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 5HT1A
autoreceptors at the time of treatment initiation.
Pindolol, an antagonist at somatodendritic pre-synaptic 5HT1A 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. 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. 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 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., Maes et al., Perez et al., Tome et al. ], 3 tried to underscore shortening of the onset [Bordet, Zanardi ] and 3 tried to underscore the augmentation of efficacy [Maes et al., Moreno et al., Perez et al. ]. 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. Three studies were carried out with
fluoxetine, 1 with
fluvoxamine, 3 with
paroxetine, 1 with
trazodone. Two -studies were investigated with several
antidepressant treatments. The results of the studies indicate one acceleration of
antidepressant response in 6 studies, one augmentation of efficacy in 5 studies. Two studies clearly demonstrate that
pindolol may -augment and accelerate
antidepressant response. Three studies did not confirm these observations. Several points can be examined. For
pindolol: 3 authors 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 yen 2,5 mg day-1) might be insufficient to induce a substantial occupancy of 5-HTA receptors (Rabiner et al. 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. 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. We observed three anterior episodes of depression in negatives studies of the association
pindolol/
antidepressant therapy. 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. 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 accele-rates, 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.