Context Atypical antipsychotic medications are commonly used for off-label conditions such as agitation in dementia, anxiety, and obsessive-compulsive disorder.
Objective To perform a systematic review on the efficacy and safety of atypical antipsychotic medications for use in conditions lacking approval for labeling and marketing by the US Food and Drug Administration.
Data Sources and Study Selection Relevant studies published in the English language were identified by searches of 6 databases (PubMed, EMBASE, CINAHL, PsycInfo, Cochrane DARE, and CENTRAL) from inception through May 2011. Controlled trials comparing an atypical antipsychotic medication (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, or paliperidone) with placebo, another atypical antipsychotic medication, or other pharmacotherapy for adult off-label conditions were included. Observational studies with sample sizes of greater than 1000 patients were included to assess adverse events.
Data Extraction Independent article review and study quality assessment by 2 investigators.
Data Synthesis Of 12 228 citations identified, 162 contributed data to the efficacy review. Among 14 placebo-controlled trials of elderly patients with dementia reporting a total global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effects sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, a pooled analysis of 3 trials showed that quetiapine was associated with a 26% greater likelihood of a favorable response (defined as at least 50% improvement on the Hamilton Anxiety Scale) compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of a favorable response (defined as a 25% improvement on the Yale-Brown Obsessive Compulsive Scale) compared with placebo. In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH] = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine; NNH = 20 for risperidone), and urinary tract symptoms (NNH range = 16-36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (for aripiprazole), and extrapyramidal symptoms.
Conclusions Benefits and harms vary among atypical antipsychotic medications for off-label use. For global behavioral symptom scores associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of obsessive-compulsive disorder; however, adverse events were common.
Atypical antipsychotic medications are approved for marketing and labeling by the US Food and Drug Administration (FDA) for treating schizophrenia, bipolar disorder, and depression under drug-specific circumstances. The use of atypical antipsychotic medications is rapidly increasing in the United States, with 1 study estimating an increase from 6.2 million to 14.3 million treatment visits between 1995 and 2008. The estimated use of these drugs for off-label indications, meaning those without FDA approval for these indications, doubled during this period.1 The most commonly prescribed atypical antipsychotic medications are quetiapine, risperidone, aripiprazole, and olanzapine.1 Other atypical antipsychotic medications include asenapine, clozapine, iloperidone, paliperidone, and ziprasidone.
This review summarizes the efficacy and adverse events associated with off-label use of atypical antipsychotic medications for behavioral symptoms in dementia, anxiety, obsessive-compulsive disorder (OCD), eating disorders, posttraumatic stress disorder (PTSD), insomnia, personality disorders, depression, and substance abuse. Off-label prescribing of atypical antipsychotic medications most commonly occurs for adults with these conditions.2 We assessed both efficacy (comparisons of an atypical antipsychotic medication with a placebo) and comparative effectiveness (studies comparing one atypical antipsychotic medication with another active medication).
The complete methods are provided in the evidence report.2 A protocol for this review is available online.3 We searched PubMed, EMBASE, CINAHL, PsycInfo, Cochrane DARE, and CENTRAL through May 2011 for studies of atypical antipsychotic medications including aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. Clozapine was excluded due to its almost exclusive use for schizophrenia. Search terms included the drug names and terms for the conditions previously described. We included depression for drugs without FDA approval for this indication. Regulatory documents from the FDA and Health Canada were searched. We performed reference mining of relevant reviews. We included only studies published in the English language. Clinical trials were used to assess efficacy outcomes. Adverse events were abstracted from clinical trials and large observational studies.
Relevant outcomes were selected by expert psychiatrists. Four investigators (A.R.M., M.M., J.-H.H., and Z.W.) independently reviewed titles and abstracts for potentially relevant articles. These investigators abstracted data from the full-text articles using structured review forms and disagreements were resolved by consensus. Statisticians abstracted outcome data (verified by a clinician-investigator) for the pooled analyses. One investigator (M.S.) abstracted data on adverse events; these data were checked by a second reviewer (A.R.M.).
To assess internal validity of the clinical trials, we abstracted data on the adequacy of the randomization method, the adequacy of blinding and allocation concealment, and the reporting of patients lost to follow-up. The Jadad scale4 (score range, 0-5; 5 = best score) was used to quantify the quality of the clinical trials. The Newcastle-Ottawa Scale5 was used to assess internal validity of observational studies.
For studies reporting a continuous outcome, effect sizes were calculated for each comparison. For subgroups involving data pooling across several scales, we calculated a standardized mean difference using the Hedges effect size. Effect sizes of 0.20 or less were considered small and effect sizes of 0.50 or greater were considered large.6 For efficacy outcomes that reported the number of events, relative risks (RRs) were calculated. The strength of the evidence was assessed using criteria from the Evidence-based Practice Centers Program,7 which was modeled on the Grading of Recommendations Assessment, Development, and Evaluation system.8 The strength of the evidence was classified as high, moderate, or low and considered 4 primary domains (risk of bias, consistency of effect, directness of evidence, and precision of the result) as well as secondary domains that included the strength of the association and the potential for publication bias.
The ability to pool the data across studies was determined by the project team. In the dementia studies, we generally used the Neuropsychiatric Inventory (NPI) total score for the total global outcome, the NPI psychosis scale for the psychosis outcome, and the Cohen-Mansfield agitation inventory for the agitation outcome. If these scales were not included in a study, results from alternative psychiatric and behavioral measures were used. For other conditions, we used standard outcome scales such as the Yale-Brown Obsessive Compulsive Scale. At least 3 studies were required for an efficacy meta-analysis.
For trials that were sufficiently clinically similar to warrant meta-analysis, we calculated a pooled random-effects estimate of the overall effect size or an RR for efficacy outcome measures. The individual trial outcomes were weighted by both within-study and between-study variation. For adverse events that occurred in 2 or more trials, we used exact conditional inference to estimate the pooled odds ratio (OR).
We assessed publication bias using the Begg adjusted rank correlation test and the Egger regression asymmetry test. Heterogeneity was assessed using the I2 statistic. The number needed to treat was calculated for significant RRs. To calculate the number needed to treat, we used the pooled RR and the assumed control risk from the placebo group. Analogous methods were used to calculate the number needed to harm (NNH).
All meta-analyses were conducted using Stata statistical software version 10.0 (StataCorp, College Station, Texas) and StatXact Procs version 9 (Cytel Software Corporation, Cambridge, Massachusetts).
Our searches identified 12 228 titles, of which 2066 articles underwent full text review. This study included 162 trials with efficacy outcomes and 231 trials or large observational studies with adverse events (eSupplement and eFigure). We did not find any relevant trials of asenapine, iloperidone, or paliperidone.
Psychosis, Agitation, and Global Behavioral Symptoms in Dementia
Efficacy. Prior systematic reviews and meta-analyses found either small but statistically significant effects for some atypical antipsychotic medications but not others,9-11 or no statistically significant benefits12 for treatment of behavioral symptoms in dementia. We identified 38 eligible trials,13-36 including 13 trials37-50 that were not included in prior systematic reviews. The mean sample size was 238 (range, 16-815). Follow-up ranged from 2 days to 1 year. Trial quality ranged from 0 to 5 on the Jadad scale.
Eighteen placebo-controlled trials14-18,23,25,26,28-32,39,43,46,48,51 reported outcomes between 6 and 12 weeks of follow-up and were included in the pooled analyses. Quiz Ref IDWe examined 3 types of outcomes: improvement in psychosis (delusions and hallucinations, principally), improvement in agitation (including physical aggression, verbal aggression, excitability, oppositional behaviors, and excessive motor activity), and a total global score, which included cumulative psychiatric symptoms of delusions, hallucinations, suspiciousness, dysphoria, anxiety, motor agitation, aggression, hostility, euphoria, disinhibition, irritability, apathy, and other behavioral disturbances. The details of these studies appear in the evidence report.2
Most of the studies used flexible dosing schedules that ranged from 2 to 15 mg/d for aripiprazole, 1 to 15 mg/d for olanzapine, 25 to 600 mg/d for quetiapine, and 0.5 to 2.5 mg/d for risperidone. Results of our pooled analysis for the total global scores are presented in Figure 1.52-55 For aripiprazole, olanzapine, and risperidone, the pooled estimate of the effect size was small but statistically significant (range, 0.12-0.20). The pooled estimate of effect for quetiapine was similar (0.11) but was not statistically different than zero. Consistent with these findings, the mean change in the NPI total score in patients treated with an antipsychotic medication was a 35% improvement compared with baseline, while the difference in the pooled NPI total score between treatment and placebo was 3.41 points. These values are slightly above and below (respectively) the thresholds for 30% improvement (compared with baseline) and 4-point improvement (compared with placebo) that are considered to be the minimum clinically observable change.56 The findings together are consistent with the conclusion that the effect size for atypical antipsychotic medications is on average a small improvement in global symptoms.
We classified the strength of evidence for this outcome as high based on the number and size of the trials, their quality, and the consistency of their results. Individual studies suggested that higher doses of aripiprazole (10 mg/d)14 or risperidone (2 mg/d)32 may be more effective than lower doses. However, these findings have not been replicated, dose effects are not addressed in most trials, and dose-response trends are inconsistent across studies. The pooled analysis for risperidone had substantial heterogeneity (I2 = 74.6%). There was no evidence of publication bias.
For the outcome of psychosis, the pooled effect size was 0.20 (95% CI, 0.05 to 0.36) for risperidone (5 trials), 0.20 (95% CI, −0.02 to 0.42) for aripiprazole (3 trials), 0.05 (95% CI, −0.07 to 0.17) for olanzapine (5 trials), and −0.03 (95% CI, −0.24 to 0.18) for quetiapine (3 trials). Aripiprazole, olanzapine, and risperidone were all associated with statistically significant improvement in agitation (range of pooled effect sizes, 0.19 to 0.31). The pooled effect for quetiapine was 0.05 (95% CI, −0.14 to 0.25). Details of these analyses are presented in our evidence report.2
Comparative Effectiveness. Three trials compared risperidone with olanzapine23,26 or risperidone with quetiapine.26,38 There were no significant differences in these comparisons. Five trials30,40,41,46,47 compared an atypical antipsychotic medication with haloperidol for the total global outcome. The results were inconsistent. Some trials reported statistically significant results favoring haloperidol,46 others reported results favoring the atypical antipsychotic medication,40,41 and some trials reported no statistically significant differences.30,47
Generalized Anxiety Disorder
Efficacy. One prior systematic review57 reported that quetiapine monotherapy was superior to placebo. We identified 14 trials evaluating olanzapine,58 quetiapine,59-67 risperidone,68-70 or ziprasidone71 for treatment of generalized anxiety disorder. Most used flexible dosing schedules. Sample sizes ranged from 12 to 951 patients. Clinical trial quality scores ranged from 2 to 5 on the Jadad scale. Twelve trials were placebo-controlled with a mean follow-up of 6 to 18 weeks. Of these, 5 reported the percentage of patients responding based on an improvement in the Hamilton Anxiety (HAM-A) Rating Scale score of at least 50%. These trials are shown in Figure 2.
One small trial (n = 24) reported results favoring treatment with 2.5 to 20 mg/d of olanzapine, but this finding was not statistically significant.58 One trial70 with dose ranges of 0.25 to 2 mg/d of risperidone showed no statistically or clinically significant results. Three large trials (n = 710, n = 854, and n = 873) assessed quetiapine.61,62,64Quiz Ref IDThe pooled result of these quetiapine trials was a 26% increase in the chance of a favorable response at 8 weeks (number needed to treat = 8). This is approximately equivalent to an effect size of 0.30. Doses of quetiapine ranged from 50 to 300 mg/d. The I2 for the quetiapine analysis was 78.2% (P = .01), which indicates unexplained heterogeneity. There was no evidence of publication bias. We classified the strength of evidence for this outcome as moderate based on the inconsistency of results and because all were funded by manufacturers.
One study of ziprasidone,71 6 studies of quetiapine,59,60,63,65-67 and 2 studies of risperidone68,69 reported results that could not be pooled. The flexible-dose (20-80 mg/d) ziprasidone study reported no difference compared with placebo in HAM-A scores at 8 weeks.71 The flexible-dose (0.5-1.5 mg/d) risperidone study (n = 40) reported better improvements in HAM-A scores at 8-week follow-up when low-dose risperidone was used adjunctively in patients without an adequate response to 4 weeks of standard treatment.69 A study on anxiety in patients with bipolar disorder found that risperidone was no more effective than placebo.68 The 6 quetiapine studies represented heterogeneous trials assessing the ability of quetiapine to improve response to selective serotonin reuptake inhibitors (SSRIs),59,60,66,67 the treatment of anxiety in patients with bipolar disorder,63 and the use of quetiapine for maintenance therapy.65 Doses of quetiapine ranged from 25 to 600 mg/d. The results were inconclusive.
Comparative Effectiveness. No studies that directly compared atypical antipsychotic medications for treating generalized anxiety disorder were identified. One trial compared 50 or 150 mg/d of quetiapine with 20 mg/d of paroxetine,62 while another compared 150 or 300 mg/d of quetiapine with 10 mg/d of escitalopram.61 Quetiapine was equally effective as paroxetine at 8 weeks, with fewer reported sexual adverse effects. Both quetiapine and escitalopram were effective at 8 weeks.
Obsessive-Compulsive Disorder
Efficacy. Four prior meta-analyses assessed various atypical antipsychotic medications either singly (eg, quetiapine alone) or as a class. These analyses generally concluded that there was statistically significant evidence of benefit. We identified 16 trials72-87 of atypical antipsychotic medications as treatment for OCD, of which 6 trials82-87 were not included in prior systematic reviews. Ten were placebo-controlled trials of an atypical antipsychotic medication as augmentation therapy for patients with OCD who did not respond to SSRIs. Sample sizes ranged from 16 to 82 patients. Follow-up times ranged from 6 weeks to 6 months. Quality varied from 1 to 5 on the Jadad scale. All studies assessed outcomes using the proportion of patients responding as measured by the Yale-Brown Obsessive Compulsive Scale (response varied from an improvement of 25%-35%). The results are presented in Figure 3.
Quiz Ref IDTwo studies of olanzapine found no statistically significant difference compared with placebo (mean daily doses: 11.2 and 6.1 mg). Five studies assessing doses of between 90 mg/d and 600 mg/d of quetiapine were pooled. While the pooled results favored treatment with quetiapine, these were not statistically significant. The I2 for the quetiapine analysis was 61.3% (P = .04), which indicates unexplained heterogeneity. Three pooled studies of risperidone resulted in an approximate 4-fold increase in the chance of responding compared with placebo (the number needed to treat: 5). This is approximately equivalent to an effect size of 1.14. Doses ranged from 0.5 to 2.25 mg/d. Both the Begg and Egger tests indicated the possibility of publication bias (P = .002 for both). We classified the strength of evidence for this outcome as moderate based on the potential for publication bias. Two other trials evaluated the treatment of OCD with 300 to 450 mg/d of quetiapine plus citalopram or placebo plus citalopram.85,87 These studies found that quetiapine augmentation was superior to placebo.
Comparative Effectiveness. We identified 1 trial82 of SSRI augmentation that compared treatment with 2.5 to 10 mg/d of olanzapine with 1 to 3 mg/d of risperidone. There were no statistically significant differences between the treatment groups. Another trial84 compared an atypical antipsychotic medication plus an SSRI plus cognitive behavioral therapy for the treatment of OCD with an SSRI plus cognitive behavioral therapy (but no atypical antipsychotic medication). Those receiving the atypical antipsychotic medication were treatment resistant and sicker than the other group, and had a mean reduction in Yale-Brown Obsessive Compulsive Scale score of 10 points. One small trial compared quetiapine (dose: 50-200 mg/d) plus an SSRI with clomipramine (25-75 mg/d) plus an SSRI.86 Quetiapine augmentation was associated with a significant decline in the Yale-Brown Obsessive Compulsive Scale score, while clomipramine augmentation was not.
We identified 5 trials of olanzapine and 1 of quetiapine for eating disorders, 12 trials for personality disorder, 1 existing meta-analysis and 10 trials of risperidone or olanzapine for PTSD, and 36 trials of atypical antipsychotic medications for depression, of which 7 trials assessed drugs without an FDA-approved indication and 33 trials assessed aripiprazole, olanzapine, quetiapine, or risperidone for treating substance abuse disorders. We identified 1 small trial (n = 13) of atypical antipsychotic medications for insomnia, which was inconclusive (eReferences).
Details for these conditions are presented in the evidence report.2 Evidence does not support the use of olanzapine for eating disorders. The level of evidence is mixed regarding personality disorders and is moderate for an association of risperidone with improving PTSD. Evidence does not support the use of atypical antipsychotic medications for substance abuse.
We considered adverse events in 2 categories: elderly patients with dementia and all other nonelderly adult patients. Adverse events were grouped by drug within age category and then across conditions.
Elderly Patients With Dementia. In 2005, the FDA issued a public health advisory for treating behavioral disturbances in dementia with atypical antipsychotic medications after studies reported an increased risk of death. In 15 placebo-controlled trials, death occurred in 3.5% of patients randomized to atypical antipsychotic medications compared with 2.3% of patients randomized to placebo. The pooled OR for death was 1.54 (95% CI, 1.06-2.23; NNH = 87).88 We also identified 2 large high-quality cohort studies that reported higher mortality in patients taking atypical antipsychotic medications compared with those not taking these drugs.89,90 We combined data from placebo-controlled trials in a meta-analysis on cardiovascular symptoms, edema, and vasodilatation. These outcomes were significantly more common in patients taking olanzapine and risperidone compared with placebo. Quetiapine and aripiprazole were not associated with cardiovascular outcomes (Table 1). Risperidone (not olanzapine, aripiprazole, or quetiapine) was associated with an increased risk of stroke (pooled OR, 3.12 [95% CI, 1.32-8.21]; NNH = 53). The numbers of trials and patients were small and the 95% CIs were wide.
Our meta-analysis found that olanzapine (pooled OR, 4.70 [95% CI, 1.87-14.14]; NNH = 24) and risperidone (pooled OR, 3.40 [95% CI, 1.08-12.75]; NNH = 25) were associated with increases in appetite and weight. Only one trial48 studied the association of these drugs with the development of diabetes in elderly patients; this trial showed no difference between risperidone and placebo. One study25 of olanzapine showed significantly greater central and peripheral anticholinergic effects (OR, 3.30 [95% CI, 1.62-7.17]; NNH = 6) compared with placebo. Aripiprazole, olanzapine, quetiapine, and risperidone were each associated with sedation and fatigue in patients with dementia. Olanzapine and risperidone were associated with an increase in extrapyramidal symptoms (NNH = 10 and 20, respectively). Risperidone, quetiapine, and olanzapine were associated with increases in urinary tract symptoms (Table 1; NNH range: 16-36). A large government-funded trial (Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer's Disease91; CATIE-AD) comparing olanzapine, quetiapine, and risperidone reported cognitive decline in patients with dementia who were treated with these drugs.
Comparative Harms. We found 6 head-to-head trials of atypical antipsychotic medications for dementia that reported adverse events, including the CATIE-AD trial.52 Patients taking olanzapine had greater odds of having a neurological symptom such as confusion, dizziness, headaches, lightheadedness, orthostatic dizziness, seizure, or tinnitus than those taking risperidone (OR, 1.54; 95% CI, 1.02-2.34). Of 6 large high-quality cohort studies, 4 found an increased risk of death with conventional antipsychotic medications compared with atypical antipsychotic medications.89,92-94 The remaining 2 cohort studies90,95 found a similar risk of death in the comparison between use of conventional antipsychotic medications and use of atypical antipsychotic medications. One study90 reported higher mortality rates with use of conventional and atypical antipsychotic medications compared with use of other psychotropic medications.
Nonelderly Adults. Death, stroke, and other cardiovascular symptoms have rarely been assessed in nonelderly adults taking atypical antipsychotic medications. One large cohort study95 of patients aged 30 to 74 years reported higher rates of sudden cardiac death in those who had taken any antipsychotic medication (either conventional or atypical) compared with patients with nonuse. Differences between conventional and atypical antipsychotic medications were not statistically significant. For both classes of antipsychotic medications, risk increased with dose. Another cohort study of patients aged 16 to 85 years found that users of antipsychotic medications (either conventional or atypical) had greater odds of venous thromboembolism after adjusting for comorbidity and concomitant drug exposure.96 Weight gain, fatigue, sedation, akathisia, and extrapyramidal symptoms are adverse effects of these drugs. Therefore, we focused on these outcomes in our meta-analyses of 85 trials (Table 2).
We found statistically significant associations with aripiprazole, quetiapine, risperidone, and olanzapine and weight gain. Olanzapine was particularly associated with weight gain (pooled OR, 11.3 [95% CI, 8.22-15.74]; NNH = 3). Only 1 trial of olanzapine reported outcomes for diabetes. While the OR was 5.14 (95% CI, 0.57-244.28), this was not statistically significant. Two studies of ziprasidone found no association with weight gain. Sedation was associated with every atypical antipsychotic medication. Most atypical antipsychotic medications (except risperidone) were associated with fatigue. Only aripiprazole was associated with akathisia (pooled OR from 5 studies, 11.80; 95% CI, 7.40-19.61). Aripiprazole, quetiapine, and ziprasidone were associated with extrapyramidal symptoms.
Comparative Harms. We identified 1 head-to-head trial comparing olanzapine with ziprasidone and 2 head-to-head trials comparing quetiapine with risperidone. Olanzapine was associated with an increased odds of weight gain (OR, 4.02; 95% CI, 2.25-7.48) compared with ziprasidone.97 Compared with risperidone, quetiapine was associated with a higher odds of decreased salivation, neurological events, sedation, and agitation.
This systematic review demonstrates evidence for the efficacy of atypical antipsychotic medications for only a few of the off-label conditions that are currently being treated. First, aripiprazole, olanzapine, and risperidone are associated with small but statistically significant benefits for the treatment of behavioral symptoms in dementia. Drug doses vary, but are generally about 50% lower than those used in treating younger adults with schizophrenia or bipolar disorder. Second, 3 large trials of quetiapine demonstrated a significant benefit for treatment of generalized anxiety disorder. Third, risperidone is associated with significant improvement in OCD. Quiz Ref IDEvidence did not support using atypical antipsychotic medications for substance abuse or eating disorders. We found only an inconclusive pilot trial regarding insomnia. The use of atypical antipsychotic medications for any of these conditions cannot be justified as evidence-based. This systematic review also identified some clinically important differences regarding potential benefits and adverse events between the atypical antipsychotic medications for off-label uses.
Quiz Ref IDThe use of atypical antipsychotic medications is associated with adverse outcomes, including a small but statistically significant increased risk of death in elderly patients with dementia. Other cardiovascular symptoms, sedation, fatigue, extrapyramidal symptoms, and urinary tract symptoms are also associated with some or all of the studied atypical antipsychotic medications, with the latter 2 occurring in up to 8% and 18% of elderly patients, respectively. Concern for these adverse effects may have contributed to recent declines in atypical antipsychotic medication use in patients with dementia.98 In nonelderly adults, fatigue and sedation are common. Akathisia is associated with aripiprazole use, and weight gain is common with several drugs, particularly olanzapine, in which more than 40% of patients may report increased appetite or weight gain. An individual patient's specific target symptoms, the effectiveness of other interventions, the value of modest symptomatic improvement, the individual's particular susceptibility and consequences of adverse events, and the goals of care should be considered in the antipsychotic medication treatment decision.
There are several distinct conclusions between this review and our prior review in 2006. Most notably, the use of any atypical antipsychotic medication for major depressive disorder was considered inconclusive in 2006. Numerous new trials have been sufficient to gain FDA approval for quetiapine and aripiprazole as augmentation therapy in major depressive disorder. A second change is the new evidence regarding the benefit of quetiapine for treating generalized anxiety disorder. Other clinically significant differences include: (1) the strength of evidence has increased from moderate to high for the efficacy of atypical antipsychotic medications in treating behavioral symptoms in patients with dementia, (2) the strength of evidence has decreased from moderate to low for quetiapine in patients with OCD, and (3) new evidence has emerged that atypical antipsychotic medications are ineffective for eating disorders and substance abuse disorder.
There are several limitations to our findings. First, unidentified, unpublished, or excluded studies might have reported results different from those included here. Second, studies published after June 1, 2011, including a recent large randomized controlled trial99 of risperidone therapy for patients with military-related PTSD and symptoms resistant to SSRIs, were not included in our review. Third, we detected unexplained heterogeneity, which may indicate the presence of publication bias, in our pooled results for OCD. This finding accordingly tempers our conclusion about OCD. Fourth, our meta-analysis, particularly for dementia, distills broad heterogeneities across patient and treatment circumstances, and the studies used variable definitions and measures of agitation, which complicates the clinical interpretation and application of the findings. Even so, the evidence is reasonably consistent regarding a small improvement, on average, in clinically relevant symptoms for patients with dementia. Fifth, we did not compare atypical antipsychotic medications to nonpharmacological therapy. Sixth, we found no studies on off-label use for the 3 newer atypical antipsychotic medications (asenapine, iloperidone, or paliperidone). Lastly, most studies were sponsored by drug manufacturers (for example, 27 of 38 dementia trials and 12 of 14 anxiety trials). The existence of the CATIE-AD study, which was federally sponsored and reported results consistent with the industry-sponsored studies, increases our confidence in the conclusions regarding atypical antipsychotic medications for elderly patients with dementia.
In summary, we identified a large amount of literature on the off-label uses of atypical antipsychotic medications. The benefits and harms vary among atypical antipsychotic medications for off-label use. For symptoms of psychosis, agitation, and global behavioral symptoms in elderly patients with dementia, small but statistically significant benefits were observed for risperidone, aripiprazole, and olanzapine. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of OCD. Importantly, adverse effects of atypical antipsychotic medications are common. This evidence should prove useful for clinicians considering off-label prescribing of atypical antipsychotic medications, and should contribute to optimal treatment decision making for individual patients with specific clinical symptoms and unique risk profiles.
Corresponding Author: Alicia Ruelaz Maher, MD, RAND Health, Southern California Evidence-Based Practice Center, 1776 Main St, Santa Monica, CA 90401 (Alicia.Ruelaz@cshs.org).
Author Contributions: Drs Maher and Shekelle had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Maher, Maglione, Bagley, Suttorp, Sultzer, Shekelle.
Acquisition of data: Maher, Hu, Munjas, Wang, Shekelle.
Analysis and interpretation of data: Maher, Maglione, Bagley, Suttorp, Munjas, Wang, Timmer, Sultzer, Shekelle.
Drafting of the manuscript: Maher, Maglione, Suttorp, Hu, Munjas, Wang, Shekelle.
Critical revision of the manuscript for important intellectual content: Maher, Maglione, Bagley, Suttorp, Timmer, Sultzer, Shekelle.
Statistical analysis: Suttorp, Munjas.
Obtained funding: Maglione, Shekelle.
Administrative, technical, or material support: Maher, Maglione, Hu, Timmer, Sultzer, Shekelle.
Study supervision: Maher, Maglione, Bagley, Shekelle.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sultzer reported that he received research support for an Alzheimer disease study from Eli Lilly (no direct or indirect salary was paid to him) and consulting fees from RAND Corporation for his work as member of a technical expert panel for the Agency for Healthcare Research and Quality that performed the initial analysis. No other disclosures were reported.
Funding/Support: This article is based on research conducted by the Southern California Evidence-Based Practice Center under contract HHSA2902007100621 with the Agency for Healthcare Research and Quality. This work was commissioned by the Agency for Healthcare Research and Quality as an update to an earlier report. Drs Sultzer and Shekelle are also supported by the Department of Veterans Affairs.
Role of the Sponsor: The Agency for Healthcare Research and Quality had a role, through its sponsorship of the Evidence-based Practice Centers program, in the general methods of the systematic reviews of the program and in the development of the key questions for each review. However, neither the Agency for Healthcare Research and Quality nor the Department of Veterans Affairs had a role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Disclaimer: The authors of this article are responsible for its content. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality, the US Department of Health and Human Services, or the Department of Veterans Affairs.
Additional Contributions: Roberta Shanman, MLS, director of Reference Services for the RAND Library, conducted the literature searches. Tanja Perry, BHM, Aneesa Motala, BA, Di Valentine, JD (Southern California Evidence-Based Practice Center, RAND Health, Santa Monica, California) contributed to the evidence report and the manuscript. They received compensation for their contributions as RAND employees.
1.Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS. Increasing off-label use of antipsychotic medications in the United States, 1995-2008.
Pharmacoepidemiol Drug Saf. 2011;20(2):177-18421254289
PubMedGoogle ScholarCrossref 4.Jadad AR, Moore RA, Carroll D,
et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?
Control Clin Trials. 1996;17(1):1-128721797
PubMedGoogle ScholarCrossref 6.Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates Inc; 1988
7.Owens DK, Lohr KN, Atkins D,
et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the effective health-care program.
J Clin Epidemiol. 2010;63(5):513-52319595577
PubMedGoogle ScholarCrossref 8.Atkins D, Best D, Briss PA,
et al; GRADE Working Group. Grading quality of evidence and strength of recommendations.
BMJ. 2004;328(7454):149015205295
PubMedGoogle ScholarCrossref 9.Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease.
Cochrane Database Syst Rev. 2006;(1):CD00347616437455
PubMedGoogle Scholar 10.Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials.
Am J Geriatr Psychiatry. 2006;14(3):191-21016505124
PubMedGoogle ScholarCrossref 11.De Deyn PP, Katz IR, Brodaty H, Lyons B, Greenspan A, Burns A. Management of agitation, aggression, and psychosis associated with dementia: a pooled analysis including three randomized, placebo-controlled double-blind trials in nursing home residents treated with risperidone.
Clin Neurol Neurosurg. 2005;107(6):497-50815922506
PubMedGoogle ScholarCrossref 12.Yury CA, Fisher JE. Meta-analysis of the effectiveness of atypical antipsychotics for the treatment of behavioural problems in persons with dementia.
Psychother Psychosom. 2007;76(4):213-21817570959
PubMedGoogle Scholar 13.Streim JE, McQuade RD, Stock E,
et al. Aripiprazole treatment of institutionalized patients with psychosis of Alzheimer's dementia. Poster presented at: Annual Meeting of the American Association of Geriatric Psychiatry; February 21-24, 2004; Baltimore, MD
14.Mintzer JE, Tune LE, Breder CD,
et al. Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses.
Am J Geriatr Psychiatry. 2007;15(11):918-93117974864
PubMedGoogle ScholarCrossref 15.Streim JEP, Porsteinsson AP, Breder CD,
et al. A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease.
Am J Geriatr Psychiatry. 2008;16(7):537-55018591574
PubMedGoogle ScholarCrossref 16.De Deyn PPJ, Mintzer DV. Aripiprazole in dementia of the Alzheimer's type. Paper presented at: 16th Annual Meeting of the American Association for Geriatric Psychiatry; March 1-4, 2003; Honolulu, HI
17.Street JS, Clark WS, Gannon KS,
et al; HGEU Study Group. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial.
Arch Gen Psychiatry. 2000;57(10):968-97611015815
PubMedGoogle ScholarCrossref 18.De Deyn PP, Carrasco MM, Deberdt W,
et al. Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer's disease.
Int J Geriatr Psychiatry. 2004;19(2):115-12614758577
PubMedGoogle ScholarCrossref 19.Sanger Todd M, Clark W. Reduction of psychotic symptoms by olanzapine in patients with possible lewy body dementia. Paper presented at: 155th Annual Meeting of the American Psychiatric Association; May 18-23, 2002; Philadelphia, PA
20.Howanitz EW. Olanzapine vs placebo in the treatment of behavioral disturbances associated with vascular dementia. Paper presented at: 14th Annual Meeting of the American Association for Geriatric Psychiatry; February 23-26, 2001; San Francisco, CA
21.Satterlee WG, Reams SG, Burns PR,
et al. A clinical update on olanzapine treatment in schizophrenia and in elderly Alzheimer's disease patients.
Psychopharmacol Bull. 1995;31:534
Google Scholar 22.Herz LRV, Frankenburg L, Colon F, Kittur S. A 6-week, double-blind comparison of olanzapine, risperidone, and placebo for behavioral disturbances in Alzheimer's disease.
J Clin Psychiatry. 2002;63:1065
Google Scholar 23.Deberdt WG, Dysken MW, Rappaport SA,
et al. Comparison of olanzapine and risperidone in the treatment of psychosis and associated behavioral disturbances in patients with dementia.
Am J Geriatr Psychiatry. 2005;13(8):722-73016085789
PubMedGoogle Scholar 24.Street JS, Kinon F, Stauffer V. Olanzapine in dementia. In: Tran P, ed. Olanzapine (Zyprexa): A Novel Antipsychotic. Philadelphia, PA: Lippincott Wiliams & Wilkins; 2000:416-426
25.Kennedy JD, Deberdt W, Siegal A,
et al. Olanzapine does not enhance cognition in non-agitated and non-psychotic patients with mild to moderate Alzheimer's dementia.
Int J Geriatr Psychiatry. 2005;20(11):1020-102716250069
PubMedGoogle ScholarCrossref 26.Sultzer DL, Davis SM, Tariot PN,
et al; CATIE-AD Study Group. Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial.
Am J Psychiatry. 2008;165(7):844-85418519523
PubMedGoogle ScholarCrossref 27.Mulsant BHG, Gharabawi GM, Bossie CA,
et al. Correlates of anticholinergic activity in patients with dementia and psychosis treated with risperidone or olanzapine.
J Clin Psychiatry. 2004;65(12):1708-171415641877
PubMedGoogle ScholarCrossref 28.Ballard C, Margallo-Lana M, Juszczak E,
et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial.
BMJ. 2005;330(7496):87415722369
PubMedGoogle ScholarCrossref 29.Tariot PS, Katz L, Mintzer I, Street J. Quetiapine in nursing home residents with Alzheimer's dementia and psychosis. Paper presented at: Annual Meeting of the American Association of Geriatric Psychiatry; February 24-27, 2002; Orlando, FL
30.De Deyn PP, Rabheru K, Rasmussen A,
et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia.
Neurology. 1999;53(5):946-95510496251
PubMedGoogle ScholarCrossref 31.Brodaty H, Ames D, Snowdon J,
et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia.
J Clin Psychiatry. 2003;64(2):134-14312633121
PubMedGoogle ScholarCrossref 32.Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M.Risperidone Study Group. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial.
J Clin Psychiatry. 1999;60(2):107-11510084637
PubMedGoogle ScholarCrossref 33.van Reekum RC, Clarke D, Conn D,
et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia.
Int Psychogeriatr. 2002;14(2):197-21012243210
PubMedGoogle ScholarCrossref 34.Ballard CGT, Thomas A, Fossey J,
et al. A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the Neuropsychiatric Inventory median cutoff is a predictor of clinical outcome.
J Clin Psychiatry. 2004;65(1):114-11914744180
PubMedGoogle ScholarCrossref 35.Gareri PC, Cotroneo A, Lacava R,
et al. Comparison of the efficacy of new and conventional antipsychotic drugs in the treatment of behavioral and psychological symptoms of dementia (BPSD).
Arch Gerontol Geriatr Suppl. 2004;(9):207-21515207416
PubMedGoogle Scholar 36.Street JST, Tohen M,
et al. Olanzapine for psychotic conditions in the elderly.
Psychiatr Ann. 2000;30:191-196
Google Scholar 37.Naber DG, Greenspan A, Schreiner A. Efficacy and safety of risperidone in the treatment of elderly patients suffering from organic brain disease (organic brain syndrome): results from a double-blind, randomized, placebo-controlled clinical trial.
Psychopharmacology (Berl). 2007;191(4):1027-102917333131
PubMedGoogle ScholarCrossref 38.Rainer MH, Haushofer M, Pfolz H, Struhal C, Wick W. Quetiapine versus risperidone in elderly patients with behavioural and psychological symptoms of dementia: efficacy, safety and cognitive function.
Eur Psychiatry. 2007;22(6):395-40317482432
PubMedGoogle ScholarCrossref 39.Zhong KX, Tariot PN, Mintzer J, Minkwitz MC, Devine NA. Quetiapine to treat agitation in dementia: a randomized, double-blind, placebo-controlled study.
Curr Alzheimer Res. 2007;4(1):81-9317316169
PubMedGoogle ScholarCrossref 40.Moretti RT, Torre P, Antonello RM, Cattaruzza T, Cazzato G. Olanzapine as a possible treatment of behavioral symptoms in vascular dementia: risks of cerebrovascular events: a controlled, open-label study.
J Neurol. 2005;252(10):1186-119315809822
PubMedGoogle ScholarCrossref 41.Savaskan ES, Schnitzler C, Schröder C, Cajochen C, Müller-Spahn F, Wirz-Justice A. Treatment of behavioural, cognitive and circadian rest-activity cycle disturbances in Alzheimer's disease: haloperidol vs quetiapine.
Int J Neuropsychopharmacol. 2006;9(5):507-51616316485
PubMedGoogle ScholarCrossref 42.Rappaport SA, Marcus RN, Manos G, McQuade RD, Oren DA. A randomized, double-blind, placebo-controlled tolerability study of intramuscular aripiprazole in acutely agitated patients with Alzheimer’s, vascular, or mixed dementia.
J Am Med Dir Assoc. 2009;10(1):21-2719111849
PubMedGoogle ScholarCrossref 43.Paleacu DB, Barak Y, Mirecky I, Mazeh D. Quetiapine treatment for behavioural and psychological symptoms of dementia in Alzheimer's disease patients: a 6-week, double-blind, placebo-controlled study.
Int J Geriatr Psychiatry. 2008;23(4):393-40017879256
PubMedGoogle ScholarCrossref 44.Suh G-H, Greenspan AJ, Choi S-K. Comparative efficacy of risperidone versus haloperidol on behavioural and psychological symptoms of dementia.
Int J Geriatr Psychiatry. 2007;22(5):494-49517471597
PubMedGoogle ScholarCrossref 45.Pollock BG, Mulsant BH, Rosen J,
et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia.
Am J Geriatr Psychiatry. 2007;15(11):942-95217846102
PubMedGoogle ScholarCrossref 46.Tariot PN, Schneider L, Katz IR,
et al. Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial.
Am J Geriatr Psychiatry. 2006;14(9):767-77616905684
PubMedGoogle ScholarCrossref 47.Verhey FRJ, Verkaaik M, Lousberg R.Olanzapine-Haloperidol in Dementia Study group. Olanzapine versus haloperidol in the treatment of agitation in elderly patients with dementia: results of a randomized controlled double-blind trial.
Dement Geriatr Cogn Disord. 2006;21(1):1-816244481
PubMedGoogle ScholarCrossref 48.Mintzer J, Greenspan A, Caers I,
et al. Risperidone in the treatment of psychosis of Alzheimer disease: results from a prospective clinical trial.
Am J Geriatr Psychiatry. 2006;14(3):280-29116505133
PubMedGoogle ScholarCrossref 49.Holmes CW, Wilkinson D, Dean C,
et al. Risperidone and rivastigmine and agitated behaviour in severe Alzheimer's disease: a randomised double blind placebo controlled study.
Int J Geriatr Psychiatry. 2007;22(4):380-38117380475
PubMedGoogle ScholarCrossref 50.Mowla A, Pani A. Comparison of topiramate and risperidone for the treatment of behavioral disturbances of patients with Alzheimer disease: a double-blind, randomized clinical trial.
J Clin Psychopharmacol. 2010;30(1):40-4320075646
PubMedGoogle ScholarCrossref 51.Mintzer J. Efficacy and safety of a flexible dose of risperidone vs placebo in the treatment of psychosis of Alzheimer's disease. Poster presented at: 4th Annual Meeting of the International College for Geriatric Psychoneuropharmacology; October 14-17, 2004; Basel, Switzerland
52.Schneider LS, Tariot PN, Dagerman KS,
et al; CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease.
N Engl J Med. 2006;355(15):1525-153817035647
PubMedGoogle ScholarCrossref 53.Streim JE, Breder C, Swanink R, McQuade RD, Iwamoto T, Carson W. Flexible dose aripiprazole in psychosis of Alzheimer's dementia. Paper presented at: American Psychiatric Association Annual Meeting; May 1-6, 2004; New York, NY
54.Zhong XT, Minkwitz P, Devine MC, Mintzer NA. Quetiapine for the treatment of agitation in elderly institutionalized patients with dementia: a randomized, double-blind trial. J. Paper presented at: 56th Institute in Psychiatric Services; October 6-10, 2004; Atlanta, GA
55.Brodaty H, Ames D, Snowdon J,
et al. Risperidone for psychosis of Alzheimer's disease and mixed dementia: results of a double-blind, placebo-controlled trial.
Int J Geriatr Psychiatry. 2005;20(12):1153-1157
Google ScholarCrossref 57.Depping AM, Komossa K, Kissling W, Leucht S. Second-generation antipsychotics for anxiety disorders.
Cochrane Database Syst Rev. 2010;12(12):CD00812021154392
PubMedGoogle Scholar 58.Pollack MH, Simon NM, Zalta AK,
et al. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study.
Biol Psychiatry. 2006;59(3):211-21516139813
PubMedGoogle ScholarCrossref 59.Simon NM, Connor KM, LeBeau RT,
et al. Quetiapine augmentation of paroxetine CR for the treatment of refractory generalized anxiety disorder: preliminary findings.
Psychopharmacology (Berl). 2008;197(4):675-68118246327
PubMedGoogle ScholarCrossref 60. McIntyre A, Gendron A, McIntyre A. Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study.
Depress Anxiety. 2007;24(7):487-49417177199
PubMedGoogle ScholarCrossref 61.Merideth C, Cutler A, Neijber A, She F, Eriksson H. Efficacy and tolerability of extended release quetiapine fumarate monotherapy in the treatment of GAD.
Eur Neuropsychopharmacol. 2008;18:(suppl 4)
S499-S500
Google ScholarCrossref 62.Bandelow B, Chouinard G, Bobes J,
et al. Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder: data from a randomized, double-blind, placebo- and active-controlled study.
Int J Neuropsychopharmacol. 2010;13(3):305-32019691907
PubMedGoogle ScholarCrossref 63.Hirschfeld RM, Weisler RH, Raines SR, Macfadden W.BOLDER Study Group. Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: a secondary analysis from a randomized, double-blind, placebo-controlled study.
J Clin Psychiatry. 2006;67(3):355-36216649820
PubMedGoogle ScholarCrossref 64.Joyce M, Khan A, Eggens I,
et al. Efficacy and safety of extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder (GAD). Poster presented at: 161st Annual Meeting of the American Psychiatric Association; May 3-8, 2008; Washington, DC
65.Katzman MA, Brawman-Mintzer O, Reyes EB, Olausson B, Liu S, Eriksson H. Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial.
Int Clin Psychopharmacol. 2011;26(1):11-2420881846
PubMedGoogle ScholarCrossref 66.Altamura AC, Serati M, Buoli M, Dell'Osso B. Augmentative quetiapine in partial/nonresponders with generalized anxiety disorder: a randomized, placebo-controlled study.
Int Clin Psychopharmacol. 2011;26(4):201-20521403524
PubMedGoogle ScholarCrossref 67.Khan A, Atkinson S, Mezhebovsky I, She F, Leathers T, Pathak S. Efficacy and safety of once-daily extended release quetiapine fumarate (quetiapine XR) as an adjunct therapy in patients with treatment non-responsive generalized anxiety disorder (GAD). Poster presented at: 49th Annual New Clinical Drug Evaluation Unit Meeting; June 29-July 2, 2009; Hollywood, FL
68.Sheehan DV, McElroy SL, Harnett-Sheehan K,
et al. Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety.
J Affect Disord. 2009;115(3):376-38519042026
PubMedGoogle ScholarCrossref 69.Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study.
J Clin Psychiatry. 2005;66(10):1321-132516259547
PubMedGoogle ScholarCrossref 70.Pandina GJ, Canuso CM, Turkoz I, Kujawa M, Mahmoud RA. Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial.
Psychopharmacol Bull. 2007;40(3):41-5718007568
PubMedGoogle Scholar 71.Lohoff FW, Etemad B, Mandos LA, Gallop R, Rickels K. Ziprasidone treatment of refractory generalized anxiety disorder: a placebo-controlled, double-blind study.
J Clin Psychopharmacol. 2010;30(2):185-18920520293
PubMedGoogle ScholarCrossref 72. McDougle CJE, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder.
Arch Gen Psychiatry. 2000;57(8):794-80110920469
PubMedGoogle ScholarCrossref 73.Erzegovesi SG, Guglielmo E, Siliprandi F, Bellodi L. Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study.
Eur Neuropsychopharmacol. 2005;15(1):69-7415572275
PubMedGoogle ScholarCrossref 74.Cavedini PB, Bassi T, Zorzi C, Bellodi L. The advantages of choosing antiobsessive therapy according to decision-making functioning.
J Clin Psychopharmacol. 2004;24(6):628-63115538125
PubMedGoogle ScholarCrossref 75.Denys D, de Geus F, van Megen HJ, Westenberg HG. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors.
J Clin Psychiatry. 2004;65(8):1040-104815323587
PubMedGoogle ScholarCrossref 76.Bystritsky AA, Ackerman DL, Rosen RM,
et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial.
J Clin Psychiatry. 2004;65(4):565-56815119922
PubMedGoogle ScholarCrossref 77.Shapira NA, Ward HE, Mandoki M,
et al. A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder.
Biol Psychiatry. 2004;55(5):553-55515023585
PubMedGoogle ScholarCrossref 78.Hollander ER, Baldini Rossi N, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study.
Int J Neuropsychopharmacol. 2003;6(4):397-40114604454
PubMedGoogle ScholarCrossref 79.Atmaca MK, Kuloglu M, Tezcan E, Gecici O. Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study.
Int Clin Psychopharmacol. 2002;17(3):115-11911981352
PubMedGoogle ScholarCrossref 80.Fineberg NA, Sivakumaran T, Roberts A, Gale T. Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: a randomized controlled treatment study.
Int Clin Psychopharmacol. 2005;20(4):223-22615933483
PubMedGoogle ScholarCrossref 81.Carey PD, Vythilingum B, Seedat S, Muller JE, van Ameringen M, Stein DJ. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebo-controlled study [ISRCTN83050762].
BMC Psychiatry. 2005;5(1):515667657
PubMedGoogle ScholarCrossref 82.Maina G, Pessina E, Albert U, Bogetto F. 8-week, single-blind, randomized trial comparing risperidone versus olanzapine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder.
Eur Neuropsychopharmacol. 2008;18(5):364-37218280710
PubMedGoogle ScholarCrossref 83.Kordon A, Wahl K, Koch N,
et al. Quetiapine addition to serotonin reuptake inhibitors in patients with severe obsessive-compulsive disorder: a double-blind, randomized, placebo-controlled study.
J Clin Psychopharmacol. 2008;28(5):550-55418794652
PubMedGoogle ScholarCrossref 84.Matsunaga H, Nagata T, Hayashida K, Ohya K, Kiriike N, Stein DJ. A long-term trial of the effectiveness and safety of atypical antipsychotic agents in augmenting SSRI-refractory obsessive-compulsive disorder.
J Clin Psychiatry. 2009;70(6):863-86819422759
PubMedGoogle ScholarCrossref 85.Vulink NC, Denys D, Fluitman SB, Meinardi JC, Westenberg HG. Quetiapine augments the effect of citalopram in non-refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled study of 76 patients.
J Clin Psychiatry. 2009;70(7):1001-100819497245
PubMedGoogle ScholarCrossref 86.Diniz JB, Shavitt RG, Pereira CA,
et al. Quetiapine versus clomipramine in the augmentation of selective serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder: a randomized, open-label trial.
J Psychopharmacol. 2010;24(3):297-30719164490
PubMedGoogle ScholarCrossref 87.Denys D, Vulink N, Fluitman S,
et al. Quetiapine addition to serotonin reuptake inhibitors in non-refractory obsessive compulsive disorder.
Neuropsychopharmacology. 2006;31(suppl 1):S104
Google Scholar 88.Schneider LSD, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.
JAMA. 2005;294(15):1934-194316234500
PubMedGoogle ScholarCrossref 89.Gill SS, Bronskill SE, Normand SL,
et al. Antipsychotic drug use and mortality in older adults with dementia.
Ann Intern Med. 2007;146(11):775-78617548409
PubMedGoogle ScholarCrossref 90.Kales HC, Valenstein M, Kim HM,
et al. Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications.
Am J Psychiatry. 2007;164(10):1568-157617898349
PubMedGoogle ScholarCrossref 91.Vigen CL, Mack WJ, Keefe RS,
et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer's disease: outcomes from CATIE-AD.
Am J Psychiatry. 2011;168(8):831-83921572163
PubMedGoogle ScholarCrossref 92.Liperoti R, Onder G, Landi F,
et al. All-cause mortality associated with atypical and conventional antipsychotics among nursing home residents with dementia: a retrospective cohort study.
J Clin Psychiatry. 2009;70(10):1340-134719906339
PubMedGoogle ScholarCrossref 93.Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients.
CMAJ. 2007;176(5):627-63217325327
PubMedGoogle ScholarCrossref 94.Huybrechts KF, Rothman KJ, Silliman RA, Brookhart MA, Schneeweiss S. Risk of death and hospital admission for major medical events after initiation of psychotropic medications in older adults admitted to nursing homes.
CMAJ. 2011;183(7):E411-E41921444611
PubMedGoogle Scholar 95.Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death.
N Engl J Med. 2009;360(3):225-23519144938
PubMedGoogle ScholarCrossref 96.Parker C, Coupland C, Hippisley-Cox J. Antipsychotic drugs and risk of venous thromboembolism: nested case-control study.
BMJ. 2010;341:c424520858909
PubMedGoogle ScholarCrossref 97.Kinon BJL, Edwards I. Improvement of comorbid depression with olanzapine vs ziprasidone treatment in patients with schizophrenia or schizoaffective disorder. Paper presented at: International Congress on Schizophrenia Research; April 2-6, 2005; Savannah, GA
98.Kales HC, Zivin K, Kim HM,
et al. Trends in antipsychotic use in dementia 1999-2007 [published correction appears in
Arch Gen Psychiatry. 2011;68{5}:466].
Arch Gen Psychiatry. 2011;68(2):190-19721300946
PubMedGoogle ScholarCrossref 99.Krystal JH, Rosenheck RA, Cramer JA,
et al; Veterans Affairs Cooperative Study No. 504 Group. Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial.
JAMA. 2011;306(5):493-50221813427
PubMedGoogle ScholarCrossref