Manejo spcd2015

Notas del editor

• #2: Los síntomas psicológicos y conductuales de la demencia (SPCD) generan sufrimiento en el paciente y en el cuidador, agravan el deterioro cognitivo y funcional, y precipitan la institucionalización. Frente a las manifestaciones cognitivas y funcionales de la demencia, determinadas por el sustrato biológico y en gran medida predecibles, los SPCD pueden aparecer prácticamente en cualquier momento de la enfermedad, con un patrón de agrupación muy variable. Esta variabilidad es fruto de la importante influencia de factores psicologicos y ambientales susceptibles de modificación, que ofrece una oportunidad para el tratamiento. La conferencia de consenso convocada por la Asociacion Internacional de Psicogeriatria en 1996 acuñó el término ‘behavioral and psychological symptoms of dementia’ (SPCD en castellano) para aludir a un conjunto de síntomas y signos, previamente denominados de forma diversa (por ejemplo, síntomas psiquiátricos, complicaciones conductuales, problemas de conducta) que pueden aparecer en las personas con demencia. El nuevo termino implicaba dos clases de síntomas: los síntomas psicológicos, mas complejos y elaborados desde el punto de vista mental, obtenidos a través de la entrevista con el paciente y sus cuidadores (por ejemplo, depresión, ansiedad, psicosis); y los ‘síntomas’ (en realidad signos) conductuales, mas básicos, obtenidos mediante la observación directa del paciente (por ejemplo, agresividad, hiperactividad motora, desinhibición). Hoy en día, los SPCD constituyen un terreno abierto y multidisciplinario, de potencial interés incluso en las fases prodrómicas [4] e imprescindible en el manejo clínico de las demencias [5]. Los SPCD aparecen en todos los estadios de la EA, algunas veces, 2 años antes del diagnostico. El pico de frecuencia de los trastornos se muestran en el momento de aparición en la evolución de la enfermedad. Por ejemplo, el aislamiento social ocurre 33 meses antes del diagnostico y constituye el síntoma psicológico reconocible mas temprano. Ideación suicida, depresión, paranoia y trastornos del ritmo del sueño aparecen también tempranamente en el curso de la enfermedad; mientras que agitación, alucinaciones y agresividad suelen aparecer en promedio 1-2 años después del diagnostico.
• #6: Son escasos los factores biológicos identificados que dan lugar a SPCD fácilmente caracterizables y útiles para el diagnostico etiológico. El ejemplo paradigmático es el trastorno de conducta del sueno REM, hasta la fecha solo descrito en el contexto de α-sinucleinopatias (enfermedad de Parkinson, demencia con cuerpos de Lewy y degeneración multisistémica) y con buena respuesta al clonacepam. Otros trastornos, como la hiperfagia, la desinhibición, las conductas estereotipadas (daño frontal) y la afectividad pseudobulbar (daño subcortical o en el tronco cerebral), encajan aceptablemente en el modelo biológico. Sin embargo, en la mayoría de los casos, los SPCD aparecen como resultado de una interacción compleja de factores biológicos, psicológicos, sociales y ambientales que actúan sobre un organismo biológicamente predispuesto, por lo que el abordaje debe ser claramente multidisciplinario.
• #7: Antes de cualquier intervención, debe estar seguro de : Es una descripción exacta y cierta de la manifestación? Identificación de la conducta alterada principal y las secundarias. Esta conducta alterada requiere intervención? Diario detallado de la conducta alterada. Excluir las causas no demencia. Evaluación correcta de privación sensorial: Audición, Visión
• #8: Desde la perspectiva biológica, los SPCD se explican por una combinación de factores anatómicos, bioquímicos y genéticos, estos últimos mucho menos conocidos. El daño o disfunción frontal ha sido descrito como el principal determinante de alteraciones conductuales, ya sea debido a una alteración en los impulsos (apatía, hiperactividad, desinhibición, cambios en la alimentación) o a un deficiente juicio o contraste con la realidad (alteración del pensamiento, fabulación). La disfunción frontal actuaría en solitario (hiperfagia, apatia, etc.) o en combinación (por ejemplo, en el trastorno de identificación asociado al daño o disfunción temporal derecha, o en la fabulación asociada a la alteración del circuito de Papez). Las diferentes entidades anatomo-clínicas se acompañan de tipos o combinaciones de SPCD en la medida en que muestran preferencia por distintas regiones cerebrales. Además de los ejemplos ya mencionados, son relativamente especificas las alucinaciones visuales (demencia con cuerpos de Lewy) y las identificaciones erróneas (enfermedad de Alzheimer). La fragmentación del sueno tiende también a aparecer con mayor frecuencia en la enfermedad de Alzheimer, debido al deficit colinérgico y a la degeneración del núcleo supraquiásmatico. Asimismo, se han descrito en la enfermedad de Alzheimer alteraciones en neurotransmisores, y asociaciones entre polimorfismos genéticos y SPCD. Las vías mas implicadas son las de la serotonina, noradrenalina, dopamina y glutamato.
• #9: De forma menos especifica, cualquier proceso medico intercurrente que provoque cambios toxico-metabólicos, malestar o dolor desencadenara SPCD por un mecanismo de daño difuso, que típicamente dará lugar a estados de agitación o retraimiento, acompañados de una semiología rica y variable (alteración de la percepción y el pensamiento, ansiedad, signos físicos, etc.). La posibilidad de una causa medica aguda añadida a la demencia ha de estar siempre presente, en cuyo caso se tratara de un síndrome confusional. La distinción entre el síndrome confusional y los SPCD no siempre es fácil, pero de ello puede depender el pronostico funcional e incluso vital.
• #10: Los modelos de la reducción del umbral para el estres y de las necesidades no cubiertas, y la teoría del aprendizaje ayudan a comprender como se generan y mantienen los SPCD. Sucesos vitales estresantes o simplemente estímulos que el paciente no sea capaz de procesar o comprender pueden dar lugar a SPCD. En el extremo opuesto, la perdida de relaciones o de otros estímulos, actividades o funciones relevantes para el individuo generará también SPCD. El modelo de las necesidades no cubiertas distingue entre las necesidades biológicas (alimentación, adecuada temperatura, iluminación, actividad física, etc.), psicológicas (seguridad, empatía, refuerzo afectivo, presencia de otros, etc.) y sociales (compañía, valoración, respeto, etc.). En un reciente estudio, el numero de necesidades no cubiertas fue el principal factor asociado a SPCD. Las necesidades mas frecuentemente detectadas fueron la realización de actividades, la compañía y la ayuda con el distres psicológico. La teoría del aprendizaje, derivada del modelo conductual, explica como los estímulos ambientales pueden mantener, extinguir o cambiar las conductas en función del tipo de refuerzo (placentero o displacentero) asociado. El cuidador, ya sea familiar o profesional, desempeña un papel fundamental tanto en la prevención como en la causa de muchos SPCD. La mayoría de los estudios de SPCD y cuidadores se centran en los efectos de estos sobre el cuidador. Hay escasa bibliografía en el sentido inverso, pero, en opinión de los autores, es clave. Por ejemplo, un cuidador podría estar reforzando una conducta agitada si solo presta atención a su familiar con demencia en los momentos en que este se muestra inquieto o agitado. Otras conductas del cuidador que pueden crear o mantener SPCD son: trato paternalista, autoritario o «aniñado», exasperación, ignorar al paciente, imponer cosas o luchas de poder, o preguntar frecuentemente lo mismo para que el paciente lo recuerde. Mas allá del entorno personal, otros factores ambientales pueden ser también determinantes. La utilización de luz por encima de niveles considerados normales y la reducción del ruido (megafonía, música no deseada, etc.) mejoran el sueño y reducen los SPCD en pacientes institucionalizados. Residencias pequeñas, habitaciones individuales y un menor numero de pacientes por sala se asocian a una menor agresividad, mientras que, a mayores medidas de seguridad, la frecuencia de conductas arriesgadas y auto-lesivas resulta mayor. Las sujeciones físicas, utilizadas como supuestas medidas de seguridad, también pueden aumentar las conductas auto-lesivas, la agitación y la ansiedad.
• #12: La perspectiva psicológica ofrece explicaciones plausibles para la comprensión de los SPCD. Durante la vida, el ser humano va forjando su personalidad y va adquiriendo recursos para afrontar los retos y las adversidades (identificación y resolución de problemas, red social, humor, creencias, etc.). También –añade la corriente dinámica–, el ser humano se esfuerza por adaptar los rasgos de personalidad a los requerimientos del entorno. Los SPCD se explicarían como intentos fracasados de manejar o adaptarse a los cambios fisiopatológicos y ambientales. La perdida de capacidades cognitivas podría compensarse inicialmente con la puesta en juego de recursos, pero los rasgos mas básicos de la personalidad terminarían aflorando. Por ejemplo, una persona suspicaz que no recuerda donde coloco un objeto ya no será capaz de suprimir o de elaborar este rasgo de personalidad y dirá que le han robado (interpretación delirante). También en esta línea, la apatía se interpreta como la evitación, mas o menos consciente, de situaciones difíciles o estresantes.
• #30: Introduction: A wide variety of atypical antipsychotic drugs (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone and clozapine) are widely used in the management of neuropsychiatric symptoms, which are commonly seen in dementia, but results from randomised controlled trials (RCTs) on the efficacy and safety of these agents are conflicting. We aimed to quantify the efficacy and safety of atypical antipsychotic drugs on neuropsychiatric symptoms in dementia patients. Methods: PubMed, EMBASE, the Cochrane Controlled Trials Register and the Cochrane Database of Systematic Reviews for reports published before August 2014 were searched for eligible randomized controlled trials of atypical antipsychotic drugs therapy in patients with psychotic symptoms of dementia. Two reviewers independently assessed the quality of the trials and extracted information. Results: Overall, 23 relevant RCTs with 5,819 participants were identified. This meta-analysis demonstrated a significant efficacy of atypical antipsychotics on psychiatric symptoms and cognitive functions compared to placebo. In the meta-analysis, the weighted mean differences (WMDs) in change scores for psychiatric symptoms were in favor of aripiprazole (−4.4, 95% confidence interval (CI) – 7.04 to −1.77) and risperidone (−1.48, 95% CI −2.35 to −0.61) compared to placebo. In cognitive effects, WMDs in change scores for the Clinical Global Impression-Change (CGI-C) were in favor of aripiprazole, risperidone, olanzapine and quetiapine which ranged from a −0.30 points mean difference (95% CI:-0.59 to −0.01) in the aripiprazole trials to −0.43 (95% CI:-0.62 to −0.25) in the risperidone group. Patients receiving atypical antipsychotics showed no difference in risk for injuries or falls (P > 0.05), significantly higher risks (P < 0.05) for somnolence, urinary tract infection, edema and abnormal gait. However, there was no significant evidence for death reported. Conclusion: Aripiprazole and risperidone are able to improve psychiatric symptoms and slow decline in cognition function at average 12 weeks in patients with neuropsychiatric symptoms of dementia. However, high adverse events may offset the efficacy of atypical antipsychotics in dementia.
• #31: For psychiatric symptoms, 15 studies measured and reported the mean change in NPI-total score from baseline to end point for intervention compared with placebo: three studies on aripiprazole [14-16], five studies on olanzapine [17-21], two studies on quetiapine (50 mg) [17,19], three studies on quetiapine (100 mg) [22,23,25] and two studies on risperidone [17,19]. All of these studies included participants with moderate to severe dementia. NPI-total scores were only significant for aripiprazole by meta-analysis in the available data (−4.4, 95% CI = −7.04 to −1.77). In the quetiapine trials, the differences by meta-analysis were −4.3 (95% CI = −8.81 to 0.21) for the 50 mg daily group and −0.12 (95% CI = −1.74 to 1.50) for the 100 mg daily group. In addition, the difference between the olanzapine group and placebo was −2.61 (95% CI = −5.23 to −0.00). The pooled study NPI-total score was −1.68, which was of great significance (P = 0.004). Psychiatric symptoms occur on average in 70% of dementia patients during the primary illness [6]. The use of atypical antipsychotic medications is therefore increasing rapidly. Atypical antipsychotics have been considered preferred pharmacologic treatments for behavioral disturbances associated with dementia because of clinical trial evidence for perceived safety advantages compared with other medications and expert clinical opinion. However, the role of currently available atypical antipsychotics for dementia has been controversial and health economists always question whether the small clinical effects are economically worthwhile. In our present study, we have obtained the treatment effects of 23 trials including 5,819 patients with dementia. Our results show obvious benefits for symptomatic efficacy on psychiatric symptoms and cognitive functions of aripiprazole and risperidone after statistically combining the trials. The safety of atypical antipsychotics may offset the usage of drugs. A previous study by Schneider and colleagues analyzed 15 RCTs (from published articles or presentations at medical meetings) of three aripiprazole trials, five olanzapine trials, three quetiapine trials and four risperidone and found modest benefits for aripiprazole and risperidone, but also that adverse events and dropouts blocked their efficacy [32]. Furthermore, Maher and colleagues conducted a meta-analysis on efficacy and comparative effectiveness of atypical antipsychotics for off-label uses in psychosis, agitation and global behavioral symptoms in dementia. They found small but statistically significant pooled effect size for aripiprazole, olanzapine and risperidone [33]. A previous paper indicated that aripiprazole shows modest efficacy in the treatment of AD related psychosis [34]. The benefit of aripiprazole in dementia was consistent in the previous study and our meta-analysis. However, olanzapine was not associated with efficacy overall in our study. Besides, there was a lack of evidence for or against quetiapine because five among the seven trials were dose-ranging and used different selection criteria. The outcomes could not be statistically combined using a common rating scale. Furthermore, Katz and colleagues found that risperidone showed improvement in psychotic symptoms and general clinical improvement in patients with psychosis of AD [28]. However, in our study, risperidone showed improvement in behavior symptoms on dementia. In addition, aripiprazole, olanzapine and quetiapine were more effective for particular symptoms, such as anger and aggression. They all proved to have significant effect on neuropsychiatric symptoms in early studies. As a result, our study is in line with findings from a former review [32] and long-standing clinical experience.
• #32: Thirteen studies measured and reported the mean change in CGI-C from baseline to end point for intervention compared with placebo: one study on aripiprazole [15], three studies on olanzapine [17,19,21], five studies on quetiapine [19,22-25] and four studies on risperidone [17,19,27-30]. CGI-C scores were all significant for these trials by meta-analysis in the available data. The difference between the pooled group and placebo was −0.36 (95% CI = −0.47 to −0.25)
• #33: Furthermore, 13 trials reported MMSE change scores: three aripiprazole contrasts [14-16], three olanzapine contrasts [17,18,20], two risperidone contrasts [17,20] and five quetiapine contrasts [19,22-25]. The overall effect of drugs compared with placebo was a WMD of −0.34 (95% CI = −0.65 to −0.03, P = 0.03) in favor of placebo. The three aripiprazole trials showed statistical significance of MMSE in favor of placebo (WMD= −0.99, 95% CI = −1.65 to −0.33, P = 0.003). To date, we perform a more comprehensive analysis covering a variety of outcome domains that included many previous studies without a higher risk of bias. Besides, we identified and included five recent studies to conduct an updated meta-analysis, and our results further supported this. There was some evidence to support the efficacy of the atypical antipsychotics when compared with placebo on change in neuropsychiatric symptom scores in the previous reviews [36,37]. These trials offered updated information of atypical antipsychotics in psychiatric symptoms and cognitive functions, which may have contributed to the differences between our review and previous reviews. More importantly, compared with the previous reviews, our study added quality assessment analysis. Quality assessment by GRADE software was used to establish the robustness of the primary outcome, and higher robustness means study drugs have more definite effects on the diseases. Because the magnitude of statistical effect does not always imply a similar magnitude clinical effect, we also reviewed and analyzed each drug separately and by specific outcomes to better address the psychiatric symptoms.
• #34: Obvious benefits were observed for symptomatic efficacy on psychiatric symptoms and cognitive functions of aripiprazole and risperidone after statistically combining the trials. The higher risks for adverse events may offset the efficacy of atypical antipsychotics for treatment of dementia. Hopefully, the design of a multicenter study could use currently available levels of treatment and care, in order to provide a broader generalizability of the results in the future. Future research should focus more on neuropsychiatric outcomes. It is important to continue efforts to perform high-quality trials of drug therapy, and the safety evaluation of the drugs cannot be ignored.
• #35: The double-blind, placebo-controlled study in dementia patients continuing or stopping antipsychotics (DART-AD) investigated, as a secondary endpoint, whether or not discontinuing antipsychotics was associated with an exacerbation of neuropsychiatric symptoms (Ballard et al., 2008). The results showed that patients continuing on antipsychotic treatment experienced a significant deterioration in verbal fluency (p=0.002), and also showed a non-significant decline in language functions, but there was no significant worsening of neuropsychiatric symptoms with treatment withdrawal (Ballard et al., 2008). Widely reported side effects of antipsychotics include extrapyramidal symptoms, sedation, tardive dyskinesia, gait disturbances, and falls, with many agents also producing anticholinergic side effects, such as delirium (Tune et al., 1991). Prolongation of the QT interval has been reported as a significant problem with several antipsychotics, in particular droperidol and thioridazine (Reilly et al., 2000). A metaanalysis also identified an increase in febrile illness compared to placebo-treated patients, and found that peripheral edema was increased amongst people treated with risperidone (Ballard and Howard, 2006). Some atypical antipsychotics, in particular olanzapine, clozapine, and quetiapine, are associated with metabolic abnormalities, including insulin resistance and type II diabetes, and hyperlipidemia (Sernyak et al., 2002). Cerebrovascular events. Serious concerns have arisen in the past few years regarding analyses suggesting an increase in cerebrovascular events in AD patients treated with antipsychotics. In 2004, the EMEA issued a warning against the use of atypical antipsychotics (risperidone and olanzapine) in elderly patients with dementia due to the risk of stroke (EMEA, 2004). Combining data from placebo-controlled trials, risperidone was associated with a three-fold increased risk of serious cerebrovascular adverse events compared to placebo (Ballard and Howard, 2006; MHRA, 2004). A similar increase in the incidence of cerebrovascular adverse events was noted in placebo-controlled trials of olanzapine in elderly patients with dementia (olanzapine 1.3% vs placebo 0.4%) (Wooltorton, 2004). By contrast, a large retrospective study (using healthcare databases) of older people in Canada did not identify an excess of strokes in patients treated with atypical antipsychotics over those treated with typical antipsychotics (Gill et al., 2005), but the absence of diagnostic data prohibited a specific evaluation for patients with dementia. The balance of evidence supports the conclusion that there is an increased risk of cerebrovascular adverse events in patients with dementia treated with risperidone or olanzapine. However, it is unclear whether this is a class effect or an effect specific to a limited subset of drugs. One study of aripiprazole reported cerebrovascular adverse events in four patients on a dose of 10 mg/day, compared with no events in placebo-treated patients (Mintzer et al., 2007). In the absence of clear clinical trial data, there needs to be a high level of caution regarding the likelihood of an increased risk of adverse cerebrovascular events. Similarly, there is limited evidence regarding the potential impact of typical antipsychotics on stroke risk. The results of a large retrospective Canadian study indicated a similar stroke incidence in people with dementia who were prescribed typical or atypical antipsychotics (Herrmann et al., 2004). However, the absence of an “untreated” comparison group in this study makes the results difficult to interpret. Mortality. In 2005, the FDA published a warning to highlight a significant increase in mortality risk (OR: 1.6–1.7) for elderly patients with dementia treated with atypical antipsychotics compared to placebo-treated patients in randomized controlled trials (FDA, 2005), forcing a change to the Summary of Product Characteristics (SPC) of atypical antipsychotics. This analysis was based on data from 17 placebo-controlled trials with atypical agents. However, as individual trial data were not provided, it is unclear whether or not the risk differs among the individual drugs. A review of 15 of the 17 trials confirmed a significant increase in mortality (OR: 1.54; 95% CI: 1.06–2.23; p=0.02), and found no difference among atypical agents (Schneider et al., 2005). In 2008, the Committee for Medicinal Products for Human Use (CHMP) assessment report on conventional antipsychotics (EMEA, 2008) raised a concern regarding physicians switching patients from atypical to typical antipsychotics for NPS management, in response to the FDA warning. These medication changes were taking place based on a lack of evidence that typical agents were associated with a comparable mortality risk, rather than on evidence that they were not associated with this risk (EMEA, 2008). Subsequent to such concerns, from 2005 onward, further observational studies have been conducted to determine the degree of mortality risk associated with typical antipsychotics (EMEA, 2008). Increased mortality associated with typical antipsychotics has been demonstrated in some studies (e.g. Wang et al., 2005), although with some heterogeneity. A retrospective review of Australian veterans and war widows aged 65 years and older, who were dispensed an antipsychotic drug, reported considerable heterogeneity in risk of death from antipsychotics. The greatest risk was found for haloperidol, even when controlling for its use in terminal-state agitation (Hollis et al., 2007). Studies have shown that the differences among antipsychotics were not restricted to clear group differences between typical and atypical agents. For example, when compared to olanzapine, haloperidol was clearly associated with a significantly increased mortality risk (relative risk [RR] = 2.26, 95% CI 2.08–2.47; p≤0.001), whilst there was a more modest, but also significant, increased, mortality risk for risperidone (RR = 1.23, 95% CI 1.07–1.40; p=0.003) (Hollis et al., 2007). Furthermore, combined therapies – defined as people taking more than one study drug – were associated with an increase in mortality risk when compared to olanzapine only (RR = 1.45, 95% CI: 1.10–1.98) (Hollis et al., 2007). A placebo-controlled study of aripiprazole reported three deaths in the placebo-treated group and eight deaths on aripiprazole 10 mg/day, with an odds ratio of 2.7 (Mintzer et al., 2007). As highlighted by Schneider et al. (2005), the absolute number of excess deaths over 10–12 weeks in antipsychotic-treated AD patients is small (Schneider et al., 2005). A key question is whether or not this excess risk persists or changes with longer-term therapy. The recent extension of the DART-AD study, reporting followup for up to 54 months for individual participants, reported a similar overall relative risk to the reports by Schneider et al. (2005) and the FDA (2005), but indicated that the absolute risk increased dramatically with longer-term treatment. For example, after 36 months of exposure, 59% of people randomized to placebo were still alive whereas only 30% of people randomized to continue an antipsychotic were still alive (Ballard et al., 2009b). The cause of the increased risk of death is unknown. Hypothetically, treatment may lead to somnolence, and the consequent reductions in activity levels may precipitate a cascade of events, including increased vulnerability to chest infections and increased use of diuretics, which combine to confer an increased mortality risk (Ballard and Howard, 2006). Overall, antipsychotics clearly confer significant treatment benefit for the short-term (up to 12 weeks) treatment of aggression in people with AD, although the benefits must be weighed against the not insubstantial risk of serious adverse events. The evidence base is less robust for longer-term therapy, and for the treatment of psychosis, but the longer-termuse of antipsychotics in people with AD is probably inadvisable, other than in exceptional clinical circumstances. Clinical trials to identify other safe and effective pharmacological and nonpharmacological treatments for neuropsychiatric symptoms in AD are an urgent clinical research priority.
• #37: Somnolence The 13 available comparisons all showed increased risk for somnolence, and all of them were statistically significant. The odds ratio by meta-analysis was 3.7 (95% CI = 2.94 to 4.66, P <0.00001) with significant heterogeneity. Significant risk differences were found among aripiprazole (OR = 3.51, 95% CI = 1.64 to 7.50), olanzapine (OR = 3.61, 95% CI = 1.83 to 7.13) and quetiapine (OR = 5.88, 95% CI = 2.39 to 14.47) with small heterogeneity (I2 = 0%). Injury or falls Outcomes are consistent in the 15 contrasts that provided data for injury/accidental injury and falls. They did not show an increase or decrease in risk overall or in the result of a particular drug or trial (OR = 0.89, 95% CI =0.75 to 1.05, P = 0.17). Abnormal gait There was an overall increased risk for abnormal gait in the pooled analysis (OR = 1.84, 95% CI = 1.26 to 2.68, P = 0.002) from 10 trials. There was increased risk in three olanzapine trials, and no increased risk in one aripiprazole trial, three risperidone trials and three quetiapine trials. Edema Nine trials reported edema. Increased risks was observed by meta-analysis for edema (OR = 0.63, 95% CI = 0.44 to 0.91, P = 0.01). The increased risk was associated with risperidone. Two of three aripiprazole trials, three of five olanzapine trials, four of eight risperidone trials and five of seven quetiapine trials did not report edema. Urinary tract infections Urinary tract infections were reported in 11 contrasts, including three aripiprazole trials, two olanzapine trials, four risperidone trials and two quetiapine trials. There was overall increased risk for urinary tract infections in the antipsychotic-treated patients (OR = 1.91, 95% CI = 1.48 to 2.46, P <0.00001). The effect was not significant with aripiprazole and quetiapine, but was significant when the events were combined. Urinary tract infections were not reported in one olanzapine trial (one trial included risperidone), but urinary incontinence both was and was not reported in the trials of the other drugs. Stroke Stroke was reported in 13 contrasts including three aripiprazole trials, two olanzapine trials, four risperidone trials and four quetiapine trials. There was overall increased risk for stroke in the antipsychotic-treated patients. Meta-analysis demonstrated a significantly higher risk of stroke in the pooled antipsychotic group (OR = 2.62, 95% CI = 1.45 to 4.75, P = 0.001) and in the risperidone subgroup (P = 0.002). However, the effect was not significant with aripiprazole, olanzapine and quetiapine. Deaths The overall OR by meta-analysis for death in patients treated with antipsychotics compared with placebo was 1.06 (95% CI = 0.65 to 1.73; Z = 0.24, P = 0.81). There was no increased risk of death with any individual drug. Besides, in most studies, adverse reactions occurring in less than 20% of patients were not taken into account when not finding a significantly higher prevalence of mortality. All-cause dropouts In overall meta-analyses on safety, there were no significant differences in the number of dropouts caused by any reason between any medicine treatment group and placebo treatment group (OR = 0.95, 95% CI = 0.82 to 1.09; Z = 0.75, P = 0.45). In subgroups, we observed similar results (aripiprazole, 95% CI = 0.63 to 1.39; olanzapine, 95% CI = 0.57 to 1.13; risperidone, 95% CI = 0.79 to 1.22; quetiapine, 95% CI = 0.74 to 1.36) Safety is as important as the efficacy of the interventions in clinical studies. The five main adverse events were analyzed here and the pooled study showed evidence in increasing somnolence, edema, urinary infection and abnormal gait. Patients receiving atypical antipsychotics showed no difference in risk for injuries or falls (P >0.05), and significantly higher risks (P <0.05) for somnolence, urinary tract infection or urinary incontinence, edema and abnormal gait. Notably, risperidone had a higher risk on adverse events. However, no drugs improved or aggravated injuries or falls compared with placebos. These events were usually of mild or moderate severity, and the risk disappeared on serious adverse events. Finally, none of these drugs seemed to increase the risk of death in this study, yet the difference did not achieve statistically significant levels. Similarly, Schneider and colleagues found a significant risk for somnolence, abnormal gait, edema, urinary tract infection or urinary incontinence on atypical antipsychotics versus placebo [32]. In general, the results of our meta-analysis demonstrated statistical increased risks of 1.1-fold to 1.5-fold for these adverse events. Thus, an increased risk of AEs in atypical antipsychotics is observed during these years. Importantly, a follow-up study indicated that there was an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication [35]. These results further supported the need to seek less harmful alternatives for the long term treatment of neuropsychiatric symptoms in dementia patients.
• #38: Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer’s disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality. Methods Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrolment of the last participant (range 24–54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770. Findings 165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58–80%) in the continue treatment group versus 77% (64–85%) in the placebo group for the mITT population. Kaplan–Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0·03; ITT p=0·02). The hazard ratio for the mITT group was 0·58 (95% CI 0·35 to 0·95) and 0·58 (0·36 to 0·92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46% vs 71%; 36-month survival 30% vs 59%). Interpretation There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients.
• #43: In summary, most double-blind, placebo-controlled trials and open-label assessments that have included behavioral outcome measures indicate a behavioral benefit with treatment with antidementia agents. Not all studies have demonstrated a drug-placebo difference, and further investigation of the behavioral benefits of these therapies is warranted. A variety of factors must be considered when constructing trials to explore the psychotropic effects of antidementia agents including profile of behavioral symptoms at baseline, baseline behavioral symptom severity, baseline dementia severity, residential status, linguistic and cultural diversity of study sites, and whether psychotropic drugs are allowed at baseline. Attention to these elements in clinical trials will allow more definitive conclusions to be drawn regarding the behavioral benefits of antidementia treatments.
• #47: If in line with treatment indications and disease severity, ChEI therapy will be initiated at the time of AD diagnosis; behavioral changes may or may not be present at this stage. Early initiation of ChEI treatment may defer the emergence of behavioral changes as the disease progresses (Cummings et al., 2004a). In the presence of NPS, therapy with a ChEI, with or without memantine, should be implemented prior to the use of psychotropic agents, since both cognitive and behavioral benefit may ensue, and the use of psychotropic agents may be avoided in some patients. Similarly, the use of ChEI therapy may make it possible to use lower doses of psychotropic agents (Bergman et al., 2003), or to minimize duration of psychotropic treatment periods, thereby minimizing risks associated with these agents. It may be possible to discontinue therapy with psychotropic medications if patients are being treated with these agents when ChEIs are introduced. The withdrawal of ChEIs has been associated with behavioral deterioration and, therefore, patients should be closely monitored for the emergence of new behavioral changes if ChEIs are withdrawn (Holmes et al., 2004). The appearance of new or worsening behavioral disturbances in the course of withdrawal indicates that the patient is deriving behavioral benefit from treatment, and the ChEI should be continued. ChEIs reduce behavioral changes in AD as well as improving or delaying decline in cognition and function. Behavioral improvement associated with ChEI treatment has been documented primarily in patients with mild to moderate AD (Matthews et al., 2000; Cummings et al., 2004a; Holmes et al., 2004; Herrmann et al., 2005). The greatest effects have been on depression, apathy and aberrantmotor behavior (e.g.Matthews et al., 2000; Aupperle et al., 2004; Cummings et al., 2004a; Holmes et al., 2004; Feldman et al., 2005). In some studies, total NPI scores have also been reduced (Aupperle et al., 2004; Cummings et al., 2005). The observed variation is not necessarily an indication of differential efficacy of the ChEIs used, but may indicate the spectrum of positive and negative behavioral changes reported in clinical studies of ChEIs. The behavioral symptoms most likely to improve with ChEI treatment appear to be apathy, depression, and aberrant motor behavior (e.g. Feldman et al., 2005; Holmes et al., 2004; Matthews et al., 2000; Aupperle et al., 2004; Cummings et al., 2004a). There are few predictors of response to ChEIs. Patients with more severe behavioral changes at baseline tend to have more robust responses to therapy. The presence of visual hallucinations also appears to predict a better cognitive response to treatment with ChEIs (Emre et al., 2007). Cognitive and behavioral responses to ChEI therapy are only weakly correlated, and patients may exhibit behavioral improvement while experiencing only limited or no cognitive improvement (Spalleta et al., 2004).
• #48: The most difficult to manage NPS in dementia are agitation (aggressive and non-aggressive) and psychosis (delusions and hallucinations). Hallucinations may resolve over a few months, but delusions and agitation are more persistent. Antipsychotics are often used as the first-line pharmacological approach to treat agitation and psychosis in people with dementia. As regards agitation generally, two placebo-controlled trials of antipsychotics in AD over a period of six months or longer have been conducted (Ballard et al., 2005; Schneider et al., 2006b). One study compared six months of treatment with quetiapine, rivastigmine, and placebo in 93 AD patients with significant agitation, and showed no evidence of benefit in symptoms of agitation (Ballard et al., 2005). However, the dose of quetiapine used (50 mg twice daily between Week 12 and Week 26) was lower than many authorities would consider optimal. The second study (CATIE-AD, Comparative Atypical Trial for Intervention Effectiveness in Alzheimer’s Disease study) compared nine months of treatment with risperidone, olanzapine, and quetiapine, against placebo in AD patients with clinically significant aggression or agitation (Schneider et al., 2006b).