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GME Research Review

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.


ISSUE 15, JUNE 2013 — Guest Commentator: D.P. Devanand, MD, Columbia University, New York, NY


Prophylaxis with Antipsychotic Medication Reduces the Risk of Post-operative Delirium in Elderly Patients: a Meta-analysis

Teslyar P, Stock VM, Wilk CM, et al
Psychosomatics. 2013;54(2):124-131.

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.


  • A systematic literature review of articles from January 1950 to April 2012 was conducted in PubMed, PsychInfo, and Cochrane Controlled Trials and databases.
  • Key words used in the search were: "delirium," "encephalopathy," "ICU psychosis," "prevention," and "prophylaxis."
  • Five studies (1,491 participants) met inclusion criteria for the data analysis. Medications administered included haloperidol (3 studies), risperidone (1 study), and olanzapine (1 study). The studies took place in five different countries, and all examined older post-surgical patients.
  • Only randomized controlled trials of antipsychotic medication administered pre-operatively or immediately post-operatively, with the intent to prevent delirium, were included.  Antipsychotic doses were converted to haloperidol dose equivalents for data analysis. 
  • Studies had to describe a validated method of diagnosing delirium.


  • Pooled data from the five studies showed a 50% reduction in the relative risk of delirium among those receiving antipsychotic medication compared with placebo (RR 95% CI, 0.51 [0.33-0.79]; heterogeneity, P<0.01, random effects model).
  • Examination of the funnel plot across the five studies did not indicate publication bias, i.e., the results were not inconsistent across studies.

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.

Clinical Commentary
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.



Differential Risk of Death in Older Residents in Nursing Homes Prescribed Specific Antipsychotic Drugs: Population-Based Cohort Study

Huybrechts KF, Gerhard T, Crystal S, et al
BMJ. 2012 Feb 23;344:e977.

Objective: To assess mortality risk associated with the use of individual antipsychotic drugs in elderly residents in nursing homes.


  • This was a population-based cohort study from nursing homes in the United States, with linked data from Medicaid, Medicare, the Minimum Data Set (a Federally mandated extensive health assessment tool required in all nursing home patients), the National Death Index, and an online annual report describing the operational, staffing, and aggregate resident characteristics in the nursing home.
  • The sample included 75,445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). Participants were ≥65 years of age, eligible for both Medicare and Medicaid, and lived in a nursing home between the years 2001­-2005. 
  • Incident (new) use of antipsychotics was examined, and patients prescribed conventional and atypical antipsychotics simultaneously were excluded.
  • Risperidone was the reference drug for comparison of all other antipsychotics.
  • Exclusion criteria included pre-existing diagnoses of cancer, schizophrenia, or bipolar disorder.


  • 80% of patients did not remain on the individual antipsychotic examined throughout the 180 days of observation used in this study, most commonly due to discontinuation of antipsychotic, hospital admission, treatment switches, or augmentation precluding examination of individual antipsychotic effects and death. 
  • Compared with risperidone, patients receiving haloperidol had double the risk of mortality over the 180-day period (hazard ratio 2.07; 95% CI, 1.89-2.26).
  • Compared with risperidone, patients receiving quetiapine had a 25% decreased risk (0.81, 95% CI, 0.75-0.88).
  • The effects were strongest shortly after the start of treatment, remained after adjustment for antipsychotic dose (though they diminished in patients receiving low doses), and were seen for all causes of death examined.
  • No clinically meaningful differences were observed for the other antipsychotic drugs.
  • There was a dose effect on mortality for all drugs except quetiapine; this effect was strongest for haloperidol.

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.

Clinical Commentary
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.


Impact of Safety Warnings on Antipsychotic Prescriptions in Dementia: Nothing has Changed but the Years and the Substances

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]

To examine antipsychotic prescription trends over time in patients with dementia in the context of official national and international warnings.


  • Study data for 2004-2009 were obtained from a German statutory health insurance company.
  • Trends in demographics, age, sex, need for care, and the use of typical and atypical antipsychotics were examined.
  • Prescription volumes were calculated by number of packages as well as defined daily doses using multiple linear regressions for trends in prescription amounts. 

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.


Prescription Trends



P Value

Any antipsychotic




Typical antipsychotics




Atypical antipsychotics




Mean daily dose




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.

Clinical Commentary
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.


Relapse Risk After Discontinuation of Risperidone in Alzheimer's Disease

Devanand DP, Mintzer J, Schultz SK, et al
N Engl J Med. 2012;367(16):1497-1507.

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.


  • In a multi-center study, patients with Alzheimer's disease and psychosis or agitation-aggression identified on the Neuropsychiatric Inventory scale received open-label flexible dose treatment with risperidone for 16 weeks (study acronym: ADAD trial).
  • Patients who responded to risperidone treatment were then randomly assigned, in a double-blind fashion, to one of three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3).
  • The primary outcome was the time to relapse of psychosis or agitation.
  • In patients who continued versus discontinued (switched to placebo) risperidone, the main analysis compared the first 16 weeks after randomization and the secondary analysis compared the next (final) 16 weeks after randomization.

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)

 P Value

Hazard Ratio

1st 16 Weeks


60% (24/40)


1.94 (95% CI, 1.09-3.45)


33% (23/70)



Next 16 Weeks

Switch to placebo

48% (13/27)


4.88 (95% CI, 1.08-21.98)

Continued on Risperidone

15% (2/13)




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.

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.

Clinical Commentary
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.


Discontinuation of Antidepressants in People with Dementia and Neuropsychiatric Symptoms (DESEP study): Double-Blind, Randomized, Parallel Group, Placebo Controlled Trial

Bergh S, Selbæk G, Engedal K.
BMJ. 2012 Mar 9;344:e1566. doi: 10.1136/bmj.e1566.

To determine the effect of discontinuing antidepressant treatment in people with dementia and neuropsychiatric symptoms.


  • A double blind, randomized, parallel group, placebo-controlled trial was conducted in 16 study nursing homes in Norway from August 2008 to June 2010.
  • Study participants were 128 patients with Alzheimer's disease, dementia, or vascular dementia, and neuropsychiatric symptoms (but no depressive disorder), who had been prescribed escitalopram, citalopram, sertraline, or paroxetine for 3 months or more.
  • Patients with severe somatic disease or terminal illness, or who were unable to take tablets or capsules as prescribed, were excluded.
  • Antidepressant treatment was discontinued over 1 week in 63 patients, and continued in 68 patients. Patients were assessed at baseline, 4, 7, 13, and 25 weeks.
  • Primary outcomes were score differences between study groups in the Cornell scale of depression in dementia and the neuropsychiatric inventory (10-item version) after 25 weeks.
  • Secondary outcomes were score differences in the clinical dementia rating scale, unified Parkinson's disease rating scale, quality of life-Alzheimer's disease scale, Lawton and Brody's physical self-maintenance scale, and the severe impairment battery to assess cognition.


  • Using a linear multilevel model analysis, the discontinued group had significantly higher scores on the Cornell depression scale after 25 weeks than the continuation group (difference -2.89, 95% confidence interval -4.76 to -1.02; P=0.003).
  • A similar result was obtained in the mean total score for the neuropsychiatric inventory after 25 weeks, but this difference was non-significant (-5.96 95% CI -12.35 to 0.44; P=0.068).
  • The results were confirmed by non-response analysis (>30% worsening on the Cornell scale). Significantly more patients worsened in the discontinuation group than in the continuation group (32 [54%] vs 17 [29%]; P=0.006).
  • There were no significant differences between the groups for secondary outcomes. Forty-seven (37%) patients withdrew from the study early.

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.

Clinical Commentary
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.


Efficacy of Psychosocial Intervention in Patients with Mild Alzheimer's Disease: The Multicentre, Rater-Blinded, Randomized Danish Alzheimer Intervention Study (DAISY)

Waldorff FB, Buss DV, Eckermann A, et al
BMJ. 2012;345:e4693. doi: 10.1136/bmj.e4693.

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.


  • This multicenter, randomized, controlled, rater-blinded trial was conducted in primary care and memory clinics in five Danish districts.
  • The sample comprised 330 outpatients with mild Alzheimer's disease and their 330 primary care givers. Frontotemporal dementia was rigorously excluded; mixed dementia (Alzheimer’s plus vascular) apparently was included.
  • Participating dyads (patient and primary care giver) were randomized to control support during follow-up or to control support plus DAISY intervention (multifaceted and semi-tailored counseling, education, and support). 
  • The DAISY intervention included 7 counseling sessions, 5 educational courses with sharing of experiences among study participants, discussion and strategies to deal with patient-specific problems, and monthly discussion with the study coordinator to review clinical status and progress.
  • The control group had review sessions and discussion at 6 months and 12 months.
  • Raters were blind to group assignment.
  • Primary outcomes at 12 months for patients were change from baseline in mini mental state examination (MMSE) score, Cornell depression scale score, and proxy-rated European quality of life visual analogue scale (EQ-VAS) score. For caregivers, outcomes were change from baseline in geriatric depression scale (GDS 30 items) score and EQ-VAS score.


  • At 12 months there were no significant differences between the two allocation groups in changes from baseline in the primary and secondary outcomes.
  • Although non-significant with the adjusted P limit for multiple comparisons, a small difference was observed for one of the primary patient outcomes (Cornell Depression Scale score) in patients favoring the DAISY intervention group before and after adjusting for attrition (P=.0146 and P=.0103 respectively).

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.

Clinical Commentary
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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