Fluvoxamine in the treatment of demented elderly patients: a double-blind, placebo-controlled study Olafsson K, Jerrgensen S, Jensen HV, Bille A, Arup P, Andersen J. Fluvoxamine in the treatment of demented elderly patients: a double-blind, placebo-controlled study. Acta Psychiatr Scand 1992: 85: 453-456. The efficacy of fluvoxamine on cognitive functioning and behavioral changes was evaluated in a double-blind, placebo-controlled study of 46 elderly demented patients. The patients had a DSM-I11 diagnosis of primary degenerative dementia or multi-infarct dementia and were aged 2 65 years. Twenty-two patients were given 150 mg fluvoxamine per day and 24 received placebo tablets; 14 and 15 patients, respectively, completed 6 weeks of treatment. Within treatments, there were no significant changes in median scores on neuropsychological tests (picture recall and recognition, trail making and finger tapping) or the GBS scale scores (degrees of dementia) or GBS subscale score (clinical profiles, including symptoms common in dementia, motor, emotional and intellectual functioning). Between treatments, the median changes in psychometric test scores did not differ significantly. However, within and between treatments, there were trends favoring fluvoxamine on symptoms common in dementia (confusion, irritability, anxiety, fear-panic, mood level and restlessness). In conclusion, the study does not support the hypothesis that fluvoxamine improves cognitive functioning or behavioral changes in elderly dementia patients.
In patients with multi-infarct dementia (MID) and senile dementia of the Alzheimer type (SDAT) several neurotransmitter systems are impaired, including the serotonergic system (1-3). It has been suggested that deficits in the serotonergic system could be related to the decline in cognitive functioning and behavioral changes seen in dementia (4-6). In line with this assumption, one strategy in the search for effective treatments of dementia disorders has been to restore serotonergic functions by giving selective serotonin reuptake inhibitors (4, 5, 7-10). In an open study by us, 4 of 8 demented elderly people treated with the serotonin reuptake inhibitor fluvoxamine improved significantly measured on neuropsychological tests and the GBS rating scale (1 1). These findings prompted us to study in a double-blind, placebo-controlled design the efficacy of fluvoxamine on cognitive functioning and behavioral changes in elderly dementia patients. Material and methods Patients
The patient population consisted of inpatients at the Psychogeriatric Departments of Vordingborg Psy-
K. Olafsson’, S. J~rgensen’, H. V. Jensen’, A. Bille’, P. Arup’, J. Andersen
’
’ Psychogeriatric Department, Vordingsborg
Psychiatric Hospital, * Psychogeriatric Department, Frederiksberg Hospital, Denmark
Key words: dementia; multi-infarct dementia; dementia of Alzheimer type: fluvoxamine; serotonin K. Olafsson, M.D., Vordingborg Psychiatric Hospital, DK-4760 Vordingborg, Denmark Accepted for publication January 10, 1992
chiatric Hospital and Frederiksberg Hospital, Denmark. The patients had a DSM-I11 diagnosis of primary degenerative dementia or multi-infarct dementia ( 12) and were aged 1 6 5 years. Patients for whom psychiatric or medical consultation (including biochemical screening) suggested a cause of dementia other than MID and SDAT were excluded from the study. Further, patients with a history of manic-depressive disorder (including current depressive symptoms) or alcohol abuse were also excluded. The study protocol was registered by the local ethics committees and the National Board of Health, Denmark. Treatment
After a 2-week washout period, the patients were randomly allocated (in blocks of 4 patients) to 6 weeks of treatment with either fluvoxamine or placebo. Over the first 5 days of treatment, the dosage of fluvoxamine was increased gradually from 50 mg to 150 mg per day; tablets were given at bedtime. If sedation was necessary oxazepam was allowed.
453
Olafsson et al. Assessment
The patients were evaluated at baseline and after 6 weeks of treatment by applying neuropsychological tests, including picture recall and recognition, trailmaking and finger-tapping (13-16). The picture recognition test presents 8 pictures of common objects to the patients and the patient is asked to name each object (13). Immediately afterwards (immediate recall) and after an intermediate task (delayed recall), the patient is asked to verbally recall as many objects as possible. Subsequently, the 8 pictures are presented again interspersed with 16 other pictures of common objects (distractors) and the patient is asked to indicate the drawing seen previously (delayed recognition). The number of correct answers determine the score. The Trail-making Test is a test of visual conception and visuomotor tracking (14, 15). In the Trialmaking Test the patient is asked to draw lines to connect consecutively numbered circles as quickly as possible without lifting the pencil from the paper. To avoid floor effects maximally 30 s is allowed to complete each of the 2 forms used in this test, after the procedure is explained and the patient trained on the task. The mean number of correct connections from both forms determine the score. The finger-tapping speed has been found to be a good measure of organic pathology among geriatric patients (16). The number of times the patient can depress a handle counter key in 15 s with both the dominant and the nondominant index finger (2 trials with each hand) serves as a measure of simple motor speed. The neuropsychological tests were carried out by a psychologist. Further, degrees of dementia and clinical profiles were assessed on the GBS rating scale (17, 18). The GBS rating scale is a quantitative rating scale for dementia syndromes; it is divided into 4 subscales measuring motor, intellectual and emotional functioning and symptoms common in dementia. The GBS ratings took place at conferences, where the psychiatrist interviewed the nurses of the ward.
were used for paired comparison within one group (Wilcoxon-Pratt test), for unpaired comparison between 2 groups (Mann-Withney test) and for correlation analysis (Spearman test). Results Patients
Forty-six patients entered the study; 22 patients (8 men and 14 women; median age: 81 years, range: 65-93) were allocated to treatment with fluvoxamine and 24 (1 1 men and 13 women; median age; 80 years, range: 70-89) received placebo tablets. Fourteen and 15 patients, respectively, completed 6 weeks of treatment with fluvoxamine or placebo. Seven patients dropped out of the study during fluvoxamine treatment because of: administrative reasons, 3 ; somatic disease, 2; nausea, 1; and aggressiveness, 1. During placebo treatment 9 patients dropped out: somatic disease, 4; paranoia, 2; depressive symptoms, 1; aggressiveness, 1; and administrative reasons, 1. For patients completing 6 weeks of treatment, 8 patients in the fluvoxamine group and 10 in the placebo group were given oxazepam in addition to fluvoxamine or placebo. Efficacy
The median scores on neuropsychological tests and the GBS rating scale at baseline and after 6 weeks of treatments are shown in Tables 1 and 2. Within treatments, there were no statistically significant changes in median scores on neuropsychological tests (picture recall and recognition, trailmaking and finger-tapping) or the GBS rating scale scores (degrees of dementia) or GBS subscale scores (clinical profiles, including symptoms common in
Table 1. The neuropsychological test scores (median values, ranges in parentheses) during 6 weeks of treatment with fluvoxamine or placebo ~~uvoxarnine (n= 14) Baseline
6 weeks
Baseline
6 weeks
Picture recall Immediate recall Delayed recall
0.4 10-4) 0.2 (0-3)
0.6 (0-4) 0.4 (0-4)
0.2 10-51 0.1 10-2)
0.2 10-41 0.1 10-4)
Picture recognition Correct recognition Concept distractors Other distractors
3.7 11-8) 0.8 10-4) 1.3 (0-61
4.8 10-8) 1.O (0-8) 1.o (0-81
2.5 (0-8) 1.5 (0-7) 2.2 (0-8)
4.8 10-8) 2.5 10-71 3.0(0-6)
Trail-making Test
8.3 10-15)
5.0 10-17)
2.8 (0-16)
0.8 10-8)
Finger-tapping Dominant index finger Nondominant index finger
20 10-60) 20 10-50)
14 10-64) 16 (0-54)
31 112-59) 25 10-481
30 15-67) 31 10-51)
Statistical analysis
The median scores and the median changes in scores on the neuropsychological tests and the GBS scale were compared within treatments and between treatments, respectively. To test whether efficacy of treatment was related to degrees of dementia, correlation analysis between the total GBS scores at baseline and the relative change in total GBS scores (i.e. (total GBS score at baseline - total GBS score after 42 days)/total GBS score at baseline) were carried out. Nonparametric methods of statistical analysis
454
Placebo (n= 15)
Fluvoxamine in the treatment of demented elderly Table 2. The scores on the GBS rating scale and subscales (median values, ranges in parentheses) before and after 6 weeks of treatment with fluvoxamine or placebo Fluvoxamine in= 14) Baseline
6 weeks
Placebo (n= 15) Baseline
6 weeks
Total score 78 113-132) 68 (19-120) 63 (22-104) 68 (17-102) Symptoms common in dementia 12(1-23) 8(1-24) lO(2-15) lO(2-16) 16 11-34] 14 10-29) 10 (0-22) Motor functioning 7 (0-21) Intellectual functioning 43 (3-62) 38 (10-62) 40 (15-62) 42 112-60) Emotional functioning 8 (0-15) 4 (1-14) 6 (0-14) 6 (0-17)
dementia, motor, emotional and intellectual functioning) (Wilcoxon-Pratt test). Between treatments, the median changes in psychometric test scores did not differ significantly (Mann-Whitney test). However, within and between treatments, there were trends favoring fluvoxamine on symptoms common in dementia (confusion, irritability, fearpanic, mood level and restlessness) ( P = 0.08 and P = 0.07, respectively). There was no significant correlation between the total GB S scores at baseline and the relative changes in total GBS scores (i.e. (total GBS score at baseline - total GBS score after 42 days)/total GBS score at baseline) in the fluvoxamine group (Spearman test). Discussion
Our data do not support the hypothesis that fluvoxamine improves cognitive functioning or behavioral changes in elderly dementia patients. These findings are in accordance with the results by Nyth et al. (lo), who, in a double-blind, placebo-controlled study, found that citalopram, another selective serotonin reuptake inhibitor, did not improve motor performance or intellectual capacities in patients with primary degenerative dementia or MID. However, in the study by Nyth et al. (lo), in patients with primary degenerative dementia, citalopram produced significant improvements on emotional disturbances, confusion, irritability, restlessness and fear-panic, and the mood level was raised (within treatment), whereas citalopram was superior to placebo only on irritability and depressed mood (between treatments); there was no effect in patients with MID. In our study, a trend in favor of fluvoxamine on the GBS subscale including these symptoms could be shown (symptoms common in dementia) (within and between treatments). However, the size of our patient sample did not justify separate statistical analysis for patients with primary degenerative dementia and MID, which could mask possible differences in treatment outcome between these diagnostic groups. On
the other hand, however, the diagnostic validity of differentiating between primary degenerative dementia and MID on clinical grounds is probably relatively low (19), and, further, the serotonergic changes found in postmortem brains from patients with primary degenerative dementia and MID have shown common characteristics ( 3 ) , which should tend to reduce differences in treatment outcome between these groups. Other differences between the studies by Nyth et al. (10) and ours could also cause variance in treatment results on emotional disturbances. Thus, in our study, patients with a history a manic-depressive disorder or current depressive symptoms were excluded, whereas the study by Nyth et al. (10) included such patients; depressive symptoms were considered to be part of the dementia syndrome. Further, different methods of statistical analysis were applied (parametric vs nonparametric methods). Thus, the only 2 controlled studies carried out until now indicate that treatment of dementia disorders with selective serotonin reuptake inhibitors is no better than placebo on cognitive functioning or motor performance, but it may possibly reduce some emotional disturbances in patients with primary degenerative dementia. In our study, a considerable number of patients were too demented to score at all on several neuropsychological tests, such as the picture recall and recognition tests, leading to constantly low median scores, which therefore reduce the validity of these test results. The neuropsychological tests were chosen on the basis of a pilot study (1 1) but, retrospectively, it appears that the present study compared with the pilot study included patients with a much broader range of dementia degrees, and, especially, a majority of patients with severe dementia. It has been suggested that drug treatment of the intellectual reduction in dementia disorders is more likely to be effective in patients with only a mild degree of dementia, in whom it is thought that neurons have survived in sufficient numbers to respond to treatment (20). In our study no correlation between total GBS scores at baseline and relative change in total GBS scores during treatment could be shown, suggesting that degree of dementia does not effect responsiveness to treatment with selective serotonin reuptake inhibitors. Finally, during fluvoxamine treatment only one patient withdrew because of side effects (nausea), suggesting that a daily dose of 150 mg of fluvoxamine is well tolerated in elderly dementia patients. In conclusion, the study does not support the hypothesis that fluvoxamine improves cognitive functioning or behavioral changes in demented elderly people.
455
Olafsson et al. References 1. GOTTFRIES CG, ADOLFSSON R, AQUILONIUS SM et al. Biochemical changes in dementia disorders of the Alzheimer type (AD/SDAT). Neurobiol Aging 1983: 4: 261-271. 2. WALLIN A, ALAFUZOFF I, CARLSON A et al. Neurotransmitter deficit in a non-multi-infarct category of vascular dementia. Acta Neurol Scand 1989: 79: 397-406. 3. GOTTFRIES CG. Disturbance of the 5-hydroxytryptamine metabolism in brains from patients with Alzheimer’s dementia. J Neural Transm 1990: suppl 30: 33-43. 4. ALTMANHJ, NORMILE HJ. Serotonin, learning and memory: Implications for the treatment of dementia. In CROOK T, BARTON R, FERRIS S, GERSHON S, ed. Treatment development strategies in Alzheimer’s disease. Madison, CT: Mark Powley Associates, 1986: 361-383. HJ, NORMILE HJ. What is the nature of the role 5. ALTMAN of the serotonergic nervous system in learning and memory: prospects for development of an effective treatment strategy for senile dementia. Neurobiol Aging 1988: 9: 627-639. 6. BERCMAN I, BRANEG, GOTTFRIES CG et al. Alaproclate: a pharmacokinetic and biochemical study in patients with dementia of Alzheimer type. Psychopharmacology 1983: 80: 279-283. 7. STRATMANN GC. Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol 1988: 23: 616-620. 8. HARENKO A, ELCEN K. On a clinical phase I1 study of citalopram in elderly depressed patients. Copenhagen: H. Lundbeck A/S, 1984 (H. Lundbeck A/S Report 1984: 19: 83 1). 9. NYTHAL, BALLDINJ, ELGENK etal. Behandling med Citalopram vid demens. Normalisering av DST. Nord Psykiatr Tidsskr 1987: 42: 423-430.
456
10. NYTHAL, GOTTFRIES CG. The clinical efficacy of citalopram in the treatment of emotional disturbances in dementia disorders. A Nordic multi-center study. Br J Psychiatry 1990: 157: 894-901. 11. OLAFSSON K, BILLE A, PALSBY A et al. Serotonin reuptakeinhibitor in the treatment of dementia. Nord Psykiatr Tidsskr 1988: 42: 533-535. 12. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd edn. Washington, DC: APA, 1980. 13. SNODGRASS JG, VANDERWARD JG. Human learning and memory. J Exp Psychol 1980: 6: 174-215. 14. ARMITAGE SU. An analysis of certain psychological tests used for evaluation of brain injury. Psychol Monogr 1946: 60: 277. 15. REITANRM. Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 1958: 8: 271-276. 16. LEHMAN HT, BANTA. Psychometric tests in evaluation of brain pathology response to drugs. Geriatrics 1970: 25: 142147. 17. GOTTFRIES CG, BRANEG, GULLBERC B et al. A new rating scale for dementia syndromes. Arch Gerontol Geriatr 1982: 1: 311-330. 18. BRANEG, GOTTFR~ES CG. The GBS scale: a new rating scale for dementia syndromes. Nord Psykiatr Tidsskr 1986: 40: 125-134. 19. LAUTERH. What do we know about Alzheimer’s disease today? Dan Med Bull 1985: 32, suppl. 1: 1-21. JL. Drug treatments of dementia. Br J Psychia20. WHALLEY try 1989: 155: 595-611.
In patients with multi-infarct dementia (MID) and senile dementia of the Alzheimer type (SDAT) several neurotransmitter systems are impaired, including the serotonergic system (1-3). It has been suggested that deficits in the serotonergic system could be related to the decline in cognitive functioning and behavioral changes seen in dementia (4-6). In line with this assumption, one strategy in the search for effective treatments of dementia disorders has been to restore serotonergic functions by giving selective serotonin reuptake inhibitors (4, 5, 7-10). In an open study by us, 4 of 8 demented elderly people treated with the serotonin reuptake inhibitor fluvoxamine improved significantly measured on neuropsychological tests and the GBS rating scale (1 1). These findings prompted us to study in a double-blind, placebo-controlled design the efficacy of fluvoxamine on cognitive functioning and behavioral changes in elderly dementia patients. Material and methods Patients
The patient population consisted of inpatients at the Psychogeriatric Departments of Vordingborg Psy-
K. Olafsson’, S. J~rgensen’, H. V. Jensen’, A. Bille’, P. Arup’, J. Andersen
’
’ Psychogeriatric Department, Vordingsborg
Psychiatric Hospital, * Psychogeriatric Department, Frederiksberg Hospital, Denmark
Key words: dementia; multi-infarct dementia; dementia of Alzheimer type: fluvoxamine; serotonin K. Olafsson, M.D., Vordingborg Psychiatric Hospital, DK-4760 Vordingborg, Denmark Accepted for publication January 10, 1992
chiatric Hospital and Frederiksberg Hospital, Denmark. The patients had a DSM-I11 diagnosis of primary degenerative dementia or multi-infarct dementia ( 12) and were aged 1 6 5 years. Patients for whom psychiatric or medical consultation (including biochemical screening) suggested a cause of dementia other than MID and SDAT were excluded from the study. Further, patients with a history of manic-depressive disorder (including current depressive symptoms) or alcohol abuse were also excluded. The study protocol was registered by the local ethics committees and the National Board of Health, Denmark. Treatment
After a 2-week washout period, the patients were randomly allocated (in blocks of 4 patients) to 6 weeks of treatment with either fluvoxamine or placebo. Over the first 5 days of treatment, the dosage of fluvoxamine was increased gradually from 50 mg to 150 mg per day; tablets were given at bedtime. If sedation was necessary oxazepam was allowed.
453
Olafsson et al. Assessment
The patients were evaluated at baseline and after 6 weeks of treatment by applying neuropsychological tests, including picture recall and recognition, trailmaking and finger-tapping (13-16). The picture recognition test presents 8 pictures of common objects to the patients and the patient is asked to name each object (13). Immediately afterwards (immediate recall) and after an intermediate task (delayed recall), the patient is asked to verbally recall as many objects as possible. Subsequently, the 8 pictures are presented again interspersed with 16 other pictures of common objects (distractors) and the patient is asked to indicate the drawing seen previously (delayed recognition). The number of correct answers determine the score. The Trail-making Test is a test of visual conception and visuomotor tracking (14, 15). In the Trialmaking Test the patient is asked to draw lines to connect consecutively numbered circles as quickly as possible without lifting the pencil from the paper. To avoid floor effects maximally 30 s is allowed to complete each of the 2 forms used in this test, after the procedure is explained and the patient trained on the task. The mean number of correct connections from both forms determine the score. The finger-tapping speed has been found to be a good measure of organic pathology among geriatric patients (16). The number of times the patient can depress a handle counter key in 15 s with both the dominant and the nondominant index finger (2 trials with each hand) serves as a measure of simple motor speed. The neuropsychological tests were carried out by a psychologist. Further, degrees of dementia and clinical profiles were assessed on the GBS rating scale (17, 18). The GBS rating scale is a quantitative rating scale for dementia syndromes; it is divided into 4 subscales measuring motor, intellectual and emotional functioning and symptoms common in dementia. The GBS ratings took place at conferences, where the psychiatrist interviewed the nurses of the ward.
were used for paired comparison within one group (Wilcoxon-Pratt test), for unpaired comparison between 2 groups (Mann-Withney test) and for correlation analysis (Spearman test). Results Patients
Forty-six patients entered the study; 22 patients (8 men and 14 women; median age: 81 years, range: 65-93) were allocated to treatment with fluvoxamine and 24 (1 1 men and 13 women; median age; 80 years, range: 70-89) received placebo tablets. Fourteen and 15 patients, respectively, completed 6 weeks of treatment with fluvoxamine or placebo. Seven patients dropped out of the study during fluvoxamine treatment because of: administrative reasons, 3 ; somatic disease, 2; nausea, 1; and aggressiveness, 1. During placebo treatment 9 patients dropped out: somatic disease, 4; paranoia, 2; depressive symptoms, 1; aggressiveness, 1; and administrative reasons, 1. For patients completing 6 weeks of treatment, 8 patients in the fluvoxamine group and 10 in the placebo group were given oxazepam in addition to fluvoxamine or placebo. Efficacy
The median scores on neuropsychological tests and the GBS rating scale at baseline and after 6 weeks of treatments are shown in Tables 1 and 2. Within treatments, there were no statistically significant changes in median scores on neuropsychological tests (picture recall and recognition, trailmaking and finger-tapping) or the GBS rating scale scores (degrees of dementia) or GBS subscale scores (clinical profiles, including symptoms common in
Table 1. The neuropsychological test scores (median values, ranges in parentheses) during 6 weeks of treatment with fluvoxamine or placebo ~~uvoxarnine (n= 14) Baseline
6 weeks
Baseline
6 weeks
Picture recall Immediate recall Delayed recall
0.4 10-4) 0.2 (0-3)
0.6 (0-4) 0.4 (0-4)
0.2 10-51 0.1 10-2)
0.2 10-41 0.1 10-4)
Picture recognition Correct recognition Concept distractors Other distractors
3.7 11-8) 0.8 10-4) 1.3 (0-61
4.8 10-8) 1.O (0-8) 1.o (0-81
2.5 (0-8) 1.5 (0-7) 2.2 (0-8)
4.8 10-8) 2.5 10-71 3.0(0-6)
Trail-making Test
8.3 10-15)
5.0 10-17)
2.8 (0-16)
0.8 10-8)
Finger-tapping Dominant index finger Nondominant index finger
20 10-60) 20 10-50)
14 10-64) 16 (0-54)
31 112-59) 25 10-481
30 15-67) 31 10-51)
Statistical analysis
The median scores and the median changes in scores on the neuropsychological tests and the GBS scale were compared within treatments and between treatments, respectively. To test whether efficacy of treatment was related to degrees of dementia, correlation analysis between the total GBS scores at baseline and the relative change in total GBS scores (i.e. (total GBS score at baseline - total GBS score after 42 days)/total GBS score at baseline) were carried out. Nonparametric methods of statistical analysis
454
Placebo (n= 15)
Fluvoxamine in the treatment of demented elderly Table 2. The scores on the GBS rating scale and subscales (median values, ranges in parentheses) before and after 6 weeks of treatment with fluvoxamine or placebo Fluvoxamine in= 14) Baseline
6 weeks
Placebo (n= 15) Baseline
6 weeks
Total score 78 113-132) 68 (19-120) 63 (22-104) 68 (17-102) Symptoms common in dementia 12(1-23) 8(1-24) lO(2-15) lO(2-16) 16 11-34] 14 10-29) 10 (0-22) Motor functioning 7 (0-21) Intellectual functioning 43 (3-62) 38 (10-62) 40 (15-62) 42 112-60) Emotional functioning 8 (0-15) 4 (1-14) 6 (0-14) 6 (0-17)
dementia, motor, emotional and intellectual functioning) (Wilcoxon-Pratt test). Between treatments, the median changes in psychometric test scores did not differ significantly (Mann-Whitney test). However, within and between treatments, there were trends favoring fluvoxamine on symptoms common in dementia (confusion, irritability, fearpanic, mood level and restlessness) ( P = 0.08 and P = 0.07, respectively). There was no significant correlation between the total GB S scores at baseline and the relative changes in total GBS scores (i.e. (total GBS score at baseline - total GBS score after 42 days)/total GBS score at baseline) in the fluvoxamine group (Spearman test). Discussion
Our data do not support the hypothesis that fluvoxamine improves cognitive functioning or behavioral changes in elderly dementia patients. These findings are in accordance with the results by Nyth et al. (lo), who, in a double-blind, placebo-controlled study, found that citalopram, another selective serotonin reuptake inhibitor, did not improve motor performance or intellectual capacities in patients with primary degenerative dementia or MID. However, in the study by Nyth et al. (lo), in patients with primary degenerative dementia, citalopram produced significant improvements on emotional disturbances, confusion, irritability, restlessness and fear-panic, and the mood level was raised (within treatment), whereas citalopram was superior to placebo only on irritability and depressed mood (between treatments); there was no effect in patients with MID. In our study, a trend in favor of fluvoxamine on the GBS subscale including these symptoms could be shown (symptoms common in dementia) (within and between treatments). However, the size of our patient sample did not justify separate statistical analysis for patients with primary degenerative dementia and MID, which could mask possible differences in treatment outcome between these diagnostic groups. On
the other hand, however, the diagnostic validity of differentiating between primary degenerative dementia and MID on clinical grounds is probably relatively low (19), and, further, the serotonergic changes found in postmortem brains from patients with primary degenerative dementia and MID have shown common characteristics ( 3 ) , which should tend to reduce differences in treatment outcome between these groups. Other differences between the studies by Nyth et al. (10) and ours could also cause variance in treatment results on emotional disturbances. Thus, in our study, patients with a history a manic-depressive disorder or current depressive symptoms were excluded, whereas the study by Nyth et al. (10) included such patients; depressive symptoms were considered to be part of the dementia syndrome. Further, different methods of statistical analysis were applied (parametric vs nonparametric methods). Thus, the only 2 controlled studies carried out until now indicate that treatment of dementia disorders with selective serotonin reuptake inhibitors is no better than placebo on cognitive functioning or motor performance, but it may possibly reduce some emotional disturbances in patients with primary degenerative dementia. In our study, a considerable number of patients were too demented to score at all on several neuropsychological tests, such as the picture recall and recognition tests, leading to constantly low median scores, which therefore reduce the validity of these test results. The neuropsychological tests were chosen on the basis of a pilot study (1 1) but, retrospectively, it appears that the present study compared with the pilot study included patients with a much broader range of dementia degrees, and, especially, a majority of patients with severe dementia. It has been suggested that drug treatment of the intellectual reduction in dementia disorders is more likely to be effective in patients with only a mild degree of dementia, in whom it is thought that neurons have survived in sufficient numbers to respond to treatment (20). In our study no correlation between total GBS scores at baseline and relative change in total GBS scores during treatment could be shown, suggesting that degree of dementia does not effect responsiveness to treatment with selective serotonin reuptake inhibitors. Finally, during fluvoxamine treatment only one patient withdrew because of side effects (nausea), suggesting that a daily dose of 150 mg of fluvoxamine is well tolerated in elderly dementia patients. In conclusion, the study does not support the hypothesis that fluvoxamine improves cognitive functioning or behavioral changes in demented elderly people.
455
Olafsson et al. References 1. GOTTFRIES CG, ADOLFSSON R, AQUILONIUS SM et al. Biochemical changes in dementia disorders of the Alzheimer type (AD/SDAT). Neurobiol Aging 1983: 4: 261-271. 2. WALLIN A, ALAFUZOFF I, CARLSON A et al. Neurotransmitter deficit in a non-multi-infarct category of vascular dementia. Acta Neurol Scand 1989: 79: 397-406. 3. GOTTFRIES CG. Disturbance of the 5-hydroxytryptamine metabolism in brains from patients with Alzheimer’s dementia. J Neural Transm 1990: suppl 30: 33-43. 4. ALTMANHJ, NORMILE HJ. Serotonin, learning and memory: Implications for the treatment of dementia. In CROOK T, BARTON R, FERRIS S, GERSHON S, ed. Treatment development strategies in Alzheimer’s disease. Madison, CT: Mark Powley Associates, 1986: 361-383. HJ, NORMILE HJ. What is the nature of the role 5. ALTMAN of the serotonergic nervous system in learning and memory: prospects for development of an effective treatment strategy for senile dementia. Neurobiol Aging 1988: 9: 627-639. 6. BERCMAN I, BRANEG, GOTTFRIES CG et al. Alaproclate: a pharmacokinetic and biochemical study in patients with dementia of Alzheimer type. Psychopharmacology 1983: 80: 279-283. 7. STRATMANN GC. Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol 1988: 23: 616-620. 8. HARENKO A, ELCEN K. On a clinical phase I1 study of citalopram in elderly depressed patients. Copenhagen: H. Lundbeck A/S, 1984 (H. Lundbeck A/S Report 1984: 19: 83 1). 9. NYTHAL, BALLDINJ, ELGENK etal. Behandling med Citalopram vid demens. Normalisering av DST. Nord Psykiatr Tidsskr 1987: 42: 423-430.
456
10. NYTHAL, GOTTFRIES CG. The clinical efficacy of citalopram in the treatment of emotional disturbances in dementia disorders. A Nordic multi-center study. Br J Psychiatry 1990: 157: 894-901. 11. OLAFSSON K, BILLE A, PALSBY A et al. Serotonin reuptakeinhibitor in the treatment of dementia. Nord Psykiatr Tidsskr 1988: 42: 533-535. 12. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd edn. Washington, DC: APA, 1980. 13. SNODGRASS JG, VANDERWARD JG. Human learning and memory. J Exp Psychol 1980: 6: 174-215. 14. ARMITAGE SU. An analysis of certain psychological tests used for evaluation of brain injury. Psychol Monogr 1946: 60: 277. 15. REITANRM. Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 1958: 8: 271-276. 16. LEHMAN HT, BANTA. Psychometric tests in evaluation of brain pathology response to drugs. Geriatrics 1970: 25: 142147. 17. GOTTFRIES CG, BRANEG, GULLBERC B et al. A new rating scale for dementia syndromes. Arch Gerontol Geriatr 1982: 1: 311-330. 18. BRANEG, GOTTFR~ES CG. The GBS scale: a new rating scale for dementia syndromes. Nord Psykiatr Tidsskr 1986: 40: 125-134. 19. LAUTERH. What do we know about Alzheimer’s disease today? Dan Med Bull 1985: 32, suppl. 1: 1-21. JL. Drug treatments of dementia. Br J Psychia20. WHALLEY try 1989: 155: 595-611.
