Psychosomatics 44:388-401, October 2003
© 2003 The Academy of Psychosomatic Medicine
Delusions and Hallucinations in Alzheimer's Disease: Review of the Brain Decade
Medhat M. Bassiony, M.B.B.Ch., M.Sc., M.D., and
Constantine G. Lyketsos, M.D., M.H.S.
Received March 15, 2002; revision received Dec. 3, 2002; accepted Dec. 13, 2002. From the Department of Psychiatry, Faculty of Medicine, Zagazig University, Sharkia, Zagazig, Egypt; and the Neuropsychiatry Service, Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University. Address reprint requests to Dr. Lyketsos, Osler 320, Johns Hopkins Hospital, Baltimore, MD 21287; kostas{at}jhmi.edu (e-mail).
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ABSTRACT
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The authors reviewed studies published from 1990 to 2001 that address the epidemiology, phenomenology, course, etiology, assessment, and treatment of delusions and hallucinations in Alzheimer's disease. The prevalence of delusions in Alzheimer's disease patients ranged from 16% to 70% (median=36.5%) in the reviewed reports, and the prevalence of hallucinations ranged from 4% to 76% (median=23%). Delusions and hallucinations tended to persist over time, tended to recur often during the course of Alzheimer's disease, and were associated with sociodemographic and clinical correlates that differed from one study to another and with substantial consequences such as functional impairment and aggression. Psychosocial methods and both typical and atypical antipsychotics are effective in the treatment of delusions and hallucinations in Alzheimer's disease.
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INTRODUCTION
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Delusions and hallucinations are among the most common noncognitive neuropsychiatric symptoms seen in patients with dementia and have been reported to occur in a large proportion of patients with Alzheimer's disease. Delusions and hallucinations strongly contribute to early institutionalization,1 reduce patients' well-being, and increase the burden of the caregiver in managing the patient.2 Furthermore, these disturbances are associated with more rapid progression of the dementia syndrome.3 Recent advances in the treatment of Alzheimer's disease, and of its associated neuropsychiatric symptoms, include both pharmacologic and nonpharmacologic interventions. Thus, the topic of delusions and hallucinations in Alzheimer's disease is timely for several reasons. These symptoms are an important public health problem and are associated with additional disability in patients with Alzheimer's disease. Effective treatments have been developed and are increasingly widely applied. Finally, study of the relationship between delusions or hallucinations and Alzheimer's disease is likely to lead to improvements in our understanding of brain-behavior relationships. With these issues in mind, we review findings published from 1990 to 2001 regarding delusions and hallucinations in the context of Alzheimer's disease with the aim of clarifying current knowledge in this area. Although earlier literature in this area did not differentiate the occurrence of delusions or hallucinations by type of dementia, it is now believed that such differentiation is important since the etiopathogenesis of the different types of dementia may be relevant in the etiopathogenesis of these phenomena as well. Thus, this review is focused as much as possible on Alzheimer's disease.
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METHOD
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A computerized MEDLINE search was performed for English-language articles published between 1990 and the end of 2001 on delusions and/or hallucinations in Alzheimer's disease. Other papers were identified from the bibliographies of these articles. More than 100 articles were reviewed. The review focused on studies investigating delusions and hallucinations separately in the context of Alzheimer's disease. In some cases, especially where the data were limited or inconsistent, studies investigating psychosis or dementia in general were also included. Studies of the epidemiology and phenomenology of psychosis in Alzheimer's disease that were published before 1990 have been reviewed by Wragg and Jeste.4
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STANDARDIZED ASSESSMENT
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The assessment of delusions and hallucinations in the context of dementia can be accomplished with good reliability and validity. Several standardized measures for this purpose have been published and are widely used.5–13 Table 1 provides a list of measures with acceptable psychometric properties that have been developed since 1990. Although we include here only those instruments that were developed since 1990, many others were developed earlier, generally for the assessment of psychosis in the elderly. Burns et al.14 have provided more information about earlier measures. Further discussion of these measures is beyond the scope of this review. They are mentioned here to highlight the fact that assessment of delusions and hallucinations in Alzheimer's disease can be accomplished with good reliability and validity.
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NOSOLOGIC ISSUES
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The study of delusions and hallucinations in the context of Alzheimer's disease is conducted in the face of a significant methodological issue: whether to study delusions and hallucinations separately or to construe these phenomena as part of a broader category of "psychosis." Current psychiatric nosology offers little guidance. DSM-IV15 recommends additional coding if delusions are a predominant feature of dementia, but it provides no criteria for this subcategory. In addition, if hallucinations are present and believed to be caused by Alzheimer's disease, DSM-IV specifies that they be classified as "hallucinations due to Alzheimer's disease" by using a different group of codes.
The earlier literature tended to group the study of delusions and hallucinations within the broader category of psychosis. In addition, an effort that grew out of a consensus conference of experts16 led to a proposed set of diagnostic criteria for "psychosis of Alzheimer's disease,"17 in which either delusions or hallucinations would be considered a basis for the presence of a psychotic syndrome.
In contrast, it has been proposed that delusions and hallucinations differ in their predisposing factors and etiopathogenesis.18 This position now has empirical support. A recent population-based study found that patients with Alzheimer's disease can be empirically classified into three groups on the basis of their neuropsychiatric symptom profile: a group with an affective disturbance, a group with a psychotic disturbance, and a group with no or other neuropsychiatric disturbances.19 The presence of hallucinations predicted membership in the second group, whether or not delusions were present. In contrast, patients with delusions were present in all three groups. On the basis of this work, empirically derived criteria for an Alzheimer's disease-associated affective and psychotic syndrome have been proposed, with hallucinations being critical to the presence of the psychotic syndrome.20 In addition, Bassiony et al.21 found that delusions and hallucinations had different risk factors and consequences and that delusions, but not hallucinations, were closely associated with depression.22 Therefore, delusions and hallucinations may best be approached separately, with hallucinations being most indicative of a psychotic syndrome and delusions being indicative of either a psychotic disturbance or an affective disturbance.
At present, this nosologic question remains unresolved. Therefore, in the remainder of this article a broad approach to the issue is taken, with delusions and hallucinations considered as separate phenomena whenever possible.
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EPIDEMIOLOGY AND CLINICAL EPIDEMIOLOGY
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Prevalence
Several studies of clinical populations, such as patients in geriatric psychiatry units or dementia clinics, have reported on the prevalence of delusions and hallucinations in Alzheimer's disease. A review of 35 studies revealed that the prevalence of delusions at some time during the course of illness ranged from 16% to 70% (median=36.5%); similar estimates for the prevalence of hallucinations in 33 studies ranged from 4% to 76% (median=23%).18,21,23–55 These estimates vary because of the different ways in which delusions, hallucinations, and Alzheimer's disease were diagnosed in the different studies, in addition to the heterogeneity of the populations studied.
Table 2 summarizes data from 35 studies on the prevalence of delusions and hallucinations in Alzheimer's disease.18,21,23–55 The findings of these studies may be affected by selection bias, since delusions and hallucinations likely increase the probability that an Alzheimer's disease patient may be seen in a clinical setting. It is therefore important to estimate the prevalence of delusions and hallucinations in population samples that are less subject to selection bias. Two such studies have been reported, both with comparable estimates. The prevalence of delusions in Alzheimer's disease in these studies ranged from 16%23 to 22%,50 and the prevalence of hallucinations ranged from 13%50 to 16%.23 The population estimates were lower than the clinical estimates, consistent with what might be expected due to selection bias.
Incidence
In the studies reviewed here, the annual incidence of delusions and hallucinations in Alzheimer's disease varied from 1% to 5.3%23,32,28,56 to 25%57 or as high as 34%.58 Paulsen et al.,59 in a longitudinal study, found that 23% of Alzheimer's disease patients had delusions or hallucinations at baseline evaluation, 18% developed delusions or hallucinations within 2.5 years after their first visit, and 59% never showed any delusions or hallucinations during the course of their visits (5–10 years). By using Cox survival analysis, Paulsen et al. found that the cumulative incidence of delusions and hallucinations was 20.1% at 1 year, 36.1% at 2, 49.5% at 3, and 51.3% at 4 years.
Devanand et al.43 estimated the transition probability of delusions and hallucinations in Alzheimer's disease over 5 years of follow-up and found that the transition probability was 0.17 for delusions and 0.09 for hallucinations. Transition probabilities ranged from 0 to 1. A transition probability of 0.17 indicates that 17% of the patients without delusions manifest a delusion at the next visit (after a 6-month interval). A transition probability of 0.09 indicates that 9% of the patients without hallucinations manifested a hallucination at the next visit.
In what is, to our knowledge, the only population study of incidence of delusions and hallucinations in Alzheimer's disease (published last month in The Journal of Neuropsychiatry and Clinical Neurosciences, pp 340–345), Steinberg et al. found a 28% incidence of delusions and a 16% incidence of hallucinations over 18 months.
The estimates of incidence in the studies reviewed here varied because of differences in the ways in which delusions, hallucinations, and Alzheimer's disease were diagnosed, the heterogeneity of the populations studied, differences in the duration of the periods over which incidence was estimated, and whether delusions and hallucinations were considered together or separately.
Phenomenology
Types of delusions
The most frequent psychotic symptom reported in Alzheimer's disease is persecutory delusion,26,32,45 and the most frequent delusion in Alzheimer's disease is the delusion of theft.3 Among Alzheimer's disease patients, the reported prevalence of paranoid delusions varied from 14.5% to 46%,33,43 persecutory delusions from 7% to 40%,32,36,48 delusions of stealing from 2% to 39%,32,36,48,60 delusions of infidelity or jealousy from 1.1% to 26%,28,32,36,60 delusions of reference from 2%36 to 18.7%,32 and somatic delusions from 1.3%43 to 3.3%.60 One study estimated the prevalence of grandiose delusions as 0.4%.48
Among delusional Alzheimer's disease patients, the prevalence for delusions of stealing ranged from 34.5%24 to 76%,48 persecutory delusions from 18.5%24 to 79%,48 delusions of reference from 14.9%29 to 54%,32 delusions of infidelity from 7.7%24 to 45%,28 delusions of grandiosity from 1%48 to 29%,39 and other delusions from 1.7%48 to 28.4%.27 The reported prevalence of somatic delusions among delusional Alzheimer's disease patients was 1.4%.27
Types of hallucinations
Visual and auditory hallucinations are most common, but somatic, olfactory, and tactile hallucinations have been reported.23,27 A review of 16 studies23–25,27,29–33,35,36,41,48,52,53,60 revealed that the prevalence for visual hallucinations ranged from 4% to 59% (median=19%), auditory hallucinations from 1% to 29% (median=12%), and other types of hallucinations from 0.4% to 8% (median=4%) (Table 3).
Timing of Occurrence and Course
Delusions and hallucinations have been reported to occur at all stages of Alzheimer's disease dementia. Drevets and Rubin61 reported that at least half of Alzheimer's disease patients with no prior psychiatric history display psychosis at some point during the course of Alzheimer's disease. In one study, these phenomena were present around the time of diagnosis, perhaps even prompting referral for diagnosis, in 45% of patients.62 Other studies reported that hallucinations, more often visual than auditory, rarely manifest early in the illness but may be more common in severe dementia.23,60,63
Devanand et al.43,64 found that delusions and hallucinations in Alzheimer's disease fluctuate with time but that their overall prevalence increases slowly with dementia progression. Marin et al.65 found that psychotic symptoms show little progressive worsening over time and tend to be episodic. Levy et al.57 reported that over 1 year the recurrence rate for psychosis was 95% in Alzheimer's disease patients. These findings indicate that once psychotic symptoms are present in Alzheimer's disease patients, they frequently recur.
Risk Factors
Sociodemographic variables
Age, race, gender, and educational level have been assessed in several studies as possible risk factors for delusions or hallucinations. In some studies of dementia, psychosis was associated with older age38,45,49,57 and female gender.48 In contrast, Gormley and Rizwan47 found that men were more likely to have psychotic symptoms than women. Other analyses found no association between psychosis and gender,38 educational level,49 current age,47 or age at onset of Alzheimer's disease.47 Studies of Alzheimer's disease have reported that delusions are associated with older age,18,21,26,60 female gender,58 or less education.18,28 In two studies, African Americans with Alzheimer's disease were more likely to have delusions, compared to whites.26,27 Other studies did not find an association between delusions and age,39 gender,66 and educational level39 in Alzheimer's disease. Hallucinations were associated with less education in one study21 but were equally prevalent in men and women in another study.34 Bassiony et al.67 found that Alzheimer's disease patients with isolated hallucinosis were more likely to be African American than Alzheimer's disease patients with neither delusions nor hallucinations, even after the effects of several possible confounding factors were controlled. Thus, the only consistent finding appears to be an association between delusions or hallucinations and African American race.
Cognitive impairment
Psychosis has been associated with more severe cognitive impairment in some studies of dementia,25,34,48,62,68 but not others.23,38,39,69 Delusions in Alzheimer's disease have been consistently associated with more severe cognitive impairment,31,32,61 especially involving frontal and temporal dysfunction.25 Hallucinations in Alzheimer's disease have also been associated with greater cognitive impairment,26,28,29,37,53 but this finding is not consistent across studies.2,23,60 The varying relationship between psychosis and cognitive impairment in studies of dementia may well be due to a strong relationship between delusions and more severe cognitive impairment but a weak relationship between hallucinations and cognitive impairment.
Stage and duration of illness
Psychotic symptoms were considered to be uncommon in both the very mild70 and very severe32,71 stages of Alzheimer's disease. Delusions in Alzheimer's disease have been reported to be relatively more frequent during the moderate stage.61 Hallucinations in Alzheimer's disease rarely manifest early in the illness but may be more common in severe dementia.21,60 Four studies reported an association between psychosis,48 delusions,39 or hallucinations21,29 and longer duration of illness in Alzheimer's disease. Five studies31,32,60,68,69 failed to show a significant association between duration of illness and psychosis. Therefore, there are no consistent findings linking delusions and hallucinations to stage or duration of dementia.
Past and family history of mental illness
Three studies found no association between delusions, hallucinations,21 and psychosis31,38 in Alzheimer's disease and past or family history of mental illness.
Extrapyramidal signs
Caligiuri and Peavy72 found that severity of clinically rated parkinsonism and a measure of bradykinesia were significantly correlated with severity of psychotic symptoms. In contrast, three studies21,32,58 found no association between psychosis and extrapyramidal signs.
Effects on Clinical Course
Psychosis has been associated with more rapid progression of cognitive and functional decline in Alzheimer's disease.73,74 Delusional patients were found to be more aggressive21,27,50,75,76 and to exhibit more severe wandering, purposeless activity, and inappropriate activity28 than nondelusional patients. Delusions in Alzheimer's disease have also been associated with greater functional impairment,2,77 more asocial behavior,38 worse general health,21 and more severe depression.21,78 Bassiony et al.22 reported that Alzheimer's disease patients with delusions were more likely to be depressed than nonpsychotic Alzheimer's disease patients even after the effects of other factors that might affect this relationship were controlled.
Hallucinations have been associated with verbal outbursts,37 aggressive behavior,41 functional impairment,79 asocial behavior,38 and falls.21 Other studies have not reported an association between hallucinations and functional impairment in Alzheimer's disease.2,23,60
The contradictory findings among studies may be due to differences in the ways in which delusions, hallucinations, and Alzheimer's disease were diagnosed; whether delusions and hallucinations were considered as a single category (psychosis) or differentiated as separate symptoms; differences in the periods of time during which the frequency of delusions and hallucinations was estimated; heterogeneity of the populations studied; and differences in study designs.
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ETIOPATHOGENESIS
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General Concepts
Two hypotheses for the genesis of "noncognitive" psychiatric symptoms of Alzheimer's disease have been proposed:80 1) that these phenomena are "nonspecific" symptoms of brain disease and that the pathology of Alzheimer's disease triggers them just as other pathology anywhere in the brain could trigger similar symptoms and 2) that specific symptoms arise from lesions in particular brain regions or neural systems. More specifically, Cummings and Victoroff81 outlined four explanations for the presence of delusions in Alzheimer's disease: they may be 1) the result of a logical attempt by patients to understand their environment; 2) secondary to mood changes; 3) coincidental, with causes unrelated to the dementia; or 4) directly caused by the underlying brain damage. The empirical data reviewed in the following sections have not been sufficient to disprove any of these explanatory approaches, partly because most studies have focused on the presence of symptoms and not of disturbances, as discussed in the introductory section of this article.
Alzheimer's Disease Pathology
Esiri et al.82 reported that the pathological process in Alzheimer's disease may spread along a sequence of corticocortical connections between the main sensory areas and the hippocampal formation. The disease process may also spread along the reciprocal connections between the amygdala and the neocortex. This explanation is supported by findings that the number of neurofibrillary tangles in different areas of the neocortex closely parallel the density of their connections with the amygdala. Specific cerebral lesions may play a role in the development of psychotic features in Alzheimer's disease. The histopathological changes in Alzheimer's disease have a particular predilection for mesial temporal limbic structures, extending to the multimodal association areas of the frontal, temporal, and parietal lobes.83 These areas are associated with the presence of delusions and hallucinations in other organic psychoses.84
Zubenko et al.85 found that development of psychosis in Alzheimer's disease is associated with significant increases in the mean densities of senile plaques and neurofibrillary tangles in the presubiculum and middle frontal cortex, respectively. They also reported trends toward increases in the densities of these morphologic lesions in the other examined cortical regions, but these findings did not reach statistical significance. Farber et al.52 reported that Alzheimer's disease patients with psychosis had a 2.3-fold greater density of neocortical neurofibrillary tangles than did subjects without psychosis. Forstl et al.36 reported that delusions and hallucinations in Alzheimer's disease patients are associated with less severe cell loss in the parahippocampal gyrus and with lower cell counts in the dorsal raphe nucleus.
These findings support an association between psychosis and neocortical neurofibrillary tangles, which has also been supported by findings of abnormalities in cerebral blood flow and metabolite levels in the cortex of Alzheimer's disease subjects with psychosis, compared to those without psychosis.86,87 To explain the increase in neocortical neurofibrillary tangles in Alzheimer's disease patients with psychosis, Farber et al.52 suggested an interaction between mechanisms in the brain that regulate psychosis and disease mechanisms specific to Alzheimer's disease. In contrast, Sweet et al.88 found no difference between psychotic and nonpsychotic Alzheimer's disease patients in the density of senile plaques and neurofibrillary tangles.
Neurotransmitter Changes Associated With Alzheimer's Disease
Other findings suggest that delusions and hallucinations may be due to disturbances in neurotransmitters. Alzheimer's disease is known to affect brainstem nuclei that manufacture the neurotransmitters that are commonly implicated in psychiatric illness, and adrenergic and serotoninergic systems as well as cholinergic structures are involved in Alzheimer's disease.89 This concept is supported by the observation that psychosis in Alzheimer's disease is often treatable by psychotropic agents that have little effect on cognition or the underlying degenerative process of the disease.57
Adrenergic and serotoninergic function
Zubenko et al.85 reported that Alzheimer's disease patients with psychosis have significantly higher levels of norepinephrine in the substantia nigra and nonsignificantly higher levels in other regions. Psychosis was associated with trends toward higher levels of norepinephrine metabolite (3-methoxy-4-hydroxyphenylglycol) in four regions of the brain, but none of these findings reached statistical significance. In contrast, psychosis was not associated with a significant change in the dopamine level or its metabolites. However, Sweet et al.90 found that dopamine receptor (D3) density was selectively increased in Alzheimer's disease patients with a history of psychosis, independent of the presence or absence of Lewy bodies. In addition, they found that neuroleptics reduced D3 affinity with no effect on D3 density. The emergence of psychosis was associated with a significant reduction of serotonin (5-HT) in the presubiculum that was associated with trends toward reduced levels of 5-HT and its metabolite (5-hydroxyindoleacetic acid) in all studied brain regions.85
Cholinergic function
Pharmacologic, biochemical, and structural observations implicate cholinergic deficiency in the psychosis of Alzheimer's disease. Cummings et al.91 found that physostigmine (a cholinesterase inhibitor) ameliorates psychosis in Alzheimer's disease. The occurrence of psychosis correlated best with metabolic and perfusion abnormalities in the frontal and temporal cortex—areas where there is a marked cholinergic deficit.86,87
Muscarinic receptors have been implicated in the regulation of cognition and psychosis in Alzheimer's disease on the basis of pharmacological evidence. Muscarinic agonists have shown promise in improving cognition and reducing psychosis in Alzheimer's disease patients.92 In addition, Lai et al.55 found that M2 (muscarinic) receptor density was increased in the frontal and temporal cortex of Alzheimer's disease patients with psychosis, compared with Alzheimer's disease patients without psychosis.
Genetic Risk Factors
Apolipoprotein E genes and other risk factors
The apolipoprotein E4 allele is the most consistently identified genetic risk factor for Alzheimer's disease. However, this allele has not been consistently associated with any of the neuropsychiatric manifestations of Alzheimer's disease. With regard to delusions and hallucinations, three studies found an association between psychosis and apolipoprotein E genotype,74,93,94 although four studies reported that psychosis is not significantly associated with apolipoprotein E genotype.44,48,95,96 These inconsistencies were also found when delusions or hallucinations were assessed separately.
To our knowledge, the relationship between delusions/ hallucinations and other genetic risk factors for Alzheimer's disease, such as presenilin-1 and presenilin-2, has not been assessed in published reports.
Dopamine receptor genes
Two reports54,97 investigated the relationship between psychosis and dopamine receptor genes. Sweet et al.97 found that psychosis was associated with dopamine receptor genes DRD1 and DRD3 among white Alzheimer's disease patients. The joint risk for psychosis linked with both the DRD1 and DRD3 polymorphisms exceeded the risks due to either locus alone, suggesting an interaction. Neither the DRD2 nor the DRD4 gene was associated with psychosis.97 Holmes et al.54 replicated these findings and added that carriers of the DRD1 B2 allele were more likely to experience hallucinations, whereas homozygous carriers of the DRD3 1 allele were more likely to experience delusions. These findings would suggest that genetic vulnerability in the dopamine receptor genes might be critical to the development of psychosis in Alzheimer's disease, indicating a diathesis-stress model in which specific genetic vulnerability combined with the Alzheimer's disease brain pathology leads to psychosis.
Electroencephalography Findings
Spectral analysis of EEGs in Alzheimer's disease patients with delusions and/or hallucinations has shown diffuse increased amounts of delta and theta activity.30 Alzheimer's disease patients with psychosis showed greater overall absolute and relative delta power but no regional predominance of slowing, compared with those without psychosis.98 Those with psychosis had a concomitant decrease in relative alpha power. These differences remained after adjustment for different levels of dementia severity in the two groups.98 Thus, delusions and hallucinations may be associated with widespread cerebral dysfunction in Alzheimer's disease.
Findings From Imaging Studies
Structural imaging studies
Structural brain imaging findings in Alzheimer's disease patients with and without delusions and hallucinations have been few and contradictory. Thus, firm conclusions cannot be drawn. One study that used computerized tomography (CT) reported less severe brain atrophy in delusional, compared to nondelusional Alzheimer's disease patients.23 In another study with CT, Alzheimer's disease patients with delusions had asymmetric involvement of the temporal lobe regions with greater atrophy in the right temporal lobe.99 In contrast, Alzheimer's disease patients with delusions had a predominantly left-sided distribution of subcortical white matter abnormalities in a magnetic resonance imaging (MRI) study, while patients with no delusions had a bilaterally symmetrical distribution of these lesions.3 In the latter study, analysis of the location of these lesions revealed bitemporal predominance for patients with delusions and bifrontal predominance for patients with no delusions. The correlation of delusions with left-sided anatomical abnormalities fits well with findings from patients with other types of brain lesions in which delusions are more often associated with left-sided than right-sided lesions.100 However, these symptoms have been reported to occur with unilateral right-sided pathology as well.101 In what is to our knowledge the only MRI study involving hallucinations, Barber et al.102 reported that occipital white matter hyperintensities were associated with an absence of visual hallucinations and delusions in all types of dementia, including Alzheimer's disease.
Functional imaging studies
Studies using functional imaging methods such as positron emission tomography (PET) have shown more consistent results pointing to associations between dysfunction in specific brain regions and delusions or hallucinations in Alzheimer's disease. In a PET study, Mega et al.103 found that psychotic Alzheimer's disease patients showed lower regional perfusion in the right and left dorsolateral frontal, left anterior cingular, and left ventral striatal regions along with the left pulvinar and dorsolateral parietal cortex, compared to a nonpsychotic group. The authors concluded that psychosis may reflect disproportionate dysfunction of frontal lobes and related subcortical and parietal structures.103 This interpretation is supported by another study in which psychosis in Alzheimer's disease was correlated with frontal hypometabolism86 and by the work of Lopez et al.,87 who reported that left prefrontal-temporal cortex dysfunction may be a common denominator for the development of the psychotic phenomena of Alzheimer's disease. Possible causes of the disagreement among those studies include differences in techniques for measurement of regional cerebral blood flow or metabolism, differences in the distribution of delusions or psychoses among the study subjects, differences in statistical techniques, small numbers of subjects, and the use of retrospective analysis.104
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TREATMENT
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The treatment of delusions and hallucinations in Alzheimer's disease has received increased attention since 1990. Most treatment studies have focused on pharmacologic interventions, particularly the use of antipsychotics. However, other treatment options, both nonpharmacologic and pharmacologic, may be used, depending on the clinical presentation.105
Nonpharmacologic Treatment
Good clinical care dictates that nonpharmacologic interventions for the treatment of psychiatric and behavioral symptoms of dementia be considered and implemented first. Such interventions include 1) environmental and behavioral modification, 2) caregiver education, and 3) clinicians' empathic interactions with patients and their caregivers.3 The objective of treatment is to provide supportive care to the patient and caregivers and to facilitate the establishment of a long-term relationship involving the patient, caregivers, and clinicians while implementing empirical procedures to reduce the patient's symptoms and disability and the caregiver's stress.3 One strategy is to teach caregivers to finesse accusations and other offensive statements made by delusional or hallucinating Alzheimer's disease patients and to respond in a fashion that does not increase suspiciousness. Reassurance, distraction, discussion about other matters, and conversation about the feelings behind the false beliefs are other techniques that are helpful in decreasing the frequency or persistence of these symptoms.80
In a recent review of 83 studies, Cohen-Mansfield106 found that psychosocial interventions have a positive effect in the treatment of psychiatric symptoms in dementia. However, the studies that were reviewed had several methodological shortcomings, including a wide range of inclusion criteria, limited description of the interventions, the use of unvalidated interventions, short-term follow-up, and lack of appropriate controls. Cohen-Mansfield concluded that additional studies with improved research designs are needed and that better matching of these interventions to patients' needs and capabilities is required. None of the reviewed studies assessed the benefits of nonpharmacologic interventions for delusions and/or hallucinations specifically.
Pharmacological Treatment
Pharmacological interventions become necessary when symptoms are not alleviated by nonpharmacologic approaches. They are also necessary when delusions or hallucinations cause significant distress to the patient or are associated with dangerousness.105 Pharmacological treatments whose efficacy has been assessed include typical and atypical antipsychotics, cholinesterase inhibitors, and selective muscarinic agonists (M1/M4 receptor agonists).
Typical antipsychotics
In a widely cited study, Schneider et al.107 reported on a meta-analysis of treatment studies of typical neuroleptics for psychosis or agitation in dementia. They found that these medications have at best modest efficacy and that no agent was clearly superior to others. In a more recent study, regular-dose haloperidol (2–3 mg/day) had the most favorable therapeutic profile for delusions and hallucinations in Alzheimer's disease patients. This dose improved psychosis scores by 60%, while low-dose haloperidol (0.5–0.75 mg/day) and placebo were associated with only a 30% improvement.108 Twenty percent of patients receiving a regular dose of haloperidol developed moderate to severe extrapyramidal signs, a significantly higher proportion than in the low-dose haloperidol group or the placebo group. Thus, regular-dose haloperidol is an effective treatment for psychosis in Alzheimer's disease but is associated with a notable incidence of motor side effects. In light of the findings discussed in the next sections, however, haloperidol may be an appropriate third-line therapy after nonpharmacologic treatment and atypical antipsychotics.
Atypical antipsychotics
Two placebo-controlled studies51,109 and one open-label study110 have reported that atypical antipsychotics are effective in the treatment of delusions and hallucinations in dementia. Katz et al.109 reported that risperidone significantly improved symptoms of psychosis in patients with dementia. In that study, 1 mg/day of risperidone was the dose with the most favorable risk-benefit profile, since a dose of 2 mg/day of risperidone added no benefit and was associated with more extrapyramidal symptoms, somnolence, and peripheral edema. Street et al.51 found that low-dose olanzapine (5 and 10 mg/day) was superior to placebo and well tolerated in the treatment of psychosis in Alzheimer's disease patients. The effects of high-dose (15 mg/day) olanzapine were not different from those of placebo, and high-dose olanzapine was associated with more somnolence and abnormal gait. In an open-label study, Tariot et al.110 reported that quetiapine was effective in the treatment of dementia and psychosis in elderly patients.
De Deyn et al.111 compared placebo and flexible-dose (0.5–4.0 mg/day) risperidone or haloperidol in the treatment of behavioral symptoms in dementia. The percentage of risperidone-treated (mean dose, 1.1 mg/day) and haloperidol-treated (mean dose, 1.2 mg/day) patients demonstrating clinical improvement ( 30% reduction from baseline to endpoint in Behavioral Pathology in Alzheimer's Disease Rating Scale112 total score) was not significantly greater than that of patients who received placebo. Aggression scores were significantly improved for risperidone-treated patients relative to those who received placebo, and the rate of extrapyramidal symptoms was significantly higher in patients receiving haloperidol than in those receiving risperidone or placebo.
Given the modest effect sizes for neuroleptic interventions, atypical antipsychotics are safer and better tolerated and therefore should be used in preference to typical antipsychotics when neuroleptics are indicated for treatment of psychosis in Alzheimer's disease patients. Further studies of optimal neuroleptic doses and the optimal duration of treatment and additional placebo-controlled studies comparing neuroleptics to other classes of medications are still needed.
Cholinesterase inhibitors and selective muscarinic agonists
The basal forebrain nuclei are atrophic in Alzheimer's disease, leading to a widespread cholinergic deficit. The cholinergic disturbance may contribute to neuropsychiatric manifestations of the disease.113 Cummings et al.91 found that physostigmine ameliorated delusions in two Alzheimer's disease patients. In one open-label study, Alzheimer's disease patients with delusions showed significant improvement of their delusions when treated with tacrine hydrochloride, compared with those treated with placebo.114 In a randomized, controlled trial, metrifonate, a novel cholinesterase inhibitor, has shown efficacy in the treatment of delusions, compared with placebo.115 Also, tacrine and the newer cholinesterase inhibitors such as donepezil have been demonstrated to improve hallucinations,113,116 especially in dementia with Lewy bodies. However, to our knowledge, no studies have specifically assessed the efficacy of cholinesterase inhibitors for delusions or hallucinations in Alzheimer's disease. All of the studies discussed in this section assessed efficacy for these symptoms in the context of large-scale clinical trials assessing treatments for the cognitive symptoms of Alzheimer's disease, and the severity of delusions and hallucinations in the study subjects at entry into the trials was typically mild.
In one study conducted in the context of the development of the muscarinic agonist xanomeline (M1/M4 receptor agonist) as a treatment for Alzheimer's disease, treatment was associated with significant dose-dependent reductions in delusions and hallucinations.117 The apparent favorable effects of muscarinic agonists or cholinesterase inhibitors on psychosis suggest that manipulation of the cholinergic system may be a novel approach for treatment of psychosis in Alzheimer's disease.117 However, clinical experience suggests that the effects of this approach are at best modest and that this approach should be reserved for patients with delusions/hallucinations of milder intensity.
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CONCLUSIONS
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Research since 1990 has added significant information to our knowledge of the nosology, epidemiology, and treatment of delusions and hallucinations in Alzheimer's disease. It has also raised the question of whether delusions and hallucinations should be approached separately, as they have different risk factors, consequences, and imaging characteristics. Future study should focus on refinement of our understanding of the nosology, etiopathogenesis, and treatment of delusions and hallucinations in Alzheimer's disease. This work will be best carried out in large, population-based, longitudinal studies, as well as in clinical samples. The use of imaging, genetic, and autopsy methods will be critical to the study of etiopathogenesis. Finally, research is needed on the combined use of nonpharmacologic and pharmacologic interventions as well as on use of medication from different classes and the use of combinations of medications. Specific information about dosing strategies, duration of treatment, long-term side effects, and long-term outcomes for the different medications used in the treatment of delusions and hallucinations in Alzheimer's disease is also needed.
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ABSTRACT
INTRODUCTION