IMPORTANCE: Atypical antipsychotics offer modest effectiveness compared with placebo but with serious safety risks, including a boxed warning for the risk of death in the treatment of behavioral and psychological symptoms of dementia (BPSD). Their comparative effectiveness and safety are not fully known.
OBJECTIVE: To assess the relative benefits and safety of atypical antipsychotics in the treatment of BPSD shown in randomized clinical trials using network meta-analysis.
DATA SOURCES: PubMed/MEDLINE, Embase, PsychINFO, and Cochrane Library were searched from their inception until May 31, 2018. Key terms included dementia and atypical antipsychotics.
STUDY SELECTION: Randomized clinical trials comparing any atypical antipsychotic with another atypical antipsychotic or with placebo were included in the analysis.
DATA EXTRACTION AND SYNTHESIS: Two independent reviewers used a standardized data extraction and quality assessment form. Random-effects network meta-analyses were performed. Effect sizes were reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% CIs. In addition to ORs, the surface under the cumulative ranking curve (SUCRA) was ascertained, which represents the percentage of the effectiveness or safety for each treatment compared with a hypothetical treatment that would be ranked first without uncertainty.
MAIN OUTCOMES AND MEASURES: The primary effectiveness outcome assessed was the Neuropsychiatric Inventory (NPI); secondary effectiveness outcomes were the Brief Psychiatric Rating Scale (BPRS) and Cohen-Mansfield Agitation Inventory (CMAI). The primary safety outcomes were death and cerebrovascular adverse events (CVAEs). Secondary safety outcomes were extrapyramidal signs/symptoms; somnolence/sedation; falls, fracture, or injury; and urinary tract infection/incontinence.
RESULTS: Seventeen studies (5373 patients) were included. The mean (SD) age of all participants was 80.8 (3.1) years, and most were women (3748 [69.8%]). Compared with placebo, aripiprazole was associated with improvement in outcomes on the NPI (SMD, -0.17; 95% CI, -0.31 to -0.02), BPRS (SMD, -0.20; 95% CI, -0.35 to -0.05), and CMAI (SMD, -0.30; 95% CI, -0.55 to -0.05); quetiapine was associated with improvement in outcomes on the BPRS (SMD, -0.24; 95% CI, -0.46 to -0.01), and risperidone was associated with improvement in outcomes on the CMAI (SMD, -0.26; 95% CI, -0.37 to -0.15). Differences between atypical antipsychotics were not significant for effectiveness, death, or CVAE. Compared with placebo, risperidone (OR, 3.85; 95% CI, 1.55-9.55) and olanzapine (OR, 4.28; 95% CI, 1.26-14.56) were associated with increased risk of CVAEs. The SUCRA estimated relative ranking of treatments suggested that aripiprazole might be the most effective and safe atypical antipsychotic and that olanzapine provides the least benefit overall; however, these results should be interpreted with caution where point estimates (OR and SMD) show that there is no statistically significant difference.
CONCLUSIONS AND RELEVANCE: This network meta-analysis supports the existence of a trade-off between the effectiveness and safety of atypical antipsychotics in the treatment of BPSD and confirms that a single most effective and safe treatment option does not exist. Clinicians should individualize the assessment of safety risks against expected benefits when prescribing these medications to patients with dementia.
BACKGROUND: Although delirium is typically an acute reversible cognitive impairment, its presence is associated with devastating impact on both short-term and long-term outcomes for critically ill patients. Advances in our understanding of the negative impact of delirium on patient outcomes have prompted trials evaluating multiple pharmacological interventions. However, considerable uncertainty surrounds the relative benefits and safety of available pharmacological interventions for this population.
OBJECTIVES: Primary objective1. To assess the effects of pharmacological interventions for treatment of delirium on duration of delirium in critically ill adults with confirmed or documented high risk of deliriumSecondary objectivesTo assess the following:1. effects of pharmacological interventions on delirium-free and coma-free days; days with coma; delirium relapse; duration of mechanical ventilation; intensive care unit (ICU) and hospital length of stay; mortality; and long-term outcomes (e.g. cognitive; discharge disposition; health-related quality of life); and2. the safety of such treatments for critically ill adult patients.
SEARCH METHODS: We searched the following databases from their inception date to 21 March 2019: Ovid MEDLINE®, Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Embase Classic+Embase, and PsycINFO using the Ovid platform. We also searched the Cochrane Library on Wiley, the International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk/PROSPERO/), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. We performed a grey literature search of relevant databases and websites using the resources listed in Grey Matters developed by the Canadian Agency for Drugs and Technologies in Health (CADTH). We also searched trial registries and abstracts from annual scientific critical care and delirium society meetings.
SELECTION CRITERIA: We sought randomized controlled trials (RCTs), including quasi-RCTs, of any pharmacological (drug) for treatment of delirium in critically ill adults. The drug intervention was to be compared to another active drug treatment, placebo, or a non-pharmacological intervention (e.g. mobilization). We did not apply any restrictions in terms of drug class, dose, route of administration, or duration of delirium or drug exposure. We defined critically ill patients as those treated in an ICU of any specialty (e.g. burn, cardiac, medical, surgical, trauma) or high-dependency unit.
DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies from the search results; four review authors (in pairs) performed data extraction and assessed risk of bias independently. We performed data synthesis through pairwise meta-analysis and network meta-analysis (NMA). Our hypothetical network structure was designed to be analysed at the drug class level and illustrated a network diagram of 'nodes' (i.e. drug classes) and 'edges' (i.e. comparisons between different drug classes from existing trials), thus describing a treatment network of all possible comparisons between drug classes. We assessed the quality of the body of evidence according to GRADE, as very low, low, moderate, or high.
MAIN RESULTS: We screened 7674 citations, from which 14 trials with 1844 participants met our inclusion criteria. Ten RCTs were placebo-controlled, and four reported comparisons of different drugs. Drugs examined in these trials were the following: antipsychotics (n = 10), alpha2 agonists (n = 3; all dexmedetomidine), statins (n = 2), opioids (n = 1; morphine), serotonin antagonists (n = 1; ondansetron), and cholinesterase (CHE) inhibitors (n = 1; rivastigmine). Only one of these trials consistently used non-pharmacological interventions that are known to improve patient outcomes in both intervention and control groups.Eleven studies (n = 1153 participants) contributed to analysis of the primary outcome. Results of the NMA showed that the intervention with the smallest ratio of means (RoM) (i.e. most preferred) compared with placebo was the alpha2 agonist dexmedetomidine (0.58; 95% credible interval (CrI) 0.26 to 1.27; surface under the cumulative ranking curve (SUCRA) 0.895; moderate-quality evidence). In order of descending SUCRA values (best to worst), the next best interventions were atypical antipsychotics (RoM 0.80, 95% CrI 0.50 to 1.11; SUCRA 0.738; moderate-quality evidence), opioids (RoM 0.88, 95% CrI 0.37 to 2.01; SUCRA 0.578; very-low quality evidence), and typical antipsychotics (RoM 0.96, 95% CrI 0.64 to1.36; SUCRA 0.468; high-quality evidence).The NMAs of multiple secondary outcomes revealed that only the alpha2 agonist dexmedetomidine was associated with a shorter duration of mechanical ventilation (RoM 0.55, 95% CrI 0.34 to 0.89; moderate-quality evidence), and the CHE inhibitor rivastigmine was associated with a longer ICU stay (RoM 2.19, 95% CrI 1.47 to 3.27; moderate-quality evidence). Adverse events often were not reported in these trials or, when reported, were rare; pair-wise analysis of QTc prolongation in seven studies did not show significant differences between antipsychotics, ondansetron, dexmedetomidine, and placebo.
AUTHORS' CONCLUSIONS: We identified trials of varying quality that examined six different drug classes for treatment of delirium in critically ill adults. We found evidence that the alpha2 agonist dexmedetomidine may shorten delirium duration, although this small effect (compared with placebo) was seen in pairwise analyses based on a single study and was not seen in the NMA results. Alpha2 agonists also ranked best for duration of mechanical ventilation and length of ICU stay, whereas the CHE inhibitor rivastigmine was associated with longer ICU stay. We found no evidence of a difference between placebo and any drug in terms of delirium-free and coma-free days, days with coma, physical restraint use, length of stay, long-term cognitive outcomes, or mortality. No studies reported delirium relapse, resolution of symptoms, or quality of life. The ten ongoing studies and the six studies awaiting classification that we identified, once published and assessed, may alter the conclusions of the review.
BACKGROUND: Guidelines suggest limited and cautious use of antipsychotics for treatment of delirium where nonpharmacological interventions have failed and symptoms remain distressing or dangerous, or both. It is unclear how well these recommendations are supported by current evidence.
OBJECTIVES: Our primary objective was to assess the efficacy of antipsychotics versus nonantipsychotics or placebo on the duration of delirium in hospitalised adults. Our secondary objectives were to compare the efficacy of: 1) antipsychotics versus nonantipsychotics or placebo on delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects; and 2) atypical vs. typical antipsychotics for reducing delirium duration, severity, and resolution, hospital mortality and length of stay, discharge disposition, health-related quality of life, and adverse effects.
SEARCH METHODS: We searched MEDLINE, Embase, Cochrane EBM Reviews, CINAHL, Thomson Reuters Web of Science and the Latin American and Caribbean Health Sciences Literature (LILACS) from their respective inception dates until July 2017. We also searched the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database, Web of Science ISI Proceedings, and other grey literature.
SELECTION CRITERIA: We included randomised and quasi-randomised trials comparing 1) antipsychotics to nonantipsychotics or placebo and 2) typical to atypical antipsychotics for the treatment of delirium in adult hospitalised (but not critically ill) patients.
DATA COLLECTION AND ANALYSIS: We examined titles and abstracts of identified studies to determine eligibility. We extracted data independently in duplicate. Disagreements were settled by further discussion and consensus. We used risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect for dichotomous outcomes, and between-group standardised mean differences (SMD) with 95% CI for continuous outcomes.
MAIN RESULTS: We included nine trials that recruited 727 participants. Four of the nine trials included a comparison of an antipsychotic to a nonantipsychotic drug or placebo and seven included a comparison of a typical to an atypical antipsychotic. The study populations included hospitalised medical, surgical, and palliative patients.No trial reported on duration of delirium. Antipsychotic treatment did not reduce delirium severity compared to nonantipsychotic drugs (standard mean difference (SMD) -1.08, 95% CI -2.55 to 0.39; four studies; 494 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (SMD -0.17, 95% CI -0.37 to 0.02; seven studies; 542 participants; low-quality evidence). There was no evidence antipsychotics resolved delirium symptoms compared to nonantipsychotic drug regimens (RR 0.95, 95% CI 0.30 to 2.98; three studies; 247 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (RR 1.10, 95% CI 0.79 to 1.52; five studies; 349 participants; low-quality evidence). The pooled results indicated that antipsychotics did not alter mortality compared to nonantipsychotic regimens (RR 1.29, 95% CI 0.73 to 2.27; three studies; 319 participants; low-quality evidence) nor was there a difference between typical and atypical antipsychotics (RR 1.71, 95% CI 0.82 to 3.35; four studies; 342 participants; low-quality evidence).No trial reported on hospital length of stay, hospital discharge disposition, or health-related quality of life. Adverse event reporting was limited and measured with inconsistent methods; in those reporting events, the number of events were low. No trial reported on physical restraint use, long-term cognitive outcomes, cerebrovascular events, or QTc prolongation (i.e. increased time in the heart's electrical cycle). Only one trial reported on arrhythmias and seizures, with no difference between typical or atypical antipsychotics. We found antipsychotics did not have a higher risk of extrapyramidal symptoms (EPS) compared to nonantipsychotic drugs (RR 1.70, 95% CI 0.04 to 65.57; three studies; 247 participants; very-low quality evidence); pooled results showed no increased risk of EPS with typical antipsychotics compared to atypical antipsychotics (RR 12.16, 95% CI 0.55 to 269.52; two studies; 198 participants; very low-quality evidence).
AUTHORS' CONCLUSIONS: There were no reported data to determine whether antipsychotics altered the duration of delirium, length of hospital stay, discharge disposition, or health-related quality of life as studies did not report on these outcomes. From the poor quality data available, we found antipsychotics did not reduce delirium severity, resolve symptoms, or alter mortality. Adverse effects were poorly or rarely reported in the trials. Extrapyramidal symptoms were not more frequent with antipsychotics compared to nonantipsychotic drug regimens, and no different for typical compared to atypical antipsychotics.
AIMS: To determine the most efficacious and acceptable treatments of agitation in dementia.
METHODS: MEDLINE, EMBASE, PsycINFO, CENTRAL and clinicaltrials.gov were searched to 7 February 2017. Two independent reviewers selected randomised controlled trials (RCTs) of treatments to alleviate agitation in people with all-types dementia. Data were extracted using standardised forms and study quality was assessed using the revised Cochrane Risk of Bias Tool for RCTs. Data were pooled using multivariate random-effects meta-regressions. The primary outcome, efficacy, was 8-week response rates defined as a 50% reduction in baseline agitation score. The secondary outcome was treatment acceptability defined as treatment continuation for eight weeks.
RESULTS: Thirty-six RCTs comprising 5,585 participants (30.9% male; mean [SD] age, 81.8 [4.9] years) were included. Dextromethorphan/quinidine (OR 3.04; 95% CI, 1.63-5.66), risperidone (OR 1.96; 95% CI, 1.49-2.59) and selective serotonin reuptake inhibitors (SSRIs) as a class (OR 1.61; 95% CI, 1.02-2.53) were found to be significantly more efficacious than placebo. Haloperidol appeared less efficacious than nearly all comparators. Most treatments had non-inferior treatment continuation compared to placebo, except oxcarbazepine, which was inferior. Findings were supported by subgroup and sensitivity analyses.
CONCLUSIONS: Risperidone, SSRIs as a class and dextromethorphan/quinidine demonstrated evidence of efficacy for agitation in dementia, although findings for dextromethorphan/quinidine were based on a single RCT. Our findings do not support prescribing haloperidol due to lack of efficacy, or oxcarbazepine due to lack of acceptability. The decision to prescribe should be based on comprehensive consideration of the benefits and risks, including those not evaluated in this meta-analysis.
BACKGROUND: Delirium is a common clinical syndrome defined as alterations in attention with an additional disturbance in cognition or perception, which develop over a short period of time and tend to fluctuate during the course of the episode. Delirium is commonly treated in hospitals or community settings and is often associated with multiple adverse outcomes such as increased cost, morbidity, and even mortality. The first-line intervention involves a multicomponent non-pharmacological approach that includes ensuring effective communication and reorientation in addition to providing reassurance or a suitable care environment. There are currently no drugs approved specifically for the treatment of delirium. Clinically, however, various medications are employed to provide symptomatic relief, such as antipsychotic medications and cholinesterase inhibitors, among others.
OBJECTIVES: To evaluate the effectiveness and safety of cholinesterase inhibitors for treating people with established delirium in a non-intensive care unit (ICU) setting.
SEARCH METHODS: We searched ALOIS, which is the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, on 26 October 2017. We also cross-checked the reference lists of included studies to identify any potentially eligible trials.
SELECTION CRITERIA: We included randomised controlled trials, published or unpublished, reported in English or Chinese, which compared cholinesterase inhibitors to placebo or other drugs intended to treat people with established delirium in a non-ICU setting.
DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were duration of delirium, severity of delirium, and adverse events. The secondary outcomes were use of rescue medications, persistent cognitive impairment, length of hospitalisation, institutionalisation, mortality, cost of intervention, leaving the study early, and quality of life. For dichotomous outcomes, we calculated the risk ratio (RR) with 95% confidence intervals (CIs); for continuous outcomes we calculated the mean difference (MD) with 95% CIs. We assessed the quality of evidence using GRADE to generate a 'Summary of findings' table.
MAIN RESULTS: We included one study involving 15 participants from the UK. The included participants were diagnosed with delirium based on the Confusion Assessment Method (CAM) criteria. Eight males and seven females were included, with a mean age of 82.5 years. Seven of the 15 participants had comorbid dementia at baseline. The risk of bias was low in all domains.The study compared rivastigmine with placebo. We did not find any clear differences between the two groups in terms of duration of delirium (MD -3.6, 95% CI -15.6 to 8.4), adverse events (nausea, RR 0.30, 95% CI 0.01 to 6.29), use of rescue medications (RR 0.13, 95% CI 0.01 to 2.1), mortality (RR 0.10, 95% CI 0.01 to 1.56), and leaving the study early (RR 0.88, 95% CI 0.07 to 11.54). Evidence was not available regarding the severity of delirium, persistent cognitive impairment, length of hospitalisation, cost of intervention, or other predefined secondary outcomes.The quality of evidence is low due to the very small sample size.
AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of cholinesterase inhibitors for the treatment of delirium in non-ICU settings. No clear benefits or harms associated with cholinesterase inhibitors were observed when compared with placebo due to the lack of data. More trials are required.
BACKGROUND: People experiencing psychosis may become aggressive. Antipsychotics, such as aripiprazole in intramuscular form, can be used in such situations.
OBJECTIVES: To evaluate the effects of intramuscular aripiprazole in the treatment of psychosis-induced aggression or agitation (rapid tranquillisation).
SEARCH METHODS: On 11 December 2014 and 11 April 2017, we searched the Cochrane Schizophrenia Group's Study-based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials.
SELECTION CRITERIA: All randomised controlled trials (RCTs) that randomised people with psychosis-induced aggression or agitation to receive either intramuscular aripiprazole or another intramuscular intervention.
DATA COLLECTION AND ANALYSIS: We independently inspected citations and, where possible, abstracts, ordered papers and re-inspected and quality assessed these. We included studies that met our selection criteria. At least two review authors independently extracted data from the included studies. We chose a fixed-effect model. We analysed dichotomous data using risk ratio (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their CIs. We assessed risk of bias for included studies and used GRADE to create 'Summary of findings' tables.
MAIN RESULTS: Searching found 63 records referring to 21 possible trials. We could only include three studies, all completed over the last decade, with 885 participants, of which 707 were included for quantitative analyses in this systematic review. Due to limited comparisons, small size of trials and a paucity of investigated and reported 'pragmatic' outcomes, evidence was mostly graded as low or very low quality. No trials reported useful data for one of our primary outcomes of tranquil or asleep by 30 minutes. Economic outcomes were also not reported in the trials.When compared with placebo, fewer people in the aripiprazole group needed additional injections compared to the placebo group (2 RCTs, n = 382, RR 0.69, 95% CI 0.56 to 0.85, very low-quality evidence). Clinically important improvement in agitation at two hours favoured the aripiprazole group (2 RCTs, n = 382, RR 1.50, 95% CI 1.17 to 1.92, very low-quality evidence). The numbers of non-responders after the first injection also favoured aripiprazole (1 RCT, n = 263, RR 0.49, 95% CI 0.34 to 0.71, low-quality evidence). Although no effect was found, more people in the aripiprazole compared to the placebo group experienced adverse effects (1 RCT, n = 117, RR 1.51, 95% CI 0.93 to 2.46, very low-quality evidence).Aripiprazole required more injections compared to haloperidol (2 RCTs, n = 477, RR 1.28, 95% CI 1.00 to 1.63, very low-quality evidence), with no significant difference in agitation (2 RCTs, n = 477, RR 0.94, 95% CI 0.80 to 1.11, very low-quality evidence), and similar non-responders after first injection (1 RCT, n = 360, RR 1.18, 95% CI 0.78 to 1.79, low-quality evidence). Aripiprazole and haloperidol did not differ when taking into account the overall number of people that experienced at least one adverse effect (1 RCT, n = 113, RR 0.91, 95% CI 0.61 to 1.35, very low-quality evidence).Compared to aripiprazole, olanzapine was better at reducing agitation (1 RCT, n = 80, RR 0.77, 95% CI 0.60 to 0.99, low-quality evidence) and had a more favourable effect on global state change scores (1 RCT, n = 80, MD 0.58, 95% CI 0.01 to 1.15, low-quality evidence), both at two hours. No differences were found in terms of experiencing at least one adverse effect during the 24 hours after treatment (1 RCT, n = 80, RR 0.75, 95% CI 0.45 to 1.24, very low-quality evidence). However, participants allocated to aripiprazole experienced less somnolence (1 RCT, n = 80, RR 0.25, 95% CI 0.08 to 0.82, low-quality evidence).
AUTHORS' CONCLUSIONS: The available evidence is of poor quality but there is some evidence aripiprazole is effective compared to placebo and haloperidol, but not when compared to olanzapine. However, considering that evidence comes from only three studies, caution is required in generalising these results to real-world practice. This review firmly highlights the need for more high-quality trials on intramuscular aripiprazole in the management of people with acute aggression or agitation.
BACKGROUND: Aggressive, agitated or violent behaviour due to psychosis constitutes an emergency psychiatric treatment where fast-acting interventions are required. Risperidone is a widely accessible antipsychotic that can be used to manage psychosis-induced aggression or agitation.
OBJECTIVES: To examine whether oral risperidone alone is an effective treatment for psychosis-induced aggression or agitation.
SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 2017); this register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. There are no language, date, document type, or publication status limitations for inclusion of records into the register.
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing rapid use of risperidone and other drugs, combinations of drugs or placebo for people exhibiting aggression or agitation (or both) thought to be due to psychosis.
DATA COLLECTION AND ANALYSIS: We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR) and for continuous data we calculated mean difference (MD), all with 95% confidence intervals (CI) and used a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce a ’Summary of findings’ tables.
MAIN RESULTS: The review now contains data from nine trials (total n = 582) reporting on five comparisons. Due to risk of bias, small size of trials, indirectness of outcome measures and a paucity of investigated and reported 'pragmatic' outcomes, evidence was graded as very-low quality. None of the included studies provided useable data on our primary outcome 'tranquillisation or asleep' by 30 minutes, repeated need for tranquillisation or any economic outcomes. Data were available for our other main outcomes of agitation or aggression, needing restraint, and incidence of adverse effects.Risperidone versus haloperidol (up to 24 hours follow-up)For the outcome, specific behaviour - agitation, no clear difference was found between risperidone and haloperidol in terms of efficacy, measured as at least 50% reduction in the Positive and Negative Syndrome Scale - Psychotic Agitation Sub-score (PANSS-PAS) (RR 1.04, 95% CI 0.86 to 1.26; participants = 124; studies = 1; very low-quality evidence) and no effect was observed for need to use restraints (RR 2.00, 95% CI 0.43 to 9.21; participants = 28; studies = 1; very low-quality evidence). Incidence of adverse effects was similar between treatment groups (RR 0.94, 95% CI 0.54 to 1.66; participants = 124; studies = 1; very low-quality evidence).Risperidone versus olanzapineOne small trial (n = 29) reported useable data for the comparison risperidone versus olanzapine. No effect was observed for agitation measured as PANSS-PAS endpoint score at two hours (MD 2.50, 95% CI -2.46 to 7.46; very low-quality evidence); need to use restraints at four days (RR 1.43, 95% CI 0.39 to 5.28; very-low quality evidence); specific movement disorders measured as Behavioural Activity Rating Scale (BARS) endpoint score at four days (MD 0.20, 95% CI -0.43 to 0.83; very low-quality evidence).Risperidone versus quetiapineOne trial reported (n = 40) useable data for the comparison risperidone versus quetiapine. Aggression was measured using the Modified Overt Aggression Scale (MOAS) endpoint score at two weeks. A clear difference, favouring quetiapine was observed (MD 1.80, 95% CI 0.20 to 3.40; very-low quality evidence). No evidence of a difference between treatment groups could be observed for incidence of akathisia after 24 hours (RR 1.67, 95% CI 0.46 to 6.06; very low-quality evidence). Two participants allocated to risperidone and one allocated to quetiapine experienced myocardial ischaemia during the trial.Risperidone versus risperidone + oxcarbazepineOne trial (n = 68) measured agitation using the Positive and Negative Syndrome Scale - Excited Component.(PANSS-EC) endpoint score and found a clear difference, favouring the combination treatment at one week (MD 2.70, 95% CI 0.42 to 4.98; very low-quality evidence), but no effect was observed for global state using Clinical Global Impression - Improvement (CGI-I) endpoint score at one week (MD -0.20, 95% CI -0.61 to 0.21; very-low quality evidence). Incidence of extrapyramidal symptoms after 24 hours was similar between treatment groups (RR 1.59, 95% CI 0.49 to 5.14; very-low quality evidence).Risperidone versus risperidone + valproic acidTwo trials compared risperidone with a combination of risperidone plus valproic acid. No clear differences between the treatment groups were observed for aggression (MOAS endpoint score at three days: MD 1.07, 95% CI -0.20 to 2.34; participants = 54; studies = 1; very low-quality evidence) or incidence of akathisia after 24 hours: RR 0.75, 95% CI 0.28 to 2.03; participants = 122; studies = 2; very low-quality evidence).
AUTHORS' CONCLUSIONS: Overall, results for the main outcomes show no real effect for risperidone. The only data available for use in this review are from nine under-sampled trials and the evidence available is of very low quality. This casts uncertainty on the role of risperidone in rapid tranquillisation for people with psychosis-induced aggression. High-quality pragmatic RCTs are feasible and are needed before clear recommendations can be drawn on the use of risperidone for psychosis-induced aggression or agitation.
ANTECEDENTES: La enfermedad psicótica aguda, especialmente cuando se asocia con conducta agitada o violenta, puede requerir tranquilización o sedación farmacológica urgente. En varios países, los médicos a menudo usan benzodiazepinas (ya sea solo o en combinación con antipsicóticos) para este resultado.
OBJETIVOS: Estimar los efectos de las benzodiazepinas, solas o en combinación con antipsicóticos, en comparación con placebo o antipsicóticos, solo o en combinación con antihistamínicos para controlar la conducta alterada y reducir los síntomas psicóticos.
ESTRATEGIA DE BÚSQUEDA: Se realizaron búsquedas de registros (enero de 2012), listas de referencias inspeccionadas por el Grupo Cochrane de Esquizofrenia de los estudios incluidos y excluidos y contacto con los autores de los estudios relevantes.
Criterios de selección: Se incluyeron todos los ensayos clínicos aleatorios (ECA) que compararon las benzodiazepinas solas o en combinación con antipsicóticos, en comparación con los antipsicóticos solos o en combinación con otros antipsicóticos, benzodiazepinas o antihistamínicos para las personas con enfermedades psicóticas agudas.
Recopilación y análisis de datos: Se seleccionaron los estudios, evaluaron su calidad y extrajeron los datos evaluados. Para los resultados binarios, se calcularon las estimaciones estándar del riesgo relativo (RR) y los intervalos de confianza (IC) del 95% mediante un modelo de efectos fijos. Para los resultados continuos, se calculó la diferencia de medias ponderada (DMP) entre los grupos. Si se identificó heterogeneidad, esto se exploró mediante un modelo de efectos aleatorios.
Resultados principales: Se incluyeron 21 ensayos con un total de n = 1968 participantes. No hubo diferencia significativa en la mayoría de los resultados en el único ensayo que comparó benzodiazepinas con placebo, aunque no había un mayor riesgo de ninguna mejoría en las personas que recibieron placebo en el mediano plazo (de uno a 48 horas) (n = 102, 1 ECA, RR 0,62, IC del 95%: 0,40 a 0,97, pruebas de muy baja calidad). No hubo diferencias en el número de participantes que no habían mejorado en el mediano plazo, cuando se compararon las benzodiazepinas con los antipsicóticos (n = 308, 5 ECAs, RR 1,10, IC del 95%: 0,85 a 1,42; pruebas de baja calidad), sin embargo, las personas que reciben benzodiazepinas fueron menos propensos a experimentar efectos extrapiramidales (EPS) en el mediano plazo (n = 536, 8 ECA, RR 0,15, IC del 95%: 0,06 a 0,39, calidad de evidencia moderada). Los datos que comparan las benzodiazepinas y los antipsicóticos combinados frente a las benzodiazepinas solas no dió ningún resultado significativo. Al comparar las benzodiazepinas / antipsicóticos (todos los estudios compararon el haloperidol) combinados con los mismos antipsicóticos solos (haloperidol), no hubo diferencia entre los grupos en la mejora a medio plazo (n = 155, 3 ECA, RR 1,27, IC del 95%: 0,94 a 1,70 , pruebas de calidad muy baja), pero la sedación fue más probable en personas que recibieron la terapia combinada (n = 172, 3 ECA, RR 1,75, IC del 95% 1.14 a 2.67, pruebas de muy baja calidad). Sin embargo, más participantes que recibieron benzodiazepinas combinados y haloperidol no habían mejorado en un mediano plazo, en comparación con los participantes que recibieron olanzapina (n = 60,1 ECA, RR 25,00; IC del 95%: 1,55 a 403,99, pruebas de muy baja calidad) o ziprasidona (n = 60 , 1 ECA, RR 4,00, IC del 95%: 1,25 a pruebas 12.75very baja calidad). Cuando haloperidol y midazolam fueron comparados con olanzapina, hubo algunas pruebas de que la combinación era superior en cuanto a la mejoría, la sedación y la conducta.
Conclusiones de los revisores: La evidencia de los ensayos para el uso de benzodiacepinas por sí solo no es bueno. Había relativamente pocos datos fiables y la mayoría de los ensayos son demasiado pequeños para resaltar las diferencias en efectos positivos o negativos. Adición de una benzodiazepina a otros fármacos no parecen conferir a la clara ventaja y tiene potencial para la adición de efectos adversos innecesarios. Uso exclusivo de los antipsicóticos más antiguos sin fármacos anticolinérgicos parece difícil de justificar. Se necesita mucha más investigación de alta calidad en esta área.
ANTECEDENTES: Se recomienda el haloperidol solo para ayudar a calmar situaciones de agresión o agitación en personas con psicosis. Es ampliamente accesible y puede ser el único medicamento antipsicótico disponible en áreas de recursos limitados. OBJETIVOS: Examinar si el haloperidol solo es un tratamiento eficaz para la agresión o agitación inducida por la psicosis, en la que se requiere que los médicos intervengan para prevenir el daño a sí mismo ya otros. Métodos de búsqueda: Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Esquizofrenia (26 de mayo de 2016). Este registro se compila mediante búsquedas sistemáticas de los principales recursos (incluyendo AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed y registros de ensayos clínicos) y sus actualizaciones mensuales, búsquedas manuales, literatura gris y actas de conferencias, sin idioma, fecha , El tipo de documento o las limitaciones del estado de publicación para la inclusión de registros en el registro. Los ensayos controlados aleatorios (ECA) que involucran a personas que exhiben agresión y / o agitación que se cree que son debidas a psicosis, asignaron el uso rápido de haloperidol solo (por cualquier vía), en comparación con cualquier otro tratamiento. Los resultados de interés incluyen la tranquilización o el sueño por 30 minutos, la necesidad repetida de tranquilización rápida dentro de 24 horas, comportamientos específicos (amenaza o lesión a otros / sí mismo), efectos adversos. Se incluyeron ensayos que cumplieron con los criterios de selección y proporcionaron datos utilizables. Recopilación y análisis de datos: Analizamos independientemente todas las citas de las búsquedas, identificamos resúmenes relevantes y extrajimos los datos de todos los estudios incluidos. Para los datos binarios se calculó la razón de riesgo (RR), para los datos continuos se calculó la diferencia de medias (MD), y para los resultados cognitivos se obtuvieron los tamaños del efecto de la diferencia de medias estandarizada (SMD), todos con intervalos de confianza del 95% - modelo del efecto. Se evaluó el riesgo de sesgo para los estudios incluidos y se utilizó el enfoque GRADE para producir tablas de "Resumen de hallazgos" que incluían nuestros principales resultados de interés previamente especificados. RESULTADOS PRINCIPALES: Se encontraron nueve nuevos ECA de la búsqueda de actualización de 2016, dando un total de 41 estudios incluidos y 24 comparaciones. Pocos estudios se llevaron a cabo en circunstancias que reflejen la práctica del mundo real, y con excepciones notables, la mayoría eran pequeñas y llevaban un considerable riesgo de sesgo. En comparación con el placebo, más personas en el grupo de haloperidol estaban dormidas a las dos horas (2 ECA, n = 220, RR 0,88, IC del 95%: 0,82 a 0,95 , Evidencia de muy baja calidad) y distonía experimentada (2 ECAs, n = 207, RR 7,49, IC del 95%: 0,93 a 60,21, evidencia de muy baja calidad). En comparación con el aripiprazol, las personas del grupo de haloperidol requirieron menos inyecciones El grupo de aripiprazol (2 ECAs, n = 473, RR 0,78, IC del 95%: 0,62 a 0,99, evidencia de baja calidad). Cuatro ensayos (n = 207) compararon el haloperidol con el lorazepam sin diferencias significativas con respecto a los resultados obtenidos en el grupo de haloperidol (2 ECA, n = 477, RR 6,63; IC del 95%: 1,52 a 28,86; (1 ECA, n = 60, RR 1,05, IC del 95%: 0,76 a 1,44, evidencia de muy baja calidad) o aquellos que requirieron inyecciones adicionales (1 ECA, n = 66, RR 1,14, 95 (P.ej. distonía 1 ECA, n = 67, RR 8,25, IC del 95%: 0,46 a 147,45, evidencia de muy baja calidad de la evidencia). Los efectos adversos del hooperidol no fueron compensados por la adición de lorazepam ). La adición de prometazina se investigó en dos ensayos (n = 376). Más personas en el grupo de haloperidol no estaban tranquilas o dormidas en 20 minutos (1 ECA, n = 316, RR 1,60, IC del 95%: 1,18 a 2,16, evidencia de calidad moderada). La distonía aguda fue demasiado común en el grupo tratado con haloperidol solo para que el ensayo continuara más allá del análisis intermedio (1 ECA, n = 316, RR 19,48, IC del 95%: 1,14 a 331,92, evidencia de baja calidad). CONCLUSIONES DE LOS AUTORES: Los datos adicionales de nuevos estudios no alteran las conclusiones anteriores de esta revisión. Si no existe otra alternativa, el uso exclusivo de haloperidol intramuscular podría salvar vidas. Cuando se dispone de fármacos adicionales, el uso exclusivo de haloperidol para situaciones de emergencia extrema podría considerarse poco ético. La adición de la prometazina sedante tiene el apoyo de pruebas de mejor calidad de los ensayos aleatorios. El uso de un fármaco antipsicótico alternativo sólo está parcialmente respaldado por pruebas fragmentadas y de bajo grado. La adición de una benzodiazepina al haloperidol no tiene evidencia fuerte del beneficio y lleva el riesgo del daño adicional. Después de seis décadas de uso para la tranquilización rápida de la emergencia, éste sigue siendo un área que necesita buenos ensayos independientes relevantes a la práctica del mundo real.
ANTECEDENTES: La medicación utilizada para la agresión aguda en psiquiatría debe proporcionar un rápido inicio del efecto, la baja frecuencia de administración y bajos niveles de efectos adversos. Acetato de zuclopentixol se dice que tiene estas propiedades.
OBJETIVOS: Estimar los efectos clínicos del acetato de zuclopentixol para el tratamiento de la agresión aguda o violencia, cree que es debido a enfermedades mentales graves, en comparación con otros fármacos utilizados para tratar enfermedades similares.
MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en el Cochrane de Esquizofrenia Registro de Ensayos del Grupo (julio de 2011). Esta información se complementó con búsquedas de referencias y el contacto personal con los autores y compañías farmacéuticas relevantes.
CRITERIOS DE SELECCIÓN: Todos los ensayos clínicos aleatorios que incluyeron la gente cree que tienen enfermedades mentales graves que compararon acetato de zuclopentixol con otros fármacos.
RECOPILACIÓN Y ANÁLISIS DE DATOS: Dos revisores extrajeron de manera independiente y controlaron de forma cruzada los datos. Se calcularon los efectos fijos riesgo relativo (RR) y el 95% intervalos de confianza (IC) para los datos dicotómicos. Se analizaron por intención de tratar. Hemos utilizado las diferencias de medias (DM) para las variables continuas.
RESULTADOS PRINCIPALES: No se encontraron datos para el resultado primario tranquilizantes,. En comparación con el haloperidol, el acetato de zuclopentixol no era más sedante a las dos horas (n = 40, 1 ECA, RR 0,60, IC 95%: 0,27 a 1,34). Personas asignadas a acetato de zuclopentixol no estaban en riesgo reducido de recibir antipsicóticos complementarios (n = 134, 3 ECA, RR 1,49, IC 95%: 0,97 a 2,30), aunque el uso adicional de benzodiazepinas fue menor (n = 50, 1 ECA; RR 0,03; 95%: 0,00 a 0,47). Las personas que recibieron acetato de zuclopentixol recibieron menos inyecciones en siete días en comparación con los asignados a haloperidol IM (n = 70, 1 ECA, RR 0,39, IC 95%: 0,18 a 0,84, NNT 4; IC: 3 a 14). No se encontraron datos de más episodios de agresión o daño a sí mismo oa los demás. Un ensayo (n = 148) informó que no hubo diferencias significativas en los efectos adversos para las personas que recibieron acetato de zuclopentixol en comparación con las asignadas a haloperidol a uno, tres y seis días (RR 0,74, IC 95%: 0,43 a 1,27). Comparado con haloperidol o clotiapina, las personas asignadas a zuclopentixol no parecen correr un mayor riesgo de una serie de trastornos del movimiento (<20%). Tres estudios no encontraron diferencias en la proporción de personas que presentaron visión borrosa / sequedad bucal (n = 192, 2 ECA, RR 0.90 a las 24 horas, el 95%: 0,48 a 1,70). Del mismo modo, el mareo fue igualmente poco frecuentes en los que el acetato de zuclopentixol asignado en comparación con el haloperidol (n = 192, 2 ECA, RR a las 24 horas 1,15, IC 95%: 0,46 a 2,88). No hubo diferencias entre los tratamientos para el abandono del estudio antes de su finalización (n = 522, RR 0,85, IC 95%: 0,31 a 2,31). Un estudio informó que no hubo diferencia en los efectos adversos y las puntuaciones de los resultados, cuando la dosis alta (50-100 mg / inyección) acetato de zuclopentixol se comparó con dosis bajas (25-50 mg / inyección) acetato de zuclopentixol.
CONCLUSIONES DE LOS: Recomendaciones sobre el uso de acetato de zuclopentixol para el tratamiento de emergencias psiquiátricas en preferencia a "los autores estándar" de tratamiento tienen que ser considerados con cautela. La mayoría de los pequeños ensayos presenta defectos metodológicos importantes y las conclusiones se informó de manera deficiente. Esta revisión no se encontró ninguna sugerencia de que el acetato de zuclopentixol es más o menos eficaz en el control de la psicosis aguda agresiva, o en la prevención de efectos adversos que haloperidol intramuscular, y no parecía tener un rápido inicio de acción. El uso de acetato de zuclopentixol puede resultar en inyecciones coercitivas menos numerosas y las dosis bajas del fármaco puede ser tan eficaz como las dosis altas. Bien realizados ensayos controlados aleatorios pragmáticos son necesarias.
Atypical antipsychotics offer modest effectiveness compared with placebo but with serious safety risks, including a boxed warning for the risk of death in the treatment of behavioral and psychological symptoms of dementia (BPSD). Their comparative effectiveness and safety are not fully known.
OBJECTIVE:
To assess the relative benefits and safety of atypical antipsychotics in the treatment of BPSD shown in randomized clinical trials using network meta-analysis.
DATA SOURCES:
PubMed/MEDLINE, Embase, PsychINFO, and Cochrane Library were searched from their inception until May 31, 2018. Key terms included dementia and atypical antipsychotics.
STUDY SELECTION:
Randomized clinical trials comparing any atypical antipsychotic with another atypical antipsychotic or with placebo were included in the analysis.
DATA EXTRACTION AND SYNTHESIS:
Two independent reviewers used a standardized data extraction and quality assessment form. Random-effects network meta-analyses were performed. Effect sizes were reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% CIs. In addition to ORs, the surface under the cumulative ranking curve (SUCRA) was ascertained, which represents the percentage of the effectiveness or safety for each treatment compared with a hypothetical treatment that would be ranked first without uncertainty.
MAIN OUTCOMES AND MEASURES:
The primary effectiveness outcome assessed was the Neuropsychiatric Inventory (NPI); secondary effectiveness outcomes were the Brief Psychiatric Rating Scale (BPRS) and Cohen-Mansfield Agitation Inventory (CMAI). The primary safety outcomes were death and cerebrovascular adverse events (CVAEs). Secondary safety outcomes were extrapyramidal signs/symptoms; somnolence/sedation; falls, fracture, or injury; and urinary tract infection/incontinence.
RESULTS:
Seventeen studies (5373 patients) were included. The mean (SD) age of all participants was 80.8 (3.1) years, and most were women (3748 [69.8%]). Compared with placebo, aripiprazole was associated with improvement in outcomes on the NPI (SMD, -0.17; 95% CI, -0.31 to -0.02), BPRS (SMD, -0.20; 95% CI, -0.35 to -0.05), and CMAI (SMD, -0.30; 95% CI, -0.55 to -0.05); quetiapine was associated with improvement in outcomes on the BPRS (SMD, -0.24; 95% CI, -0.46 to -0.01), and risperidone was associated with improvement in outcomes on the CMAI (SMD, -0.26; 95% CI, -0.37 to -0.15). Differences between atypical antipsychotics were not significant for effectiveness, death, or CVAE. Compared with placebo, risperidone (OR, 3.85; 95% CI, 1.55-9.55) and olanzapine (OR, 4.28; 95% CI, 1.26-14.56) were associated with increased risk of CVAEs. The SUCRA estimated relative ranking of treatments suggested that aripiprazole might be the most effective and safe atypical antipsychotic and that olanzapine provides the least benefit overall; however, these results should be interpreted with caution where point estimates (OR and SMD) show that there is no statistically significant difference.
CONCLUSIONS AND RELEVANCE:
This network meta-analysis supports the existence of a trade-off between the effectiveness and safety of atypical antipsychotics in the treatment of BPSD and confirms that a single most effective and safe treatment option does not exist. Clinicians should individualize the assessment of safety risks against expected benefits when prescribing these medications to patients with dementia.
