental disorders in elderly people: the European MentDis_ICF65+ study. Brit. J. Psychiatry J. Ment. Sci. 210 (2), 125–131. doi:10. 1192/bjp.bp.115.180463. Barak, Y., Shamir, E., Weizman, R., 2000. Risperidone compared with typical neuroleptic treatment in elderly schizophrenic patients. Int. J. Neuropsychopharmacol. 3, S122 (Abstracts of the XXIInd CINP Congress, Brussels, Belgium, July 9-13, 2000). Barak, Y., Shamir, E., Zemishlani, H., Mirecki, I., Toren, P., Weizman, R., 2002. Olanzapine vs. haloperidol in the treatment of elderly chronic schizophrenia patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 26 (6), 1199–1202. Berman, I., Merson, A., Allan, E., Alexis, C., Losonczy, M., 1995. Effect of risperidone on cognitive performance in elderly schizophrenic patients: a double-blind comparison study with haloperidol. Psychopharmacol. Bull. 31 (3), 552. Bian, Z.X., Li, Y.P., Moher, D., Dagenais, S., Liu, L., Wu, T.X., Miao, J.X., Kwan, A.K., Song, L., 2006. Improving the quality of randomized controlled trials in Chinese herbal medicine, part I: clinical trial design and methodology. Zhong xi yi jie he xue bao. J. Chin. Integr. Med. 4 (2), 120–129. Bora, G., 1968. Comparison of dosage ranges of carphenazine and trifluoperazine in elderly chronic schizophrenics. Dis. Nerv. Syst. 29 (10), 695–697. Branchey, M.H., Lee, J.H., Amin, R., Simpson, G.M., 1978. Highand low-potency neuroleptics in elderly psychiatric patients. JAMA 239 (18), 1860–1862. Cohen, J., 2013. Statistical Power Analysis for the Behavioral Sciences. Elsevier Science, Burlington, p. 459. Colenda, C.C., Mickus, M.A., Marcus, S.C., Tanielian, T.L., Pincus, H.A., 2002. Comparison of adult and geriatric psychiatric practice patterns: findings from the American Psychiatric Association’s Practice Research Network. Am. J. Geriatric Psychiatry Off. J. Am. Assoc. Geriatric Psychiatry 10 (5), 609–617. DerSimonian, R., Laird, N., 1986. Meta-analysis in clinical trials. Controll. Clin. Trials 7 (3), 177–188. doi:10.1016/0197-2456(86) 90046-2. Divine, G.W., Brown, J.T., Frazier, L.M., 1992. The unit of analysis error in studies about physicians’ patient care behavior. J. General Internal Med. 7 (6), 623–629. Elbourne, D.R., Altman, D.G., Higgins, J.P.T., Curtin, F., Worthington, H.V., Vail, A., 2002. Meta-analyses involving cross-over trials: methodological issues. Int. J. Epidemiol. 31 (1), 140–149. Essali, A., Ali, G., 2012. Antipsychotic drug treatment for elderly people with late-onset schizophrenia. Cochrane Database Syst. Rev. 2, CD004162. doi:10.1002/14651858.CD004162.pub2. Feldman, P.D., Kaiser, C.J., Kennedy, J.S., Sutton, V.K., Tran, P.V., Tollefson, G.D., Zhang, F., Breier, A., 2003. Comparison of risperidone and olanzapine in the control of negative symptoms of chronic schizophrenia and related psychotic disorders in patients aged 50 to 65 years. J. Clin. Psychiatry 64 (9), 998–1004. Furukawa, T.A., Barbui, C., Cipriani, A., Brambilla, P., Watanabe, N., 2006. Imputing missing standard deviations in metaanalyses can provide accurate results. J. Clin. Epidemiol. 59 (1), 7–10. doi:10.1016/j.jclinepi.2005.06.006.
[m6+;September 19, 2018;17:35]
M. Krause et al. Fusar-Poli, P., Papanastasiou, E., Stahl, D., Rocchetti, M., Carpenter, W., Shergill, S., McGuire, P., 2015. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr. Bull. 41 (4), 892–899. doi:10.1093/schbul/sbu170. Higgins, JPT, 2011. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Wiley and Sons, Chichester, UK [updated March 2011]. Howanitz, E., Pardo, M., Smelson, D.A., Engelhart, C., Eisenstein, N., Losonczy, M.F., 1999. The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia. Erratum. J. Clin. Psychiatry 60 (5), 341. Jeste, D.V., Barak, Y., Madhusoodanan, S., Grossman, F., Gharabawi, G., 2003. International multisite double-blind trial of the atypical antipsychotics risperidone and olanzapine in 175 elderly patients with chronic schizophrenia. [Erratum appears in Am J Geriatr Psychiatry. 2004 Jan-Feb;12(1): 49]. Am. J. Geriatr. Psychiatry 11 (6), 638–647. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13 (2), 261–276. Kennedy, J.S., Jeste, D., Kaiser, C.J., Golshan, S., Maguire, G.A., Tollefson, G., Sanger, T., Bymaster, F.P., Kinon, B.J., Dossenbach, M., Gilmore, J.A., Breier, A., 2003. Olanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial. Int. J. Geriatr. Psychiatry 18 (11), 1013–1020. Kinon, B.J., Stauffer, V.L., Kaiser, C., Kollack-Walker, S., 2003. Incidence of presumptive tardive dyskinesia in elderly patients treated with olanzapine or conventional antipsychotics. In: Proceedings of the 156th Annual Meeting of the American Psychiatric Association. San Francisco CA Nr55. Lacro, J., 2001. Antipsychotic Treatment in Late Life Schizophrenia. CRISP Database. Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., Samara, M., Barbui, C., Engel, R.R., Geddes, J.R., Kissling, W., Stapf, M.P., Lässig, B., Salanti, G., Davis, J.M., 2013. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet 382 (9896), 951–962. Leucht, S., Förstl, H., Bäuml, J., 2012. Kurzlehrbuch Psychiatrie und Psychotherapie [+ campus.thieme.de]. Thieme, Stuttgart, p. 87 chapter 4, ISBN-10: 3131483814. Leucht, S., Pitschel-Walz, G., Engel, R.R., Kissling, W., 2002. Amisulpride, an unusual “atypical” antipsychotic: a metaanalysis of randomized controlled trials. Am. J. Psychiatry 159 (2), 180–190. doi:10.1176/appi.ajp.159.2.180. McGrath, J., Saha, S., Chant, D., Welham, J., 2008. Schizophrenia: A concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 30, 67–76. doi:10.1093/epirev/mxn001. Mintzer, J.E., Mullen, J.A., Sweitzer, D.E., 2004. A comparison of extrapyramidal symptoms in older outpatients treated with quetiapine or risperidone. Curr. Med. Res. Opin. 20 (9), 1483–1491. Overall, J.E., 1962. The brief psychiatric rating scale. PR 10 (3), 799. doi:10.2466/PR0.10.3.799-812. Remington, G., Foussias, G., Fervaha, G., Agid, O., Takeuchi, H., Lee, J., Hahn, M., 2016. Treating negative symptoms in schizophrenia: an update. Curr. Treat. Options Psychiatry 3, 133– 150. doi:10.1007/s40501- 016- 0075- 8. Riedel, M., Eich, F.X., Moller, H.J., 2009. A pilot study of the safety and efficacy of amisulpride and risperidone in elderly psychotic patients. Eur. Psychiatry 24 (3), 149–153. doi:10.1016/j.eurpsy. 2008.10.005. Ritchie, C.W., Chiu, E., Harrigan, S., Hall, K., Hassett, A., Macfarlane, S., Mastwyk, M., O’Connor, D.W., Opie, J., Ames, D., 2003. The impact upon extra-pyramidal side effects, clinical
Please cite this article as: M. Krause et al., Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.09.007
JID: NEUPSY
ARTICLE IN PRESS
Antipsychotic drugs for elderly patients with schizophrenia symptoms and quality of life of a switch from conventional to atypical antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia. Int. J. Geriatr. Psychiatry 18 (5), 432–440. Salganik, I., Modai, I., Bercovici, B.R., Kutzuk, D., Weizman, A., 1998. Clozapine vs haloperidol therapy in elderly chronic schizophrenic inpatients - Preliminary results. A double-blind, cross-over randomized study. Int. J. Geriatr. Psychopharmacol. 1 (4), 185–187. Sieber, C.C., 2007. Der ältere Patient–wer ist das? Der. Internist 48 (11), 1192–1194. doi:10.1007/s00108- 007- 1945- 3, 1190. Leucht, S., Huhn, M., Rothe, P., Schneider, J., Zhu, Y, 2016. Which are the most important first-generation antipsychotic drugs? Survey of international schizophrenia experts. In: Abstracts from the 5th Biennial SIRS Conference - Poster Abstracts. NPJ Schizophrenia 25.
[m6+;September 19, 2018;17:35]
11 Tzimos, A., Samokhvalov, V., Kramer, M., Ford, L., GassmannMayer, C., Lim, P., Eerdekens, M., 2008. Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension. Am. J. Geriatr. Psychiatry 16 (1), 31–43. doi:10.1097/JGP.0b013e31815a3e7a. United Nations, Department of Economic and Social Affairs, Population Division, 2015. World population ageing, 2015. United Nations, New York, 1 online resource (164). Wu, T., Li, Y., Bian, Z., Liu, G., Moher, D., 2009. Randomized trials published in some Chinese journals: how many are randomized? Trials 10, 46. doi:10.1186/1745- 6215- 10- 46. Zohar, J., Nutt, D.J., Kupfer, D.J., Moller, H.-J., Yamawaki, S., Spedding, M., Stahl, S.M., 2014. A proposal for an updated neuropsychopharmacological nomenclature. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 24 (7), 1005–1014. doi:10.1016/j.euroneuro.2013.08.004.
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