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The aim of this study was to review the efficacy and safety of atypical antipsychotics, comparing within class, placebo, or compared to another active treatment for delirium. A literature search was conducted using PubMed, EMBASE, and the Cochrane database (1 January 1990–5 November 2012). Selection criteria for review were prospective, controlled studies (comparison studies), using validated delirium rating scales as outcome measures. A total of six prospective, randomized controlled studies were included in the review. It was found that atypical antipsychotics are effective and safe in treating delirium, even though there seemed to be no difference between each agent. In particular, comparison studies with haloperidol showed that the efficacy of atypical antipsychotics was similar to that of low-dose haloperidol. It was concluded that atypical antipsychotics appear to be effective and tolerable in the management of delirium, even though the evidence is limited.
DELIRIUM IS AN acute, confusional state that is characterized by consciousness disturbance, changes in cognition and attention, and reduced awareness or perceptual disturbances that develop acutely and have a fluctuating course. Delirium is a common neuropsychiatric condition observed in medically ill patients. Lipowski reported that, among patients hospitalized for medical and surgical reasons, the incidence of delirium ranged from 10% to 18% and that the development of delirium is associated with a high mortality and morbidity. The elderly are known to be at high risk for developing delirium. According to Han and Kim, 10–40% of hospitalized elderly patients develop delirium during hospitalization.
For non-pharmacological interventions for delirium, clinicians should correct and treat the underlying medical condition responsible for the delirium.[4, 5] Conservative management such as preventing medical complications and providing patients with a supportive environment is also very important. In terms of pharmacological interventions, antipsychotic agents have been regarded as the treatment of choice, because various antipsychotic agents have been shown to ameliorate a range of delirium symptoms effectively in many previous studies.[6-8] Among antipsychotics, haloperidol has been the most widely used because of its higher dopamine receptor potency, lower anticholinergic effects, and the availability of various routes of use. Side-effects, however, have been reported, especially extrapyramidal effects. Due to the side-effects of typical antipsychotics, the use of atypical antipsychotics in the treatment of delirium has been increasing because of the lower incidence of extrapyramidal symptoms with atypical compared to typical antipsychotics.[11, 12]
Despite the increasing usage of atypical antipsychotics for delirium in clinical practice, limited evidence is available on their efficacy and tolerability.[11, 12] Accordingly, the primary aim of this paper was to review the existing published literature on the role of atypical antipsychotics in the management of delirium.
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In this review, we discussed studies that tested the efficacy and safety of atypical antipsychotics in the treatment of delirium. Since their introduction, atypical antipsychotics have replaced typical antipsychotics in various clinical uses because of their favorable side-effect profiles. For the same reasons, the use of second-generation antipsychotics in the management of delirium has increased, which reflects a change in prescription patterns. Since one of the first studies of the use of atypical antipsychotics for delirium, there have been numerous published reports regarding their clinical efficacy and tolerability; but when we consider that many etiologies are known to cause delirium and that delirium has a fluctuating nature, it is difficult to affirm that the significant improvement in delirium symptoms observed in many previous clinical trials after the use of atypical antipsychotics is purely due to the effect of atypical antipsychotics. Thus, we selected only well-controlled studies to separate the influence of atypical antipsychotics on delirium symptoms from other variables that could influence the treatment response and course of delirium.
We conducted a literature search and found a total of six randomized controlled, prospective clinical trials that tested the utility of atypical antipsychotics in delirium.
Among the six studies reviewed, only one was a placebo-controlled study. The rest were comparison studies, some of which compared the efficacy of atypical antipsychotics to haloperidol,[3, 18, 19] and the others compared different atypical antipsychotics to each other.[17, 19, 21]
The only placebo-controlled study examined the efficacy of quetiapine among general hospital inpatients whose DRS-R 98 total scores were ≥15. Although the quetiapine and placebo groups did not differ in their delirium severity at any time point, the quetiapine group had a more rapid improvement in symptoms. But because that study was prematurely discontinued, we are unable to draw any definitive conclusions.
Three studies were comparison studies that directly compared two antipsychotics to each other.[17, 19, 21] One study used haloperidol as an active comparator. All three comparison studies showed improvements in delirium symptoms after use of atypical antipsychotics, and there were no between-group differences in efficacy and tolerability.
The other two studies were haloperidol-controlled studies that examined the effectiveness of olanzapine and risperidone.[3, 18] Both studies reported similar efficacy of each atypical antipsychotic agent compared to haloperidol, suggesting the potential use of each atypical antipsychotic agent as a safe alternative to haloperidol.
Across the six studies, extrapyramidal symptoms were one of the most common adverse events reported, while the metabolic side-effects were much less frequently reported. That might be because the treatment duration for delirium in these studies was relatively shorter than the duration for other major psychiatric disorders, such as affective disorders or psychotic disorders.
While reviewing the extant literature, we identified several concerns and methodological limitations. First, most studies had small sample sizes. The sample sizes across the six studies were between 20 and 80, which is too small a sample to generalize the results. Second, there was significant heterogeneity across studies in terms of the characteristics of the study groups and the etiology of delirium. Participants across the six studies presented with delirium symptomatology at admission to medical or surgical wards or developed delirium while undergoing treatment in intensive care units. The underlying etiology of delirium for each participant also varied, and included etiologies such as malignant tumors, orthopedic problems, pneumonia, neurosurgical conditions, and other medical and surgical conditions. Third, no study reported controlling for these heterogeneous differences in their analyses or controlling for any treatment (including non-specific, non-pharmacological treatments) given to patients to manage an underlying medical/surgical condition. Because these can be confounding variables, future studies should describe and explain these variables in their assessment and analyses. Fourth, we found that there were few studies that investigated the tolerability systematically. There were no validated assessment tools for drug side-effects used in the six studies except the scales assessing the extrapyramidal symptoms.
There are some limitations to the present review. First, we included only randomized controlled, prospective studies that were written in English. We may have excluded important studies written in other languages or with uncontrolled, naturalistic, or retrospective designs, which can also provide valuable information about the utility of atypical antipsychotics. Second, we included only studies that used validated delirium rating scales as efficacy outcome measures. Thus, we excluded some trials that included critically ill patients with delirium with whom validated delirium rating scales could not be used.
Despite these limitations, overall we found that atypical antipsychotics are efficacious and relatively safe in treating delirium. Specifically, it appears that atypical antipsychotics are as equally efficacious as haloperidol, which is the most widely used medication for treating delirium. Furthermore, there seemed to be no significant difference in the efficacy and tolerability among atypical antipsychotics, although very few studies directly compared two atypical antipsychotics to each other.
Meanwhile there have been some reports of delirium caused or induced by atypical antipsychotics, during the treatment of major psychiatric disorders with atypical antipsychotics.[59-64] Thus, these reports could lead to medical concern for the potential of atypical antipsychotics in aggravating the delirium symptoms or complicating the treatment of delirium during the delirium management. In most studies reviewed here, however, the efficacy of atypical antipsychotics for delirium was shown at a lower dosage than the usual dosage used for the management of major psychiatric disorders or for controlling psychotic symptoms. But we think that it is important for clinicians to pay special attention to the elderly patients or medically vulnerable patients when using atypical antipsychotics for delirium and to monitor the course of delirium closely.
In summary, considering several methodological limitations and problems with previous studies mentioned here, future studies need to be well-controlled, have large sample sizes, use more systematic assessment tools for side-effects, and explore the effects of various factors (e.g. underlying medical disorder-related or medical treatment-related factors) on the resolution of delirium to further clarify the role of atypical antipsychotics in the treatment of delirium. In addition, future studies are also warranted to further investigate the differences in the effectiveness of atypical antipsychotics for the treatment of delirium according to the motor subtypes or various delirium etiologies.