Article

Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors

Archives of General Psychiatry (Impact Factor: 13.75). 04/1994; 51(3):248-51.
Source: PubMed
0 Followers
 · 
53 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vortioxetine, a novel antidepressant for the treatment of major depressive disorder (MDD), is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and serotonin (5-HT) transporter (SERT) inhibitor. Here we review its preclinical and clinical properties and discuss translational aspects. Vortioxetine increases serotonergic, noradrenergic, dopaminergic, cholinergic, histaminergic and glutamatergic neurotransmission in brain structures associated with MDD. These multiple effects likely derive from its interaction with 5-HT-receptor-mediated negative feedback mechanisms controlling neuronal activity. In particular, 5-HT3 receptors may play a prominent role, since their blockade i) increases pyramidal neuron activity by removing 5-HT3 receptor-mediated excitation of GABA interneurons, and ii) augments SSRI effects on extracellular 5-HT. However, modulation of the other 5-HT receptor subtypes also likely contributes to vortioxetine's pharmacological effects. Preclinical animal models reveal differences from SSRIs and SNRIs, including antidepressant-like activity, increased synaptic plasticity and improved cognitive function. Vortioxetine had clinical efficacy in patients with MDD: 11 placebo-controlled studies (including one in elderly) with efficacy in 8 (7 positive, 1 supportive), 1 positive active comparator study plus a positive relapse prevention study. In two positive studies, vortioxetine was superior to placebo in pre-defined cognitive outcome measures. The clinically effective dose range (5-20mg/day) spans ~50 to >80% SERT occupancy. SERT and 5-HT3 receptors are primarily occupied at 5mg, while at 20mg, all targets are likely occupied at functionally relevant levels. The side-effect profile is similar to that of SSRIs, with gastrointestinal symptoms being most common, and a low incidence of sexual dysfunction and sleep disruption possibly ascribed to vortioxetine's receptor modulation. [250 words].
    Pharmacology [?] Therapeutics 07/2014; 145. DOI:10.1016/j.pharmthera.2014.07.001 · 7.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 5-Hydroxytryptamine (5-HT) has the most diverse set of receptors in comparison with any other neurotransmitter or hormone in the body. To date, seven families of 5-HT receptors have been characterized. A great number of studies have been published regarding the role of 5-HT and its receptors in seizures. However, with a few exceptions, the net effect of activating or inhibiting each 5-HT receptor subtype on the development or severity of seizures remains controversial. Additionally, the results of studies, which have used knockout animals to investigate the role of 5-HT receptors in seizures, have sometimes been contradictory to those which have used pharmacological tools. The present study aims to review the available data regarding the influence of each receptor subtype on seizure development and, when possible, reconcile between the apparently different results obtained in these studies.
    Experimental Brain Research 11/2013; DOI:10.1007/s00221-013-3757-0 · 2.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 (clinicaltrials.gov 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 · 4.99 Impact Factor