Psychiatry (Edgemont) 2010;7(2):32–40

Dr. Carroll is Associate Professor of Psychiatry (Volunteer), University of Cincinnati, College of Medicine, and Chief, Psychiatry Service, MHCL, Chillicothe VAMC, Chillicothe, OH; Dr. Surber is of the Cleveland Clinic Foundation, Cleveland, OH.

Drs. Moturi and Ivanenko are from the Division of Child and Adolescent Psychiatry, Children’s Memorial Hospital, Chicago, Illinois. Dr. Ivanenko is also from the Children’s Memorial at Central DuPage Hospital, Winfield, Illinois.

Dr. Lasser is with Shire Pharmaceuticals (Dr. Lasser was with Johnson & Johnson at the time of the development of this manuscript); Dr. Schooler is with SUNY Downstate Medical Center, Brooklyn, New York; Dr. Kujawa is with Hoffman-La Roche, Nutley, New Jersey (Dr. Kujawa was with Ortho-McNeil Janssen Pharmaceutical Affairs, LLC, at the time of the development of this manuscript); K. Jarboe is with Quintiles, Inc., Atlanta, Georgia; Dr. Docherty is with Joan and Sanford I. Weill Medical College of Cornell University, New York, New York; and Dr. Weiden is with the University of Illinois, Chicago, Illinois.

Dr. Markowitz is Attending Psychiatrist at the James A. Haley Veterans Administration Hospital and Assistant Professor of Psychiatry at the University of South Florida, Tampa, Florida; and Dr. Narasimhan is Professor of Neuropsychiatry and Behavioral Sciences at the University of South Carolina, Columbia, South Carolina.

Psychiatry (Edgemont) 2008;5(10):29–36

Financial Disclosure
The author has no financial conflicts of interest with the material presented in this review.

Abstract
Delirium is a very common medical condition encountered throughout the world and, undoubtedly, is one of the most frequent reasons psychiatrists are consulted by primary care physicians. Recognizing delirium and treating the underlying medical cause are the first steps in the management of this potentially fatal syndrome. The selection of an appropriate medication to target the perceptual, behavioral, and cognitive abnormalities is crucial. In addition to several of the older, typical antipsychotics, which have been found to be effective for the treatment of delirium, some of the newer, atypical antipsychotic agents have been demonstrated to be efficacious. This paper will review both the typical and atypical antipsychotics with the best evidence for efficacy and safety in the treatment of delirium. Finally, environmental treatments are discussed to present the full armamentarium of therapeutic options available to the practicing clinician.

Key Words
delirium, antipsychotics, epidemiology, somatic treatment

Introduction
Delirium is best described as a disturbance of consciousness with reduced attention, changes in cognition, and perceptual disturbances. Delirium is more common than may be predicted as 10 to 15 percent of medically ill inpatients can be delirious, and 30 to 50 percent of acutely ill geriatric patients are delirious at any given time in the hospital. Patients without delirium in the hospital have a two-percent mortality rate, with an additional three-percent mortality at three months after discharge. The mortality rate in delirious patients in the hospital has been found to be 11 percent, with 11 percent mortality at three months after discharge.[1]

Delirium reflects brain dysfunction that is almost always due to identifiable systemic or cerebral disease or to drug intoxication or withdrawal states. The disturbance is caused by the direct physiological consequences of a general medical condition.[2,3] The onset of delirium is typically rapid and is characterized by a fluctuating course throughout the day with disturbances in consciousness and cognition (Table 1).

Risk factors for delirium include greater severity of physical illness, older age, and baseline cognitive impairment.[3] In particular, burn victims, postoperative and sensory-deprived patients, and patients with human immunodeficiency virus (HIV), head injury, seizures, renal failure, hepatic failure, or cardiac failure are at risk for delirium.[4] Recognizing delirium, which may be subtle in less agitated forms, is particularly important as it may be the only evidence of a life-threatening condition.[5] Differentiating delirium from dementia is of paramount importance and can be accomplished by noting the temporal pattern of the condition, as well as the attention span of the patient. Delirium differs from dementia in that delirium is characterized by fluctuations in the mental status of the patient (e.g., alertness, orientation), whereas dementia is characterized by a static mental status. Delirium is typically more acute in onset and may be rapidly fatal if not reversed, whereas dementia has a longer and more insidious course. It should be noted that it can be very difficult to distinguish delirium from dementia, especially when the condition is comorbid as is common in the elderly population.

Prompt treatment of delirium is crucial as this syndrome has a significant mortality rate. As a first step, the physician should search for contributing causes, obtain a complete history, including a careful review of medication usage and illicit drug history, and perform full physical and neurological exams. Laboratory tests with neuroimaging studies and a lumbar puncture may be necessary. The most basic treatment principals begin with identifying and treating the causal or contributing medical conditions. If the patient is being treated with sedatives or other medications affecting the central nervous system, the physician should discontinue these agents. The exception to this rule is the patient who is delirious due to sedative-hypnotic or alcohol withdrawal.[2]

Neuropathogenesis

The list of illnesses, medications, and conditions that can cause delirium is extensive. Nonetheless, there is great controversy over how the brain becomes trapped in this altered state of consciousness. Both cortical and subcortical dysfunction have been implicated by regional cerebral blood flow studies, single photon emission computed tomography, positron-emission tomography, electroencephalogram, and evoked potentials.[7]

Among the neurotransmitters most strongly implicated in delirium pathogenesis are acetylcholine and dopamine. While decreased acetylcholine activity is presumed to play a role in delirium, hyperactivity in the dopamine system is also a strong etiologic candidate. Less certain is the role of serotonin and gamma-aminobutyric acid (GABA) in which an either increased or decreased activity of these neurotransmitters may be involved in delirium pathogenesis. Finally, excess glutamate activity or decreased histamine activity also may be etiologic factors in delirium (Figure 1).[7]

A complete list of all the possible causes of delirium would be very difficult and lengthy to compile due to the variety of causes potentially responsible for the condition. The most frequent causes of delirium include infectious disease, particularly of the central nervous system, cardiovascular compromise, endocrine abnormalities, trauma, and metabolic derangements from toxins, electrolyte imbalance, or withdrawal states. Some of the more common causes and etiologic factors are expanded upon and summarized in Table 2.

Pharmacologic Treatment Options

With regard to the pharmacological management of delirium, antipsychotics are the drugs of choice and should be administered at the lowest adequate dosages. For more threatening agitation, a combination of antipsychotics and benzodiazepines along with ventilatory support has been utilized.[8]

Haloperidol, a typical antipsychotic, is the most frequently used and best studied antipsychotic medication for delirium due to its few anticholinergic side effects, few active metabolites, and small likelihood of causing sedation. Most studies have used doses of haloperidol from 0.25 to 0.50mg every four hours for the elderly or seriously medically compromised patients to doses of 2 to 3mg per day in healthier patients. For very agitated patients, bolus doses of 5 to 10mg per hour intravenously have been used in hospital settings.[9,10] The main outcome measures for these studies were the Brief Psychiatric Rating Scale, Schedule for Affective Disorders Scale, Clinical Dementia Rating Scale, and the Behavioral Syndromes Scale for Dementia. A study with haloperidol, chlorpromazine, and lorazepam groups have demonstrated improvements in the mental status as measured by the Delirium Rating Scale in the haloperidol and chlorpromazine groups but not the lorazepam groups.[11] A criticism of this study is that the mean doses of haloperidol and chlorpromazine were low 1.4mg per day and 36mg per day respectively, while the dose of lorazepam was more moderate at 4.6mg per day. As mentioned in a review paper on delirium by Pae, et al., in a larger, placebo-controlled study comparing haloperidol to olanzapine, an atypical antipsychotic discussed in more detail later, little difference between active medication groups but superiority to placebo was demonstrated.[12,13] In this study, low to moderate doses of haloperidol and olanzapine were used, 4.5mg versus 7.1mg respectively, and the instrument measure was the Delirium Rating Scale. The size of the active medication groups for haloperidol and olanzapine were 72 versus 74 patients with 29 patients receiving placebo and the mean time to improvement being 3.4 days versus 2.8 days and 5.2 days for those receiving placebo.

Other typical antipsychotics have been the subject of investigation for treatment of delirium (acute organic mental syndrome), but many of these studies are 20 to 30 years old and do not always utilize diagnostic nomenclature compatible with contemporary medical practice. In the 1980s, a single blind study of haloperidol and thiothixene on 14 patients showed that both drugs were effective in relieving delirium with a possible slight advantage for thiothixene as measured by the Brief Psychiatric Rating Scale.[14] The dose of haloperidol was between 4.8 and 15mg and the thiothixene dose was between 2 and 7mg per day.

Earlier studies from the 1970s of thiothixene, loxapine, and thioridazine are difficult to incorporate into the evidence base given their admitted diagnostic heterogeneity and small sample sizes. One double-blind, placebo-controlled study of thiothixene dosed at 2 to 5mg up to three times a day failed to find superiority of the drug for chronic organic brain syndrome. The outcome measures of this study were the Brief Psychiatric Rating Scale and Nursing Observational Scale for Inpatient Evaluation.[15] Another study contained two individual, double-blind trials of loxapine versus thioridazine for the treatment of chronic organic brain syndromes. One of these studies found loxapine at 10 to 150mg per day to be superior to thioridazine at 150 to 750mg per day for the treatment of chronic organic brain syndrome while the other demonstrated equal efficacy. The outcome measures were the Brief Psychiatric Rating Scale and Nursing Observational Scale for Inpatient Evaluation along with the Clinical Global Impressions Scale.[16] Finally, one case report describes a patient who did not respond to higher-dose olanzapine, 20mg per day, but did respond to lower-dose loxapine, 45mg per day. Because rating scales for delirium were not utilized, equivalent doses of these medications were not established, and olanzapine is particularly sedating at higher doses, this case report is difficult to interpret.[17]

A brief case series of four patients with HIV-associated delirium demonstrated that molindone in doses of 40 to 140mg per day was effective in controlling delirium in each of the patients treated. Caution should be applied in coming to a conclusion from this report as the patients were on other typical antipsychotics at times, such as haloperidol and thioridazine, and no delirium rating scales were utilized.[18] The evidence for use of typical antipsychotics in delirium is presented in Table 3.

With the advent of atypical antipsychotics and their decreased risk of extrapyramidal side effects, there has been increased interest in using these agents for delirium. After clozapine, which clearly has serious limitations (lethal agranulocytosis) to its use for any disorder other than refractory schizophrenia or schizoaffective disorder, risperidone was the next atypical antipsychotic approved for use in the United States. An early case report in two patients with hypoxic brain injury demonstrated the potential capability of risperidone to be effective in treating delirium.[19] After this, five separate studies in patients with a variety of underlying medical illnesses demonstrated the effectiveness of risperidone at doses ranging from 0.75mg per day to 3.1mg per day in the treatment of delirium with the majority of patients showing moderate to marked improvement of their delirium on the Clinical Global Impressions Scale, Brief Psychiatric Rating Scale, and Trzepacz Delirium Rating Scale. Common side effects of risperidone included sedation, dizziness, and extrapyramidal symptoms (EPS). The average length of treatment in these studies was approximately one week.[20–24] In a small case series conducted in Israel, three elderly patients were administered risperidone and subsequently developed delirium. One of these patients was also receiving lithium at a therapeutic level, another was in the middle of a course of electroconvulsive therapy (ECT) treatment, and the last was mildly hyponatremic and receiving fluvoxamine and diuretics along with the risperidone. Clearly, other etiological factors for the delirium could have been operative.[25] A double-blind trial of risperidone and haloperidol demonstrated equivalence in treatments in efficacy and response rates. The mean daily dose of risperidone was 1.02mg and the mean daily dose of haloperidol was 1.71mg.[26] The Trzepacz Delirium Rating Scale was again the main rating scale utilized. One large double-blind, placebo-controlled study using risperidone for the treatment of delirium in doses of 0.5mg to 4.0mg per day did not demonstrate efficacy for this agent. Nonetheless, a major confounding factor was the fact that the Positive and Negative Symptom Scale was used to measure delirium though this scale is not a measure of delirium specifically and measures multiple other aspects of mental functioning.[27]

Olanzapine would appear to have sufficient evidence to sustain a claim for delirium treatment. An early case report of the successful treatment of delirium in a cancer patient with olanzapine appeared in the literature in 1998.[28] In two open trials of hospitalized patients using similar doses of olanzapine, the outcome was a 50-percent reduction in the Delirium Rating Scale and a marked reduction in the Memorial Delirium Assessment Scale.[29,30] Two other studies of olanzapine at mean doses of 4.5mg per day to 8.2mg per day demonstrated comparable reductions in delirium when measured against haloperidol at mean doses of 4.5mg per day to 5.1mg per day on the Delirium Rating Scale and Memorial Delirium Assessment Scale. The peak response time of both groups was similar at nearly seven days. In addition, those on olanzapine had less extrapyramidal side effects and less sedation than the haloperidol group.[31,32]

Quetiapine, with its very low incidence of extrapyramidal side effects, should be an attractive choice for the delirious elderly patient if proven clinically efficacious. Two sets of case reports with two patients each demonstrated quetiapine to be safe and effective for the treatment of delirium at doses of 50 to 100mg per day within one week of initiation. One of these reports utilized the Delirium Rating Scale and Mini Mental Scale Examination as rating scales while the other used no rating scales.[33,34] When compared to haloperidol, delirious patients on quetiapine showed similar improvements on the Delirium Rating Scale but quetiapine was better tolerated.[35] Four open-label trials of between 12 and 22 patients using quetiapine at 25 to 200mg per day demonstrated the effectiveness of this agent in almost all patients after approximately seven days of treatment with much improved Delirium Rating Scales, Mini Mental Scale Examination scales, and Clinical Global Impression scales.[36–39]

The two latest additions to the antipsychotic armamentarium, ziprasidone and aripiprazole, have less information published regarding delirium. A case report of a delirious 34-year-old HIV-positive man with possible cryptococcal meningitis had to be abandoned due to cardiac side effects. Ziprasidone treatment, initiated at 20mg per day and then titrated up to 100mg per day, led to an improvement in the delirium as demonstrated by a significant reduction in the Delirium Rating Scale. Nonetheless, there is too little information to draw a definitive conclusion.[40] A case report in the anesthesiology literature reported the successful use of ziprasidone for delirium. Ziprasidone was given intravenously at 20mg after a failed course of haloperidol and then tapered orally over the course of a week. The patient improved but there were no details given on the doses of the taper or if any rating scale was used to measure the delirium.[41]

Aripiprazole, the newest atypical antipsychotic, likewise, has evidence of its usefulness in the treatment of delirium with two case studies each having two patients given 15 to 30mg of the agent per day and utilizing the Delirium Rating Scale and Mini Mental Scale Examination as rating scales.[42,43] A case series examining 14 patients with delirium of varying etiologies treated with 5 to 15mg of aripiprazole per day demonstrated the efficacy of this agent in nearly all patients treated. The response time ranged from several days to two weeks and was gauged with the Delirium Rating Scale and Clinical Global Impressions Scale.[44] The evidence for use of atypical antipsychotics in delirium is presented in Table 4.

Despite the fact that antipsychotics are useful for the treatment of delirium, these medications are associated increased risk of mortality in elderly patients with dementia, a common comorbid condition. One recent study documents the risk of a serious adverse event, defined as an event leading to acute care hospital admission or death, to be 2.4 times more likely for patients on typical antipsychotics than placebo and 1.9 times more likely for patients on atypical antipsychotics than placebo.[45]

Nonpharmacological treatments for delirium also exist and should not be overlooked in treating this serious condition. It should be recognized, however, that nonpharmacological treatments are adjuncts to, not substitutes for, prompt pharmacological treatment for delirium. The patient should be provided a quiet environment free of excess stimulation and be reoriented frequently.

While providing a safe environment for the recovering patient is crucial, the patient should not be either overly stimulated or actively ignored. At the most basic level, the room that the patient is placed in should be well lit, moderately furnished, and contain a clock and a calendar. Contact with family and staff is helpful. Providing extra supportive physical care, such as nutrition and fluid intake, may be necessary. The use of physical restraints should be limited for diagnostic testing, performing procedures, and patient or staff safety. Document carefully and frequently in the chart the use and rationale for employing physical restraints.

Summary
Delirium is a common medical condition likely to be encountered on the wards in any hospital. Several typical antipsychotics have been demonstrated to be effective but have the potential problems of extrapyramidal side effects and cardiac conduction delays. Atypical antipsychotics are effective for delirium and are associated with less extrapyramidal side effects. While there is little in the way of head to head trials of typical antipsychotics versus atypical antipsychotics for the treatment of delirium, those that do exist seem to suggest equivalence.[46,47] Haloperidol continues to be the “gold standard” medication for the treatment of delirium, but atypical antipsychotics may supplant the typical antipsychotics due to their effective and safe management of this condition.[48] Numerous studies support the assertion that risperidone, olanzapine, and quetiapine have the best data for the treatment of delirium among the atypical antipsychotics.[49]

Acknowledgments
The author would like to thank Brandon Cox, BA, for his assistance with graphic artwork and technology.

References
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22. Horikawa N, Yamazaki T, Miyamoto K et al. Treatment for delirium with risperidone. Gen Hosp Psychiatry. 2003;25(4):289–292.
23. Mittal D, Jimerson NA, Neely EP, et al. Risperidone in the treatment of delirium: results from a prospective open-label trial. J Clin Psychiatry. 2004;65(5):662–667.
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41. Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3):794–795.
42. Alao AO, Soderberg M, Pohl EL, et al. Aripiprazole in the treatment of delirium. Int J Psychiatry Med. 2005;35(4):429–433.
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45. Rochon PA, Normand S, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Int Med. 2008;168(10):1090–1096.
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Ms. Cascade is Vice President, Quintiles Inc./iGuard, Falls Church, Virginia; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles Inc., San Diego, California, and Professor of Psychiatry, University of California, San Diego; and Dr. Cummings is from the Departments of Neurology and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California.

Psychiatry (Edgemont) 2008;5(7):28-31

FINANCIAL DISCLOSURES

Dr. Cummings has provided consultation to Abbott, Acadia, Accera, ADAMAS, Astellas, Avanir, CoMentis, Eisai, Elan, EnVivo, Forest, Janssen, Lilly, Lundbeck, Medivation, Merck, Myriad, Novartis, Pfizer, Prana, Sonexa, Takeda, Wyeth pharmaceutical companies. Dr. Cummings owns stock in ADAMAS, Prana, Sonexa. Dr. Cummings owns the copyright of the Neuropsychiatric Inventory.

ABSTRACT

Recent research on dementia patients suggests that use of antipsychotics may increase risk of hospitalization or death. While bipolar disorder and schizophrenia combine to represent more than 70 percent of atypical antipsychotic uses in younger patients, these same indications represent only 38 percent of product use in patients age 65 and older. The difference between the two age groups is driven primarily by use in cognitive impairment: Dementia and Alzheimer’s combine to account for 28 percent of atypical antipsychotic use in older patients. Although ICD-9 coding tends to group patients into less specific diagnoses, we did isolate a small group of approximately 10 percent of patients that were classified based on the presence or absence of behavior disturbances. Eighteen percent of dementia patients without behavioral disturbances received atypical antipsychotics as compared to 66 percent of patients with behavioral disturbances. A discussion of the results is provided.

KEY WORDS

Alzheimer’s, dementia, antipsychotics

INTRODUCTION

Recent research on dementia patients suggests that use of antipsychotics may increase risk of hospitalization or death. In this article, we examine prevalence of atypical antipsychotic use in patients over the age of 65 and reasons for product use.

METHODS

We obtained data from two different sources: 1) patients taking atypical antipsychotics from Verispan’s Total Patient Tracker, May, 2007, to April, 2008, and 2) May, 2007, to April, 2008, data from Verispan’s Prescription Drug and Diagnosis Audit (PDDA) regarding reasons for use of atypical antipsychotics. PDDA captures data on disease state and associated therapy from 3,100 office-based physicians representing 29 specialties across the United States.

RESULTS

Over the past year, 5.5 million Americans filled at least one prescription for an atypical antipsychotic; 19 percent of whom (approximately 1 million) were age 65 and older. Figure 1 displays reasons for use of atypical antipsychotics in patients under age 65 and age 65 and older. As seen in Figure 1, while bipolar disorder and schizophrenia combine to represent over 70 percent of atypical antipsychotic uses in younger patients, these same indications represent only 38 percent of product use in older patients. The difference between the two age groups is driven primarily by the additional 28 percent of use among patients with cognitive impairment (dementia and Alzheimer’s combined).

We examined the data further to determine whether there were differences in use of atypical antipsychotics by dementia patients with and without and behavioral disturbances. Although ICD-9 coding tends to group patients into less specific diagnoses, we did isolate a small group of approximately 10 percent of patients who were classified based on the presence or absence of behavioral disturbances. Figure 2 displays the prevalence of atypical antipsychotic use among these patient groups. As seen in Figure 2, 18 percent of dementia patients without behavioral disturbances received atypical antipsychotics as compared to 66 percent of patients with behavioral disturbances.

COMMENTARY

This article focuses on an area of continuing unmet need in the elderly population: agents that effectively treat behavioral disturbances in elderly patients without compromising safety. All current atypical antipsychotics carry a “black box” type of warning required by the Food and Drug Administration (FDA), indicating that these agents have been associated with an increased risk of mortality in the elderly. The label asserts the following: Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5 percent, compared to a rate of about 2.6 percent in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Note that the exposures were for 10 weeks and it is uncertain from the available data if more deaths are to be expected with longer exposures or if patients at risk express their vulnerabilities early and succumb soon after exposure. The absolute risk remains small (4.5% compared to the placebo rate of 2.6%) but the relative risk—an almost two-fold increase—is not trivial. Also uncertain from the available data is the mechanism by which mortality is exacerbated, although even mild drug-induced parkinsonism with attendant immobility and swallowing difficulties may contribute to the elevated rates of pneumonia reported among elderly patients receiving atypical agents.[1] Not all analyses of the data have supported the conclusions drawn by the FDA, but an analysis by Schneider, et al.,[2] came to nearly identical conclusions.

Although the mortality warning is mandated only for atypical antipsychotics, similar increases in death rates have been identified among dementia patients treated with conventional neuroleptic agents.[3,4]
The warning on atypicals and the concern over conventional neuroleptics has created tremendous uncertainty in the prescribing community. The safety concerns are heightened by recent studies raising serious questions about the effectiveness of these agents as currently used in clinical practice. They are often given in doses that are too low for periods of time that are too short to draw therapeutic conclusions, thus possibly exposing patients to the risks while not providing the putative benefits of these agents.[5]

There are no therapies approved by the FDA for treatment of behavioral disturbances in dementia, and alternative medications, such as mood-stabilizing anticonvulsants, have lacked efficacy in recent randomized, controlled trials.[6,7] Antidementia drugs, such as memantine, may have anti-agitation effects,[8] but many patients develop treatment-requiring behavioral syndromes despite treatment with these drugs. Thus, clinicians are faced with the dilemma that the most common behavioral disturbance in dementia for which medications are needed has no satisfactory treatment. Antipsychotics are used because they have been shown in some trials to be efficacious and because the clinician has few if any viable options.[9–11]

Not treating psychosis and agitation in dementia patients may also have consequences: injury to patient and spouse, premature institutionalization, and use of restraints, among others. Thus, the decision to use these agents must be based on a dialogue between informed caregivers and patients and their physicians with candid discussions of data regarding efficacy and risks. A ban on use of these agents would be as inappropriate as their intemperate use. Figures 1 and 2 demonstrate that this is the course adopted by most current practitioners. The American College of Neuropsychopharmacology Work Group and a recent Best Practices Panel endorsed this approach in recent guidelines for use of atypicals in patients with dementia.[12,13]

The current situation is untenable. The rising number of elderly and the concomitant anticipated dramatic rise in the number of patients with dementia makes a marked increase in the number of elderly cognitively impaired persons requiring treatment for behavioral disturbances inevitable. Progress in understanding the neurobiology of Alzheimer’s disease and enhanced understanding of the neurobiology of psychosis may lead to discovery of agents with psychotropic properties and safety profiles superior to those currently available.[14]

REFERENCES

1. Knol W, van Marum RJ, Jansen PA, et al. Antipsychotic drug use and risk of pneumonia in elderly people. J Am Geriatr Soc. 2008;56:661–666.
2. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294:1934–1943.
3. 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;164:1568–1576.
4. Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005;353:2335–2341.
5. 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;355:1525–1538.
6. Herrmann N, Lanctôt KL, Rothenburg LS, Eryavec G. A placebo-controlled trial of valproate for agitation and aggression in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2007;23:116–119.
7. Tariot PN, Raman R, Jakimovich L, et al; Alzheimer’s Disease Cooperative Study; Valproate Nursing Home Study Group. Divalproex sodium in nursing home residents with possible or probable Alzheimer’s disease complicated by agitation: a randomized, controlled trial. Am J Geriatr Psychiatry. 2005;13:942–949.
8. Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry. 2008;23:537–545.
9. 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;15:918–931.
10. De Deyn PP, Katz IR, Brodaty H, Lyons B, et al. 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;107:497–508.
11. 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;4:81–93.
12. Jeste DV, Blazer D, Casey D, et al ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology. 2008;33:957–970.
13. Salzman C, Jeste DV, Meyer RE, et al. Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy. J Clin Psychiatry. 200813:e1–e10. [Epub ahead of print]
14. Cummings JL, Zhong K. Treatments for behavioural disorders in neurodegenerative diseases: drug development strategies. Nat Rev Drug Discov. 2006;5:64–74.

Ms. Cascade is Vice President, Quintiles Inc./iGuard, Falls Church, Virginia; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles Inc., San Diego, California, and Professor of Psychiatry, University of California, San Diego; and Dr. Buckley is Professor and Chairman, Department of Psychiatry,
Medical College of Georgia, Augusta, Georgia.

Financial Disclosures

Dr. Buckley has received grant/research support from AstraZeneca, National Institute of Mental Health, Pfizer, Solvay, and Wyeth, is a consultant to AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen Pharmaceutica, Lundbeck, Pfizer, Solvay, and Wyeth, and has received honorarium/expenses from Bristol Myers Squibb, Janssen Pharmaceutica, Lundbeck, and Pfizer.

Abstract

We investigated the current practice for treatment of schizophrenia. According to our data, 47 percent of patients with schizophrenia are treated with only antipsychotic medication. An additional 43 percent of patients receive one additional class to supplement their antipsychotic medication, and 10 percent of patients are prescribed two or more classes of drugs in addition to an antipsychotic medication. The most common classes used to supplement antipsychotic medications in the management of schizophrenia include antidepressants (28%), mood stabilizers (18%), agents to treat extrapyramidal symptoms (7%), and sleep aids (5%).

Key words

schizophrenia, monotherapy, combination therapy, augmentation, antipsychotics, antidepressants

Introduction

To better understand current practice for the management of schizophrenia, we investigated the use of antipsychotics alone and the need for supplementation with other classes of agents to control symptoms.

Methods

We obtained data on product treatment regimen from Verispan’s Prescription Drug and Diagnosis Audit (PDDA) database from March, 2007, to February, 2008, for schizophrenia as defined by ICD-9 diagnosis code 295. PDDA captures data on disease state and associated therapy from 3,100 office-based physicians representing 29 specialties across the United States.

Results

As seen in Figure 1, 47 percent of patients with schizophrenia are treated with only antipsychotic medication. An additional 43 percent of patients receive one additional class to supplement their antipsychotic medication, and 10 percent of patients are prescribed two or more classes of drugs in addition to an antipsychotic. According to our data, 28 percent of patients with schizophrenia are prescribed an antidepressant in combination with their antipsychotic (Figure 2). Other therapeutic classes used to supplement antipsychotics in the management of schizophrenia include mood stabilizers (including lithium or antiepileptics, 18%), agents to treat extrapyramidal symptoms (7%), and sleep aids (5%).

Commentary

These data, drawn from clinical practice-prescription profile analyses, “jive well” with what is currently happening in our clinics and in our hospitals. The treatment of schizophrenia and bipolar disorder have (paradoxically) become increasingly complex with the greater availability and choice among antipsychotic medications. At the same time, there is still a substantial unmet need, as confirmed by recent, large, pragmatic trials in schizophrenia and bipolar disorder, that provides the therapeutic context for antipsychotic polypharmacy as well as the use of other psychotropic medications alongside antipsychotics. For patients and clinicians, then, the question of “why and when do I combine medications?” is now very challenging. As these data also bear out, other available evidence suggests that antipsychotic polypharmacy is common in clinical practice. Additionally, it is a topic of enduring interest among clinicians who are always eager to understand the information contributing to key therapeutic strategies. These data also attest to the high rates of concomitant use of other psychotropic agents, particularly antidepressant medications.

At the present time, we are lacking robust research literature to guide this decision-making process that is the clinician’s dilemma: Why, when, and how should I use antipsychotic polypharmacy to its best advantage in my practice? Available scientific evidence for polypharmacy strategies in schizophrenia is scant and does not preferentially endorse any single strategy. This latter point is particularly relevant when proponents of polypharmacy say “Hey, this approach works for my patients” yet cannot articulate a single drug option, and so it again resides in the individualization of care for patients with schizophrenia. Another consideration to bear in mind here is that some polypharmacy is not so much driven by augmentation strategies, but rather by “suspended” switching strategies. That is, you and your patient decide to switch medications but you ended up stopping this midway, and so the patient stays on both medications…and ends up in the so called psychopharmacological purguratory as Dr. Peter Weiden has aptly termed this.

The sizeable rate of concomitant use of antidepressants recorded in these analyses is also worthy of comment. It is well known that patients with schizophrenia get depressed. Depression in schizophrenia worsens the outcome, both in terms of heightening the risk of psychotic relapses and also greatly increasing the risk of suicide. Accordingly, the prescription of antidepressant medications for patients with schizophrenia who become depressed is an important therapeutic strategy. Interestingly, recent work on antidepressant therapy for mood disorders suggests that these drugs may have neuroprotective effects, perhaps through increasing the brain’s neurotrophins, such as brain-derived neurotrophic factor (BDNF). Interestingly, the clinical and translational impact of antidepressant therapy has not yet been studied in the context of second generation antipsychotic medications (beyond clozapine). These data would suggest that clinicians are using these agents regularly in the treatment of patients with schizophrenia.

It would be useful to have some data from pragmatic trials to inform this fundamental practice strategy for clinicians and to examine the extent to which polypharmacy truly impacts both efficacy and tolerability considerations in treating patients with schizophrenia.