Selegiline hydrochloride and cognition Lees AJ. Selegiline hydrochloride and cognition. Acta Neurol Scand 1991. 84: Suppl 136: 91-94.
A. J. Lees
Selegiline HCI, 10 mg per day has been reported to improve attention and cpisodic memory in Parkinson’s disease and early Alzheimer’s disease. Selegiline also improves motor reaction times in Parkinson’s and subjective feelings of increased vitality, euphoria and energy. At doses of between 10 and 40 mg a day it has also been shown to improve depression particularly when psychomotor retardation is prominent and anxiety minimal.
Key words: cognition; selegiline; bradyphrenia; Alzheimer‘s disease; Parkinson’s disease; depression
Introduction Selegiline hydrochloride, a type-B monoamine oxidase (MAO-B) inhibitor, which is catabolised to (-)methamphetamine and (-)amphetamine, was originally introduced into clinical practice as an antidepressant and found t o have psychic energising properties (1). In 1977, as a prelude to therapeutic trials of the drug in Parkinson’s disease, I took 10 mg a day of selegiline for a week and was struck by its beneficial effects on alertness and mental energy. However, we were subsequently unable to demonstrate any significant antidepressant effects in a group of patients with Parkinson’s disease at a dose of 10 mg a day, although individual patients commented on increased feelings of wellbeing and vigour (2). Nevertheless, use of selegiline over the last fifteen years in tile management of Parkinson’s disease has further convinced me that in a significant number of patients selegiline can improve speed of reaction and produces a nonspecific awakening effect (3). Eisler and colleagues (4)have claimed that the beneficial anti-parkinsonian effects of selegiline are in fact all due to a non-selective antidepressant action. While this may certainly be one useful therapeutic contribution, my own opinion would be that this is not the most important effect. The beneficial effects on the wearing-off phenomenon in L-dopa treated patients are not due to the amphetamine catabolites (5). Selegiline clearly inhibits MAO-B, which is important since most of the dopamine in human brain is metabolised by MAO-B and not by MAO-A as in e.g. rat brain (6). Furthermore, selegiline has been shown to inhibit the reuptake of dopamine and noradrenaline in the presynaptic nerve (6). Due to the inhibition of MAO-B the concentrations of phenylethylamine (PEA) increase. PEA has been shown to have direct, postsynaptic dopamine receptor stimulating action (7). It has been also shown that PEA releases catecholamines in the same way as
Department of Neurology, The Middlesex Hospital, London, UK
A. J. ILees, Department of Neurology, The Middlesex Hospital, Mortimer Street, London, W1N 8AA, UK
amphetamines (8). When selegiline is given in high doses also MAO-A is inhibited to a significant degree (9), which may well account for the antidepressant efficacy of selegiline. Selegiline and bradyphrenia Bradyphrenia is a cognitive ’non-motor’ slowing of central information processing time which may be an integral component of both Parkinson’s disease and severe depressive illness (10). Its pathophysiology is poorly understood but difficulties in initiating cognitive sets and progressing smoothly from one to the next are probably important components. Effortful tasks and those which maximise the amount of selfdirected task planning are particularly affected. Deficits of effortful memory and attention have also been described as contributing to the cognitive impairment in Parkinson’s disease. As already mentioned, many previously untreated patients on starting selegiline as monotherapy comment on increased energy and improved alertness. Some of the beneficial effects of selegiline reported in the DATATOP study might be due to these types of effect, which are extremely difficult to pick up with rating scales. Portin and Rinne (11) demonstrated selective improvement in memory, motor speed and naming ability in three non-demented patients with Parkinson’s disease treated with selegiline 10 mg a day for three weeks. They also commented on increased arousal, paradoxical periods of tiredness and deterioration in vigilance and set-shifting abilities. In four patients with a progressive parkinsonian dementia no benefits from selegiline were detected. In order to investigate the neuropsychological phenomenon of bradyphrenia it is necessary to try to tease out the motor and cognitive coniponents of a
91
Lees response t o a given task. We were interested to see if selegiline might improve bradyphrenia in Parkinson's disease and studied five previously untreated, mildly disabled patients in a double-blind trial. The patients had a mean duration of disease of 2 years, and were given either selegiline 10 mg per day or indistinguishable placebo for 7 days prior to testing on computerised tasks to assess cognitive processing time. A two-week washout period occurred between each trial. Valuation of cognitive processing consisted of four increasingly complex reaction time tasks which ranged from a one-choice motor response to a three-choice one. The first test measured a simple response reaction time, requiring a one-choice motor response with a joy stick. Patients were asked to respond as quickly as possible to the stimulus appearing on the screen. The second test was a two-choice reaction time measure, in which the screen was divided into two and the response was determined by the position of the stimulus, either to the right or to the left. A second part required the response to be opposite to the position of the stimulus. the third task was the same as the second except that patients had to recognise the stimulus as either the letter 'L' or the letter 'R'. Test 4 was a threechoice reaction time measure, requiring similar responses if 'L' or 'R' appeared on the appropriate side of the screen, but in addition a third response when they appeared on the opposite side of the screen. Patients were asked to fix their vision on the dot in the centre of the screen throughout the tasks. Simple reaction time was assumed to reflect time taken for the motor component of the response. This value was subtracted from the reaction times of more complex tasks in order to obtain a measure of cognitive processing time. Patients were also asked to complete the Hamilton Depression Rating Scale during both treatment arms. No significant differences in cognitive processing speed were seen, but a clear improvement in simple reaction time occurred with selegiline (12). We are now extending these observations by assessing cognitive event related potentials and motor reaction time before and again after 1-2 months of selegiline in de novo patients (Pirtosek, Barrett & Lees, unpublished). Selective visual auditory attention tasks and a 3-stimulus odd-ball paradigm are being used. The results are at present preliminary, but already show clearly that selegiline improves motor reaction time. At the present time it can be concluded that selegiline unequivocally improves motor reaction times, but whether it has additional effects on cognitive processing will require further evaluation. It is interesting, however, that preliminary results from the large multicenter trial, DATATOP (13) show that selegiline significantly improved some memory functions after 12 month treatment as compared to those not receiving selegiline (14).
92
Selegiline and depression Early clinical trials in Hungary showed selegiline to be an effective antidepressant. Tringer and colleagues (15) 69 treated thirty middle-aged patients with endogenous depression for a fortnight with 20 mg per day of selegiline. Twenty-one were substantially improved as judged by scores on the Hamilton Rating Scale. in a controlled study, Mendlewicz & Youdim (I 6) confirmed beneficial antidepressant effects in twenty-seven in-patients; in another study on patients with moderately severe depression eight of ten patients who received up to 15 mg of selegiline a day over three weeks improved and benefits began to occur within the first two to three days of starting therapy. In this study one patient became more depressed and another severely anxious. Initial insomnia, increased libido and anorexia were relatively common secondary effects (17). Mendis and colleagues (18), however, were unable to demonstrate benefit in twenty-two mildly or moderately depressed patients with a mean age of forty-two years. In a group of seventeen atypical depressives known to respond to the monoamine oxidase inhibitor phenelzine, improvement was seen in 59 070 of patients at doses above 20 mg a day, with a tendency for those with low baseline anxiety levels to do better. The reported adverse reactions included a dry mouth and insomnia (19). Mann et al. (20) carried out a doubleblind parallel trial; the dose of selegiline was increased during the 6 week trial according to clinical response but not over 50 mg daily. The patients were instructed in a low-tyramine diet. Depression as judged ..vith Hamilton Depression Rating Scale was significantly more improved in the selegiline group than in the placebo group. A significantly greater reduction of the depression scores was detected with higher ( 2 30 mg) than with lower (I 30 mg) doses of selegiline. There were more insomnia, dryness of mouth, blurred vision and drowsiness in the selegiline group and more hyperactivity and headache in the placebo group, but the differences were not statistically significant. Forty primary depressives known to respond to phenelzine, who had been receiving the drug for six months, were studied at University College Hospital, London (Stern, Prasad & Lees, unpublished). Phenelzine was withdrawn for three weeks and the patients were then randomised to one of three trial arms: selegiline 30-60 mg per day, phenelzine 30 mg per day or tranylcypromine 20 mg a day. The usual dietary restrictions for monoamine oxidase inhibitors were applied throughout the study and evaluation was carried out using the Hamilton Anxiety Scale and the Montgomery-Asberg Depression Scale. Selegiline seems to be the most effective antidepressant but the least effective anxiolytic, with phenelzine having the opposite
Selegiline and cognition profile and tranylcypromine lying somewhere in between the other two. These studies raised the possibility that at doses of 20 mg a day selegiline may possess useful antidepressant properties, particularly when psychomotor retardation is a major symptom. It is much less likely to be helpful in the presence of severe anxiety or melancholia.
Selegiline and Alzheimer’s disease Brain monoamine oxidase B activity increases with age (21) and patients with Alzheimer-type dementia have even higher brain and platelet MAO-B levels when compared with age-matched controls (22,23). In addition, a number of patients with Alzheimer’s disease are significantly depressed and have mild signs of Parkinson’s syndrome; in the absence of any really effective therapy, trial of selegiline would thus seem worthwhile. A few trials have already been carried out investigating the effect of different doses of selegiline on early Alzheimer’s disease. In a double-blind serial treatment design study, Tariot and colleagues (24) treated seven patients who fulfilled the DSMIII criteria for dementia and the NINICDS-ADRDA (25) criteria for probable Alzheimer’s disease and who did not have major depressive disorder. The patients had a mean age of 59 years, a mean duration of symptoms of 4 years, a Global deterioration score of 4.3 (3-5) and a mean Hamilton depression score of 10 (1-16). On a wide range of neuropsychological tests statistically significant improvement occurred in episodic memory and the complex learning task with 10 mg a day of selegiline, but not with 40 mg a day, the higher dose leading to orthostatic hypotension in two patients. There was also a generally increased social interaction and activity and decreased depression and anxiety during selegiline therapy. Confirmation of these findings has recently come from two further studies. Twenty patients fulfilling research criteria for Alzheimer’s disease, with a mean duration of symptoms of 2.5 years, a mean Mini-Mental Score of 20.9 (15-25) and a mean Hamilton depression score of 5.4 (0-11), were treated in a double-blind crossover study with 10 mg of selegiline. Statistically significant improvement in memory and attention after three months of selegiline treatment were reported, which the authors considered could not be explained by concomitant antidepressant effects (26). Using an identical protocol, Agnoli and colleagues (27) also treated 20 patients with a mean Global deterioration score of 3.6, a mean Mini-Mental score of 20, a mean Hamilton depression score of 24.4 and a mean duration of symptoms of 28 months. Significant improvement in attention and memory measures was again
found in the selegiline treated patients, with beneficial effects appearing within the first 30 days of therapy. Furthermore, a recent report by Mangoni (28) showed that selegiline significantly improved the activities of daily living, dementia symptoms and many cognitive functions including memory, attention and visuospatial ability. If these results can be confirmed with further controlled studies, and long-term benefit demonstrated, selegiline might prove to have a role in early mild Alzheimer’s disease and in benign senescent forgetfulness.
References 1. VARCAE, TRINGER L. Clinical trial of a new type of promptly acting psycho-energetic agent (L-phenylisopropyl- methyl-propinylamine HCI E280). Acta Med Acad Sci Hung 1967:23:289-295. 2. LEESAJ, SHAWKM, KOHOUT LJ et al. Deprenyl in Parkinson’s disease. Lancet 1977:ii:227-239. 3. LEES AJ, FRANKEL JP, EATOUGHVM, STERNGM. New approaches in the use of selegiline for the treatment of Parkinson’s disease. Acta Neurol Scand 1989:126:139-145. H, NELSONR et al. Deprenyl in Parkin4. EISLERT, TERAVAINEN son’s disease. Neurology 1981:31:19-23. 5 . REYNOLDS M, LEESAJ, GP, ELSWORTH JD, BLAUK, SANDLER STERNGM. Deprenyl is metabolised to methamphetamine and amphetamine in man. Br J Clin Pharmacol 1978:6:542-544. 6. KNOLLJ. The possible mechanism of action of (-)deprenyl in Parkinson’s disease. J Neural Transm 1978:43:3-4:177-198, SM, EDWARDS DJ, LIN M. Phenylethylamine: evi7. ANTELMAN dence for a direct, postsynaptic dopamine-receptor stimulating action. Brain Res 1977:127:317-322. 8. FUXE K , GROBECKERH, JONSSONJ. Effect of betaphenylethylamine on central and peripheral monoamine-containing neurons. Eur J Pharmacol 1967:2:203-207. 9. SUNDERLAND T, MULLER EA, COHENRM, JIMERSON DC, PICKAR D, MURHYDL. Tyramine pressor sensitivity changes during deprenyl treatment. Psychopharmacology 1985:86:432-437. 10. ROGERSD, LEES AJ, SMITHE, TRIMBLEMR, STERNGM. Bradyphrenia in Parkinson’s disease and psychomotor retardation in depressive illness: an experimental study. Brain 1987:110:761-776. 11. PORTIN R, RINNEUK. The effect of deprenyl (selegiline) on cognition and emotion in Parkinsonian patients undergoing long-term levodopa treatment. Acta Neurol Scand 1983: (Suppl) 95:135-144. J P et al. Effect of L12. EATOUGH VM, KEMPSTER PA, FRANKEL deprenyl on Parkinsonian bradyphrenia. In: Parkinson’s disease: Anatomy, pathology & therapy. Eds. Streifler MB, Korczyn AD, Melamed E, Youdim MBH. Adv Neurol 199053. New York: Raven Press, 1990:441-443. 13. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. New Engl J Med 1989:321:1364-1371. 14. The Parkinson Study Group. Effect of Neuropsychological Function in early Parkinson’s disease. The 4th Annual Symposium on Etiology, Pathogenesis and Prvention of Parkinson’s Disease and Symposium o n Hyperkinetic Movement Disorders. Atlanta, Georgia, 1990.
93
Lees 15. TRINGER L, HAITSG, VARGAE. The effect of L-E-280 (L phenylisopropyl-methyl-propinylamine) in depression. SOC Pharmacol Hungarica 1971:lll-113. J, YOUDIM MBH. Ldeprenyl, a selective monoa16. MENDLEWICZ mine oxidase Type B inhibitor in the treatment of depression. A double-blind evaluation. Br J Psychiatr 1983:142:508-511. S. L-deprenyl, a selective monoamine oxi17. MANNJ, GERSHON dase Type B inhibitor in endogenous depression. Life Sci 198026:877-882. 18. MENDIS M, PARECMP, SANDLER M, GLOVER V, STERNGM. Is the failure of (-)deprenyl, a selective monoamine oxidase B inhibitor, to alleviate depression related to its freedom from the ’cheese effect’? Psychopharmacology (Berlin) 1981:73:87-96. 19. QUITKIN F, LIEBOWITZ MR, STEWART JW et al. L-deprenyl in atypical depressives. Arch Gen Psychiatr 1984:41:777-781. SF, WILNER PJ et al. A controlled studyof 20. MANNJJ, AARONS the antidepressant efficacy and side effects of (-bdeprenyl. Arch Gen Psychiatry 1989:46:45-50. DS, DAVISJM, NIESA et al. Ageing, monoamines, 21. ROBINSON and monoamine oxidase levels. Lancet (1972):i:290-291.
94
22. ADOLFSSON R, GOTTFRIESCG, ORELAND L, WIBERC A, WINBLAND B. Increased activity of brain platelet monoamine oxidase in dementia of Alzheimer type. Life Sci 1980:27:1029-1034. GS, LIEBERMAN KW, YOUNGRC. Platelet MA0 23. ALEXOPOULOS activity in primary degenerative dementia. A J Psychiatr 1984:141:97-99. H et al. Cognitive 24. TARIOTPN, SUNDERLAND T, WEINGARTNER effects of L-deprenyl in Alzheimer’s disease. Psychopharmacology 1987:91:489-495. G , PICCIRILLI M. Neuropsychological ef26. PICCININ GL, FINALI fects of L-deprenyl in Alzheimer’s type dementia. Clin Neuropharma;ology 199013:147-163. 27. AGNOLI A, MARTUCCI N, FABBRINI G, BUCKLEY AE, FIORAVANTI M. Monoamine oxidase and dementia: treatment with an inhibitor of MAO-B activity. Dementia 1990:1:109-114. A, GRASSI MP, FRATTOLA L et al. Effects of a MAO28. MANCONI B inhibitor in the treatment of Alzheimer disease. Eur Neurol 1991:31:100-107.
A. J. Lees
Selegiline HCI, 10 mg per day has been reported to improve attention and cpisodic memory in Parkinson’s disease and early Alzheimer’s disease. Selegiline also improves motor reaction times in Parkinson’s and subjective feelings of increased vitality, euphoria and energy. At doses of between 10 and 40 mg a day it has also been shown to improve depression particularly when psychomotor retardation is prominent and anxiety minimal.
Key words: cognition; selegiline; bradyphrenia; Alzheimer‘s disease; Parkinson’s disease; depression
Introduction Selegiline hydrochloride, a type-B monoamine oxidase (MAO-B) inhibitor, which is catabolised to (-)methamphetamine and (-)amphetamine, was originally introduced into clinical practice as an antidepressant and found t o have psychic energising properties (1). In 1977, as a prelude to therapeutic trials of the drug in Parkinson’s disease, I took 10 mg a day of selegiline for a week and was struck by its beneficial effects on alertness and mental energy. However, we were subsequently unable to demonstrate any significant antidepressant effects in a group of patients with Parkinson’s disease at a dose of 10 mg a day, although individual patients commented on increased feelings of wellbeing and vigour (2). Nevertheless, use of selegiline over the last fifteen years in tile management of Parkinson’s disease has further convinced me that in a significant number of patients selegiline can improve speed of reaction and produces a nonspecific awakening effect (3). Eisler and colleagues (4)have claimed that the beneficial anti-parkinsonian effects of selegiline are in fact all due to a non-selective antidepressant action. While this may certainly be one useful therapeutic contribution, my own opinion would be that this is not the most important effect. The beneficial effects on the wearing-off phenomenon in L-dopa treated patients are not due to the amphetamine catabolites (5). Selegiline clearly inhibits MAO-B, which is important since most of the dopamine in human brain is metabolised by MAO-B and not by MAO-A as in e.g. rat brain (6). Furthermore, selegiline has been shown to inhibit the reuptake of dopamine and noradrenaline in the presynaptic nerve (6). Due to the inhibition of MAO-B the concentrations of phenylethylamine (PEA) increase. PEA has been shown to have direct, postsynaptic dopamine receptor stimulating action (7). It has been also shown that PEA releases catecholamines in the same way as
Department of Neurology, The Middlesex Hospital, London, UK
A. J. ILees, Department of Neurology, The Middlesex Hospital, Mortimer Street, London, W1N 8AA, UK
amphetamines (8). When selegiline is given in high doses also MAO-A is inhibited to a significant degree (9), which may well account for the antidepressant efficacy of selegiline. Selegiline and bradyphrenia Bradyphrenia is a cognitive ’non-motor’ slowing of central information processing time which may be an integral component of both Parkinson’s disease and severe depressive illness (10). Its pathophysiology is poorly understood but difficulties in initiating cognitive sets and progressing smoothly from one to the next are probably important components. Effortful tasks and those which maximise the amount of selfdirected task planning are particularly affected. Deficits of effortful memory and attention have also been described as contributing to the cognitive impairment in Parkinson’s disease. As already mentioned, many previously untreated patients on starting selegiline as monotherapy comment on increased energy and improved alertness. Some of the beneficial effects of selegiline reported in the DATATOP study might be due to these types of effect, which are extremely difficult to pick up with rating scales. Portin and Rinne (11) demonstrated selective improvement in memory, motor speed and naming ability in three non-demented patients with Parkinson’s disease treated with selegiline 10 mg a day for three weeks. They also commented on increased arousal, paradoxical periods of tiredness and deterioration in vigilance and set-shifting abilities. In four patients with a progressive parkinsonian dementia no benefits from selegiline were detected. In order to investigate the neuropsychological phenomenon of bradyphrenia it is necessary to try to tease out the motor and cognitive coniponents of a
91
Lees response t o a given task. We were interested to see if selegiline might improve bradyphrenia in Parkinson's disease and studied five previously untreated, mildly disabled patients in a double-blind trial. The patients had a mean duration of disease of 2 years, and were given either selegiline 10 mg per day or indistinguishable placebo for 7 days prior to testing on computerised tasks to assess cognitive processing time. A two-week washout period occurred between each trial. Valuation of cognitive processing consisted of four increasingly complex reaction time tasks which ranged from a one-choice motor response to a three-choice one. The first test measured a simple response reaction time, requiring a one-choice motor response with a joy stick. Patients were asked to respond as quickly as possible to the stimulus appearing on the screen. The second test was a two-choice reaction time measure, in which the screen was divided into two and the response was determined by the position of the stimulus, either to the right or to the left. A second part required the response to be opposite to the position of the stimulus. the third task was the same as the second except that patients had to recognise the stimulus as either the letter 'L' or the letter 'R'. Test 4 was a threechoice reaction time measure, requiring similar responses if 'L' or 'R' appeared on the appropriate side of the screen, but in addition a third response when they appeared on the opposite side of the screen. Patients were asked to fix their vision on the dot in the centre of the screen throughout the tasks. Simple reaction time was assumed to reflect time taken for the motor component of the response. This value was subtracted from the reaction times of more complex tasks in order to obtain a measure of cognitive processing time. Patients were also asked to complete the Hamilton Depression Rating Scale during both treatment arms. No significant differences in cognitive processing speed were seen, but a clear improvement in simple reaction time occurred with selegiline (12). We are now extending these observations by assessing cognitive event related potentials and motor reaction time before and again after 1-2 months of selegiline in de novo patients (Pirtosek, Barrett & Lees, unpublished). Selective visual auditory attention tasks and a 3-stimulus odd-ball paradigm are being used. The results are at present preliminary, but already show clearly that selegiline improves motor reaction time. At the present time it can be concluded that selegiline unequivocally improves motor reaction times, but whether it has additional effects on cognitive processing will require further evaluation. It is interesting, however, that preliminary results from the large multicenter trial, DATATOP (13) show that selegiline significantly improved some memory functions after 12 month treatment as compared to those not receiving selegiline (14).
92
Selegiline and depression Early clinical trials in Hungary showed selegiline to be an effective antidepressant. Tringer and colleagues (15) 69 treated thirty middle-aged patients with endogenous depression for a fortnight with 20 mg per day of selegiline. Twenty-one were substantially improved as judged by scores on the Hamilton Rating Scale. in a controlled study, Mendlewicz & Youdim (I 6) confirmed beneficial antidepressant effects in twenty-seven in-patients; in another study on patients with moderately severe depression eight of ten patients who received up to 15 mg of selegiline a day over three weeks improved and benefits began to occur within the first two to three days of starting therapy. In this study one patient became more depressed and another severely anxious. Initial insomnia, increased libido and anorexia were relatively common secondary effects (17). Mendis and colleagues (18), however, were unable to demonstrate benefit in twenty-two mildly or moderately depressed patients with a mean age of forty-two years. In a group of seventeen atypical depressives known to respond to the monoamine oxidase inhibitor phenelzine, improvement was seen in 59 070 of patients at doses above 20 mg a day, with a tendency for those with low baseline anxiety levels to do better. The reported adverse reactions included a dry mouth and insomnia (19). Mann et al. (20) carried out a doubleblind parallel trial; the dose of selegiline was increased during the 6 week trial according to clinical response but not over 50 mg daily. The patients were instructed in a low-tyramine diet. Depression as judged ..vith Hamilton Depression Rating Scale was significantly more improved in the selegiline group than in the placebo group. A significantly greater reduction of the depression scores was detected with higher ( 2 30 mg) than with lower (I 30 mg) doses of selegiline. There were more insomnia, dryness of mouth, blurred vision and drowsiness in the selegiline group and more hyperactivity and headache in the placebo group, but the differences were not statistically significant. Forty primary depressives known to respond to phenelzine, who had been receiving the drug for six months, were studied at University College Hospital, London (Stern, Prasad & Lees, unpublished). Phenelzine was withdrawn for three weeks and the patients were then randomised to one of three trial arms: selegiline 30-60 mg per day, phenelzine 30 mg per day or tranylcypromine 20 mg a day. The usual dietary restrictions for monoamine oxidase inhibitors were applied throughout the study and evaluation was carried out using the Hamilton Anxiety Scale and the Montgomery-Asberg Depression Scale. Selegiline seems to be the most effective antidepressant but the least effective anxiolytic, with phenelzine having the opposite
Selegiline and cognition profile and tranylcypromine lying somewhere in between the other two. These studies raised the possibility that at doses of 20 mg a day selegiline may possess useful antidepressant properties, particularly when psychomotor retardation is a major symptom. It is much less likely to be helpful in the presence of severe anxiety or melancholia.
Selegiline and Alzheimer’s disease Brain monoamine oxidase B activity increases with age (21) and patients with Alzheimer-type dementia have even higher brain and platelet MAO-B levels when compared with age-matched controls (22,23). In addition, a number of patients with Alzheimer’s disease are significantly depressed and have mild signs of Parkinson’s syndrome; in the absence of any really effective therapy, trial of selegiline would thus seem worthwhile. A few trials have already been carried out investigating the effect of different doses of selegiline on early Alzheimer’s disease. In a double-blind serial treatment design study, Tariot and colleagues (24) treated seven patients who fulfilled the DSMIII criteria for dementia and the NINICDS-ADRDA (25) criteria for probable Alzheimer’s disease and who did not have major depressive disorder. The patients had a mean age of 59 years, a mean duration of symptoms of 4 years, a Global deterioration score of 4.3 (3-5) and a mean Hamilton depression score of 10 (1-16). On a wide range of neuropsychological tests statistically significant improvement occurred in episodic memory and the complex learning task with 10 mg a day of selegiline, but not with 40 mg a day, the higher dose leading to orthostatic hypotension in two patients. There was also a generally increased social interaction and activity and decreased depression and anxiety during selegiline therapy. Confirmation of these findings has recently come from two further studies. Twenty patients fulfilling research criteria for Alzheimer’s disease, with a mean duration of symptoms of 2.5 years, a mean Mini-Mental Score of 20.9 (15-25) and a mean Hamilton depression score of 5.4 (0-11), were treated in a double-blind crossover study with 10 mg of selegiline. Statistically significant improvement in memory and attention after three months of selegiline treatment were reported, which the authors considered could not be explained by concomitant antidepressant effects (26). Using an identical protocol, Agnoli and colleagues (27) also treated 20 patients with a mean Global deterioration score of 3.6, a mean Mini-Mental score of 20, a mean Hamilton depression score of 24.4 and a mean duration of symptoms of 28 months. Significant improvement in attention and memory measures was again
found in the selegiline treated patients, with beneficial effects appearing within the first 30 days of therapy. Furthermore, a recent report by Mangoni (28) showed that selegiline significantly improved the activities of daily living, dementia symptoms and many cognitive functions including memory, attention and visuospatial ability. If these results can be confirmed with further controlled studies, and long-term benefit demonstrated, selegiline might prove to have a role in early mild Alzheimer’s disease and in benign senescent forgetfulness.
References 1. VARCAE, TRINGER L. Clinical trial of a new type of promptly acting psycho-energetic agent (L-phenylisopropyl- methyl-propinylamine HCI E280). Acta Med Acad Sci Hung 1967:23:289-295. 2. LEESAJ, SHAWKM, KOHOUT LJ et al. Deprenyl in Parkinson’s disease. Lancet 1977:ii:227-239. 3. LEES AJ, FRANKEL JP, EATOUGHVM, STERNGM. New approaches in the use of selegiline for the treatment of Parkinson’s disease. Acta Neurol Scand 1989:126:139-145. H, NELSONR et al. Deprenyl in Parkin4. EISLERT, TERAVAINEN son’s disease. Neurology 1981:31:19-23. 5 . REYNOLDS M, LEESAJ, GP, ELSWORTH JD, BLAUK, SANDLER STERNGM. Deprenyl is metabolised to methamphetamine and amphetamine in man. Br J Clin Pharmacol 1978:6:542-544. 6. KNOLLJ. The possible mechanism of action of (-)deprenyl in Parkinson’s disease. J Neural Transm 1978:43:3-4:177-198, SM, EDWARDS DJ, LIN M. Phenylethylamine: evi7. ANTELMAN dence for a direct, postsynaptic dopamine-receptor stimulating action. Brain Res 1977:127:317-322. 8. FUXE K , GROBECKERH, JONSSONJ. Effect of betaphenylethylamine on central and peripheral monoamine-containing neurons. Eur J Pharmacol 1967:2:203-207. 9. SUNDERLAND T, MULLER EA, COHENRM, JIMERSON DC, PICKAR D, MURHYDL. Tyramine pressor sensitivity changes during deprenyl treatment. Psychopharmacology 1985:86:432-437. 10. ROGERSD, LEES AJ, SMITHE, TRIMBLEMR, STERNGM. Bradyphrenia in Parkinson’s disease and psychomotor retardation in depressive illness: an experimental study. Brain 1987:110:761-776. 11. PORTIN R, RINNEUK. The effect of deprenyl (selegiline) on cognition and emotion in Parkinsonian patients undergoing long-term levodopa treatment. Acta Neurol Scand 1983: (Suppl) 95:135-144. J P et al. Effect of L12. EATOUGH VM, KEMPSTER PA, FRANKEL deprenyl on Parkinsonian bradyphrenia. In: Parkinson’s disease: Anatomy, pathology & therapy. Eds. Streifler MB, Korczyn AD, Melamed E, Youdim MBH. Adv Neurol 199053. New York: Raven Press, 1990:441-443. 13. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. New Engl J Med 1989:321:1364-1371. 14. The Parkinson Study Group. Effect of Neuropsychological Function in early Parkinson’s disease. The 4th Annual Symposium on Etiology, Pathogenesis and Prvention of Parkinson’s Disease and Symposium o n Hyperkinetic Movement Disorders. Atlanta, Georgia, 1990.
93
Lees 15. TRINGER L, HAITSG, VARGAE. The effect of L-E-280 (L phenylisopropyl-methyl-propinylamine) in depression. SOC Pharmacol Hungarica 1971:lll-113. J, YOUDIM MBH. Ldeprenyl, a selective monoa16. MENDLEWICZ mine oxidase Type B inhibitor in the treatment of depression. A double-blind evaluation. Br J Psychiatr 1983:142:508-511. S. L-deprenyl, a selective monoamine oxi17. MANNJ, GERSHON dase Type B inhibitor in endogenous depression. Life Sci 198026:877-882. 18. MENDIS M, PARECMP, SANDLER M, GLOVER V, STERNGM. Is the failure of (-)deprenyl, a selective monoamine oxidase B inhibitor, to alleviate depression related to its freedom from the ’cheese effect’? Psychopharmacology (Berlin) 1981:73:87-96. 19. QUITKIN F, LIEBOWITZ MR, STEWART JW et al. L-deprenyl in atypical depressives. Arch Gen Psychiatr 1984:41:777-781. SF, WILNER PJ et al. A controlled studyof 20. MANNJJ, AARONS the antidepressant efficacy and side effects of (-bdeprenyl. Arch Gen Psychiatry 1989:46:45-50. DS, DAVISJM, NIESA et al. Ageing, monoamines, 21. ROBINSON and monoamine oxidase levels. Lancet (1972):i:290-291.
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