La correction des 2 points faibles des antidépresseurs, à savoir un délai d'action retardé et un pourcentage élevé de résistance au traitement constitue un enjeu majeur dans le traitement de la dépression. Sur la base d'hypothèses physiopathologiques confirmées par des travaux expérimentaux, 6 études ouvertes et 12 études fermées ont étudié l'effet de l'association du pindolol (antagoniste des récepteurs 5HT 1A ) à un traitement antidépresseur tant dans le raccourcissement du délai d'action que dans l'augmentation de son efficacité. Si les études ouvertes concluent à un raccourcissement du délai d'action, les données sont contradictoires en ce qui concerne la potentialisation de l'efficacité. Les études en aveugle, quant à elles, concluent majoritairement à un raccourcissement du délai d'action mais sont moins tranchées en ce qui concerne l'augmentation de l'efficacité. L'inhomogénéité des résultats en ce qui concerne notamment les dépressions résistantes peut être expliquée par des éléments liés à l'histoire de la maladie dépressive des patients. Ainsi, les patients dépressifs aux antécédents d'épisodes dépressifs antérieurs seraient de moins bons répondeurs à l'association pindolol-antidépresseur et surtout si cet antidépresseur a été utilisé sans succès lors des épisodes antérieurs, voire lors de l'épisode actuel (dépressions résistantes).
The principal stakes of depression treatment are to accelerate and enhance the clinical effects of antidepressant drug. The onset of antidepressant action of Serotonin (5HT) selective reuptake inhibitors (SSRIs) was attributed in part to the decrease in firing activity of serotonin neurons produced by the activation of raphe 5HT 1A autoreceptors at the time of treatment initiation. Pindolol, an antagonist at somatodendritic pre-synaptic 5HT 1A receptors has been investigated as a potential accelerator or potentialisator of antidepressant response. Six open label studies and 12 controlled studies were identified for revue. The first open-label pilot study was conducted by Artigas et al. [4ARTIGAS F, PEREZ V, ALVAREZ E. Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry 1994 ; 51 : 248-51.
Haga clic aquí para ir a la sección de Referencias]. They showed promising results with pindolol, both in the acceleration of antidepressant response and in improving the efficacy of antidepressant. On the basis of these results five open-label studies were conducted [7BAKISH D, HOOPER CL, THORNTON MD et al. Fast onset : an open study of the treatment of major depressive disorder with nefazodone and pindolol combination therapy. Inter Clin Psychopharmacol 1997 ; 12 : 91-7.
Haga clic aquí para ir a la sección de Referencias] [11BLIER P, BERGERON R. Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol 1995 ; 15 : 217-22.
Haga clic aquí para ir a la sección de Referencias] [13BLIER P, BERGERON R, de MONTIGNY C. Selective activation of postsynaptic 5HT1A receptors induces rapid antidepressant response. Neuropsychopharmacology 1997 ; 16 : 333-8.
Haga clic aquí para ir a la sección de Referencias] [22DINAN TG, SCOTT LV. Does pindolol induce a rapid improvement in depressed patients resistant to serotonin reuptake inhibitors ? J Ser Res 1996 ; 3 : 119-21.
Haga clic aquí para ir a la sección de Referencias] [47VINAR O, VINAROVA E, HORACEK J. Pindolol accelerates the therapeutic action of selective serotonin reuptake inhibitors in depression. Homeostasis 1996 ; 37 : 93-5.
Haga clic aquí para ir a la sección de Referencias]. The open label studies suggest that pindolol accelerate the antidepressant response of serotoninergics therapeutics. The augmentation of antidepressant response was not clearly demonstrated by these studies particularly in the treatment of refractory depression. For example, Dinan et Scott [22DINAN TG, SCOTT LV. Does pindolol induce a rapid improvement in depressed patients resistant to serotonin reuptake inhibitors ? J Ser Res 1996 ; 3 : 119-21.
Haga clic aquí para ir a la sección de Referencias]that found the addition of pindolol in association with SSRI therapy had a poor efficacy. In the twelve controlled studies, 4 tried to underscore the shortening of the onset and the augmentation of efficacy of SSRI by pindolol [Berman et al. [8BERMAN RM, ANAND A, CAPIELLO A et al. The use of pindolol with fluoxetine in the treatment of major depression : final results from a double-blind, placebo-controlled trial. Biol Psychiatry 1999 ; 45 : 1170-7.
Haga clic aquí para ir a la sección de Referencias], Maes et al. [31MAES M, LIBBRECHT I, VAN HUSSEL F et al. Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patient, including those with treatment resistance. J Clin Psychopharmacol 1999 ; 19 : 177-82.
Haga clic aquí para ir a la sección de Referencias], Perez et al. [36PEREZ V, GILABERTE I, FARIES D et al. Randomized, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 1997 ; 349 : 1594-7.
Haga clic aquí para ir a la sección de Referencias], Tome et al. [46TOME MB, ISAAC MT, HARTE R et al. Paroxetine and pindolol : a randomized trial of serotonergic autoreceptor blockade in the reduction of antidepressant latency. Inter Clin Psychopharmacol 1997 ; 12 : 81-9.
Haga clic aquí para ir a la sección de Referencias]], 3 tried to underscore shortening of the onset [Bordet [16BORDET R, THOMAS P, DUPUIS B. Effect of pindolol on onset of action of paroxetine in the treatment of major depression : intermediate analysis of a double-blind, placebo-controlled trial. Am J Psychiatry 1998 ; 155 : 1346-51.
Haga clic aquí para ir a la sección de Referencias], Zanardi [48ZANARDI R, ARTIGAS F, FRANCHINI L et al. How long should pindolol be associated with paroxetine to improve the antidepressant response ? J Clin Psychopharmacol 1997 ; 17 (6) : 446-50.
Haga clic aquí para ir a la sección de Referencias] [49ZANARDI F, FRANCHINI L, GASPERINI M et al. Faster onset of action of fuvoxamine in combination with pindolol in the treatment of delusional depression : a controlled study. J Clin Psychopharmacol 1998 ; 18 : 441-6.
Haga clic aquí para ir a la sección de Referencias]] and 3 tried to underscore the augmentation of efficacy [Maes et al. [30MAES M, VANDOOLAEGHE E, DESNYDER R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord 1996 ; 41 : 201-10.
Haga clic aquí para ir a la sección de Referencias], Moreno et al. [33MORENO FA, GELENBERG AJ, BACHAR K et al. Pindolol augmentation of treatment-resistant depressed patients. J Clin Psychiatry 1997 ; 58 : 437-9.
Haga clic aquí para ir a la sección de Referencias], Perez et al. [37PEREZ V, SOLER J, PUIGDEMONT D et al. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry 1999 ; 56 : 375-9.
Haga clic aquí para ir a la sección de Referencias]]. One study tried to underscore the augmentation of efficacy of sleep deprivation by pindolol and another one the shortening of the onset of ECT. Six studies included depressive resistant patients [30MAES M, VANDOOLAEGHE E, DESNYDER R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord 1996 ; 41 : 201-10.
Haga clic aquí para ir a la sección de Referencias] [31MAES M, LIBBRECHT I, VAN HUSSEL F et al. Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patient, including those with treatment resistance. J Clin Psychopharmacol 1999 ; 19 : 177-82.
Haga clic aquí para ir a la sección de Referencias] [33MORENO FA, GELENBERG AJ, BACHAR K et al. Pindolol augmentation of treatment-resistant depressed patients. J Clin Psychiatry 1997 ; 58 : 437-9.
Haga clic aquí para ir a la sección de Referencias] [37PEREZ V, SOLER J, PUIGDEMONT D et al. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry 1999 ; 56 : 375-9.
Haga clic aquí para ir a la sección de Referencias] [43SHIAH IS, YATHAM LN, SRISURAPANONT M et al. Does the addition of pindolol accelerate the response to electroconvulsive therapy in patients with major depression ? A double-blind, placebo-controlled pilot study. J Clin Psychopharmacol 2000 ; 20 (3) : 373-8.
Haga clic aquí para ir a la sección de Referencias] [44SMERALDI E, BENEDETTI F, BARBINI B et al. Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial. Neuropsychopharmacoly 1999 ; 20 (4) : 380-5.
Haga clic aquí para ir a la sección de Referencias]. Three studies were carried out with fluoxetine [8BERMAN RM, ANAND A, CAPIELLO A et al. The use of pindolol with fluoxetine in the treatment of major depression : final results from a double-blind, placebo-controlled trial. Biol Psychiatry 1999 ; 45 : 1170-7.
Haga clic aquí para ir a la sección de Referencias] [31MAES M, LIBBRECHT I, VAN HUSSEL F et al. Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patient, including those with treatment resistance. J Clin Psychopharmacol 1999 ; 19 : 177-82.
Haga clic aquí para ir a la sección de Referencias] [36PEREZ V, GILABERTE I, FARIES D et al. Randomized, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 1997 ; 349 : 1594-7.
Haga clic aquí para ir a la sección de Referencias], 1 with fluvoxamine [49ZANARDI F, FRANCHINI L, GASPERINI M et al. Faster onset of action of fuvoxamine in combination with pindolol in the treatment of delusional depression : a controlled study. J Clin Psychopharmacol 1998 ; 18 : 441-6.
Haga clic aquí para ir a la sección de Referencias], 3 with paroxetine [17BORDET R, THOMAS P, DUPUIS B. Délai d'action des antidépresseurs: des données expérimentales à la prise en charge clinique. Lett Pharmacol 1999 ; 13 (7) : 167-73.
Haga clic aquí para ir a la sección de Referencias] [46TOME MB, ISAAC MT, HARTE R et al. Paroxetine and pindolol : a randomized trial of serotonergic autoreceptor blockade in the reduction of antidepressant latency. Inter Clin Psychopharmacol 1997 ; 12 : 81-9.
Haga clic aquí para ir a la sección de Referencias] [48ZANARDI R, ARTIGAS F, FRANCHINI L et al. How long should pindolol be associated with paroxetine to improve the antidepressant response ? J Clin Psychopharmacol 1997 ; 17 (6) : 446-50.
Haga clic aquí para ir a la sección de Referencias], 1 with trazodone [30MAES M, VANDOOLAEGHE E, DESNYDER R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord 1996 ; 41 : 201-10.
Haga clic aquí para ir a la sección de Referencias]. Two studies were investigated with several antidepressant treatments [33MORENO FA, GELENBERG AJ, BACHAR K et al. Pindolol augmentation of treatment-resistant depressed patients. J Clin Psychiatry 1997 ; 58 : 437-9.
Haga clic aquí para ir a la sección de Referencias] [37PEREZ V, SOLER J, PUIGDEMONT D et al. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry 1999 ; 56 : 375-9.
Haga clic aquí para ir a la sección de Referencias]. The results of the studies indicate one acceleration of antidepressant response in 6 studies [16BORDET R, THOMAS P, DUPUIS B. Effect of pindolol on onset of action of paroxetine in the treatment of major depression : intermediate analysis of a double-blind, placebo-controlled trial. Am J Psychiatry 1998 ; 155 : 1346-51.
Haga clic aquí para ir a la sección de Referencias] [36PEREZ V, GILABERTE I, FARIES D et al. Randomized, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 1997 ; 349 : 1594-7.
Haga clic aquí para ir a la sección de Referencias] [43SHIAH IS, YATHAM LN, SRISURAPANONT M et al. Does the addition of pindolol accelerate the response to electroconvulsive therapy in patients with major depression ? A double-blind, placebo-controlled pilot study. J Clin Psychopharmacol 2000 ; 20 (3) : 373-8.
Haga clic aquí para ir a la sección de Referencias] [46TOME MB, ISAAC MT, HARTE R et al. Paroxetine and pindolol : a randomized trial of serotonergic autoreceptor blockade in the reduction of antidepressant latency. Inter Clin Psychopharmacol 1997 ; 12 : 81-9.
Haga clic aquí para ir a la sección de Referencias] [48ZANARDI R, ARTIGAS F, FRANCHINI L et al. How long should pindolol be associated with paroxetine to improve the antidepressant response ? J Clin Psychopharmacol 1997 ; 17 (6) : 446-50.
Haga clic aquí para ir a la sección de Referencias] [49ZANARDI F, FRANCHINI L, GASPERINI M et al. Faster onset of action of fuvoxamine in combination with pindolol in the treatment of delusional depression : a controlled study. J Clin Psychopharmacol 1998 ; 18 : 441-6.
Haga clic aquí para ir a la sección de Referencias], one augmentation of efficacy in 5 studies [30MAES M, VANDOOLAEGHE E, DESNYDER R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord 1996 ; 41 : 201-10.
Haga clic aquí para ir a la sección de Referencias] [31MAES M, LIBBRECHT I, VAN HUSSEL F et al. Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patient, including those with treatment resistance. J Clin Psychopharmacol 1999 ; 19 : 177-82.
Haga clic aquí para ir a la sección de Referencias] [36PEREZ V, GILABERTE I, FARIES D et al. Randomized, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 1997 ; 349 : 1594-7.
Haga clic aquí para ir a la sección de Referencias] [44SMERALDI E, BENEDETTI F, BARBINI B et al. Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial. Neuropsychopharmacoly 1999 ; 20 (4) : 380-5.
Haga clic aquí para ir a la sección de Referencias] [48ZANARDI R, ARTIGAS F, FRANCHINI L et al. How long should pindolol be associated with paroxetine to improve the antidepressant response ? J Clin Psychopharmacol 1997 ; 17 (6) : 446-50.
Haga clic aquí para ir a la sección de Referencias]. Two studies clearly demonstrate that pindolol may augment and accelerate antidepressant response [36PEREZ V, GILABERTE I, FARIES D et al. Randomized, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 1997 ; 349 : 1594-7.
Haga clic aquí para ir a la sección de Referencias] [48ZANARDI R, ARTIGAS F, FRANCHINI L et al. How long should pindolol be associated with paroxetine to improve the antidepressant response ? J Clin Psychopharmacol 1997 ; 17 (6) : 446-50.
Haga clic aquí para ir a la sección de Referencias]. Three studies did not confirm these observations [8BERMAN RM, ANAND A, CAPIELLO A et al. The use of pindolol with fluoxetine in the treatment of major depression : final results from a double-blind, placebo-controlled trial. Biol Psychiatry 1999 ; 45 : 1170-7.
Haga clic aquí para ir a la sección de Referencias] [33MORENO FA, GELENBERG AJ, BACHAR K et al. Pindolol augmentation of treatment-resistant depressed patients. J Clin Psychiatry 1997 ; 58 : 437-9.
Haga clic aquí para ir a la sección de Referencias] [37PEREZ V, SOLER J, PUIGDEMONT D et al. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry 1999 ; 56 : 375-9.
Haga clic aquí para ir a la sección de Referencias]. Several points can be examined. For pindolol : 3 authors [16BORDET R, THOMAS P, DUPUIS B. Effect of pindolol on onset of action of paroxetine in the treatment of major depression : intermediate analysis of a double-blind, placebo-controlled trial. Am J Psychiatry 1998 ; 155 : 1346-51.
Haga clic aquí para ir a la sección de Referencias] [31MAES M, LIBBRECHT I, VAN HUSSEL F et al. Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patient, including those with treatment resistance. J Clin Psychopharmacol 1999 ; 19 : 177-82.
Haga clic aquí para ir a la sección de Referencias] [36PEREZ V, GILABERTE I, FARIES D et al. Randomized, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 1997 ; 349 : 1594-7.
Haga clic aquí para ir a la sección de Referencias]have demonstrated that the effect of pindolol did not rely upon small antidepressant effect mediated by b-blockers properties, because anxiety was not predominantly improved by pindolol plus SSRI while depressive symptoms were clearly improved. On the basis of data issues from recent positron emission tomography (PET) studies, several authors suggested that the dose of pindolol used in most clinical trials (3 x 2,5 mg day-1) might be insufficient to induce a substantial occupancy of 5-HTA receptors (Rabiner et al. [38RABINER EA, GUNN RN, CASTRO ME et al. b-blocker binding to human 5HT1A receptors in vivo and in vitro : implications for antidepressant therapy. Neuropsychopharmacoly 2000 ; 23 : 285-93.
Haga clic aquí para ir a la sección de Referencias] [39RABINER EA, BHAGWAGAR Z, GUNN RN. Pindolol augmentation of selective serotonin reuptake inhibitors : PET evidence that the dose used in clinical trials is too low. Am J Psychiatry 2001 ; 158 : 2080-2.
Haga clic aquí para ir a la sección de Referencias]. It is possible that higher doses will show a more evident benefit. On the whole, pindolol seemed to be well tolerated. Adverse effects most commonly reported were increased irritability, insomnia and nausea. Pindolol had poor adverse effects in cardiovascular functions. The variation of the results of the controlled studies can be explained by different points : Firstly by difficulty to determine good criterion of resistance. The most simplistic definition of treatment resistance is the failure to achieve and sustain euthymia with adequate antidepressant treatment [24FAVA M, DAVIDSON K. Definition and epidemiology of treatment-resistant depression. Psy Clin North America 1996 ; 19 (2) : 179-200.
Haga clic aquí para ir a la sección de Referencias]. Secondly by the fact that depressive patients who present antecedents of depressive illness seem to be worst responders to the association pindolol/serotoninergic antidepressant than patients suffering of first episode of depression. We observed one antecedent of depression in the group of resistant patients who were good responders to the association pindolol/antidepressant therapy [30MAES M, VANDOOLAEGHE E, DESNYDER R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord 1996 ; 41 : 201-10.
Haga clic aquí para ir a la sección de Referencias] [31MAES M, LIBBRECHT I, VAN HUSSEL F et al. Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patient, including those with treatment resistance. J Clin Psychopharmacol 1999 ; 19 : 177-82.
Haga clic aquí para ir a la sección de Referencias]. We observed three anterior episodes of depression in negatives studies of the association pindolol/antidepressant therapy [37PEREZ V, SOLER J, PUIGDEMONT D et al. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry 1999 ; 56 : 375-9.
Haga clic aquí para ir a la sección de Referencias]. Thirdly by the fact that the failure of the antidepressant treatment at the time of earlier (or actual) episode seems to be a criterion for less responsiveness to the association of this antidepressant treatment with pindolol. In fact, the open label studies who demonstrated efficacy of the association between pindolol and serotoninergic therapy in major resistant depression were realized with new antidepressant molecule for the episode. Other controlled trials could confirm these facts. Most of the studies failed to retrace clearly the historicity of depression, and it may be interesting in future investigations to analyze the response of the association compared to the status of the patient with the antidepressant therapy. Further perspective could be envisaged especially in the utilization of pindolol for the treatment of pathologies which are usually treated with a serotoninergic antidepressant therapy. For example, the antagonist 5HT 1A Way 100635 was experimented with success in animals in order to augment the efficacy of clomipramine in the treatment of chronic pain [1ARDID D, ALLOUI A, BROUSSE G et al. Potentiation of the antinociceptive effect of clomipramine by a 5HT1A antagonist in neuropathic pain in rats. Br J Pharmacol 2001 ; 132 : 1118-26.
Haga clic aquí para ir a la sección de Referencias]. In other respects several psychopharmacogenetics studies could be investigated to examine, for instance, the role of the 5-HT transporter and its implication in the response to pindolol and antidepressant association. In summary, pindolol accelerates, and in some cases enhances the clinical action of antidepressant drugs. It appears that this augmentation strategy has more limited effect on treatment resistant patient but there is experimental evidence for using higher doses in future augmentation trial.
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