Gregory H. Pelton
Alzheimer's disease (AD), the predominant form of dementia, comprises 60% to 80% of all cases of dementia (Stoppe et al., 1999). The number of patients with AD represents a growing public health problem that may reach crisis proportions in the future. In 1993, the estimated AD population in the United States was approximately 4 million, and it is estimated to reach 14 million by the year 2050 (Tariot, Podgorski, Blazina, & Leibovici, 1993). AD has been defined as the neurodegenerative illness with the most neuropsychiatric sequelae, including behavioral dyscontrol and psychosis. Behavioral complications and psychosis during AD constitute a tremendous burden to caregivers and are common precipitants of institutionalization (Burns, Jacoby, & Levy, 1990; Cohen et al., 1993; Deimling & Bass, 1986; Weiner, Alexander, & Shortell, 1996). Antipsychotic medications are the treatment of choice for psychosis or behavioral complications associated with dementia (Helms, 1985; Schneider, Pollock, & Lyness, 1990), with drug utilization studies showing that antipsychotics are used in 35% to 51% of elderly institutionalized patients (Avorn, Dreyer, Connelly, & Soumerai, 1989; Giron et al., 2001; Lantz, Louis, Lowenstein, & Kennedy, 1990).
Before any drug therapy is initiated, however, the clinician needs to determine if the psychosis or behavioral disturbance is due to other causes such as an underlying medical condition, comorbid psychiatric condition, drug effects and interactions, infections, sensory disturbances, and unmet care needs. Any secondary medical conditions should be treated and problematic medications adjusted or discontinued. Alternatively, nonpharma-cologic interventions may be effective: change in room, reduction in noise level, brief periodic nursing contacts, behavior modification, or family education (Holm et al., 1999; Leibovici & Tariot,1988; Mintzer et al., 1993; Rovner, 1996). If these interventions fail, pharmacologic treatment may be necessary.
The majority of early clinical treatment trials, conducted mainly in the 1970s and 1980s, used conventional antipsychotics as the mainstay of pharmacotherapy. The results of meta-analyses of placebo-controlled treatment trials indicated that conventional antipsychotic treatment in dementia was significantly more efficacious than placebo but that the magnitude of the advantage over placebo averaged only 18% (Lanctot, Best, & Mittmann, 1998; Schneider et al., 1990). Most studies were largely uncontrolled with high side effect and high dropout rates, and the few placebo-controlled trials conducted had several methodological flaws (Barnes, Veith, Okimoto, Raskind, & Gumbreck, 1982; Petrie et al., 1982; Rada & Kellner, 1976).
Despite limitations of these early studies, conventional antipsychotics continued to be the mainstay of treatment for hallucinations and delusions in the nursing home setting. Unfortunately, their nonjudicious use to manage unspecified behavioral symptoms in older nursing home patients (Thapa, Meador, Gideon, Fought, & Ray, 1994) led to the promulgation of the Omnibus Budget Reconciliation Act (OBRA) of 1987 (Elon & Pawlson, 1992), which became effective in 1990. OBRA required identification of target symptoms, justification for use of antipsychotics, and mandatory attempts to decrease or stop the antipsychotic medication every three months. During this time, several other medications were reported to be effective, primarily in uncontrolled studies or in controlled studies with relatively small samples: trazodone (Lawlor et al., 1994; Lebert, Pasquier, & Petit, 1994), selective serotonin reuptake inhibitors (Burke, Folks, Roccaforte, & Wengel, 1994; Geldmacher, Waldman, Doty, & Heilman, 1994; Pollock et al., 1997), lithium (Holton & George, 1985), carbamazepine (Tariot et al., 1998), valproate (Porsteinsson et al., 2001), buspirone (Lawlor et al., 1994), and propranolol (Weiler, Mungas, & Bernick, 1988). Thus, contrary to the new governmental mandates, a consensus statement by the American Association of Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatric Society noted that antipsychotic drugs were a critical pharmacological agent with established efficacy to treat psychotic symptoms, and their use was important in the armamentarium of treatment options for psychosis and agitation in dementia (Small, Rabins, & Barry, 1997). Unfortunately, it remained unclear what the appropriate antipsy-chotic dose should be or what the appropriate duration of antipsychotic treatment should be to ensure quality of care (Elon & Pawlson, 1992; Sweet & Pollock, 1995) and to guide the clinicians treating patients with dementia and psychosis.
With respect to long-term outcome, there have been very few placebo-controlled treatment trials on continuation (or discontinuation) treatment in AD patients with behavioral complications. In one controlled study of patients with dementia whose antipsychotics were discontinued in accordance with OBRA regulations, 50% were rated as much worse ( largely due to verbal and physical aggression) by blinded raters and needed to resume psy-chotropic medication, in contrast to 5% of a comparison patient group in the same setting (Horwitz, Tariot, Mead, & Cox, 1995). In three other studies involving psychotropic medication withdrawal in dementia, the primary intervention was an educational program or alteration of nursing home structure with psychotropic medication withdrawal a secondary feature, making it difficult to evaluate the impact of psychotropic medication withdrawal in isolation (Avorn et al., 1992; Fitz & Mallya, 1992). In another uncontrolled two-year follow-up study of 38 diagnostically heterogeneous geriatric inpatients receiving antipsychotics, when their medication was withdrawn, the results were mixed (Connelly, 1993). A major limitation of this study was that patients on psychotropics were withdrawn without determining whether the patients had target symptoms warranting the use of such medications in the first place. One placebo-controlled study examined both antipsychotic and benzodiazepine discontinuation. Cohen-Mansfield et al. (1999) reported that withdrawing haloperidol, thioridazine, or lorazepam in 58 nursing home patients (of whom 35 completed the trial) did not lead to worsening of behavioral symptoms during a six-week, placebo-controlled discontinuation trial. Important methodological issues may help explain these divergent results. In the Cohen-Mansfield et al. study, patients were not required to have target symptoms of psychosis or behavioral dyscontrol that warranted treatment with psychotropic medications, and "responder ' ' status was never established. Therefore, it is possible that patients without behavioral complications received antipsychotics (and benzodiazepines), and, not surprisingly, discontinuation of these medications did not lead to the emergence of symptoms because such symptoms were not present in the first place. In the only other controlled antipsychotic discontinuation study (Horwitz et al., 1995), patients were required to have behavioral dyscontrol or psychosis, and discontinuation of antipsychotics was associated with high relapse rates. In summary, the limited literature suggests a high risk of worsening of symptoms and relapse in medication-responsive patients who are discontinued from antipsychotic medication. However, there are no large-scale, systematic studies on this issue.
With the introduction of atypical antipsychotics, the use of conventional antipsychotics in geriatric patients is becoming more limited. The limiting factors in the use of conventional neuroleptics are the high incidence of serious cardiovascular and anticholinergic symptoms with the low potency antipsychotics (e.g., chlorpromazine, thioridazine) and extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) with the high potency antipsychotics (e.g., haloperidol). In addition, even though conventional antipsychotics were endorsed as effective clinical management tools in the treatment of psychosis in dementia, in a meta-analysis of the controlled and uncontrolled studies using conventional antipsychotics and examining their efficacy, the risk-to-benefit ratio associated with conventional antipsychotics was questionable (Schneider, 1993).
More recently, the atypical antipsychotics have provided new options in the treatment of psychosis of dementia, particularly AD. Clozapine was first available in the United States in 1990, with risperidone, olanzapine, and quetiapine introduced later in the 1990s. Atypical antipsychotics are now widely used because of their favorable neurological side effect profile compared to conventional antipsychotics (Casey, 1991; Glazer & Morgenstern, 1988; Jeste, Lacro, et al., 1999); for example, in a series of 255 AD patients treated with risperidone for one year, the cumulative incidence of persistent emergent TD was only 2.6% (Jeste, Rockwell, et al., 1999). Atypical anti-psychotics are in the process of replacing conventional antipsychotics and are a primary treatment option in clinical practice.
The completion of several large, double-blind placebo-controlled clinical trials (De Deyn et al., 1999; Devanand et al., 1998; Katz et al., 1999; Street et al., 2000) supports the effectiveness of antipsychotics in general in treating psychotic and behavioral disturbances in dementia. While these antipsychotic medication trials have demonstrated efficacy, a narrow therapeutic dosing window has been identified for both the conventional and newer atypical antipsychotics. Thus, lower doses of either conventional or atypical antipsychotics than those used in schizophrenic patients afford an acceptable side effect profile in the treatment of psychosis and behavioral dyscontrol of dementia. At the lower dosing schedules, atypical antipsychotics are better tolerated than conventional antipsychotics, particularly with respect to the risk of EPS and TD (De Deyn et al., 1999; Jeste,
Rockwell, et al., 1999). The propensity of the atypical antipsychotics to be well tolerated, effective, and to produce a low side effect profile has been shown most clearly with risperidone. In more than 1,000 patients in placebo-controlled trials, risperidone has consistently shown efficacy with a benign side-effect profile (Brodaty et al., 2001; De Deyn et al., 1999; Katz et al., 1999). The other atypical antipsychotics may show a similar efficacy and low side-effect profile. In the ongoing National Institute of Mental Health (NIMH) Clinical Antipsychotic Treatment Intervention Effectiveness (CATIE) multicenter medication trial, a parallel-group comparison of three atypical antipsychotics (risperidone, olanzapine, quetiapine) and placebo (with citalopram as a second phase treatment) is ongoing; on its completion, more answers will be available to the treating clinician (Schneider et al., 2001).
Psychotic and behavioral disturbances are associated with all dementing disorders, including frontal lobe dementia, basal ganglia diseases with dementia, vascular dementias, traumatic brain injury, multiple sclerosis, central nervous system (CNS) infections, and Huntington's disease (Ballard, Gray, & Ayre, 1999; Binetti et al., 1993; Sultzer, Levin, Mahler, High, & Cummings, 1993). However, this review focuses predominantly on clinical treatment trials of psychosis in AD patients. The safety and efficacy in the treatment of psychosis of AD is presumed to be similar to that in other dementia diagnoses. These diseases and their associated risks from antipsy-chotic treatments are discussed only briefly. Controlled treatment trials in other specific dementia diagnostic groups are still needed; thus, recommendations in their management are limited.
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