118
Bromocriptine in Augmentation of Antipsychotic Response in Chronic Schizophrenia: A Negative Pilot Report Barbara G. We//s. Ch.-Ch. Chu. A. Abi-Darghum, T. S. Saini Departments of Clinical Pharmacy and Psychiatry, Colleges of Pharmacy and Medicine, University ofTennessee, Memphis, USA
To further assess the usefulness of bromocriptine in treatment of schizophrenia seven inpatient chronic schizophrenics with acute exacerbation who had failed to respond to four weeks of antipsychotic therapy were treated with bromocriptine 2.5 mg daily for a treatment duration varying from one dose to four weeks while their antipsychotic dose was continued unchanged. Mean age of patients was 38.9± 11.6 years and mean number of prior psychiatrie hospitalizations was 12.0±7.2. Patients were rated with the Brief Psychiatrie Rating Scale prior to the first bromocriptine dose, at 24 hours after dosage initiation, and at weekly intervals. One patient showed cIinically significant improvement in both positive and negative schizophrenie symptoms. One patient showed slight improvement in unusual thought content, and four patients were c1inically unchanged. One patient significantly worsened after the first dose. Factors possibly contributing to response and non-response are discussed. This is areport of an open study in 7 patients. I t is the only report ofbromocriptine treatment in patients previously shown unresponsive to antipsychotics and whose antipsychotics dose was held constant throughout the study. Addition of bromocriptine to the antipsychotic regimen remains an unproven treatment approach which may be considered only in patients refractory to or inadequately controlled with antipsychotics.
Introduction The dopamine hypothesis of schizophrenia suggests that a functional excess of brain dopamine underlies the illness. Dopamine overactivity may be due to an increase in the number or sensitivity of postsynaptic receptors or an excessive discharge of dopamine which may be associated with a functional underactivity of presynaptic autoreceptors. The neuroanatomicallocations of proposed dopaminergic overactivity are suggested to be mesolimbic and/or mesocortical systems which are involved in behavioral expression and modulation (Losonszy et al., 1987). It is proposed that bromocriptine may be beneficial in treatment of schizophrenia through stimulation of inhibitory presynaptic autoreceptors which are
Pharmacopsychiat. 24 ( 1991 ) I 18 - 120 © Georg Thieme Verlag Stuttgart· N ew York
Bromocriptin bei Antipsychotikamedikation Zur weiteren Bestimmung des therapeutischen Stellenwerts von Bromocriptin bei Schizophrenie wurden 7 stationär behandelte Patienten mit akuter Verschlechterung der Erkrankung, bei denen eine vierwöchige Antipsychotikabehandlung erfolglos geblieben war, mit 2,5 mg Bromocriptin bis zu vier Wochen bei unveränderter Antipsychotikamedikation behandelt. Das durchschnittliche Alter der Patienten betrug 38,9 ± 11,6 Jahre und der Mittelwert der voraufgegangenen psychiatrischen stationären Behandlungen 12,0 ± 7,2 Jahre. Die Patienten wurden nach der Brief Psychiatrie Rating Scale vor der ersten Bromocriptingabe beurteilt, dann 24 Stunden nach Beginn der Dosierung und in Abständen von einer Woche. Bei einem Patienten war eine klinisch signifikante Besserung sowohl der positiven als auch der negativen Schizophreniesymptome zu verzeichnen. Ein Patient zeigte eine leichte Besserung seiner ungewöhnlichen Gedankeninhalte und vier Patienten blieben klinisch unverändert. Bei einem Patienten verschlimmerte sich der Zustand signifikant nach der ersten Verabreichung. Es werden die Faktoren diskutiert, die möglicherweise zum Ansprechen bzw. Nichtansprechen der Patienten beitragen könnten. Die Verabreichung von Bromocriptin zusätzlich zu Antipsychotika ist bei solchen Patienten in Betracht zu ziehen, die nicht auf Antipsychotika angesprochen haben.
more sensitive to dopamine than are postsynaptic receptors (Skirbo// et al., 1979). A biphasic effect of bromocriptine has been suggested, whereby low concentrations lead to dopaminergic inhibition through dopamine autoreceptor agonism, and high concentrations result in dopaminergic activity through postsynaptic dopamine receptor agonism (Cut/er et al., 1984). The usefulness of bromocriptine in treatment of schizophrenia has not as yet been defined. Results of studies evaluating the efficacy and safety of bromocriptine in schizophrenia are inconclusive because of methodological shortcomings including lack of controls, small sampIe size, variable dosage regimens, and short trial duration. Selected patients have responded to low dose bromocriptine both with (Cut/er et
Received: 5.9.1990 Revised version: 21. 1. 1991 28. 1. 1991 Accepted:
Downloaded by: Universite Laval. Copyrighted material.
Summary
Pharmacopsychiat. 24 (1991)
Bromocriptine in Augmentation 01Antipsychotic
Pt. 41
Oemographics and concurrent medication regimen Age (yrs)
Race
Gender
OSM-III-R Oiagnosis
Concurrent Medications
38
B
M
Schiz, CUO a
fluphenazine decanoate 75 mg q 2wk fluphenazine 10 mg po BIO
2
26
B
F
Schiz, CO b
thiothixene 20 mg BIO benztropine 2 mg BIO
3
50
W
M
Schiz, CUO a
clonidine 0.1 mg q 8h benztropine 2 mg BIO fluphenazine 10 mg TIO f1uphenazine decanoate 75 mg q 3wk clonazepam 0.5 TIO
4
26
B
M
Schiz, cuoa
fluphenazine decanoate 50 mg IM q wk
5
45
W
M
Schiz, cpc
thioridazine 600 mg/O
6
55
W
F
Schiz, CUo a
fluphenazine 50 mg/O nifedipine 30 mg QIO benztropine 2 mg BIO
7
32
B
M
Schiz, Co b
f1uphenazine 20 mg BIO and 30 mg HS benztropine 2 mg BIO
a Schizophrenia, chronic undifferentiated Schizophrenia, chronic disorganized c Schizophrenia, chronic paranoid
b
al. , 1984; Gattaz and Kollisch, 1986) and without (Mettzer et al., 1983) concomitant antipsychotic therapy. While low dose bromocriptine treatment has been inadequately studied in both these experimental conditions, its use in patients on concurrent antipsychotics has been reported in I paranoid schizophrenic (Gattaz and Kollisch, 1986), in 11 schizophrenics who received only a single dose of bromocriptine (Cut/er et al., 1984) and one double-blind placebo controlled trial in 30 patients where the haloperidol dose was not held constant (Gattaz et al., 1989). This report describes the use of low dose bromocriptine in treatment of acutely exacerbated chronic schizophrenics who remained on their prior dose of antipsychotic to which they were unresponsive.
Table 2 Brief Psychiatrie Rating Scale (BPRSj Scores
Pt41
Baseline
24 hours
1 week
2 week
3 week
4 week
Post-Bromocriptine Treatment 1 week
1 2 3 4 5 6 7
54
51 53 58 49 45 80 a
53 50 54 58 49 43
49 43 54 58 50 43
49 39
49 37
39
39
54
54
Ouring Bromocriptine Treatment
58 44
46
a BPRS increased 30 minutes post-dose to 86.
Methods Seven inpatients between 26 and 55 years of age meeting DSM-III-R (APA, 1987) criteria for chronic schizophrenia with acute exacerbation were treated in an open trial design. All patients had been treated with antipsychotics for at least four weeks without symptomatic response. None of the patients had an unstable medical illness, a history of seizure disorder, or a history of alcohol or drug abuse during the prior six months. All patients were continued on their current dose of antipsychotic medications. Bromocriptine was administered 2.5 mg po each day in the morning for four weeks. Each patient was rated by a physician investigator using the Brief Psychiatrie Rating Scale (BPRS) (Overall and Gorham, 1962) prior to the initiation of bromocriptine, 24 hours after initiation of bromocriptine, and at weekly inverals throughout each patient's bromocriptine treatment. Each patient was rated by the same rater throughout the course of his/her treatment. Adequate interrater reliability was established prior to study initiation. Bromocriptine treatment was discontinued ifa patient's total BPRS scores documented worsening of symptoms or if no improvement was documented after two weeks of bromocriptine treatment. Baseline BPRS scores and scores on later treatment days were compared for statistical significance using repeated measures analysis of variance. All means
are expressed ± standard deviations. Statistical significance was accepted at p < 0.05.
Results Seven patients, five males and two females, were treated. Patient demographies and concomitantly administered medications are shown in Table 1. Four patients were diagnosed chronic undifTerentiated schizophrenia, two were diagnosed chronic disorganized schizophrenia, and one was diagnosed chronic paranoid schizophrenia. Ages ranged from 26 to 55 years (38.9± 11.6), the number of prior psychiatrie hospitalizations ranged from six to 25 (mean = 12.0±7.2), and duration of illness ranged from nine to 30 years (mean = 16.7±6.8). One patient was discontinued after the first bromocriptine dose, one patient was treated for one week, one patient for two weeks, three patients for three weeks, and one patient for four weeks. BPRS scores at each evaluation are shown in Table 2. Patient #7 received only a single dose ofbromocriptine and within 30 minutes exhibited a clini-
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Table1
119
cally significant worsening, particularly in silly laughter, hostility, uncooperativeness, and unusual thought content. His BPRS scores increased from 80 at baseline to 86, 30 minutes post-dose, and he was discontinued from treatment. Patient # I showed a slight improvement primarily in unusual thought content at week one. This improvement was maintained throughout his three week treatment. Patient #2 was the only patient who showed clinically significant improvement which peaked at week three. This patient was followed for a total offive weeks, one week following discontinuation of bromocriptine. Improvement was maintained at week five. Improved items were emotional withdrawal, tension, suspiciousness, and blunted affect. Patients #3 - 6 were treated for one to three weeks and were not benefitted. Mean BPRS scores at 24 hours were not significantly different from the mean baseline scores in patients #1-6 (51.2±5.1 vs 51.7±4.5, N. S.). Mean scores at week one (49.5±5.6, n = 6) were also not significantly different from base1ine for these patients (51.7±4.5, N. S.). Mean scores at week two (48.8±7.6, n = 5) were not significantly different from these patients' baseline scores (52.2±4.8, N. S.). Similarly, mean scores at week three (46.5 ± 7.1, n = 4) were also not significantly different from baseline scores in these patients (50.8±4.0, N. S.). Item 3 (emotional withdrawal), item 13 (motor retardation), and item 16 (blunted affect) were considered indicative of negative symptoms of schizophrenia. Mean scores on these items on any evaluation day also showed no significant difference from mean baseline scores. Patient #2 showed mild improvement in items 3 and 16. No patient experienced side effects from the addition of bromocriptine. Discussion Non-response may be accounted for by subsensitive presynaptic dopamine autoreceptors and/or hypersensitive postsynaptic dopamine receptors. Alternatively, psychoses in our patients may not have been dopamine-dependent. Additionally, pharmacokinetic disposition of bromocriptine may have resulted in excessive or insufficient concentrations ofbromocriptine or its active metabolites at the site(s} of action. As suggested by Brambilla et al. (l983) the dopamine systems of chronic, severely deteriorated schizophrenics may lack the capacity for modulation or adaption to stimuli. In a population such as ours with illness of many years duration, postsynaptic receptors may be sufficiently hypersensitive to make response to bromocriptine unlikely regardless of dose. This study supports the report of Gattaz et al. (1989) which found no significant difference in improvement between the bromocriptine and placebo groups. Our study differs from Gattaz et al. (1989) in that our patients were previously unresponsive to antipsychotics, and antipsychotic doses were held constant throughout our trial. The only other bromocriptine trial with concurrent antipsychotic dosing was a placebo controlled single dose study with significant improvement at 60 minutes after the bromocriptine dose. Unfortunately, the trial duration was only two hours following the bromocriptine dose (Cutier et al., 1984). Several reports without concurrent antipsychotic dosing have also reported no efficacy (Brambilla et al., 1977; King, 1978; Trabucci et al., 1977; Tamminga, 1980), Me/tzer et al. (l983), however, reported improvement at two to three weeks but worsening at
Barbara G. Wells, Ch.-Ch. Chu, A. Abi-Darghum, T S. Saini week four. This accumulating body of evidence suggests that either bromocriptine holds little promise in treatment of schizophrenia or that titration of dose is much more crucial in the dopamine autoreceptor strategy than in previously embraced strategies for treatment. The question of augmentation of antipsychotic efficacy is as yet unresolved. Larger scale, doubleblind studies in populations more diagnostically homogenous will provide these answers, and studies using the more specific presynaptic dopamine agonists (Wiedemann et al., 1990) anticipated to be available in the future will he1p test the dopamine autoreceptor strategy. Future studies should investigate the possibility of greater resonse in younger patients with shorter duration of illness, as suggested by Me/tzer et al. (l983) and by our findings. At present, the usefulness of adding bromocriptine to the antipsychotic regimen in schizophrenia remains unproven. As such, this treatment approach should be reserved for patients refractory to or inadequately controlled with antipsychotics. References American Psychiatrie Association: Diagnostic and Statistieal Manual of Mental Disorders. 3rd ed. (DSM-I1I-R). APA, Washington D. C. 1987 Brambilla, F., S. Scarone, L. Pugnetti et al.: Bromocriptine therapy in chronie schizophrenia: Effects on symptomatology, sleep patterns, and prolactin response to stimulation. Psychiatrie Res. 8 (\983)159-169 Cutier, N. R., D. V. Jeste, C. A. Kau/man: Low dose bromocriptine: A study of acute effect in chronic medicated schizophrenics. Prog. Neuropsychopharmaco!. and Bio!. Psychiatry 8 (1984) 277 - 283 Gattaz, W. F., M. Kollisch: Bromocriptine in the treatment of neuroleptie-resistant schizophrenia. Bio!. Psychiatry 21 (1986) 519 - 521 Gattaz, W. F., W. Rost, Cv. K Hubner et al.: Acute and subchronic effects of low-dose bromocriptine in haloperidol-treated schiz0phrenies. Bio!. Psychiatry 25 (1989) 247 - 255 King, D. J.: Dopamine agonists for negative symptoms in schizophrenia. Br. J. Clin. Pharmaco!' 6 (1978) 541 Losonszy, M. F., M. Davidson. K L. Davis: The dopamine hypothesis of schizophrenia. In: Meltzer, H. Y. (ed) Psychopharmacology: The Third Generation of Progress. Raven Press, New York 1987 Meltzer, H. Y., T. Kolakowska, A. Robertson el al.: Effect of low-dose bromocriptine in treatment of psychosis: The dopamine autoreceptor-stimulated strategy. Psychopharmacology 81 (1983) 37 - 41 Overall, J. E., D. R. Gorham: The brief psychiatrie rating scale. Psycho!. Rep. 10(1962)799 - 812 Skirboll, L. R., A. A. Gace, B. S. Bunney: Dopamine auto- and postsynaptic receptors: Electrophysiological evidence for differential sensitivity ofdopamine agonists. Science 206 (1979) 80 - 82 Tamminga, C. A.: Antipsychotic and antidyskinetic properties of ergot dopamine agonists. In: Goldstein, M. (ed.) Ergot Compounds and Brain Function: Neuroendocrine and Neuropsychiatrie Aspects. Raven Press, New York 1980 Trabucchi, M., V. M. Andreoli, L. Frattola et ul.: Pre- and postsynaptic action of bromocriptine: its pharmacologieal effects in schizophrenia and neurologieal disease. Adv. Bioehern. Psychopharmaco!. 16(1977)661 - 665 Wiedemann, K, 0. Benkert. F. Holsboer: B-HT920-A novel dopamine autoreceptor agonist in the treatment of patients with schizophrenia. Pharmacopsychiatry 23 (1990) 50 - 55
Barbara G. Wells, Pharm.D. Department ofClinical Pharmacy U. T. College of Pharmacy 26 S. Dunlap ST., Rm 200 Memphis, TN 38163 USA
Downloaded by: Universite Laval. Copyrighted material.
120 Pharmacopsychiat. 24 (1991)
Bromocriptine in Augmentation of Antipsychotic Response in Chronic Schizophrenia: A Negative Pilot Report Barbara G. We//s. Ch.-Ch. Chu. A. Abi-Darghum, T. S. Saini Departments of Clinical Pharmacy and Psychiatry, Colleges of Pharmacy and Medicine, University ofTennessee, Memphis, USA
To further assess the usefulness of bromocriptine in treatment of schizophrenia seven inpatient chronic schizophrenics with acute exacerbation who had failed to respond to four weeks of antipsychotic therapy were treated with bromocriptine 2.5 mg daily for a treatment duration varying from one dose to four weeks while their antipsychotic dose was continued unchanged. Mean age of patients was 38.9± 11.6 years and mean number of prior psychiatrie hospitalizations was 12.0±7.2. Patients were rated with the Brief Psychiatrie Rating Scale prior to the first bromocriptine dose, at 24 hours after dosage initiation, and at weekly intervals. One patient showed cIinically significant improvement in both positive and negative schizophrenie symptoms. One patient showed slight improvement in unusual thought content, and four patients were c1inically unchanged. One patient significantly worsened after the first dose. Factors possibly contributing to response and non-response are discussed. This is areport of an open study in 7 patients. I t is the only report ofbromocriptine treatment in patients previously shown unresponsive to antipsychotics and whose antipsychotics dose was held constant throughout the study. Addition of bromocriptine to the antipsychotic regimen remains an unproven treatment approach which may be considered only in patients refractory to or inadequately controlled with antipsychotics.
Introduction The dopamine hypothesis of schizophrenia suggests that a functional excess of brain dopamine underlies the illness. Dopamine overactivity may be due to an increase in the number or sensitivity of postsynaptic receptors or an excessive discharge of dopamine which may be associated with a functional underactivity of presynaptic autoreceptors. The neuroanatomicallocations of proposed dopaminergic overactivity are suggested to be mesolimbic and/or mesocortical systems which are involved in behavioral expression and modulation (Losonszy et al., 1987). It is proposed that bromocriptine may be beneficial in treatment of schizophrenia through stimulation of inhibitory presynaptic autoreceptors which are
Pharmacopsychiat. 24 ( 1991 ) I 18 - 120 © Georg Thieme Verlag Stuttgart· N ew York
Bromocriptin bei Antipsychotikamedikation Zur weiteren Bestimmung des therapeutischen Stellenwerts von Bromocriptin bei Schizophrenie wurden 7 stationär behandelte Patienten mit akuter Verschlechterung der Erkrankung, bei denen eine vierwöchige Antipsychotikabehandlung erfolglos geblieben war, mit 2,5 mg Bromocriptin bis zu vier Wochen bei unveränderter Antipsychotikamedikation behandelt. Das durchschnittliche Alter der Patienten betrug 38,9 ± 11,6 Jahre und der Mittelwert der voraufgegangenen psychiatrischen stationären Behandlungen 12,0 ± 7,2 Jahre. Die Patienten wurden nach der Brief Psychiatrie Rating Scale vor der ersten Bromocriptingabe beurteilt, dann 24 Stunden nach Beginn der Dosierung und in Abständen von einer Woche. Bei einem Patienten war eine klinisch signifikante Besserung sowohl der positiven als auch der negativen Schizophreniesymptome zu verzeichnen. Ein Patient zeigte eine leichte Besserung seiner ungewöhnlichen Gedankeninhalte und vier Patienten blieben klinisch unverändert. Bei einem Patienten verschlimmerte sich der Zustand signifikant nach der ersten Verabreichung. Es werden die Faktoren diskutiert, die möglicherweise zum Ansprechen bzw. Nichtansprechen der Patienten beitragen könnten. Die Verabreichung von Bromocriptin zusätzlich zu Antipsychotika ist bei solchen Patienten in Betracht zu ziehen, die nicht auf Antipsychotika angesprochen haben.
more sensitive to dopamine than are postsynaptic receptors (Skirbo// et al., 1979). A biphasic effect of bromocriptine has been suggested, whereby low concentrations lead to dopaminergic inhibition through dopamine autoreceptor agonism, and high concentrations result in dopaminergic activity through postsynaptic dopamine receptor agonism (Cut/er et al., 1984). The usefulness of bromocriptine in treatment of schizophrenia has not as yet been defined. Results of studies evaluating the efficacy and safety of bromocriptine in schizophrenia are inconclusive because of methodological shortcomings including lack of controls, small sampIe size, variable dosage regimens, and short trial duration. Selected patients have responded to low dose bromocriptine both with (Cut/er et
Received: 5.9.1990 Revised version: 21. 1. 1991 28. 1. 1991 Accepted:
Downloaded by: Universite Laval. Copyrighted material.
Summary
Pharmacopsychiat. 24 (1991)
Bromocriptine in Augmentation 01Antipsychotic
Pt. 41
Oemographics and concurrent medication regimen Age (yrs)
Race
Gender
OSM-III-R Oiagnosis
Concurrent Medications
38
B
M
Schiz, CUO a
fluphenazine decanoate 75 mg q 2wk fluphenazine 10 mg po BIO
2
26
B
F
Schiz, CO b
thiothixene 20 mg BIO benztropine 2 mg BIO
3
50
W
M
Schiz, CUO a
clonidine 0.1 mg q 8h benztropine 2 mg BIO fluphenazine 10 mg TIO f1uphenazine decanoate 75 mg q 3wk clonazepam 0.5 TIO
4
26
B
M
Schiz, cuoa
fluphenazine decanoate 50 mg IM q wk
5
45
W
M
Schiz, cpc
thioridazine 600 mg/O
6
55
W
F
Schiz, CUo a
fluphenazine 50 mg/O nifedipine 30 mg QIO benztropine 2 mg BIO
7
32
B
M
Schiz, Co b
f1uphenazine 20 mg BIO and 30 mg HS benztropine 2 mg BIO
a Schizophrenia, chronic undifferentiated Schizophrenia, chronic disorganized c Schizophrenia, chronic paranoid
b
al. , 1984; Gattaz and Kollisch, 1986) and without (Mettzer et al., 1983) concomitant antipsychotic therapy. While low dose bromocriptine treatment has been inadequately studied in both these experimental conditions, its use in patients on concurrent antipsychotics has been reported in I paranoid schizophrenic (Gattaz and Kollisch, 1986), in 11 schizophrenics who received only a single dose of bromocriptine (Cut/er et al., 1984) and one double-blind placebo controlled trial in 30 patients where the haloperidol dose was not held constant (Gattaz et al., 1989). This report describes the use of low dose bromocriptine in treatment of acutely exacerbated chronic schizophrenics who remained on their prior dose of antipsychotic to which they were unresponsive.
Table 2 Brief Psychiatrie Rating Scale (BPRSj Scores
Pt41
Baseline
24 hours
1 week
2 week
3 week
4 week
Post-Bromocriptine Treatment 1 week
1 2 3 4 5 6 7
54
51 53 58 49 45 80 a
53 50 54 58 49 43
49 43 54 58 50 43
49 39
49 37
39
39
54
54
Ouring Bromocriptine Treatment
58 44
46
a BPRS increased 30 minutes post-dose to 86.
Methods Seven inpatients between 26 and 55 years of age meeting DSM-III-R (APA, 1987) criteria for chronic schizophrenia with acute exacerbation were treated in an open trial design. All patients had been treated with antipsychotics for at least four weeks without symptomatic response. None of the patients had an unstable medical illness, a history of seizure disorder, or a history of alcohol or drug abuse during the prior six months. All patients were continued on their current dose of antipsychotic medications. Bromocriptine was administered 2.5 mg po each day in the morning for four weeks. Each patient was rated by a physician investigator using the Brief Psychiatrie Rating Scale (BPRS) (Overall and Gorham, 1962) prior to the initiation of bromocriptine, 24 hours after initiation of bromocriptine, and at weekly inverals throughout each patient's bromocriptine treatment. Each patient was rated by the same rater throughout the course of his/her treatment. Adequate interrater reliability was established prior to study initiation. Bromocriptine treatment was discontinued ifa patient's total BPRS scores documented worsening of symptoms or if no improvement was documented after two weeks of bromocriptine treatment. Baseline BPRS scores and scores on later treatment days were compared for statistical significance using repeated measures analysis of variance. All means
are expressed ± standard deviations. Statistical significance was accepted at p < 0.05.
Results Seven patients, five males and two females, were treated. Patient demographies and concomitantly administered medications are shown in Table 1. Four patients were diagnosed chronic undifTerentiated schizophrenia, two were diagnosed chronic disorganized schizophrenia, and one was diagnosed chronic paranoid schizophrenia. Ages ranged from 26 to 55 years (38.9± 11.6), the number of prior psychiatrie hospitalizations ranged from six to 25 (mean = 12.0±7.2), and duration of illness ranged from nine to 30 years (mean = 16.7±6.8). One patient was discontinued after the first bromocriptine dose, one patient was treated for one week, one patient for two weeks, three patients for three weeks, and one patient for four weeks. BPRS scores at each evaluation are shown in Table 2. Patient #7 received only a single dose ofbromocriptine and within 30 minutes exhibited a clini-
Downloaded by: Universite Laval. Copyrighted material.
Table1
119
cally significant worsening, particularly in silly laughter, hostility, uncooperativeness, and unusual thought content. His BPRS scores increased from 80 at baseline to 86, 30 minutes post-dose, and he was discontinued from treatment. Patient # I showed a slight improvement primarily in unusual thought content at week one. This improvement was maintained throughout his three week treatment. Patient #2 was the only patient who showed clinically significant improvement which peaked at week three. This patient was followed for a total offive weeks, one week following discontinuation of bromocriptine. Improvement was maintained at week five. Improved items were emotional withdrawal, tension, suspiciousness, and blunted affect. Patients #3 - 6 were treated for one to three weeks and were not benefitted. Mean BPRS scores at 24 hours were not significantly different from the mean baseline scores in patients #1-6 (51.2±5.1 vs 51.7±4.5, N. S.). Mean scores at week one (49.5±5.6, n = 6) were also not significantly different from base1ine for these patients (51.7±4.5, N. S.). Mean scores at week two (48.8±7.6, n = 5) were not significantly different from these patients' baseline scores (52.2±4.8, N. S.). Similarly, mean scores at week three (46.5 ± 7.1, n = 4) were also not significantly different from baseline scores in these patients (50.8±4.0, N. S.). Item 3 (emotional withdrawal), item 13 (motor retardation), and item 16 (blunted affect) were considered indicative of negative symptoms of schizophrenia. Mean scores on these items on any evaluation day also showed no significant difference from mean baseline scores. Patient #2 showed mild improvement in items 3 and 16. No patient experienced side effects from the addition of bromocriptine. Discussion Non-response may be accounted for by subsensitive presynaptic dopamine autoreceptors and/or hypersensitive postsynaptic dopamine receptors. Alternatively, psychoses in our patients may not have been dopamine-dependent. Additionally, pharmacokinetic disposition of bromocriptine may have resulted in excessive or insufficient concentrations ofbromocriptine or its active metabolites at the site(s} of action. As suggested by Brambilla et al. (l983) the dopamine systems of chronic, severely deteriorated schizophrenics may lack the capacity for modulation or adaption to stimuli. In a population such as ours with illness of many years duration, postsynaptic receptors may be sufficiently hypersensitive to make response to bromocriptine unlikely regardless of dose. This study supports the report of Gattaz et al. (1989) which found no significant difference in improvement between the bromocriptine and placebo groups. Our study differs from Gattaz et al. (1989) in that our patients were previously unresponsive to antipsychotics, and antipsychotic doses were held constant throughout our trial. The only other bromocriptine trial with concurrent antipsychotic dosing was a placebo controlled single dose study with significant improvement at 60 minutes after the bromocriptine dose. Unfortunately, the trial duration was only two hours following the bromocriptine dose (Cutier et al., 1984). Several reports without concurrent antipsychotic dosing have also reported no efficacy (Brambilla et al., 1977; King, 1978; Trabucci et al., 1977; Tamminga, 1980), Me/tzer et al. (l983), however, reported improvement at two to three weeks but worsening at
Barbara G. Wells, Ch.-Ch. Chu, A. Abi-Darghum, T S. Saini week four. This accumulating body of evidence suggests that either bromocriptine holds little promise in treatment of schizophrenia or that titration of dose is much more crucial in the dopamine autoreceptor strategy than in previously embraced strategies for treatment. The question of augmentation of antipsychotic efficacy is as yet unresolved. Larger scale, doubleblind studies in populations more diagnostically homogenous will provide these answers, and studies using the more specific presynaptic dopamine agonists (Wiedemann et al., 1990) anticipated to be available in the future will he1p test the dopamine autoreceptor strategy. Future studies should investigate the possibility of greater resonse in younger patients with shorter duration of illness, as suggested by Me/tzer et al. (l983) and by our findings. At present, the usefulness of adding bromocriptine to the antipsychotic regimen in schizophrenia remains unproven. As such, this treatment approach should be reserved for patients refractory to or inadequately controlled with antipsychotics. References American Psychiatrie Association: Diagnostic and Statistieal Manual of Mental Disorders. 3rd ed. (DSM-I1I-R). APA, Washington D. C. 1987 Brambilla, F., S. Scarone, L. Pugnetti et al.: Bromocriptine therapy in chronie schizophrenia: Effects on symptomatology, sleep patterns, and prolactin response to stimulation. Psychiatrie Res. 8 (\983)159-169 Cutier, N. R., D. V. Jeste, C. A. Kau/man: Low dose bromocriptine: A study of acute effect in chronic medicated schizophrenics. Prog. Neuropsychopharmaco!. and Bio!. Psychiatry 8 (1984) 277 - 283 Gattaz, W. F., M. Kollisch: Bromocriptine in the treatment of neuroleptie-resistant schizophrenia. Bio!. Psychiatry 21 (1986) 519 - 521 Gattaz, W. F., W. Rost, Cv. K Hubner et al.: Acute and subchronic effects of low-dose bromocriptine in haloperidol-treated schiz0phrenies. Bio!. Psychiatry 25 (1989) 247 - 255 King, D. J.: Dopamine agonists for negative symptoms in schizophrenia. Br. J. Clin. Pharmaco!' 6 (1978) 541 Losonszy, M. F., M. Davidson. K L. Davis: The dopamine hypothesis of schizophrenia. In: Meltzer, H. Y. (ed) Psychopharmacology: The Third Generation of Progress. Raven Press, New York 1987 Meltzer, H. Y., T. Kolakowska, A. Robertson el al.: Effect of low-dose bromocriptine in treatment of psychosis: The dopamine autoreceptor-stimulated strategy. Psychopharmacology 81 (1983) 37 - 41 Overall, J. E., D. R. Gorham: The brief psychiatrie rating scale. Psycho!. Rep. 10(1962)799 - 812 Skirboll, L. R., A. A. Gace, B. S. Bunney: Dopamine auto- and postsynaptic receptors: Electrophysiological evidence for differential sensitivity ofdopamine agonists. Science 206 (1979) 80 - 82 Tamminga, C. A.: Antipsychotic and antidyskinetic properties of ergot dopamine agonists. In: Goldstein, M. (ed.) Ergot Compounds and Brain Function: Neuroendocrine and Neuropsychiatrie Aspects. Raven Press, New York 1980 Trabucchi, M., V. M. Andreoli, L. Frattola et ul.: Pre- and postsynaptic action of bromocriptine: its pharmacologieal effects in schizophrenia and neurologieal disease. Adv. Bioehern. Psychopharmaco!. 16(1977)661 - 665 Wiedemann, K, 0. Benkert. F. Holsboer: B-HT920-A novel dopamine autoreceptor agonist in the treatment of patients with schizophrenia. Pharmacopsychiatry 23 (1990) 50 - 55
Barbara G. Wells, Pharm.D. Department ofClinical Pharmacy U. T. College of Pharmacy 26 S. Dunlap ST., Rm 200 Memphis, TN 38163 USA
Downloaded by: Universite Laval. Copyrighted material.
120 Pharmacopsychiat. 24 (1991)
