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Randomized, double-blind comparison of venlafaxine and amitriptyline in outpatients with major depression
I?1 Affective disorders and antidepressants
References [I] Sapolsky,R.M.
et al. (1984), Stress down-regulated corticosterone receptors in a site-specific manner in the brain, Endocrinology, 114: 287-292.
Ip.1.113(
In vivo rat brain microdialysis studies of the new 5-HTIA receptor antagonist robalrotan
S. Hjorth. Institute ofPhysiology & Pharmacology, Dept. of Pharmacology, GGfeborg University, PO. Box 431, SE-405 30 Giiteborg, Sweden Robalzotan (generic name for NAD-299) is a novel, selective S-HTIA receptor antagonist. In radioligand binding studies, the compound displays clearcut (>400-fold) preference for the 5-HTl* receptor (I$ = ~0.6 nM) as compared to other 5-HT receptor subpopulations, but also vs. a range of other neurotransmitter binding sites [l]. Furthermore, in various functional (behavioural and in vitro biochemical) models in the rat, this agent acts as a potent, selective HTl* receptor blocker, devoid of any partial agonist properties [ 1,2]. The present study was undertaken to characterize the effects of robalzotan on the output of 5-HT and its main metabolite S-HIAA, in the rat brain in vivo. The studies were carried out by means of intra-cerebral microdialysis in awake, freely-moving rats, with dialysis probes implanted into the frontal cortex (FCx) 48 h beforehand. Given alone, robalzotan (0.1-0.3 mg/kg SC)did not significantly change the extracellular levels of 5-HT in the FCx. The selective S-HTIA receptor agonist S-OH-DPAT (0.1 mgikg SC) suppressed 5-HT release by almost 80%, an effect completely prevented by pretreatment with robalzotan (0.3 mgikg SC;Table 1). In addition, robalzotan (0.3 mg/kg SC)administered 1 h after the SSRI citalopram (5 mg/kg SC), strongly potentiated the 5-HT-elevating action of the latter vs. controls (citalopram + NaCl). Robalzotan (0.1-0.3 mg/kg SC) did not per se affect the extracellular levels of 5-HIAA in the FCx. However, the compound (0.3 mg/kg SC)blocked the 8-OH-DPAT (0.1 mgkg SC)-induced reduction of dialysate 5-HIAA. By comparison, the decrease in extracellular 5HIAA elicited by citalopram (5 m&g SC)was not significantly affected by robalzotan (0.3 m@g SC). In conclusion, the present data show that robalzotan displays potent 5-HTl* autoreceptor blocking properties, as evidenced by its ability i) to reverse the 5-HT release-suppressing and 5-HIAA-lowering action of the selective 5-HT,* receptor agonist g-OHDPAT,and ii) to antagonize increases in endogenous agonist (5-HT) tone at the ~-HTIA autoreceptors as induced by citalopram, thereby markedly enhancing the citalopram-induced 5-HT elevation in the forebrain (FCx). These findings concur with recent electrophysiological studies, demonstrating, i.a., that robalzotan reverses the 5-HT neuronal firing-inhibitory effects of citalopram in the rat dorsal raphe nucleus (Arborelius et al., this meeting). Robalzotan represents an important addition to the array of selective pharmacological tools useful for studies of central 5-HT function. Recent literature indicates that the mixed fi-adrenOCeptOr/.%HT~A receptor blocker pindolol may accelerate and perhaps also augment the clinical action of 5-HT-enhancing antidepressants (e.g. SSRIs). Robalzotan may thus be an interesting candidate to test the hypothesis that the augmenting effect of pindolol results from its ~-HT~A autoreceptor blocking properties, but also for further evaluation as single treatment in central disorders associated with altered 5-HT neurotransmission. Table 1: Robalzotan interactions with I-OH-DPAT and citalopram; summary table. WIT (max. effect, % of baseline) -OH-DPAT Citalopram
5-HIAA (max. effect, % of baseline) 8-OH-DPAT Citalopram
23 f 4+ 126 f 23* -.
61 zk ll+ 112 f 9’
[p.1.1141 Randomized, double-blind comparison of venlafaxine and amitriptyline in outpatients major depression
s17s
with
E. Benedictis, R. Moreno, V Gentil, E.D. Busnello, F.K. Correa, J.A. Campos. Wyeth; Faculdade de Medicina da Universidade de Silo Pa&, MO Paulo. Brazil
Background and Purpose: Comparative studies versus imipramine, clomipramine, trazodone, dothiepin, and fluoxetine demonstrate that the efficacy of venlafaxine is similar or greater than that of the comparators (Lecrubier et al, 1997; Mahapatra and Hackett, 1997; Schweizer et al, 1994). In comparison with tricyclic antidepressants, venlafaxine demonstrates an improved tolerability profile with a low risk for serious adverse events or toxicity. However, results of clinical trials with venlafaxine in Latin America have not previously been published. The purpose of this study was to compare the efficacy and tolerability of venlafaxine and amitriptyline in outpatients with major depression. Methods: This was an g-week, multicenter, randomized, double-blind, parallel-group comparison of venlafaxine and amitriptyline. Outpatients with DSM-IV major depression, a minimum score of 20 on the 21-item HAM-D, and depressive symptoms for at least I month were eligible. Patients were randomly assigned to venlafaxine or amitriptyline. The dose of venlafaxine was 37.5 twice daily with an option to increase to 75 mg twice daily after 2 weeks. The dose of amitriptyline was 75 mg daily, but could be increased to 150 mg daily after 2 weeks. The primary efficacy variables were the final on-therapy scores on the HAMD, MADRS, and CGI severity scale. Data were evaluated on an intentto-treat basis using the last observation carried forward method. Results: One hundred sixteen patients were randomized, and 115were evaluated for efficacy. Baseline demographic and clinical characteristics were comparable between groups. There were significant decreases in the scores of the HAM-D, MADRS, and CGI scale, indicative of improvement at all time points in both treatment groups, compared to pretreatment. Thirty-eight (67%) patients on venlafaxine and 51 (86%) on amitriptyline reported at least one adverse event (p < 0.05). In the amitriptyline group, there was a significant mean weight gain of 2.9 kg from pretreatment, while in the venlafaxine group, there was a significant mean weight loss of 1.4 kg. Conclusion: These results support the similar efficacy and better tolerability of venlafaxine in comparison with amitriptyline in the treatment of major depression. References [l]
LecrubierY,Bowin
M, Moon CAL, et al. Efficacy of venlafaxme in depressive illness in general practice. Acta Psych&r Stand 1997; 95: 485493. [2] Mahapatm S, Hackett D. A randomized, double-blind, parallel-group comparison of venlafaxine and dothiepin in geriatric patients with major depression. Int J Clin Pratt 1997; 51: 209-213. [3] Schweizer E, Feighner J, Mandos L, et al. Comparison of venlafaxine and imipramine in the acute treatment of major depression in outpatients. .I Clin Psychiatry 1994; 55104-108.
-1
The efficacy and tolerability of venlafaxine and paroxetine in outpatients with mild to moderate depression or dysthmia
C. Balltis, G. Quiros, T. de Flores, J. de la Torre, D. Palao, L. Rojo, M. GutiBrrez, L. Casais, Y. Riesgo *. CNS Group; Wyeth-Lederle Spain, Madrid, Spain
NaCl Robalzotan
391 f 35+ 878 zt 175*
’ p I 0.01 vs. baseline, and * p 5 0.01 vs. corresponding
74 f 4+ 76 zt 4 NaCl treatment group.
References [I] Johansson et al., J Pharmacol Exp Therap 283, 216-225, [2] Ahlenius et al.. Em Neuropsychopharmacol, in press
1997
Background and Purpose: Results from controlled clinical trials have shown comparable efficacy for fluoxetine 20 mg/day and venlafaxine 75 mg/day in outpatients with major depression. However at doses of 150 mg/day or greater and in hospitalized patients with severe depression and melancholia, venlafaxine has demonstrated superior efficacy to Auoxetine (Clerc et al, 1994; Costa e Silva, 1998; Dierick et al, 1996). Studies have not been reported comparing the efficacy and tolerability of venlafaxine and paroxetine in patients with mild to moderate depression or dysthmia.
References [I] Sapolsky,R.M.
et al. (1984), Stress down-regulated corticosterone receptors in a site-specific manner in the brain, Endocrinology, 114: 287-292.
Ip.1.113(
In vivo rat brain microdialysis studies of the new 5-HTIA receptor antagonist robalrotan
S. Hjorth. Institute ofPhysiology & Pharmacology, Dept. of Pharmacology, GGfeborg University, PO. Box 431, SE-405 30 Giiteborg, Sweden Robalzotan (generic name for NAD-299) is a novel, selective S-HTIA receptor antagonist. In radioligand binding studies, the compound displays clearcut (>400-fold) preference for the 5-HTl* receptor (I$ = ~0.6 nM) as compared to other 5-HT receptor subpopulations, but also vs. a range of other neurotransmitter binding sites [l]. Furthermore, in various functional (behavioural and in vitro biochemical) models in the rat, this agent acts as a potent, selective HTl* receptor blocker, devoid of any partial agonist properties [ 1,2]. The present study was undertaken to characterize the effects of robalzotan on the output of 5-HT and its main metabolite S-HIAA, in the rat brain in vivo. The studies were carried out by means of intra-cerebral microdialysis in awake, freely-moving rats, with dialysis probes implanted into the frontal cortex (FCx) 48 h beforehand. Given alone, robalzotan (0.1-0.3 mg/kg SC)did not significantly change the extracellular levels of 5-HT in the FCx. The selective S-HTIA receptor agonist S-OH-DPAT (0.1 mgikg SC) suppressed 5-HT release by almost 80%, an effect completely prevented by pretreatment with robalzotan (0.3 mgikg SC;Table 1). In addition, robalzotan (0.3 mg/kg SC)administered 1 h after the SSRI citalopram (5 mg/kg SC), strongly potentiated the 5-HT-elevating action of the latter vs. controls (citalopram + NaCl). Robalzotan (0.1-0.3 mg/kg SC) did not per se affect the extracellular levels of 5-HIAA in the FCx. However, the compound (0.3 mg/kg SC)blocked the 8-OH-DPAT (0.1 mgkg SC)-induced reduction of dialysate 5-HIAA. By comparison, the decrease in extracellular 5HIAA elicited by citalopram (5 m&g SC)was not significantly affected by robalzotan (0.3 m@g SC). In conclusion, the present data show that robalzotan displays potent 5-HTl* autoreceptor blocking properties, as evidenced by its ability i) to reverse the 5-HT release-suppressing and 5-HIAA-lowering action of the selective 5-HT,* receptor agonist g-OHDPAT,and ii) to antagonize increases in endogenous agonist (5-HT) tone at the ~-HTIA autoreceptors as induced by citalopram, thereby markedly enhancing the citalopram-induced 5-HT elevation in the forebrain (FCx). These findings concur with recent electrophysiological studies, demonstrating, i.a., that robalzotan reverses the 5-HT neuronal firing-inhibitory effects of citalopram in the rat dorsal raphe nucleus (Arborelius et al., this meeting). Robalzotan represents an important addition to the array of selective pharmacological tools useful for studies of central 5-HT function. Recent literature indicates that the mixed fi-adrenOCeptOr/.%HT~A receptor blocker pindolol may accelerate and perhaps also augment the clinical action of 5-HT-enhancing antidepressants (e.g. SSRIs). Robalzotan may thus be an interesting candidate to test the hypothesis that the augmenting effect of pindolol results from its ~-HT~A autoreceptor blocking properties, but also for further evaluation as single treatment in central disorders associated with altered 5-HT neurotransmission. Table 1: Robalzotan interactions with I-OH-DPAT and citalopram; summary table. WIT (max. effect, % of baseline) -OH-DPAT Citalopram
5-HIAA (max. effect, % of baseline) 8-OH-DPAT Citalopram
23 f 4+ 126 f 23* -.
61 zk ll+ 112 f 9’
[p.1.1141 Randomized, double-blind comparison of venlafaxine and amitriptyline in outpatients major depression
s17s
with
E. Benedictis, R. Moreno, V Gentil, E.D. Busnello, F.K. Correa, J.A. Campos. Wyeth; Faculdade de Medicina da Universidade de Silo Pa&, MO Paulo. Brazil
Background and Purpose: Comparative studies versus imipramine, clomipramine, trazodone, dothiepin, and fluoxetine demonstrate that the efficacy of venlafaxine is similar or greater than that of the comparators (Lecrubier et al, 1997; Mahapatra and Hackett, 1997; Schweizer et al, 1994). In comparison with tricyclic antidepressants, venlafaxine demonstrates an improved tolerability profile with a low risk for serious adverse events or toxicity. However, results of clinical trials with venlafaxine in Latin America have not previously been published. The purpose of this study was to compare the efficacy and tolerability of venlafaxine and amitriptyline in outpatients with major depression. Methods: This was an g-week, multicenter, randomized, double-blind, parallel-group comparison of venlafaxine and amitriptyline. Outpatients with DSM-IV major depression, a minimum score of 20 on the 21-item HAM-D, and depressive symptoms for at least I month were eligible. Patients were randomly assigned to venlafaxine or amitriptyline. The dose of venlafaxine was 37.5 twice daily with an option to increase to 75 mg twice daily after 2 weeks. The dose of amitriptyline was 75 mg daily, but could be increased to 150 mg daily after 2 weeks. The primary efficacy variables were the final on-therapy scores on the HAMD, MADRS, and CGI severity scale. Data were evaluated on an intentto-treat basis using the last observation carried forward method. Results: One hundred sixteen patients were randomized, and 115were evaluated for efficacy. Baseline demographic and clinical characteristics were comparable between groups. There were significant decreases in the scores of the HAM-D, MADRS, and CGI scale, indicative of improvement at all time points in both treatment groups, compared to pretreatment. Thirty-eight (67%) patients on venlafaxine and 51 (86%) on amitriptyline reported at least one adverse event (p < 0.05). In the amitriptyline group, there was a significant mean weight gain of 2.9 kg from pretreatment, while in the venlafaxine group, there was a significant mean weight loss of 1.4 kg. Conclusion: These results support the similar efficacy and better tolerability of venlafaxine in comparison with amitriptyline in the treatment of major depression. References [l]
LecrubierY,Bowin
M, Moon CAL, et al. Efficacy of venlafaxme in depressive illness in general practice. Acta Psych&r Stand 1997; 95: 485493. [2] Mahapatm S, Hackett D. A randomized, double-blind, parallel-group comparison of venlafaxine and dothiepin in geriatric patients with major depression. Int J Clin Pratt 1997; 51: 209-213. [3] Schweizer E, Feighner J, Mandos L, et al. Comparison of venlafaxine and imipramine in the acute treatment of major depression in outpatients. .I Clin Psychiatry 1994; 55104-108.
-1
The efficacy and tolerability of venlafaxine and paroxetine in outpatients with mild to moderate depression or dysthmia
C. Balltis, G. Quiros, T. de Flores, J. de la Torre, D. Palao, L. Rojo, M. GutiBrrez, L. Casais, Y. Riesgo *. CNS Group; Wyeth-Lederle Spain, Madrid, Spain
NaCl Robalzotan
391 f 35+ 878 zt 175*
’ p I 0.01 vs. baseline, and * p 5 0.01 vs. corresponding
74 f 4+ 76 zt 4 NaCl treatment group.
References [I] Johansson et al., J Pharmacol Exp Therap 283, 216-225, [2] Ahlenius et al.. Em Neuropsychopharmacol, in press
1997
Background and Purpose: Results from controlled clinical trials have shown comparable efficacy for fluoxetine 20 mg/day and venlafaxine 75 mg/day in outpatients with major depression. However at doses of 150 mg/day or greater and in hospitalized patients with severe depression and melancholia, venlafaxine has demonstrated superior efficacy to Auoxetine (Clerc et al, 1994; Costa e Silva, 1998; Dierick et al, 1996). Studies have not been reported comparing the efficacy and tolerability of venlafaxine and paroxetine in patients with mild to moderate depression or dysthmia.