How Long Should Pindolol Be Associated With Paroxetine to Improve the Antidepressant Response?

Abstract

A double-blind study was undertaken to investigate the period of treatment with the beta-adrenoreceptor/5-hydroxytryptamine 1A (5-HT1A) antagonist pindolol required to enhance the antidepressant effects of paroxetine. After 1 week of a placebo run-in period, 63 untreated major depressive inpatients were randomly assigned to three different groups. Group 1 received paroxetine (20 mg/day) plus placebo (4 weeks). Group 2 received paroxetine (20 mg/day) plus pindolol (7.5 mg/day) for 1 week and placebo for 3 weeks. Group 3 received both active treatments for the entire duration of the study (4 weeks). Clinical response was defined as a reduction of the score in the Hamilton Rating Scale for Depression (HAM-D) to 8 or below. Also, to preliminarily examine whether beta-adrenoreceptor blockade was involved in the action of pindolol, another group of 10 inpatients was treated in an open-label manner with paroxetine (20 mg/day) plus 50 mg/day of the beta-adrenergic antagonist metoprolol, devoid of significant affinity for 5-HT1A receptors. At endpoint, the incidence of treatment-emergent side effects did not significantly differ among the three groups. After 1 and 2 weeks of treatment, the two groups treated with paroxetine plus pindolol displayed a significantly greater response rate than the group treated with paroxetine plus placebo. At study completion, only the patients treated with pindolol for the entire period showed a significantly greater response rate (p = 0.05). HAM-D score were also significantly lower at endpoint in patients treated with the combination for 4 weeks (p = 0.00003). The group of patients treated with paroxetine and metoprolol exhibited a side-effect profile comparable to that of paroxetine alone. Response rates were also comparable. These findings support the efficacy of pindolol, but not of metoprolol, in accelerating the antidepressant effect of paroxetine and suggest that the administration of pindolol for the entire period of the acute treatment may increase the efficacy of paroxetine.

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

“…23, NO. 3 tion of Zanardi et al (1997), that metropolol failed to accelerate the antidepressant response of paroxetine.…”

“…* p Ͻ .01, compared to the suppressant effect obtained in rats pre-treated with saline, using a two-way ANOVA. tion of Zanardi et al (1997), that metropolol failed to accelerate the antidepressant response of paroxetine.…”

“…23, NO. 3 tion of Zanardi et al (1997), that metropolol failed to accelerate the antidepressant response of paroxetine.(-)Pindolol bears significant affinity for the 5-HT 1B receptor (Hoyer et al 1985) which is known to negatively regulate the release of 5-HT in terminal areas of the rat brain (Engel et al 1986). Given that in functional assays (-)pindolol acts as an antagonist at the latter receptor (Schoeffter and Hoyer 1989), it is plausible that the latter property could account, at least in part, for the potentiating effect of (-)pindolol on the suppressant effect of venlafaxine on the firing activity of hippocampal neurons that was observed in the present study.…”

“…As a direct outcome of this research endeavour, it has been reported, in six of the seven double blind clinical studies assessing this issue to date, that the addition of pindolol to selected antidepressant agents is a successful strategy to shorten the delay of therapeutic action in major depression (Maes et al 1996;Berman et al 1997;Tome et al 1997;Pérez et al 1997;Zanardi et al 1997Zanardi et al , 1998Bordet et al 1998).…”

Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

“…Thus, such a drug combination may have rapid therapeutic effects that may be detectable during the short-lasting drug withdrawal. Second, the combination of a SSRI with pindolol [antagonist at 5-HT 1A , 5-HT 1B , and ␤ -adrenergic receptors (Assie and Koek 1996;Bourin et al 1998;Gobert and Millan 1999;Hoyer and Schoeffter 1991;Newman-Tancredi et al 1998); also reported to act as a partial agonist at 5-HT 1A and ␣ -adrenergic receptors (Clifford et al 1998;Fornal et al 1999aFornal et al , 1999bFornal et al , 1999cGobert and Millan 1999; Palmier 1994a, 1994b)] accelerates the onset of antidepressant action of SSRIs in humans (Bordet et al 1998;Zanardi et al 1997Zanardi et al , 1998, or augments the antidepressant response to SSRIs in terms of both magnitude and duration of the response (Maes et al 1999;Perez et al 1997;Tome and Isaac 1998; for review, see McAskill et al 1998; however, see Berman et al 1997 however, see Berman et al , 1999Tome et al 1997aTome et al , 1997b. In the present study, instead of pindolol, which has multiple receptor actions, the relatively selective 5-HT 1A receptor antagonist p-MPPI was used.…”