Effectiveness of pindolol plus serotonin uptake inhibitors in depression: A meta-analysis of early and late outcomes from randomised controlled trials

Department of Pharmacology, University of the Basque Country, Leioa, Spain.
Journal of Affective Disorders (Impact Factor: 3.38). 05/2004; 79(1-3):137-47. DOI: 10.1016/S0165-0327(02)00404-4
Source: PubMed


Contradictory results on the efficacy of pindolol associated with selective serotonin reuptake inhibitors (SSRIs) in depressive illness have been published and no former review has produced an overall figure of its efficacy. This study aims to review the efficacy and tolerability of pindolol plus SSRIs in depressive illness.
A meta-analysis of randomised controlled trials (RCTs) comparing pindolol plus SSRIs with placebo plus SSRIs.
Nine RCTs met inclusion criteria. Outcome favoured pindolol at 2 weeks time (N=5; OR=2.8; 95% CI 1.4-5.7), but not at four to 6 weeks (N=7; OR=1.4; 95% CI 0.8-2.7). Results for early outcome studies were robust to sensitivity analysis. Nineteen more studies, averaging null results, would be needed to change the overall probability (P=0.0001) to a non-significant figure.
Pindolol seems to hasten the response to SSRIs in depression with a timing window circumscribed to the first weeks of treatment.

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    • "Moreover, curcumin has been proved to be safe and devoid of adverse effects even in high doses of up to 8 g/day taken for several weeks in human studies[36]. Pindolol seemed to hasten the response to SSRIs in depressive patients with no evidence of improved efficacy beyond the first two weeks of treatment[37] and with a limited effect in treatment-resistant patients[38]. The use of higher doses of pindolol, recommended by certain studies[2838], in future augmentation trials may lead to more adverse effects. "
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    ABSTRACT: This study was designed to study potentiation of fluoxetine's antidepressant effect by curcumin or pindolol. Twenty eight groups of mice (n=8) were used in three sets of experiments. In the first set, 9 groups were subjected to the forced swimming test after being treated intraperitoneally with three vehicles, fluoxetine (5 and 20 mg/kg), curcumin (20 mg/kg), pindolol (32 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). One hour after the test, serum and brain fluoxetine and norfluoxetine levels were measured in mice receiving fluoxetine (5 and 20 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). In the second set, the test was done after pretreatment with p-chlorophenylalanine. In the third set, the locomotor activity was measured. The immobility duration was significantly decreased in fluoxetine (20 mg/kg), curcumin (20 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg) groups. These decreases were reversed with p-chlorophenylalanine. Fluoxetine and norfluoxetine levels were significantly higher in fluoxetine (20 mg/kg) group with no differences in fluoxetine (5 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg) groups. Moreover, drugs failed to alter the locomotor activity indicating absence of central stimulation. In conclusion, curcumin, more than pindolol enhanced the antidepressant effect of a subeffective dose of fluoxetine in mice without increasing its serum or brain levels excluding any pharmacokinetic interaction. Reversal of this potentiation with p-chlorophenylalanine suggests a pharmacodynamic interaction through involvement of presynaptic 5-HT1A receptors.
    Indian Journal of Pharmaceutical Sciences 05/2014; 76(3):203-10. · 0.48 Impact Factor
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    • ", 1998 ; Zanardi et al . , 1998 ; Ballesteros and Callado , 2004 ; Portella et al . , 2011 ) . "
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    ABSTRACT: BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression ( identifier NCT01119430). KEY RESULTS DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.
    British Journal of Pharmacology 11/2011; 167(5):1021-1034. DOI:10.1111/j.1476-5381.2011.01770.x · 4.84 Impact Factor
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    • "In addition, these KOs have also been used to study the mechanism of action of the b1,2 adrenoceptor antagonist, pindolol. This compound is known to shorten the delay of action of SSRIs in depressed patients (see the recent meta-analysis of Ballesteros and Callado, 2004), but it was uncertain whether this effect was mediated by somatodendritic 5-HT1A autoreceptor blockade. We thus studied the effects of coadministration of ( + / – )-pindolol and paroxetine in 5-HT1A KO mice (Guilloux et al., 2006). "
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    ABSTRACT: Several lines of knockout (KO) mice have been evaluated as models of depression-related behavioral and neurobiological changes, and used to investigate molecular and cellular mechanisms underlying the activity of antidepressant drugs. Adult neurogenesis and brain 5-hydroxytryptamine (5-HT)/neurotrophic factor interactions have recently attracted great interest in relation to the mechanism of action of antidepressant drugs. The present review focuses primarily on genetic manipulation of the serotoninergic (5-HT) system. Basal neurochemical and behavioral changes occurring in mice lacking the 5-HT transporter (SERT), which is the main target of antidepressant drugs, as well as in those lacking G protein-coupled serotonin receptors (e.g. 5-HT1B, 5-HT1A, and 5-HT4 receptors) are described and evaluated. The importance of KO mice for neurotrophic factors, particularly for brain-derived neurotrophic factor and its high-affinity receptor (R-TrkB), is also addressed. Constitutive KO, tissue specific, or inducible KO mice targeting both 5-HT and brain-derived neurotrophic factor systems may potentially make an important contribution to knowledge of the pathophysiology and treatment of depression.
    Behavioural pharmacology 03/2009; 20(1):18-32. DOI:10.1097/FBP.0b013e3283243fcd · 2.15 Impact Factor
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