Treatment of Psychosis in the Geriatric Population

Presenters at this symposium, held in conjunction with the 51st annual meeting of the American Association for Geriatric Psychiatry, considered the challenge of treating psychosis in an elderly population, focusing on the most recent scientific advances and therapeutics, with recent evidence for efficacy and safety.

This program was supported by an unrestricted educational grant from Bristol-Myers Squibb Company and Otsuka America Pharmaceutical Co., Inc.

Introduction

Multiple and difficult challenges face geriatric psychiatrists who treat elderly persons with psychosis due to schizophrenia, Alzheimer’s disease (AD), or another cause. Dilip V. Jeste, MD, Edgar and Estelle Levi Chair in Aging, and Professor of Psychiatry and Neurosci-ences at University of California, San Diego and Chief of the Division of Geriatric Psychiatry at VA San Diego Healthcare System, and Program Chair for this symposium, delineated some of these challenges in his introduction. The clinician is first faced with the challenge of identifying the particular psychotic syndrome.

Following that, there is the primary task of relieving the symptoms, such as hallucinations, delusions, and paranoia, that are associated with disruptive behavioral manifestations of agitation and aggression.

Tolerance to drugs must be ensured in elderly patients with age- and drug-related sensitivities; in these patients especially it is important to select agents with minimal long-term safety risks. An overall objective, Dr. Jeste said, is to aim at maintaining or improving cognitive function while improving behavioral manifestations. Speakers at this program addressed these clinical goals and pointed to an expectation for better long-term data and study of agents with demonstrated efficacy in the target population of elderly persons.

Schizophrenia in the Geriatric Population: Impact of Disease and its Treatment

Approximately 1 million people aged 55 and older suffer with severe and persistent mental illness. Of this number, which is growing as lifespans lengthen, schizophrenia is the predominant diagnosis. In 30 years, according to speaker J. Michael Ryan, MD, from the University of Rochester Medical Center, the number of older persons with schizophrenia is expected to double. He noted that, while schizophrenia is often considered a disease of young adults, a substantial proportion of individuals with early-onset schizophrenia survive into middle and old age; less commonly, the affliction strikes in middle age and beyond.

Unfortunately, only about 1% of the literature on schizophrenia has been devoted to the study of treatments in older individuals. Explaining this, Dr. Ryan noted that the de-institutionalization of patients with schizophrenia over the past few decades has resulted in an almost invisible population of persons with this illness living in the community. Community-based geriatric mental health service systems, which could potentially provide a convenient site for research involvement, are too often organizationally fragmented, poorly funded and underutilized. Geriatric long-term care facilities are primarily focused on people with physical disabilities and dementia.

In spite of a dearth of study data, antipsychotic drugs are used in patients over age 65 for a number of conditions, including dementia, depression, schizophrenia, and bipolar disorder. Their side effects, especially in elderly individuals, can be manifested in both mental and physical symptoms (Table 1).

Elderly individuals exposed to antipsychotic medications are more likely to experience extrapyramidal symptoms (EPS) and tardive dyskinesia (TD), when compared to younger patients. Whereas TD is estimated to affect 10% of younger patients treated with typical antipsychotics for three years, it is a risk for up to 60% of older patients. These motor system side effects can be dangerous and may translate into “real world” problems of incoordination, feeding difficulties, disfigurement, social isolation, and falls and fractures. Other side effects associated with antipsychotic medications which may significantly impact elderly patients include sedation and orthostatic hypotension. The sedation that is more commonly encountered with typical antipsychotics can interfere with carrying out the activities of daily living. Postural hypotension poses an additional risk for falls and fractures.

Moreover, antipsychotic medications are often associated with anticholinergic effects that may act centrally, resulting in memory impairment, confusion, slowed thinking; or peripherally, bringing about difficulties such as blurred vision, urinary retention, constipation and dry mouth.

Atypical Antipsychotic Efficacy
Atypical antipsychotic medications are becoming the mainstay of treatment for psychosis in the elderly because of their lower propensity to cause extrapyramidal side effects and a reduced need to co-prescribe anticholinergic agents. But challenges remain even within this preferred class of antipsychotics, said Dr. Ryan. For example, it is not clear that atypicals are superior to typicals in the control of positive symptoms of schizophrenia. Questions also remain as to whether atypicals are primarily treating negative symptoms via some intrinsic property or properties, or, as Dr. Ryan stated, are “just avoiding the negative symptoms by being less sedating.” Other questions concern whether there is cognitive enhancement with atypical antipsychotics or a “non-worsening” of cognitive functions. Not yet fully characterized are the effects of atypical agents on mood symptoms or on the incidence of suicide.

What may be said about the safety and tolerability of atypical antipsychotic agents is that their advantages are significant. They include a low incidence of EPS and TD, a low incidence of central and peripheral anticholinergic adverse effects; a low general potential for drug interactions; less or no induction of prolactin elevation in some; and early suggestions of better compliance.

Antipsychotic Agents in Elderly Persons: FDA-Approved and Under Investigation
Of the available antipsychotics in clinical trials, few have data specific to a geriatric population and none have specific approval for use in the geriatric population. Those with current FDA approval for the treatment of schizophrenia are clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. Newer drugs under investigation include aripiprazole, iloperidone, and zolepine.

Clozapine, while producing meaningful clinical improvement in a small series of studies in older patients with schizophrenia, and demonstrated equal effectiveness as chlorpromazine, has a side effect profile that may deter some geriatric specialists from choosing this agent. As Dr. Ryan suggested, “Most geriatricians and geriatric psychiatrists find clozapine difficult to use except in the most treatment-refractory patients due to risks of agranulocytosis, seizures, and its own intrinsic and significant anticholinergic effects.”

Quetiapine, another atypical agent, was studied in a 52-week open label trial in 184 geriatric patients diagnosed with a variety of psychotic disorders, including dementia and schizophrenia. It produced significant decreases in the Brief Psychiatric Rating scale at all points along the 52-week continuum, Dr. Ryan noted. Overall, quetiapine appears to be well-tolerated and effective in an elderly population.

Risperidone and olanzapine were evaluated in a large, head-to-head international study in patients over age 60 with schizophrenia or schizoaffective disorder, and found to be equally effective. Risperidone was somewhat less prone to cause motor side effects.

Ziprasidone has not yet been studied in a geriatric population.

Newer Antipsychotic Agents under Investigation
Aripiprazole is currently under investigation in nursing home patients with neuropsychiatric symptoms. Although these geriatric data are not yet available, Dr. Ryan suggested that aripiprazole shows promise for this group, based in part on a 4-week study in hospitalized patients, ages 18-66, with schizophrenia or schizoaffective disorder. In this study, aripiprazole at both dose levels—15 and 30 milligrams—demonstrated a separation from placebo after two weeks of use, as measured by a mean change in PANSS total score. The efficacy persisted for the remainder of the trial. It was found to be comparable in efficacy to haloperidol.

In this study, aripiprazole was not more effective than haloperidol, but demonstrated a more favorable motor side effect profile. When aripiprazole, haloperidol, and placebo were evaluated using the Simpson-Angus Rating Scale, described by Dr. Ryan as the “gold standard for assessing motor toxicity,” haloperidol produced mild motor toxicity, but, “…aripiprazole, at 15 milligrams was not much different from placebo. Even at 30 milligrams, motor symptoms remained close to baseline.”

CATIE: Clinical Antipsychotic Trial of Intervention Effectiveness
Despite the decades-long availability of conventional antipsychotics, and almost a decade of clinical experience with atypical antipsychotics, data demonstrating their effectiveness and safety in the elderly population are lacking. Moreover, some of the studies that have been conducted specifically in geriatric patients have notable limitations. Many or most focus on short-term evaluations, without extension to the long-term. This is especially problematic for a population that is likely to need treatment chronically. Furthermore, most studies designed to evaluate individual agents, or to compare agents, lack representative patient samples. Trials to determine the safety and efficacy of new agents are, for the most part, pharmaceutical industry-sponsored and designed to facilitate the FDA approval process.

Healthcare professionals involved in treating persons with Alzheimer’s disease and schizophrenia are encouraged by the launch of a National Institutes of Mental Health (NIMH)-sponsored effectiveness trial of antipsychotics that may answer many of the criticisms directed against existing studies. CATIE, Clinical Antipsychotic Trials of Inter-vention Effectiveness, is charged with evaluating the effectiveness of antipsychotic medications for schizophrenia and Alzheimer’s disease in broad patient populations and in “real world” settings.

The schizophrenia trial arm of CATIE aims to recruit 1500 individuals with schizophrenia, at as many as 50 clinical sites, both academic and nonacademic. Patients will be followed up for 18 months or until treatment failure due to efficacy, tolerability, or noncompliance. Enrolled subjects will be randomized to risperidone, olanzapine, quetiapine, ziprasidone or perphenazine. The double-blind design is “creative and flexible,” Dr. Ryan said, with management principles that will “mimic the way clinicians work.”

The Alzheimer’s disease arm compares treatment with olanzapine, quetiapine, risperidone, citalopram and placebo in AD patients with delusions or hallucinations and/or clinically significant aggression or agitation. Enrolled subjects will be followed as outpatients for 36 weeks.

Efficacy in the Management of Psychotic and Behavioral Manifestations of Alzheimer’s Disease

While psychotic symptoms are present in several psychiatric disorders, the psychosis of Alzheimer’s disease is a distinct condition, said Dr. Jeste, and it has only recently been defined. Its characteristic symptoms are delusions and/or hallucinations that may be either auditory or visual. Also important is the chronology of the onset of the deficits in Alzheimer’s disease versus other forms of psychosis: patients must have dementia first and then psychosis. Symptoms of greater than one month must be sufficiently severe to be functionally disruptive. In arriving at a diagnosis of Alzheimer’s disease-related psychosis, there must be a specific exclusion of other disorders such as schizophrenia, delusional disorder, psychotic depression, delirium, or psychosis secondary to other medical conditions or to substance abuse.

Psychosis of Alzheimer’s disease is quite common in AD patients. In a study by Paulsen (Paulsen JS et al. Neurology 2000;54:1965-71), patients were observed and evaluated from the early stages of AD. When they were followed prospectively, it was found that 20% developed psychosis within 1 year; 36% within 2 years, and 50% within 3 years. After 3 years, however, the incidence of psychosis seems to plateau. Interestingly, as the Alzheimer’s disease becomes more severe, the psychosis becomes less prominent.

The shortcomings of trials with treatments for psychosis and agitation and dementia associated with Alz-heimer’s disease parallel those of studies in patients with schizophrenia, especially among older trials with typical agents. Most studies have been short-term, inappropriately controlled, used suboptimal outcome measures, and had high drop-out rates. Overall efficacy rates have been unremarkable: 41% for placebo, 57% with conventional neuroleptics (Schneider LS. J Am Geriatr Soc 1990; 38:553-63).

More recent studies with atypical agents have shown some improvements in design along with better outcomes. According to Dr. Jeste, sample sizes have enlarged, studies are better controlled, study durations are longer, outcome measures are more appropriate, and results are somewhat better, with rates of about two-thirds of patients improving, and with fewer side effects.

The atypical antipsychotic, risperidone, is a case in point. In a recent international, multicenter, double-blind, controlled trial of 12 weeks, risperidone versus placebo and haloperidol were evaluated using the Cohen-Mansfield Agitation Inventory in patients with dementia (De Deyn PP et al. J Geriatr Psychiatry 2000;15(suppl 1):S14-S22). Risperidone was found to be significantly more effective than placebo and haloperidol for improvement of agitation.

Notably, in this study and in another with risperidone based on total BEHAVE-AD scores (Katz IR et al. J Clin Psychiatry 1999;60:107-115), risperidone was most useful in a middle dose-range (.75-1.5 mg/day). Both studies, Dr. Jeste said, provide good examples of the ‘narrow dose range that is optimal in this patient population.”

Data in support of the atypical antipsychotic agent, olanzapine, also revealed a dose-response curve in a similar population. In at least two studies, 5 mg was found to be the most effective dose in AD patients with dementia (Street JS et al. Arch Gen Psychiatry 2000;57:968-78; Meeham KM et al. AAGP Poster, 2001). (The comparative efficacies of risperidone, olanzapine, and quetiapine in patients with schizophrenia or psychosis of AD will be evaluated in the AD arm of the CATIE trial.)

The new atypical antipsychotic agent, aripiprazole, currently undergoing Phase III study in AD patients with psychosis, has shown promising efficacy with lower rates of EPS in patients with schizophrenia. These properties, Dr. Jeste said, may arise from a mechanism of action that is different from other atypical antipsychotic agents. “This is an interesting drug,” Dr. Jeste said, partially because its dopamine activity probably varies in different regions of the brain. “It can serve as an antagonist when there is high dopaminergic activity [to control psychotic symptoms] and an agonist when dopamine activity is low [to improve cognitive symptoms and minimize motor effects].” These properties, which he described as allowing aripiprazole to act as a “dopa-mine/serotonin system stabilizer,” may explain its apparent potential to control positive symptoms with minimal EPS.

In managing patients who experience the psychosis of AD, Dr. Jeste concluded that the available atypical antipsychotics are more useful and safer than typical antipsychotics, but still have their own limitations in terms of therapeutic efficacy and adverse effects. In all cases, Dr. Jeste emphasized, pharmacotherapy needs to be combined with appropriate psychosocial therapies in these patients.

Safety and Tolerability Issues with Antipsychotics in the Treatment of Dementia

The principal investigator of the long-awaited CATIE trial, Lon S. Schneider, MD, from USC, began his remarks with an historical perspective on therapeutic progress in the treatment of psychotic disorders, and the safety concerns that remain even today.

The gradual shift from use of conventional antipsychotics in the 1960s and 1970s to atypical agents in the early 1990s was coincident with the introduction of risperidone and was a result, in part, of an effort to minimize motor side effects. As Dr. Schneider said, “Physicians are increasingly appreciating the better, more advantageous side effects profile associated with atypical antipsychotics.”

The predominant issue with conventional antipsychotics, including haloperidol, is the rate of tardive dyskinesia (TD). Despite its efficacy, a “dramatic” rate of TD in the elderly, of up to 40 percent in 9 months, has driven physicians to safer alternatives, such as risperidone. Dr. Schneider expressed the view of many physicians when he stated that “Many of us feel uncomfortable giving a drug that we know will cause tardive dyskinesia in a proportion of patients, even when the drug appears to be otherwise well tolerated at low doses.”

Adverse effects with both conventional and atypical antipsychotics overall are a concern—and an even greater one in an elderly population. This list is lengthy, as other speakers also noted, and includes EPS, sedation, orthostatic hypotension, falls, cognitive toxicity including delirium, impaired ADL (activities of daily living), metabolic effects such as weight gain, hyperglycemia and dyslipidemia, and cardiac effects such as QT prolongation.

Data on weight gain have been collected in younger patients. “We curiously don’t have an adequate and consolidated database on the weight changes that occur in the elderly, and more importantly, what the significance of weight change may be,” Dr. Schneider said. Recently, there have been increased reports of lipid changes, hyperglycemia, and diabetes with certain antipsychotics. Studies to evaluate the effects of antipsychotics on these measures in the elderly are limited. Overall, Dr. Schneider added, “…we are operating with a certain degree of uncertainty” in treating an elderly population.

The QT interval is prolonged with the use of several conventional antipsychotics, as it is with many other medications that may be prescribed to older individuals. The clinical impact of QT interval prolongation remains unclear, but is perhaps a greater concern in the elderly, in whom other medications as well as comorbid conditions may serve to exacerbate risk.

Somnolence is associated with antipsychotic therapy, both conventional and atypical agents to varying degrees, and is a well-known risk for falls and injuries in nursing home patients. While somnolence may be controlled to a certain extent by adjustments in dosing, Dr. Schneider pointed out that in settings such as nursing homes, the desire for a calm and non-troublesome patient may outweigh a careful titration of dose to avoid this effect.

Many questions remain to be answered regarding the responsible and effective treatment of a geriatric population with psychosis of schizophrenia or AD. Fortunately, sorely needed safety as well as efficacy data are likely to emerge from the CATIE study. Dr. Schneider predicted that these results will serve to “guide clinicians in making the right therapeutic decisions [in these patients].”