Risperidone Is Effective for Wandering and Disturbed Sleep/Wake Patterns in Alzheimer’s Disease Kenichi Meguro, MD, PhD, Mitsue Meguro, MSc, Yasuhiro Tanaka, MD, Kyoko Akanuma, Keiichiro Yamaguchi, MD, PhD, and Masatoshi Itoh, MD, PhD
ABSTRACT Behavioral and psychological symptoms of dementia (BPSD), especially aggressiveness, wandering, and sleep disturbance, are a major burden for caregivers. Daily sleep/wake patterns and wandering of institutionalized patients with Alzheimer’s disease (AD) were visually monitored, and 34 patients who manifested wandering were selected and randomly classified into 2 groups: the risperidone group and the nonrisperidone group. After an administration of low-dose risperidone for the risperidone group, the BPSD were reassessed. The binding potentials of dopamine D2 receptor for preadministration and postadministration of risperidone were assessed using positron emission tomography (PET) for 1 case. After the use of risperidone, aggressiveness and wandering were reduced and the nighttime sleeping hours were increased. The PET revealed that the binding potential of dopamine receptor was increased after administration of the drug, associated with improved sleep/wake patterns and behavioral abnormality. Possible serotonergic modulation of dopaminergic function might explain the neurobiological basis of the effect of risperidone. (J Geriatr Psychiatry Neurol 2004; 17:61-67) Keywords: Alzheimer’s disease; risperidone; BPSD; wandering; sleep; PET
Some patients with Alzheimer’s disease (AD) exhibit noncognitive symptoms such as delusion, aggressiveness, 1-3 wandering, sleep disturbance, and so forth. Recently, these symptoms have been termed the behavioral and 4 psychological symptoms of dementia (BPSD). Margallo5 Lana et al surveyed 6 homes for dementia and found that
Received February 25, 2003. Received revised January 9, 2004. Accepted for publication January 23, 2004. From the Division of Neuropsychology, Department of Disability Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Drs K. Meguro, M. Meguro, Tanaka, Ms Akanuma), and the Division of Nuclear Medicine, Cyclotron Radioisotope Center, Tohoku University, Sendai, Japan (Drs Yamaguchi and Itoh). This study was performed at the Nursing Home Nakada, Nakada, Japan. An abstract form was previously presented at the Eighth International Conference on Alzheimer’s Disease and Related Disorders, Stockholm, 2002. This study was supported by a grant of the Silver Rehabilitation Foundation, 2002. Address correspondence to: Kenichi Meguro, MD, PhD, Division of Neuropsychology, Department of Disability Medicine, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, 980-8575, Sendai, Japan; e-mail:
[email protected]. DOI: 10.1177/0891988704264535
© 2004 Sage Publications
79% of residents had significant BPSD, with 58% receiving psychotropic medication. Depression was most common in mild dementia, while delusion arose most frequently in moderate dementia and aberrant motor behavior had a 6 high prevalence in severe dementia. Brodaty et al surveyed 11 homes and reported that psychosis was found in 60% of residents, depressed mood in 42%, and activity disturbance or aggression in 82%. Among the BPSD, it is well known that aggressiveness, wandering, and sleep/wake disturbance are major burdens for family and caregivers. Various antipsychotic drugs have been used for the treatment of such symptoms based on the hypothesized, partly proved neurobiological mechanism. There were some hypotheses as to wandering behavior or disturbed 7,8 9 sleep/wake disturbance. Robbins noted a similarity of 10 the symptoms found in subcortical dementia and frontal lobe damage and proposed “frontostriatal dementia” as an even more apt description. It is possible that a functionally impaired frontostriatal circuit may be involved in the pathological behavior. Using positron emission tomography (PET), we previously reported that wandering patients with AD showed decreased frontotemporal glucose uti11 lization and decreased dopamine metabolism in the stria-
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tum.12-14 We consider that an impairment of the frontostriatal circuit, associated with dopamine transmission, is related to the BPSD. Risperidone, the serotonin-dopamine antagonist, is the atypical antipsychotic drug that is found to be effec15 16 tive for the BPSD in dementia. Shigenobu et al noted the drug to be effective for delusion of theft shown by patients with AD. Although several studies reported the 17,18 the effect on disturbed sleep/wake drug’s effectiveness, patterns with wandering has not been fully examined. We hypothesized that risperidone would be effective for disturbed sleep/wake patterns with wandering according to the serotonergic modulation of dopaminergic function. Risperidone has the antagonistic potency of serotonin and dopamine receptors. We consider that low dose of the drug predominantly blocks the serotonin system, thus resulting in an increase in the dopamine system, which is associated with behavioral abnormalities. METHODS Institutional Facility The present study was performed in a nursing home in Nakada, which is located in the countryside in northern Japan. It is a 150-bed institution, which includes a 40-bed special care unit for dementia, where medication is possible. All patients in this home receive hourly care, even at night. Patient Selection Inclusion Criteria Participants met the criteria for probable AD as per the 19 NINCDS-ADRDA. They received brain computed tomography: no patient had large infarctions or strategic infarctions, even small, in the areas such as the thalamus. Only small lacunar infarctions in the basal ganglia regions or deep white matter were noted. Patients manifested wandering behavior or aggressiveness for more than 4 days in the first assessment period (7 consecutive days, see below). Exclusion Criteria Patients were excluded from the study if (1) they had had a stroke episode or exhibited neurological signs or symptoms indicative of cerebrovascular diseases, (2) they showed signs of Parkinson’s disease, or (3) their physical symptoms had not been stable during the preceding month. During the study period, no patients had acute disorders, such as infection, heart failure, or stroke, requiring special treatment or intensive care. We identified 34 appropriate patients for inclusion in this study, consisting of 7 men and 27 women, ranging in age from 68 to 90 years (mean = 77.8 years). Seventeen patients received donepezil, an acetyl-cholinesterase inhibitor. None of the patients received sleeping drugs or drugs that had side effects to affect sleep. Written informed
consent was received from the families of all patients included in this study. Evaluation of Cognitive Impairment and the BPSD Mental status was evaluated by the Mini-Mental State 20 Examination (MMSE) and the Cognitive Abilities Screen21 ing Instrument (CASI). As for the level of activity of daily living, the patients were able to walk by themselves with or without walkers, as well as eat by themselves. 22 For screening the BPSD, we used the BEHAVE-AD, a 26-item observer rating scale containing 7 subscales: Paranoid and Delusional Ideation, Hallucinations, Activity Disturbances (wandering, etc), Aggressiveness, Diurnal Rhythm Disturbance (sleep/wake pattern), Affective Disturbance, and Anxiety and Phobias. Each of the subscales was rated from 0 to 3. Patients were assessed as positive on any of the BEHAVE-AD subscales if either morning or evening raters gave them a score of 1 or greater on any of their component items. Patients with a positive score on the Activity Disturbances, Aggressiveness, or Diurnal Rhythm Disturbance subscales were further evaluated as follows. We will not analyze the BEHAVE-AD scores themselves in this study because we have focused on the wandering and sleep/wake pattern. For the sleep/wake patterns, 1 month after admission, the patients were checked hourly for 7 consecutive days (the first assessment period; see Figure 1) as to whether they were asleep or awake. A data form with a space for each of the 168 continuous hours (24 hours × 7 days) was used. Behavioral criteria for judging sleep were described and supplied in written form to nurses and assistants. These included relative immobility of limbs and eyelids and unresponsiveness to approach. The reliability of this visual monitoring method was previously 1 observed by 24-hour electroencephalogram. For wandering behavior, some patients wandered out of their rooms even at night and showed psychiatric symptoms such as agitation and restlessness. They finally got lost inside the home and were unable to return to their rooms. Insomnia was sometimes accompanied by such behavior. If patients showed abnormal behavior as described above for more than 4 days in the first assessment period (7 consecutive days, see below), together with positive scores on the BEHAVE-AD Activity Disturbances, Aggressiveness, or Diurnal Rhythm Disturbance subscales, they were operationally defined as the wandering group in this study. Study Design After the first period of assessment of behavioral abnormality (7 consecutive days, 1 month after admission), they were given routine psychosocial care such as reality ori23,24 After 1 month, the entation and reminiscent therapy. wandering group was again checked hourly for 7 consecutive days (the second assessment period) and was ran-
Risperidone and Alzheimer’s Disease / Meguro et al
Table 1. Demographics of the Study Population
Mean Age Male/Female Risperidone group (n = 20) Nonrisperidone group (n = 14)
78.5 77.1
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Note: MMSE = Mini-Mental State Examination. No significant differences were noted between the 2 groups.
domly separated into 2 groups, that is, the risperidone group and the nonrisperidone group. As Table 1 shows, the 2 groups demonstrated about the same levels of cognitive function as shown by the MMSE. Then, 1 mg/d of risperidone was administered to the risperidone group. After 1 month, both groups were again checked hourly for 7 consecutive days (the third assessment period). As for other drugs, patients in both groups continued to receive medication for their diseases (eg, hypertension, hyperlipidemia, inactive gastric ulcer, osteoporosis, etc): such drugs had no side effects on wandering or sleep/wake patterns. Nine patients in the risperidone group and 8 patients in the nonrisperidone group continued to receive 5 mg/d of donepezil from their previous doctors. The changes between the first and second assessments were due to the effect of institutionalization without the drug for both groups, and the changes between the second and third assessments were the result of risperidone administration. Figure 1 illustrates the study procedure. PET Study We performed the PET studies twice for a single case of the risperidone group, preadministration and postadministration of risperidone (ie, during the second assessment period and the third assessment period), to reveal the effect of the drug on the striatal dopaminergic receptors. The PET devise used was a SET-2400 PET camera, 11 and the radioligand was [ C] raclopride, a specific D2 25 receptor antagonist. The PET data were acquired up to 90 minutes after intravenous injection of 4 to 5 mCi of the radioligand with decay and attenuation correction. Reconstructed images had an axial full-width half-maximum resolution of 8.0 mm, radial 6.3 mm and tangential 6.4 mm, at the center of the field view. Using the summation PET image acquired from 40 to 60 minutes, the regions of interest (ROIs) were drawn on 3 adjacent slices for both the left and right striatum (caudate and putamen) and the cerebellum with reference to magnetic resonance images. The positions of the ROIs were determined by 2 examiners blind to each other, and the mean value was used. The ratio of counts in the (striatum–cerebellum)/ cerebellum during the period of equilibrium state was 11 used as an estimate of the Bmax/Kd of [ C] raclopride for 26,27 ; Bmax is the total number of dopamine D2 receptors D2 receptors, and the Kd is the affinity of the ligand. This is justified on the grounds that the cerebellar counts reflect
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the free ligand and the nonspecific binding, whereas the striatal counts reflect the specific binding of the ligand to the D2 receptors. Using these assumptions, the (striatum – cerebellum)/cerebellum ratio can be considered to reflect the ratio of Bmax/Kd. This measure was often referred to 28 as the binding potential. The left-right mean value was presented. Analyses Data were analyzed by inspection and hand scoring of the forms. We evaluated the following. Daytime Sleep and Nighttime Sleep For the purposes of this analysis, night was defined as the period from 7:00 PM, by which time the patients were in bed, to 6:00 AM, when paper diapers of patients were changed as routine work and most of the patients were awakened. A MANOVA with 3 ´ 2 repeated measures (3 assessments, daytime and nighttime) was performed: the daytime and nighttime sleeping hours for the first, second, and third assessment periods were included in the analyses. Hours of Wandering The hours of wandering behavior as described above were counted throughout the day and night. Each patient had at least 1 caregiver attending him or her during all wandering time. RESULTS 1. The relative changes in daytime and nighttime sleeping hours for both groups are illustrated in Figure 2. For the risperidone group, after administration of risperidone, the mean daytime sleeping hours decreased by 1.2 hours, whereas the mean nighttime sleeping hours increased by 3.8 hours. 2. The mean wandering hours decreased by 2.7 hours per day. 3. The patients did not exhibit any newly emerged daytime oversleeping or extrapyramidal symptoms (side effects), which would have prevented them from participating in daily activities of the institution. 4. A typical case was presented. A 79-year-old man with probable AD was admitted to the nursing home because of aggressiveness and wandering. As illustrated in Figure 3, after administration of risperidone 1 mg/d, disturbed sleep/wake patterns with behavioral abnormality were improved. Figure 4 illustrates the PET images of preadministration and postadministration of risperidone. The binding potentials (left-right mean) were 1.7 and 2.0, respectively.
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1 month
Admission
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Figure 1. Study protocol.
hours decreased for both groups, no significant difference was noted. However, this does not mean that such psychosocial care has no meaning. We did have some patients not included in this study whose BPSD had dramatically improved after psychosocial care; some of them, however, were diagnosed with vascular dementia or BPSD other than wandering or sleep disturbance (eg, anxiety etc), and therefore they were not included in the study population. All of our patients had AD, and we targeted the BPSD as wandering and disturbed sleep/wake patterns. Thus, the effect of psychosocial care might be masked.
100
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Figure 2. Changes in sleeping hours for both groups. The relative changes of the daytime sleeping hours (circles) and the nighttime sleeping hours (squares) for both groups (closed for the nonrisperidone group, open for the risperidone group) are illustrated. There was a significant group effect (df = 4, F = 12.583, P = .001) with a significant time effect (df = 4, F = 2489.213, P = .000) and daytime/nighttime effect (df = 4, F = 2545.469, P = .000). The interaction between group and time was significant (df = 4, F = 129.765, P = .000) as was the interaction between group and daytime/nighttime effect (df = 4, F = 15.744, P = .000). Post hoc tests indicated that the nighttime sleeping hours for the first and the second assessments were significantly different between the 2 groups (P < .05), but no difference was noted for the third assessment. The nighttime sleeping hours of the wandering group as shown by the second and third assessment were significantly different (P < .05).
DISCUSSION Possible Extra Drug Effects The changes between the first and second assessments were due to the effect of institutionalization without the drug. All patients received psychosocial care, and such efforts 23,24,29 Although nighttime have been noted to be effective. sleeping hours slightly increased and daytime sleeping
Mechanism of Wandering Behavior The mechanism of wandering or sleep disturbance is 30 unclear. Burns et al noted that wanderers have more dyspraxia (visuospatial problems) than do nonwanderers. Visuospatial dysfunction is related to parietotemporal 31 hypometabolism in AD. As for our patients, the wandering group patients had a greater tendency (not significant) to show dyspraxia (figure copying test in the MMSE and CASI) than the nonwandering group patients did 32 (data not shown). Myers et al studied the relationship between social behavior and brain lesions in rhesus monkeys: after resection of the prefrontal cortex, monkeys failed to rejoin their social group and exhibited increased levels of aimless pacing activity. However, all the patients in this study had only small lacunar infarctions in the basal ganglia regions without infarctions in the frontal cortex. AD can be considered as a kind of disconnection syndrome, and the well-known parietotemporal hypometabolism together with frontal hypometabolism as shown by 33PET is associated with the grade of hippocampal atrophy. 35 Although no frontal infarctions were noted, a deteriorated neural network in the brain might affect the frontal lobe function in AD. Effect of Risperidone Risperidone is the atypical antipsychotic drug, which is reported to be effective for BPSD in dementia, the serotonindopamine antagonism being a major effect. This study
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1 2 3 4 5 6 7 Figure 3. (a) Sleep/wake patterns of a wandering patient. The vertical axis shows the 7 days of the second assessment period, and the horizontal axis indicates the time of day. Black space indicates sleeping hours, white space indicates waking state, and double circles show wandering. Wanderers showed abnormal behavior more than 4 of 7 days. (b) Sleep/wake patterns of a wandering patient after antipsychotic drugs were administered. The vertical axis shows the 7 days of the third assessment period, and the horizontal axis indicates the time of day. Black space indicates sleeping hours, white space indicates waking state. Note that wandering behavior decreased.
Figure 4. Positron emission tomography images of preadministration (left) and postadministration (right) of risperidone.
confirmed the effectiveness of the drug. Previous studies disclosed that a small dose of risperidone blocks the serotonin receptors and the dopaminergic neuron system is 36 stimulated as a result of serotonin-dopamine interaction. We previously reported that wandering patients with AD 12 had decreased dopamine synthesis in the striatum. We consider that a small dose of risperidone affects the serotonin-dopamine interaction as to increase dopamine synthesis in the brain, thus resulting in an improvement of wandering and sleep/wake patterns. A possible combined effect of donepezil should be excluded since donepezil is also reported to be effective for 37 some BPSD. Nine patients in the risperidone group and 11 patients in the nonrisperidone group received donepezil. We analyzed the effect of donepezil use by the 2 × 2 (risperi-
done vs nonrisperidone, single drug vs combined use) MANOVA with 3 × 2 repeated measures (3 assessments, daytime and nighttime). No significant combined effects were noted (data not shown); thus, we determine that the results were based on the effect of risperidone. The wandering patients in this study did not show cognitive deterioration after administration of the drug as shown by the MMSE or CASI. On the contrary, some patients showed the CASI item orientation or attention to be slightly improved (data not shown). An improvement of these frontal executive functions might support the hypothesis that frontal-subcortical dysfunction is associated with behavioral abnormality and sleep disturbance. PET Study for Preadministration and Postadministration of Risperidone The PET examinations revealed that the binding potential of the dopamine receptor was increased from 1.7 to 2.0 after administration of the drug, associated with improved sleep/wake patterns and behavioral abnormality. It would be better to have larger samples as it was practically difficult to do PET examinations twice for the same patient, with the same period of drug therapy. However, some neurological basis of the effect of the drug can be discussed. We previously reported a significant negative (biologically meaningful) correlation between the BEHAVEAD score and the binding potentials: the binding potential 38 was lower in severer BPSD patients. The mean BPSD 38 value of 5 normal subjects previously reported was 2.5
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(range, 2.3-2.8). We should consider the mechanism of increasing dopamine receptors to be effective for decreasing BPSD. The serotonin system inhibits dopaminergic function at the level of origin of the dopamine system in the midbrain as well as at the terminal dopaminergic fields in the 36 forebrain. Serotonergic antagonists release the dopamine system from this inhibition. Risperidone is a serotonindopamine antagonist that has the antagonistic potency of the serotonin and dopamine receptors. However, a low dose of the drug predominantly blocks the serotonin system rather than the dopamine system, thus resulting in an increase in the dopamine system. This serotonergic modulation of dopaminergic function might explain the neurobiological basis of the effect of risperidone.
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References 1. Meguro K, Ueda M, Yamaguchi T, et al. Disturbance in daily sleep/wake patterns in patients with cognitive impairment and decreased daily activity. J Am Geriatr Soc 1990; 38:1176-1182. 2. Meguro K, Ueda M, Kobayashi I, et al. Sleep disturbance in elderly subjects with cognitive impairment, decreased daily activity, and periventricular white matter lesions. Sleep 1995; 18(2):109114. 3. Folstein MF, Bylsma FW. Noncognitive symptoms of Alzheimer’s disease. In: Terry RD, et al, Eds. Alzheimer disease. 2nd ed. Philadelphia, Pa: Lippincott Williams & Willkins, 1999:25-37. 4. Finkel SI, Costa de Silva J, Cohen G, et al. Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Int Psychogeriatr 1996; 8(S3):497-500. 5. Margallo-Lana M, Swann A, O’Brien J, et al. Prevalence and pharmacological management of behavioral and psychological symptoms amongst dementia sufferers living in care environment. Int J Geriatr Psychiatr 2001; 16:39-44. 6. Brodaty H, Draper B, Saab D, et al. Psychosis, depression and behavioral disturbances in Sydney nursing home residents: prevalence and predictors. Int J Geriatr Psychiatr 2001; 16:504-512. 7. Vitiello MV, Bliwise DL, Prinz PN. Sleep in Alzheimer’s disease and the sundown syndrome. Neurology 1992; 42(S6):83-94. 8. Bliwise DL. Sleep in normal aging and dementia. Sleep 1993; 16:40-81. 9. Robbins TW. Drug effects on brain lateralization in the basal ganglia of schizophrenics. In: Willner P, Scheel-Krugar J, Eds. The mesolimbic dopamine system: from motivation to action. Chichester, UK: Wiley, 1991:529-538. 10. Albert MS, Feldman RG, Willis AL. The “subcortical dementia” of progressive supranuclear palsy. J Neurol Neurosurg Psychiatr 1974; 37:121-130. 11. Meguro K, Yamaguchi S, Yamazaki H, et al. Cortical glucose metabolism in psychiatric wandering patients with vascular dementia. Psychiatr Res 1996; 67:71-80. 12. Meguro K, Yamaguchi S, Itoh M, et al. Striatal dopamine metabolism correlated with frontotemporal glucose utilization in Alzheimer’s disease: a double-tracer PET study. Neurology 1997; 49:941-945. 13. Meguro K, Itoh M, Yanai K, et al. Psychiatric wandering behavior in dementia patients correlated with increased striatal dopamine D2 receptor as shown by [11C]YM-09151-2 and positron emission tomography. Eur J Neurol 1997; 4:221-226. 14. Meguro K, Yamaguchi S, Shimada M, et al. Striatal dopaminergic transmission and neocortical glucose utilization in Alzheimer’s disease: a triple-tracer positron emission tomography study. Arch Gerontol Geriatr 2000; 31:147-158.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30. 31.
32.
33.
De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999; 53:946-955. Shigenobu K, Ikeda M, Fukuhara R, et al. Reducing the burden of caring for Alzheimer’s disease through the amelioration of “delusions of theft” by drug therapy. Int J Geriatr Psychiatr 2002; 17:211-217. Zaudig M. A risk-benefit assessment of risperidone for the treatment of behavioral and psychological symptoms of dementia. Drug Safety 2000; 23:183-195. Tune LE. Risperidone for the treatment of behavioral and psychological symptoms of dementia. J Clin Psychiatr 2001; 62(suppl 21):29-32. McKhann G, Drachman D, Folstein M. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services task force on Alzheimer’s disease. Neurology 1984; 34:939944. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state,” a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-198. Teng EL, Hasegawa K, Homma A, et al. The Cognitive Ability Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr 1994; 6:4558. Reisberg B, Borenstein J, Fransses E, et al. BEHAVE-AD: a clinical rating scale for the assessment of pharmacologically remediable behavioral symptomatology in Alzheimer’s disease. In: Altman HJ, Ed. Alzheimer’s disease: problems, prospects and perspectives. New York, NY: Plenum, 1987:1-16. Ishizaki J, Meguro K, Ishii H, et al. The effects of group work therapy in patients with Alzheimer’s disease. Int J Geriatr Psychiatr 2000; 15:532-535. Ishizaki J, Meguro K, Ohe K, et al. Therapeutic psychosocial intervention for elderly subjects with very mild Alzheimer’s disease in a community: the Tajiri Project. Alzheimer Dis Assoc Disord 2002; 16:261-269. Farde L, Pauli S, Hall H, et al. Stereoselective binding of 11Craclopride in living human brain: a search for extrastriatal central D2-dopamine receptors by PET. Psychopharmacology 1988; 94:471-478. Logan J, Fowler JS, Volkow ND, et al. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996; 16:834-840. Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatr 1999; 156:286-293. Wadenberg MLG, Kapur S, Soliman A, et al. Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats. Psychopharmacology 2000; 150:422-429. Rabins PV. The treatment of noncognitive symptoms. In: Terry RD, et al, Eds. Alzheimer disease. 2nd ed. Philadelphia, Pa: Lippincott Williams & Willkins, 1999:415-421. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer’s disease: IV. Disorders of behavior. Br J Psychiatr 1990; 157:86-94. Meguro K, Shimada M, Someya K, et al. Hemispatial visualsearching impairment correlated with decreased contralateral parietal blood flow in Alzheimer disease. Neuropsychiatr Neuropsychol Behav Neurol 2001; 14:213-218. Myers RE, Swett C, Miller M. Loss of social group affinity following prefrontal lesions in free-ranging macaques. Brain Res 1973; 64:257-289. Yamaguchi S, Meguro K, Itoh M, et al. Decreased cortical glucose metabolism correlates with hippocampal atrophy in Alzheimer’s disease as shown by MRI and PET. J Neurol Neurosurg Psychiatry 1997; 62:596-600.
Risperidone and Alzheimer’s Disease / Meguro et al
34.
35.
Meguro K, Blaizot X, Kondoh Y, et al. Neocortical and hippocampal glucose metabolism following neurotoxic lesions of the entorhinal and perirhinal cortices in the non-human primate as shown by PET: implications for Alzheimer’s disease. Brain 1999; 122:1519-1531. Meguro K, LeMestric C, Landeau B, et al. Relations between hypometabolism in the posterior association neocortex and hippocampal atrophy in Alzheimer’s disease: a PET/MRI correlative study. J Neurol Neurosurg Psychiatry 2001; 71:315-321.
36. 37.
38.
67
Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatr 1996; 153:466-476. Cummings JL, Donobue JA, Brooks RL. The relationship between donepezil and behavioral disturbances in patients with Alzheimer’s disease. J Geriatr Psychiatr 2000; 8:134-140. Tanaka Y, Meguro K, Yamaguchi S, et al. Decreased striatal D2 receptor density associated with severe behavioral abnormality in Alzheimer’s disease. Ann Nucl Med 2003; 17:567-573.
