GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.
Teslyar P, Stock VM, Wilk CM, et al
Objectives: Delirium is common in hospitalized elderly patients, resulting in increased morbidity and mortality. There is limited evidence supporting pharmacologic prevention strategies for delirium in patients at high risk of developing delirium post-operatively. This review examined whether delirium in at-risk patients can be prevented with antipsychotic medication prophylaxis in the inpatient setting.
Conclusions: Few studies have examined prophylactic use of antipsychotics. This analysis suggests that perioperative use (either pre-operative or immediately post-operative) of prophylactic antipsychotics may effectively reduce the overall risk of postoperative delirium in elderly patients.
Delirium can increase hospital stay, increase morbidity and mortality, and increase the likelihood of institutionalization in a nursing home. This study demonstrates that antipsychotic prophylaxis can halve the rate of delirium compared to placebo. While the results support antipsychotic prophylaxis, antipsychotics themselves can be associated with increased morbidity due to short- and long-term side effects, as well as an increased risk of mortality as stated in the FDA black box warning on antipsychotic treatment of patients with dementia. It is likely that these risks also apply to patients with delirium, particularly if antipsychotics are continued for more than a few days post-operatively. Therefore, the overall risk profile of antipsychotics needs to be balanced against the need to prevent delirium, particularly because only a minority of patients develop persistent delirium post-operatively. Although this meta-analysis suggests utility of antipsychotics during the perioperative period, the risk/benefit ratio overall does not seem to favor such treatment in most patients. Antipsychotic prophylaxis may need to be reserved for patients at very high risk of delirium and for those with a history of postsurgical delirium.
Objective: To assess mortality risk associated with the use of individual antipsychotic drugs in elderly residents in nursing homes.
Conclusions: The data provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used unless clearly needed. The results suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.
The results of this study provide useful information about the relative mortality risks of different antipsychotics. A key finding was the marked increase in mortality associated with high antipsychotic doses, particularly haloperidol, used in a large number of nursing home patients. Based on earlier controlled clinical trials, it is generally recommended not to exceed 2 mg of haloperidol daily. The high non-completion rate (80%) on a single antipsychotic in nursing home patients also suggests that physicians are making frequent changes to treatment regimens, possibly in response to Federal OBRA regulations urging antipsychotic discontinuation every few months. The concern about mortality associated with antipsychotic use in patients with dementia arose after the FDA black box warning in 2005. This warning may have led to extra caution on the part of physicians in prescribing antipsychotics to dementia patients who develop psychosis and agitation in the context of severe medical illness, thereby reducing mortality rates. Of note,Ho the findings do not prove causality and many potential confounds could not be considered due to the retrospective, rather than prospective, nature of the study. In addition, there are other recent nursing home studies which do not show an increase in mortality with antipsychotic use. Clinically, choosing the dose of antipsychotic may be as important as the decision about which antipsychotic medication should be prescribed.
Schulze J, van den Bussche H, Glaeske G, et al
Eur Neuropsychopharmacol. 2013 Mar 13. pii: S0924-977X(13)00061-8. doi: 10.1016/j.euroneuro.2013.02.001. [Epub ahead of print]
Objective: To examine antipsychotic prescription trends over time in patients with dementia in the context of official national and international warnings.
Results: The number of patients annually ranged from 3,460 to 8,042 with a mean age of 80 years. The table below outlines prescription trends between 2004 and 2009.
Mean daily dose
Conclusions: The findings suggests that warnings of regulatory bodies nationally and internationally against adverse drug events in dementia patients receiving antipsychotics did not impact overall prescription behavior to any material degree, with decreases in typical antipsychotic prescriptions offset by increases in atypical antipsychotic prescriptions.
The use of antipsychotics in nursing homes and in outpatients with dementia has decreased only marginally both in the United States and Europe even after the FDA black box warning in 2005 on increased mortality risk and comparable warnings in European countries. Some studies show a greater decrease than reported in this German study, but the reduction has not been large in any published study. Possible explanations for this lack of change include the continuing clinical need to prescribe antipsychotics in patients with severe psychosis and agitation in the absence of any other established pharmacologic or non-pharmacologic interventions, and the willingness of caregivers to accept risks during treatment in patients with dementia akin to the risks willing to be assumed by patients and caregivers during chemotherapy treatment of cancer. These factors have not been considered sufficiently in the promulgation of regulations that impact on antipsychotic prescribing in patients with dementia.
Devanand DP, Mintzer J, Schultz SK, et al
N Engl J Med. 2012;367(16):1497-1507.
Objective: Among patients with Alzheimer's disease who have had a response to antipsychotic medication for psychosis or agitation-aggression, the risk of a recurrence of symptoms after discontinuation of the medication was studied systematically in patients who had maintained response to an open trial of the antipsychotic risperidone.
Results: 180 patients received open-label risperidone (mean dose, 0.97 mg/day). The severity of psychosis and agitation was reduced, although there was a mild increase in extrapyramidal symptoms; 112 patients met the criteria for response to treatment. Next, 110 patients underwent randomization. As the table below indicates, after the first 16 weeks the rate of relapse was higher in the patients that received placebo than in those received risperidone. In survival analysis, the hazard ratio with placebo (1.94) indicated a near-doubling of relapse risk. During the next 16 weeks, the rate of relapse was higher in patients switched from risperidone to placebo than in those that continued to receive risperidone. In survival analysis, the hazard ratio with placebo (4.88) indicated a near-five-fold increase in relapse risk.
Relapse Rate (n)
1st 16 Weeks
1.94 (95% CI, 1.09-3.45)
Next 16 Weeks
Switch to placebo
4.88 (95% CI, 1.08-21.98)
Continued on Risperidone
Of note, the rates of adverse events and death after randomization did not differ significantly among the groups, although comparisons were based on small numbers of patients, especially during the final 16 weeks.
Conclusion: In patients with Alzheimer's disease who had psychosis or agitation that had responded to risperidone therapy for 4 to 8 months, discontinuation of risperidone was associated with an increased risk of relapse.
Antipsychotic medications are the only group of drugs previously shown to be more effective than placebo to treat psychosis and agitation in Alzheimer’s disease, although with low to moderate efficacy. However, antipsychotics are not approved by the FDA for this purpose and carry a black box warning indicating an increased mortality risk. Although antipsychotic discontinuation in nursing homes is required by Federal regulations absent the documentation of urgent clinical need, there have been few systematic discontinuation studies and their results have not been definitive. This ADAD trial used a study design consistent with clinical practice: treat with antipsychotic medication and then either continue or discontinue the medication in patients who have maintained improvement over an extended period of time. The findings show a significantly increased risk of relapse after antipsychotic discontinuation in patients who respond to the antipsychotic, and this increased risk of worsening in symptoms clearly needs to be weighed against the risk of adverse effects with continued antipsychotic treatment. Nonetheless, the Center for Medicare and Medicaid Services (CMS) recently promulgated regulations requiring nursing homes to reduce antipsychotic use by 15%. This decision by CMS indicates that the clinically relevant results of the ADAD trial that showed an increased relapse risk after antipsychotic discontinuation have not had an impact on changing CMS policy.
Bergh S, Selbæk G, Engedal K.
BMJ. 2012 Mar 9;344:e1566. doi: 10.1136/bmj.e1566.
Objective: To determine the effect of discontinuing antidepressant treatment in people with dementia and neuropsychiatric symptoms.
Conclusions: Discontinuation of antidepressant treatment in patients with dementia and neuropsychiatric symptoms leads to an increase in depressive symptoms, compared with those patients who continue with treatment.
Improvement in depression in patients with dementia treated with antidepressants compared to placebo has been reported inconsistently across studies. This antidepressant discontinuation trial shows that many patients with dementia who become depressed do need antidepressant medications. The concern about prescribing all psychotropic medications, including antidepressants, has been driven not only by concerns about drug toxicity but also the worry that many physicians are prescribing these medications without a systematic evaluation and identification of the need to treat with these medications. The results of this discontinuation trial with antidepressants, and the ADAD trial with antipsychotic discontinuation, suggest that these medications when prescribed appropriately should not be discontinued routinely in all patients in response to regulatory or other concerns. Rather, the decision to continue or not continue psychotropic treatment should be based on an assessment of the likely risk of relapse after discontinuation against the likely risk of adverse effects with prolonged treatment. If a judgment is made that discontinuation is the best option, close monitoring for potential relapse is needed with rapid reinstitution of medication in those patients who do relapse.
Waldorff FB, Buss DV, Eckermann A, et al
BMJ. 2012;345:e4693. doi: 10.1136/bmj.e4693.
Objective: To assess the efficacy at 12 months of an early psychosocial counseling and support program for outpatients with mild Alzheimer's disease and their primary caregivers. The multifaceted and semi-tailored intervention program offered to patient-caregiver dyads was intended to prevent the emergence of depressive symptoms, improve the quality of life of patients and caregivers, and perhaps stabilize their cognitive functioning.
Conclusions: The extensive DAISY intervention did not have any significant effect beyond that obtained with well-structured follow-up support at 12 months after adjustment for multiple comparisons. The small positive effect found in the unadjusted primary outcome addressing depressive symptoms is intriguing and suggests the need for future research to evaluate depression prevention strategies in patients with dementia.
This is the largest and most systematic prospective study of its type. Earlier studies by other investigators that suggested possible positive effects of comparable interventions were not as large and their study designs and rating methods were not as rigorous as in this study. The finding of no significant differences in all except one measure of depression raises questions about the utility of intensive efforts of this type in patients with Alzheimer’s disease and dementia more broadly. Conceptually, these types of approaches have face value and are generally supported by most clinicians and caregivers and patients, but the research evidence to support the utility of these interventions is still not established. Alzheimer’s advocacy groups and national health systems, particularly in the U.K., have had position papers and other documents that strongly encourage the use of approaches similar to those used in this study, but the research evidence to support such interventions is limited. Cost-effectiveness also remains a major issue in supporting labor-intensive interventions with marginal to no effects. The findings of a potential decrease in depressive symptoms over time are important, because studies of antidepressant treatment in these patients show an advantage over placebo that is not consistent across all studies.
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