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Bromocriptine treatment of tricyclic and heterocyclic antidepressant-resistant depression
Bromocriptine Treatment of Tricyclic and Heterocyclic Antidepressant-Resistant Depression Takeshi Inoue, Kiyoshi Tsuchiya, Jun Miura, Satoshi Sakakibara, Kenzo Denda, Toshihiko Kasahara, and Tsukasa Koyama Key Words: Bromocriptine, refractory depression, antidepressants, dopamine, affective disorder, treatment-resistant depression BIOL PSYCHIATRY 1996;40:151--153
Introduction Bromocriptine, a dopamine-2 (D2) receptor agonist (Jackson et al 1988), has been used to treat endogenous depression in several open and double-blind studies (reviewed in Sitland-Marken et al 1990). Three double-blind studies have shown bromocriptine to have similar antidepressant efficacy as imipramine (Bouras and Bridges 1982; Waehrens and Gerlach 1981) and amitriptyline (Theohar et al 1982). Recently, bromocriptine has been found to have anti-depressant-like activity in an animal model (Muscat et al 1992). We evaluated the efficacy of bromocriptine as an antidepressant adjuvant in a preliminary open study involving unipolar depressed patients who had failed to respond to tricyclic or heterocyclic antidepressant.
Methods Three inpatients and 3 outpatients satisfying DSM-III-R criteria for major depression with melancholia consented to participate. None of the patients had ever been psychotic. They had not responded to at least one adequate treatment with tricyclic or heterocyclic antidepressant (i.e., a minimum of the equivalent of 150-200 mg of imipramine for 6 weeks). The inclusion criteria required a minimum score of 15 in the first 17 items of the Hamilton Depression Rating Scale (HDRS) (Hamilton 1960).
From the Department of Psychiatry, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo 060, Japan. Address reprint requests to Takeshi Inoue, MD, Department of Psychiatry, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo 060, Japan. Received June 13, 1995; revised December 1, 1995.
© 1996 Society of Biological Psychiatry
Depressed patients with computed tomography (CT) scan or electroencephalogram (EEG) evidence of organic brain disease were excluded from the study. Also excluded were patients with concurrent significant medical problems. Bromocriptine was initiated at 7.5 mg/day and then adjusted to 7.5-52.5 mg/day on the basis of clinical response and side effects. All patients were on maximally tolerated doses of tricyclic or heterocyclic antidepressants during the bromocriptine trial (Table 1). Evaluations were made before adding bromocriptine to the tricyclic or heterocyclic antidepressants (baseline) and at weeks 2, 4, and 6.
Results Six patients completed the 6-week study. Dose of bromocriptine ranged from 15 to 52.5 mg (mean dose at final rating = 40 rag/day). Four of the 6 subjects responded to bromocriptine treatment as defined by a 50% reduction in the HDRS (see Table 1). One subject had a partial antidepressant response with a 25% reduction in HDRS scores. Reduction in the HDRS scores was statistically significant by the 4th week of treatment and continued to be present during the study (Table 1). Of the individual items of the HDRS, delayed insomnia significantly improved at weeks 4 and 6 (p < .05, Wilcoxon test), and there appeared to be a trend (p < .07) for bromocriptine to improve depressed mood (week 6), middle insomnia (week 6), retardation (week 6), psychic anxiety (weeks 4 and 6), gastrointestinal somatic symptoms (weeks 4 and 6), and general somatic symptoms (week 6). Accordingly, bromocriptine was effective for not only retardation, but also somatic symptoms, insomnia, and anxiety. Side effects were not observed in any patients. After the bromocriptine trials, 3 patients (#1, 2, 6) continued to receive bromocriptine 0006-3223/96/15.00 SSD1 0006-3223(95)00666-4
152
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1996;40:151-153
Table 1. Clinical Data of Bromocriptine Treatment in Refractory Depressed Subjects HDRS Subject no.
Age (years)
Gender
1 2 3 4
58 59 69 54
F M F F
5 6 Mean SEM
43 53 56.0 3.5
M M
Duration of episode (months) 2 72 22 147 38 21 50.3 21.6
Week
Concurrent medication (mg)
Maximum bromocriptine (mg)
0
2
4
6
18 26 20 21
13 10 20 16
9 7 13 11
8 7 12 10
52.5 30 52.5 52.5
15 34 22.3 2.8
15 34 18 3.5
15 26 13.5a 2.8
15 10 10.3a 1.2
15 37.5 40.0 6.3
IMP (225) AMX (150) AMX (150) AMX (150) CMI (150) AMT (150) AMX (200)
Previous treatment for current episode
CMI IMP, AMT IMP, AMT IMP AMT
HDRS, Hamilton Depression Rating Scale; IMP, imipramine; AMX, amoxapine; CMI, clomipramine; AMT, amitriptyline. a p < .05, Wilcoxon test.
with tricyclic or heterocyclic antidepressants and recovered fully at weeks 8-12. Two patients (#3, 4) received the adjunctive treatment of thyroid hormones in addition to bromocriptine and tricyclic/heterocyclic antidepressants (1 recovered almost fully, and another did not respond to thyroid hormones). One patient (#5), who did not respond to bromocriptine, received monoamine oxidase inhibitors, but failed to respond.
Discussion The present study shows that the addition of bromocriptine to tficyclic or heterocyclic antidepressants in refractory depression induces another antidepressant effect. To our knowledge, this is the first study that tests the effect of bromocriptine added to tricyclic or heterocyclic antidepressants in refractory depressed patients with melancholia. Onset of response was relatively rapid and occurred within the first 2 weeks in 3 cases. This rapid onset is consistent with the results of previous studies (Sitland-Marken et al 1990). Although previous studies reported that bromocriptine treatment produced hypomania in a few patients (Sitland-Marken et al 1990), no patients became manic in the present study. Siverstone (1984) suggested that bromocriptine was more effective in bipolar depression than unipolar depression, and showed that 2 of 5 bipolar patients became manic during bromocriptine treatment but unipolar patients did not. This finding may account for no occurrence of mania in unipolar depressed patients in the present study. Other dopamine agonists (pergolide and peribedil) were also
reported to have antidepressant efficacy (Bouckoms and Mangini 1993; Post et al 1978). Consistent with the present study, Bouckoms and Mangini (1993) also reported that pergolide, a D1/D 2 agonist, had a role as antidepressant adjuvant in the treatment of refractory depression. The mechanism of action involved when bromocriptine is added to an antidepressant is still unknown, but the D 2 receptor stimulation appears to be associated with the beneficial effect of bromocriptine. Several lines of evidence have suggested dopamine's role in depression (Kapur and Mann 1992). Previous studies demonstrated reduced homovanillic acid concentrations in the cerebrospinal fluid in depressed patients as compared with controls. Furthermore, recent studies showed that noradrenaline reuptake inhibitors markedly increased extracellular dopamine concentrations in the medial prefrontal cortex via reuptake inhibition of dopamine into noradrenergic terminals (Carboni et al 1990), and that serotonin (5-HT) reuptake inhibitors increased extracellular dopamine in the prefrontal cortex by stimulating local 5-HT 3 receptors (Tanda et al 1995). These findings suggest that bromocriptine may enhance the effects of antidepressants stimulating the mesocortical dopaminergic system. In conclusion, tricyclic and heterocyclic antidepressant-resistant depression is a major clinical problem, and the antidepressant efficacy of bromocriptine in tricyclic and heterocyclic antidepressant-resistant depression is an important discovery; however, the mechanism of action involved is not clearly understood. Our data require replication in a larger sample using a carefully controlled design.
References Bouckoms A, Mangini L (1993): Pergolide: An antidepressant adjuvant for mood disorders? Psychopharmacol Bull 29:207211. Bouras N, Bridges PK (1982): Bromocriptine in depression. Curr Med Res Opin 8:150-153. Carbon E, Tanda GL, Frau R, Di Chiara G (1990): Blockade of the noradrenaline carrier increases extracellular dopamine
concentrations in the prefrontal cortex: Evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem 55:1067-1070. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Jackson DM, Jenkins OF, Ross SB (1988): The motor effects
Brief Reports
of bromocriptine A review. Psychopharmacology 95:433446. Kapur S, Mann JJ (1992): Role of the dopaminergic system in depression. Biol Psychiatry 32:1-17. Muscat R, Papp M, Willner P (1992): Antidepressant-like effects of dopamine agonists in an animal model of depression. Biol Psychiatry 31:937-946. Post RM, Gerner RH, Carman JS, et al (1978): Effects of a dopamine agonist piribedil in depressed patients. Arch Gen Psychiatry 35:609-615. Silverstone T (1984): Response to bromocriptine distinguishes bipolar from unipolar depression. Lancet i:903-904. Sitland-Marken PA, Wells BG, Froemming JH, Chu C-C, Brown
BIOL PSYCHIATRY
153
1996;40:151-153
CS (1990): Psychiatric applications of bromocriptine therapy.
J Clin Psychiatry 51:68-82. Tanda G, Frau R, Di Chiara G (1995): Local 5-HT 3 receptors mediate fluoxetine but not desipramine-induced increase of extracellular dopamine in the prefrontal cortex. Psychopharmacology 119:15-19. Tbeohar C, Fischer-Cornelssen K, Brosch H, Fischer EK, Petrovic D (1982): A comparative, multicenter trial between bromocriptine and amitriptyline in the treatment of endogenous depression. Arzneimittelforschung 32:783-787. Waehrens J, Gerlach J (1981): Bromocriptine and imipramine in endogenous depression: A double-blind controlled trial in outpatients. J Affect Disord 3:193-202.
Introduction Bromocriptine, a dopamine-2 (D2) receptor agonist (Jackson et al 1988), has been used to treat endogenous depression in several open and double-blind studies (reviewed in Sitland-Marken et al 1990). Three double-blind studies have shown bromocriptine to have similar antidepressant efficacy as imipramine (Bouras and Bridges 1982; Waehrens and Gerlach 1981) and amitriptyline (Theohar et al 1982). Recently, bromocriptine has been found to have anti-depressant-like activity in an animal model (Muscat et al 1992). We evaluated the efficacy of bromocriptine as an antidepressant adjuvant in a preliminary open study involving unipolar depressed patients who had failed to respond to tricyclic or heterocyclic antidepressant.
Methods Three inpatients and 3 outpatients satisfying DSM-III-R criteria for major depression with melancholia consented to participate. None of the patients had ever been psychotic. They had not responded to at least one adequate treatment with tricyclic or heterocyclic antidepressant (i.e., a minimum of the equivalent of 150-200 mg of imipramine for 6 weeks). The inclusion criteria required a minimum score of 15 in the first 17 items of the Hamilton Depression Rating Scale (HDRS) (Hamilton 1960).
From the Department of Psychiatry, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo 060, Japan. Address reprint requests to Takeshi Inoue, MD, Department of Psychiatry, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo 060, Japan. Received June 13, 1995; revised December 1, 1995.
© 1996 Society of Biological Psychiatry
Depressed patients with computed tomography (CT) scan or electroencephalogram (EEG) evidence of organic brain disease were excluded from the study. Also excluded were patients with concurrent significant medical problems. Bromocriptine was initiated at 7.5 mg/day and then adjusted to 7.5-52.5 mg/day on the basis of clinical response and side effects. All patients were on maximally tolerated doses of tricyclic or heterocyclic antidepressants during the bromocriptine trial (Table 1). Evaluations were made before adding bromocriptine to the tricyclic or heterocyclic antidepressants (baseline) and at weeks 2, 4, and 6.
Results Six patients completed the 6-week study. Dose of bromocriptine ranged from 15 to 52.5 mg (mean dose at final rating = 40 rag/day). Four of the 6 subjects responded to bromocriptine treatment as defined by a 50% reduction in the HDRS (see Table 1). One subject had a partial antidepressant response with a 25% reduction in HDRS scores. Reduction in the HDRS scores was statistically significant by the 4th week of treatment and continued to be present during the study (Table 1). Of the individual items of the HDRS, delayed insomnia significantly improved at weeks 4 and 6 (p < .05, Wilcoxon test), and there appeared to be a trend (p < .07) for bromocriptine to improve depressed mood (week 6), middle insomnia (week 6), retardation (week 6), psychic anxiety (weeks 4 and 6), gastrointestinal somatic symptoms (weeks 4 and 6), and general somatic symptoms (week 6). Accordingly, bromocriptine was effective for not only retardation, but also somatic symptoms, insomnia, and anxiety. Side effects were not observed in any patients. After the bromocriptine trials, 3 patients (#1, 2, 6) continued to receive bromocriptine 0006-3223/96/15.00 SSD1 0006-3223(95)00666-4
152
BIOL PSYCHIATRY
Brief Reports
1996;40:151-153
Table 1. Clinical Data of Bromocriptine Treatment in Refractory Depressed Subjects HDRS Subject no.
Age (years)
Gender
1 2 3 4
58 59 69 54
F M F F
5 6 Mean SEM
43 53 56.0 3.5
M M
Duration of episode (months) 2 72 22 147 38 21 50.3 21.6
Week
Concurrent medication (mg)
Maximum bromocriptine (mg)
0
2
4
6
18 26 20 21
13 10 20 16
9 7 13 11
8 7 12 10
52.5 30 52.5 52.5
15 34 22.3 2.8
15 34 18 3.5
15 26 13.5a 2.8
15 10 10.3a 1.2
15 37.5 40.0 6.3
IMP (225) AMX (150) AMX (150) AMX (150) CMI (150) AMT (150) AMX (200)
Previous treatment for current episode
CMI IMP, AMT IMP, AMT IMP AMT
HDRS, Hamilton Depression Rating Scale; IMP, imipramine; AMX, amoxapine; CMI, clomipramine; AMT, amitriptyline. a p < .05, Wilcoxon test.
with tricyclic or heterocyclic antidepressants and recovered fully at weeks 8-12. Two patients (#3, 4) received the adjunctive treatment of thyroid hormones in addition to bromocriptine and tricyclic/heterocyclic antidepressants (1 recovered almost fully, and another did not respond to thyroid hormones). One patient (#5), who did not respond to bromocriptine, received monoamine oxidase inhibitors, but failed to respond.
Discussion The present study shows that the addition of bromocriptine to tficyclic or heterocyclic antidepressants in refractory depression induces another antidepressant effect. To our knowledge, this is the first study that tests the effect of bromocriptine added to tricyclic or heterocyclic antidepressants in refractory depressed patients with melancholia. Onset of response was relatively rapid and occurred within the first 2 weeks in 3 cases. This rapid onset is consistent with the results of previous studies (Sitland-Marken et al 1990). Although previous studies reported that bromocriptine treatment produced hypomania in a few patients (Sitland-Marken et al 1990), no patients became manic in the present study. Siverstone (1984) suggested that bromocriptine was more effective in bipolar depression than unipolar depression, and showed that 2 of 5 bipolar patients became manic during bromocriptine treatment but unipolar patients did not. This finding may account for no occurrence of mania in unipolar depressed patients in the present study. Other dopamine agonists (pergolide and peribedil) were also
reported to have antidepressant efficacy (Bouckoms and Mangini 1993; Post et al 1978). Consistent with the present study, Bouckoms and Mangini (1993) also reported that pergolide, a D1/D 2 agonist, had a role as antidepressant adjuvant in the treatment of refractory depression. The mechanism of action involved when bromocriptine is added to an antidepressant is still unknown, but the D 2 receptor stimulation appears to be associated with the beneficial effect of bromocriptine. Several lines of evidence have suggested dopamine's role in depression (Kapur and Mann 1992). Previous studies demonstrated reduced homovanillic acid concentrations in the cerebrospinal fluid in depressed patients as compared with controls. Furthermore, recent studies showed that noradrenaline reuptake inhibitors markedly increased extracellular dopamine concentrations in the medial prefrontal cortex via reuptake inhibition of dopamine into noradrenergic terminals (Carboni et al 1990), and that serotonin (5-HT) reuptake inhibitors increased extracellular dopamine in the prefrontal cortex by stimulating local 5-HT 3 receptors (Tanda et al 1995). These findings suggest that bromocriptine may enhance the effects of antidepressants stimulating the mesocortical dopaminergic system. In conclusion, tricyclic and heterocyclic antidepressant-resistant depression is a major clinical problem, and the antidepressant efficacy of bromocriptine in tricyclic and heterocyclic antidepressant-resistant depression is an important discovery; however, the mechanism of action involved is not clearly understood. Our data require replication in a larger sample using a carefully controlled design.
References Bouckoms A, Mangini L (1993): Pergolide: An antidepressant adjuvant for mood disorders? Psychopharmacol Bull 29:207211. Bouras N, Bridges PK (1982): Bromocriptine in depression. Curr Med Res Opin 8:150-153. Carbon E, Tanda GL, Frau R, Di Chiara G (1990): Blockade of the noradrenaline carrier increases extracellular dopamine
concentrations in the prefrontal cortex: Evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem 55:1067-1070. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Jackson DM, Jenkins OF, Ross SB (1988): The motor effects
Brief Reports
of bromocriptine A review. Psychopharmacology 95:433446. Kapur S, Mann JJ (1992): Role of the dopaminergic system in depression. Biol Psychiatry 32:1-17. Muscat R, Papp M, Willner P (1992): Antidepressant-like effects of dopamine agonists in an animal model of depression. Biol Psychiatry 31:937-946. Post RM, Gerner RH, Carman JS, et al (1978): Effects of a dopamine agonist piribedil in depressed patients. Arch Gen Psychiatry 35:609-615. Silverstone T (1984): Response to bromocriptine distinguishes bipolar from unipolar depression. Lancet i:903-904. Sitland-Marken PA, Wells BG, Froemming JH, Chu C-C, Brown
BIOL PSYCHIATRY
153
1996;40:151-153
CS (1990): Psychiatric applications of bromocriptine therapy.
J Clin Psychiatry 51:68-82. Tanda G, Frau R, Di Chiara G (1995): Local 5-HT 3 receptors mediate fluoxetine but not desipramine-induced increase of extracellular dopamine in the prefrontal cortex. Psychopharmacology 119:15-19. Tbeohar C, Fischer-Cornelssen K, Brosch H, Fischer EK, Petrovic D (1982): A comparative, multicenter trial between bromocriptine and amitriptyline in the treatment of endogenous depression. Arzneimittelforschung 32:783-787. Waehrens J, Gerlach J (1981): Bromocriptine and imipramine in endogenous depression: A double-blind controlled trial in outpatients. J Affect Disord 3:193-202.