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Antiparkinsonian and antidepressant effects of high doses of bromocriptine
Journal of Affective Disorders,
5 (1983) 141-145
141
Elsevier SciencePublishers
Antiparkinsonian and Antidepressant Effects of High Doses of Bromocriptine An Independent Comparison
R. Jouvent
1, p.
Abensour l, A.M. Bonnet 2, D. Widlocher l, y . Agid 2 and F. Lhermitte 2
I Service de Psychiatrie adultes (Pr. D. Widlocher) and 2 Clinique de Neurologie et de Neuropsychologie, H6pital de la SalpOtri~re, 47, Bd de l'H6pital, F-75013 Paris (France)
(Received 18 June, 1982) (Revised, received 11 August, 1982) (Accepted 7 September, 1982)
Summary Ten depressed parkinsonian patients were treated with high doses of bromocriptine (range 85-220 mg/day). Changes in the parkinsonian and depressive symptomatologies were independently evaluated by a neurologist and a psychiatrist. Rating took place before treatment after wash-out and again 8 days later. Results show a significant mean improvement of both depressive and parkinsonian symptomatologies. However, there was no correlation between the two therapeutic effects in the l0 patients. Clinical and biological implications of these heterogeneous patterns are discussed.
Introduction The dual character of parkinsonian symptomatology, i.e. motor disability and psychopathological disorders, particularly depression is echoed at the therapeutic level. Levodopa has been described as possessing antidepressant properties (Bunney et al. 1969) while imipramine (Sigwald et al. 1959) and ECT (Lebensohn and Jenkins 1975) have favourable effects on parkinsonian symptoms. Bromocriptine, a dopaminergic (DA) agonist, is a powerful antiparkinsonian agent (Calne et al. 1979) especially at high doses (Agid et al. 1979), and is also known to have antidepressant effects in depressed patients (Colonna et al. 1979). It 0165-0327/83/0000-0000/$03.00 © 1983 ElsevierSciencePublishers
142 seemed therefore interesting to study simultaneously in the same patients two properties which had previously been described separately; this might shed some light on the relationship between the two syndromes as well as between the two properties of the drug. Patients and Methods
Ten in-patients (5 men, 5 women) aged 32 to 75 (mean 55.5 + 13.5) were included in the study. They had had parkinsonian symptoms for 1-29 years (mean 8.6). All patients had previously been treated with ievodopa alone or in combination with a peripheral decarboxylase inhibitor. Levodopa was considered of limited value in these subjects because they had responded poorly or had had adverse reactions, mainly on-off phenomena. Bromocriptine was given after a wash-out period of 2 - 4 days without drugs, the doses being increased daily by 7.5-30 rag, depending on tolerance, to reach a final mean dose of 135 m g / d a y (range: 85 220 mg). Concomitant use of antidepressant or antiparkinsonian medication in addition to bromocriptine was not permitted. Allowed associated treatments were benzodiazepines (Lorazepam 1-2.5 mg) at night and domperidone, a peripheral DA blocking agent which does not cross the b l o o d - b r a i n barrier and thus permits a more efficient dosage of bromocriptine (Agid et al. 1979). Parkinsonian patients were selected on the existence of a marked depressive state meeting Feighner's criteria for depression (Feighner et al. 1972). Depression was rated with the 17-item Hamilton Rating Scale (H.R.S.) (Hamilton 1967). A score of 17 or over was required as a minimum. The parkinsonian disability was assessed with a 22-item rating scale of neurological function (Lhermitte et al. 1978). Scoring for each item was from 0 (normal) to 4 (maximal deficit); the scores were added to yield an overall score of parkinsonian severity. The H.R.S. and the parkinsonian scale were administered independently between 10 and 11 a.m., by the same psychiatrist (R. Jouvent) and neurologist (A.M. Bonnet) throughout the trial. All patients were rated before treatment began (day 0) and again at day 7-8, when neurological improvement seemed maximal in previous studies (Agid et al. 1979). Clinical assessment was maintained for up to 2 weeks in order to identify a possible relapse. Results
At day 0, i.e. after the wash-out period, patients had parkinsonian scores between 19 and 58 (mean 31.9) and depression scores between 17 and 34 (mean 24.1). At day 8, mean improvement in parkinsonian disability was 63%, the mean parkinsonian score being significantly improved from 31.9 to 11.7 ( P < 0.001) *; this improvement was shown in all patients with a range of 49% to 82%. Mean improvement of depression was 65%, the mean depression score being significantly improved from 24.1 to 8.4 ( P < 0.001) *. Individual patients improved in a range of * t statistic for paired observation.
143 Z~ H, R.S. 100%
. . . . . . . . . . . .
~'5
. . . . . .
~ . . . .
egelO
,8 *3
I
50%
I
.6
.7
i "4 l
t [ . . . . . . . . . . . .
t--
,2 . . . . . . . . .
L, 50%
1(X)%A Park.
Fig. 1. Compared improvements (%) of parkinsonism (A Park) and depression (A HRS).
10-100%. Two of them (No. 5, 10) presented a mood inversion (hypomania) with euphoria, moderate flight of thoughts, increased sexual interest. Neither of these two patients had had previous manic or hypomanic episodes. One patient had a partial depressive relapse on the 13th day without notable change in the neurological status and recovered with clomipramine. No other patient relapsed during the week following rating. There is a striking contrast between the relatively homogeneous response to the antiparkinsonian effect of bromocriptine and the heterogeneous response to the antidepressant effect of the drug (Fig. 1). There is no correlation between the two effects on the whole group of patients. Three patients (No. 2, 4, 7) improved more on parkinsonism than on depression. Four patients had comparable amelioration of both syndromes (No. 1, 3, 6, 8). Three patients improved much more on depression than on parkinsonism (No. 5, 9, 10).
Discussion
The antidepressant effect of bromocriptine described for doses of 15 20 m g / d a y in depressed patients (Colonna et al. 1979) was also observed in our parkinsonian patients treated with higher doses of the drug necessary to induce adequate improvement of parkinsonian disability. Two observations should be made: (1) This was only a short-term evaluation of the antidepressant action of bromocriptine and further studies are needed to document its persistence beyond two weeks. (2) The favourable results may be related at least in part to the nature of the population under study. All these patients had been admitted for their parkinsonian syndrome and not for their depression and none of them exhibited psychotic depression. The two mood swings observed with bromocriptine in our patients deserve some
144
attention. It would be tempting to consider them as evidence in favour of the dopaminergic hypothesis of mania (Silverstone 1979; Post et al. 1980). Yet these two m o o d inversions led to moderate hypomanic states of short duration in patients who could not be classified as having bipolar disorder. N o firm conclusion may therefore be drawn on this point. However, our results raise clinical and pharmacological questions. One concerns the relationship between the two syndromes. Previous findings have suggested that depression in parkinsonian patients is not purely reactive to the motor defect (Horn 1974; Robins 1976) and might be of both reactive and endogenous origins (Andersen et al. 1980). Moreover, the efficacy of bromocriptine, comparable to that of imipramine, in non-parkinsonian depressed patients is in favour of a specific antidepressant action of the drug (Waehrens and Gerlach 1981). The heterogeneous responses on depression observed in our patients is in line with these findings. From the pharmacological point of view, there is some evidence that the biochemical action of bromocriptine may go beyond pure dopaminergic stimulation specially when higher doses are administered (Dolphin et al. 1977). Nevertheless, the existence of a dopaminergic deficiency affecting the mesocorticolimbic as well as the mesostriatal systems has been established (Javoy-Agid and Agid 1980). This is consistent with the cases of patients who improved similarly on both syndromes and suggests a possible role of central dopaminergic deficiency in the incidence of depression in these patients. However, the fact that this does not concern all patients also suggests that depression in parkinsonism may involve various mechanisms.
References Agid, Y., Pollak, P., Bonnet, A.M., et al., Bromocriptine associated with a peripheral dopamine blocking agent in treatment of Parkinson's disease, Lancet, i (1979) 570 572. Andersen, J., Aabro, E. and Gulmann, N., Anti-depressive treatment in Parkinson's disease, Acta Neurol. Scand., 62 (1980) 210-219. Bunney, W.E., Janowsky, D.S., Goodwin, F.K., et al., Effect of L-Dopa on depression, Lancet, i (1969) 885. Calne, D.B., Plotkin, C., Williams, A.C., et al., Long-term treatment of Parkinsonism with bromocriptine, Lancet, i (1978) 735-738. Colonna, L., Petit, M. and Lepine, J.P., Bromocriptine in affective disorders, J. Affect. Dis., 1 (1979) 173 177. Dolphin, A.C., Jenner, P., Marsden, C.C., et al., Central dopaminergic and noradrenergic components of bromocriptine induced locomotor activity in mice, Brit. J. Pharmacol., 59 (1977) 467. Feighner, J.P., Robins, E., Guze, S.B. et al., Diagnostic criteria for use in psychiatric research, Arch. Gen. Psychiat., 26 (1972) 57-63. Hamilton, M., Development of a rating scale for primary depressive illness, Brit. J. Soc. Clin. Psychol., 6 (1967) 278 296. Horn, S., Some psychological factors in Parkinsonism, J. Neurol. Neurosurg. Psychiat., 37 (1974) 27-31. Javoy-Agid, F. and Agid, Y., Is the mesocortical dopaminergic system involved in Parkinson disease? Neurology (Minneap.), 30 (1980) 1326-1330. Lebensohn, Z.M. and Jenkins, R.B., Improvement of Parkinsonism in depressed patients treated with ECT, Amer. J. Psychiat., 132 (1975) 283 285. Lhermitte, F., Agid, Y. and Signoret, J.L., Onset and end of dose induced dyskinesias, Arch. Neurol. (Chic.), 35 (1978) 261-263.
145 Post, R.M., Jimerson, D.C., Bunney, W.E. and Goodwin, F.K., Dopamine and mania - - Behavioural and biochemical effects of the dopamine receptor blocker pimozide, Psychopharmacology, 67 (1980) 297-305. Robins, A.H., Depression in patients with parkinsonism, Brit. J. Psychiat., 128 (1976) 141-145. Sigwald, J., Bouttier, D., Raumondeaud, C. et al., Etudes de l'action sur rakinbsie parkinsonienne de deux d+rivbs de l'iminodibenzyle: Imipramine et 8307 R.P., Presse Med., 67 (1959) 1697-1698. Silverstone, T., Psychopharmacology of manic-depressive illness. In: R.N. Gaind and B.L. Hudson (Eds.), Current Themes in Psychiatry, Vol. 2, Macmillan, London, 1979, pp. 271-282. Waehrens, J. and Gerlach, J., Bromocriptine and imipramine in endogenous depression - - A double blind controlled trial in out-patients, J. Affect. Dis., 3 (1981) 193-202.
5 (1983) 141-145
141
Elsevier SciencePublishers
Antiparkinsonian and Antidepressant Effects of High Doses of Bromocriptine An Independent Comparison
R. Jouvent
1, p.
Abensour l, A.M. Bonnet 2, D. Widlocher l, y . Agid 2 and F. Lhermitte 2
I Service de Psychiatrie adultes (Pr. D. Widlocher) and 2 Clinique de Neurologie et de Neuropsychologie, H6pital de la SalpOtri~re, 47, Bd de l'H6pital, F-75013 Paris (France)
(Received 18 June, 1982) (Revised, received 11 August, 1982) (Accepted 7 September, 1982)
Summary Ten depressed parkinsonian patients were treated with high doses of bromocriptine (range 85-220 mg/day). Changes in the parkinsonian and depressive symptomatologies were independently evaluated by a neurologist and a psychiatrist. Rating took place before treatment after wash-out and again 8 days later. Results show a significant mean improvement of both depressive and parkinsonian symptomatologies. However, there was no correlation between the two therapeutic effects in the l0 patients. Clinical and biological implications of these heterogeneous patterns are discussed.
Introduction The dual character of parkinsonian symptomatology, i.e. motor disability and psychopathological disorders, particularly depression is echoed at the therapeutic level. Levodopa has been described as possessing antidepressant properties (Bunney et al. 1969) while imipramine (Sigwald et al. 1959) and ECT (Lebensohn and Jenkins 1975) have favourable effects on parkinsonian symptoms. Bromocriptine, a dopaminergic (DA) agonist, is a powerful antiparkinsonian agent (Calne et al. 1979) especially at high doses (Agid et al. 1979), and is also known to have antidepressant effects in depressed patients (Colonna et al. 1979). It 0165-0327/83/0000-0000/$03.00 © 1983 ElsevierSciencePublishers
142 seemed therefore interesting to study simultaneously in the same patients two properties which had previously been described separately; this might shed some light on the relationship between the two syndromes as well as between the two properties of the drug. Patients and Methods
Ten in-patients (5 men, 5 women) aged 32 to 75 (mean 55.5 + 13.5) were included in the study. They had had parkinsonian symptoms for 1-29 years (mean 8.6). All patients had previously been treated with ievodopa alone or in combination with a peripheral decarboxylase inhibitor. Levodopa was considered of limited value in these subjects because they had responded poorly or had had adverse reactions, mainly on-off phenomena. Bromocriptine was given after a wash-out period of 2 - 4 days without drugs, the doses being increased daily by 7.5-30 rag, depending on tolerance, to reach a final mean dose of 135 m g / d a y (range: 85 220 mg). Concomitant use of antidepressant or antiparkinsonian medication in addition to bromocriptine was not permitted. Allowed associated treatments were benzodiazepines (Lorazepam 1-2.5 mg) at night and domperidone, a peripheral DA blocking agent which does not cross the b l o o d - b r a i n barrier and thus permits a more efficient dosage of bromocriptine (Agid et al. 1979). Parkinsonian patients were selected on the existence of a marked depressive state meeting Feighner's criteria for depression (Feighner et al. 1972). Depression was rated with the 17-item Hamilton Rating Scale (H.R.S.) (Hamilton 1967). A score of 17 or over was required as a minimum. The parkinsonian disability was assessed with a 22-item rating scale of neurological function (Lhermitte et al. 1978). Scoring for each item was from 0 (normal) to 4 (maximal deficit); the scores were added to yield an overall score of parkinsonian severity. The H.R.S. and the parkinsonian scale were administered independently between 10 and 11 a.m., by the same psychiatrist (R. Jouvent) and neurologist (A.M. Bonnet) throughout the trial. All patients were rated before treatment began (day 0) and again at day 7-8, when neurological improvement seemed maximal in previous studies (Agid et al. 1979). Clinical assessment was maintained for up to 2 weeks in order to identify a possible relapse. Results
At day 0, i.e. after the wash-out period, patients had parkinsonian scores between 19 and 58 (mean 31.9) and depression scores between 17 and 34 (mean 24.1). At day 8, mean improvement in parkinsonian disability was 63%, the mean parkinsonian score being significantly improved from 31.9 to 11.7 ( P < 0.001) *; this improvement was shown in all patients with a range of 49% to 82%. Mean improvement of depression was 65%, the mean depression score being significantly improved from 24.1 to 8.4 ( P < 0.001) *. Individual patients improved in a range of * t statistic for paired observation.
143 Z~ H, R.S. 100%
. . . . . . . . . . . .
~'5
. . . . . .
~ . . . .
egelO
,8 *3
I
50%
I
.6
.7
i "4 l
t [ . . . . . . . . . . . .
t--
,2 . . . . . . . . .
L, 50%
1(X)%A Park.
Fig. 1. Compared improvements (%) of parkinsonism (A Park) and depression (A HRS).
10-100%. Two of them (No. 5, 10) presented a mood inversion (hypomania) with euphoria, moderate flight of thoughts, increased sexual interest. Neither of these two patients had had previous manic or hypomanic episodes. One patient had a partial depressive relapse on the 13th day without notable change in the neurological status and recovered with clomipramine. No other patient relapsed during the week following rating. There is a striking contrast between the relatively homogeneous response to the antiparkinsonian effect of bromocriptine and the heterogeneous response to the antidepressant effect of the drug (Fig. 1). There is no correlation between the two effects on the whole group of patients. Three patients (No. 2, 4, 7) improved more on parkinsonism than on depression. Four patients had comparable amelioration of both syndromes (No. 1, 3, 6, 8). Three patients improved much more on depression than on parkinsonism (No. 5, 9, 10).
Discussion
The antidepressant effect of bromocriptine described for doses of 15 20 m g / d a y in depressed patients (Colonna et al. 1979) was also observed in our parkinsonian patients treated with higher doses of the drug necessary to induce adequate improvement of parkinsonian disability. Two observations should be made: (1) This was only a short-term evaluation of the antidepressant action of bromocriptine and further studies are needed to document its persistence beyond two weeks. (2) The favourable results may be related at least in part to the nature of the population under study. All these patients had been admitted for their parkinsonian syndrome and not for their depression and none of them exhibited psychotic depression. The two mood swings observed with bromocriptine in our patients deserve some
144
attention. It would be tempting to consider them as evidence in favour of the dopaminergic hypothesis of mania (Silverstone 1979; Post et al. 1980). Yet these two m o o d inversions led to moderate hypomanic states of short duration in patients who could not be classified as having bipolar disorder. N o firm conclusion may therefore be drawn on this point. However, our results raise clinical and pharmacological questions. One concerns the relationship between the two syndromes. Previous findings have suggested that depression in parkinsonian patients is not purely reactive to the motor defect (Horn 1974; Robins 1976) and might be of both reactive and endogenous origins (Andersen et al. 1980). Moreover, the efficacy of bromocriptine, comparable to that of imipramine, in non-parkinsonian depressed patients is in favour of a specific antidepressant action of the drug (Waehrens and Gerlach 1981). The heterogeneous responses on depression observed in our patients is in line with these findings. From the pharmacological point of view, there is some evidence that the biochemical action of bromocriptine may go beyond pure dopaminergic stimulation specially when higher doses are administered (Dolphin et al. 1977). Nevertheless, the existence of a dopaminergic deficiency affecting the mesocorticolimbic as well as the mesostriatal systems has been established (Javoy-Agid and Agid 1980). This is consistent with the cases of patients who improved similarly on both syndromes and suggests a possible role of central dopaminergic deficiency in the incidence of depression in these patients. However, the fact that this does not concern all patients also suggests that depression in parkinsonism may involve various mechanisms.
References Agid, Y., Pollak, P., Bonnet, A.M., et al., Bromocriptine associated with a peripheral dopamine blocking agent in treatment of Parkinson's disease, Lancet, i (1979) 570 572. Andersen, J., Aabro, E. and Gulmann, N., Anti-depressive treatment in Parkinson's disease, Acta Neurol. Scand., 62 (1980) 210-219. Bunney, W.E., Janowsky, D.S., Goodwin, F.K., et al., Effect of L-Dopa on depression, Lancet, i (1969) 885. Calne, D.B., Plotkin, C., Williams, A.C., et al., Long-term treatment of Parkinsonism with bromocriptine, Lancet, i (1978) 735-738. Colonna, L., Petit, M. and Lepine, J.P., Bromocriptine in affective disorders, J. Affect. Dis., 1 (1979) 173 177. Dolphin, A.C., Jenner, P., Marsden, C.C., et al., Central dopaminergic and noradrenergic components of bromocriptine induced locomotor activity in mice, Brit. J. Pharmacol., 59 (1977) 467. Feighner, J.P., Robins, E., Guze, S.B. et al., Diagnostic criteria for use in psychiatric research, Arch. Gen. Psychiat., 26 (1972) 57-63. Hamilton, M., Development of a rating scale for primary depressive illness, Brit. J. Soc. Clin. Psychol., 6 (1967) 278 296. Horn, S., Some psychological factors in Parkinsonism, J. Neurol. Neurosurg. Psychiat., 37 (1974) 27-31. Javoy-Agid, F. and Agid, Y., Is the mesocortical dopaminergic system involved in Parkinson disease? Neurology (Minneap.), 30 (1980) 1326-1330. Lebensohn, Z.M. and Jenkins, R.B., Improvement of Parkinsonism in depressed patients treated with ECT, Amer. J. Psychiat., 132 (1975) 283 285. Lhermitte, F., Agid, Y. and Signoret, J.L., Onset and end of dose induced dyskinesias, Arch. Neurol. (Chic.), 35 (1978) 261-263.
145 Post, R.M., Jimerson, D.C., Bunney, W.E. and Goodwin, F.K., Dopamine and mania - - Behavioural and biochemical effects of the dopamine receptor blocker pimozide, Psychopharmacology, 67 (1980) 297-305. Robins, A.H., Depression in patients with parkinsonism, Brit. J. Psychiat., 128 (1976) 141-145. Sigwald, J., Bouttier, D., Raumondeaud, C. et al., Etudes de l'action sur rakinbsie parkinsonienne de deux d+rivbs de l'iminodibenzyle: Imipramine et 8307 R.P., Presse Med., 67 (1959) 1697-1698. Silverstone, T., Psychopharmacology of manic-depressive illness. In: R.N. Gaind and B.L. Hudson (Eds.), Current Themes in Psychiatry, Vol. 2, Macmillan, London, 1979, pp. 271-282. Waehrens, J. and Gerlach, J., Bromocriptine and imipramine in endogenous depression - - A double blind controlled trial in out-patients, J. Affect. Dis., 3 (1981) 193-202.