Abstract
The development of selective serotonin reuptake inhibitors (SSRIs) provided a major advancement in the treatment of depression. However, these drugs suffer from a variety of drawbacks, most notably a delay in the onset of efficacy. One hypothesis suggests that this delay in efficacy is due to a paradoxical decrease in serotonergic (5-HT) neuronal impulse flow and release, following activation of inhibitory presynaptic 5-HT1A autoreceptors, following acute administration of SSRIs. According to the hypothesis, efficacy is seen only when this impulse flow is restored following desensitization of 5-HT1A autoreceptors and coincident increases in postsynaptic 5-HT levels are achieved. Clinical proof of this principal has been suggested in studies that found a significant augmenting effect when the β-adrenergic/5-HT1A receptor antagonist, pindolol, was coadministered with SSRI treatment. In this article, we review preclinical electrophysiological and microdialysis studies that have examined this desensitization hypothesis. We further discuss clinical studies that utilized pindolol as a test of this hypothesis in depressed patients and examine preclinical studies that challenge the notion that the beneficial effect of pindolol is due to functional antagonism of the 5-HT1A autoreceptors.
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References
Stahl S. M. (1998) Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J. Affect. Disord. 51, 215–235.
Hirschfeld R. M. (2000) History and evolution of the monoamine hypothesis of depression. J. Clin. Psychiatry 61, 4–6.
Masand P. S. and Gupta S. (1999) Selective serotonin-reuptake inhibitors: an update. Harv. Rev. Psychiatry 7, 69–84.
Rosen R. C., Lane R. M., and Menza M. (1999) Effects of SSRIs on sexual function: a critical review. J. Clin. Psychopharmacol. 19, 67–85.
Blier P., Pineyro G., el Mansari M., Bergeron R. and de Montigny C. (1998) Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission. Ann. NY Acad. Sci. 861, 204–216.
Artigas F., Romero L., de Montigny C., and Blier P. (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci. 19, 378–383.
Blier P. and Bergeron R. (1998) The use of pindolol to potentiate antidepressant medication. J. Clin. Psychiatry 59, 16–23.
Chaput Y., de Montigny C., and Blier P. (1986) Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: electrophysiological studies in the rat brain. Naunyn Schmiedebergs Arch. Pharmacol. 333, 342–348.
Arborelius L., Nomikos G. G., Grillner P., Hertel P., Hook B. B., Hacksell U., and Svensson T. H. (1995) 5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram. Naunyn Schmiedebergs Arch. Pharmacol. 352, 157–165.
Gartside S. E., Umbers V., Hajos M., and Sharp T. (1995) Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: effects on 5-HT cell firing and extracellular 5-HT. Br. J. Pharmacol. 115, 1064–1070.
Hajós M., Gartside S. E., and Sharp T. (1995) Inhibition of median and dorsal raphe neurones following administration of the selective serotonin reuptake inhibitor paroxetine. Naunyn Schmiedebergs Arch. Pharmacol. 351, 624–629.
Smith J. E. and Lakoski J. M. (1997) Electrophysiological effects of fluoxetine and duloxetine in the dorsal raphe nucleus and hippocampus. Eur. J. Pharmacol. 323, 69–73.
Bel N. and Artigas F. (1992) Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur. J. Pharmacol. 229, 101–103.
Romero L., Bel N., Artigas F., de Montigny C., and Blier P. (1996) Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: in vivo microdialysis and electrophysiological studies in the rat brain. Neuropsychopharmacology 15, 349–360.
Gartside S. E., Umbers V., and Sharp T. (1997) Inhibition of 5-HT cell firing in the DRN by non-selective 5-HT reuptake inhibitors: studies on the role of 5-HT1A autoreceptors and noradrenergic mechanisms. Psychopharmacology 130, 261–268.
Taber M. T., Kinney G. G., Pieschl R. L., Yocca F. D., and Gribkoff V. K. (2000) Differential effects of coadministration of fluoxetine and WAY-100635 on serotonergic neurotransmission in vivo: sensitivity to sequence of injections. Synapse 38, 17–26.
Blier P. and de Montigny C. (1983) Electrophysiological investigations on the effect of repeated zimeldine administration on serotonergic neurotransmission in the rat. J. Neurosci. 3, 1270–1278.
Blier P., de Montigny C., and Tardif D. (1984) Effects of the two antidepressant drugs mianserin and indalpine on the serotonergic system: single-cell studies in the rat. Psychopharmacology 84, 242–249.
de Montigny C. and Blier P. (1984) Effects of antidepressant treatments on 5-HT neurotransmission: electrophysiological and clinical studies, in Frontiers in Biochemical and Pharmacological Research in Depression, (Usdin, E. et al., eds.), Raven, New York, pp. 223–239.
Le Poul E., Laaris N., Doucet E., Laporte A.-M., Hamon M., and Lanfumey L. (1995) Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine. Naunyn Schmiedebergs Arch. Pharmacol. 352, 141–148.
Blier P., Chaput Y., and de Montigny C. (1988) Long-term 5-HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain. Naunyn Schmiedebergs Arch. Pharmacol. 337, 246–254.
Chaput Y., de Montigny C., and Blier P. (1991) Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 5, 219–229.
Hjorth S. and Auerbach S. B. (1994) Lack of 5-HT1A autoreceptor desensitization following chronic citalopram treatment, as determined by in vivo microdialysis. Neuropharmacology 33, 331–334.
Cremers T. I., Spoelstra E. N., de Boer P., Bosker F. J., Mork A., den Boer J. A., et al. (2000) Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram. Eur. J. Pharmacol. 397, 351–357.
Blier P. and Bergeron R. (1995) Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J. Clin. Psychopharmacol. 15, 217–222.
Clifford E. M., Gartside S. E., Umbers V., Cowen P. J., Hajos M., and Sharp T. (1998) Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5-HT1A autoreceptor in vivo. Br. J. Pharmacol. 124, 206–212.
Sprouse J., Braselton J., and Reynolds L. (1998) 5-HT1A agonist activity of pindolol: reversal of the inhibitory effects on cell firing in the dorsal raphe nucleus but not in the hippocampus by WAY-100,635. Ann. NY Acad. Sci. 861, 274,275.
Sprouse J., Braselton J., and Reynolds L. (2000) 5-HT1A agonist potential of pindolol: electrophysiologic studies in the dorsal raphe nucleus and hippocampus. Biol. Psychiatry 47, 1050–1055.
Fornal C. A., Martin F. J., Metzler C. W., and Jacobs B. L. (1999) Pindolol suppresses serotonergic neuronal activity and does not block the inhibition of serotonergic neurons produced by 8-hydroxy-2-(di-n-propylamino)tetralin in awake cats. J. Pharmacol. Exp. Ther. 291, 229–238.
Fornal C. A., Martin F. J., Metzler C. W., and Jacobs B. L. (1999) Pindolol, a putative 5-hydroxytryptamine(1A) antagonist, does not reverse the inhibition of serotonergic neuronal activity induced by fluoxetine in awake cats: comparison to WAY-100635. J. Pharmacol. Exp. Ther. 291, 220–228.
Fornal C. A., Martín F. J., Mendin A., Metzler C. W., Bjorvatn B., and Jacobs B. L. (1999) Pindolol increases extracellular 5-HT while inhibiting serotonergic neuronal activity. Eur. J. Pharmacol. 377, 187–191.
Haddjeri N., de Montigny C., and Blier P. (1999) Modulation of the firing activity of rat serotonin and noradrenaline neurons by (±)pindolol. Biol. Psychiatry 45, 1163–1169.
Arborelius L., Linner L., Wallsten C., Ahlenius S., and Svensson T. H. (2000) Partial 5-HT1A receptor agonist properties of (−)pindolol in combination with citalopram on serotonergic dorsal raphe cell firing in vivo. Psychopharmacology 151, 77–84.
Kinney G. G., Pieschl R. L., Yocca F. D., and Gribkoff V. K. (1999) An electrophysiological comparison of pindolol-induced changes in dorsal raphe nucleus neuronal activity in vivo and in vitro. Soc. Neurosci. Abst. 25, 715.
Haddjeri N., de Montigny C., and Blier P. (1998) Modulation of the firing activity of rat dorsal raphe 5-HT neurons and locus coeruleus NA neurons by (±)pindolol. Soc. Neurosci. Abst. 24, 1366.
Corradetti R., Larris N., Hanoun N., Laporte A.-M., Le Poul E., Hamon M., and Lanfumey L. (1998) Antagonist properties of (−)-pindolol and WAY 100635 at somatodendritic and postsynaptic 5-HT1A receptors in the rat brain. Br. J. Pharmacol. 123, 449–462.
Newman-Tancredi A., Chaput C., Gavaudan S., Verrièle L., and Millan M. J. (1998) Agonist and antagonist actions of (−)pindolol at recombinant, human serotonin1A (5-HT1A) receptors. Neuropsychopharmacology 18, 395–398.
Sargent P. A., Kjaer K. H., Bench C. J., Rabiner E., Messa C., Meyer J., et al. (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635. Arch. Gen. Psychiatry 57, 174–180.
Gardier A. M., Malagie I., Trillat A. C., Jacquot C., and Artigas F. (1996) Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies. Fundam. Clin. Pharmacol. 10, 16–27.
Carboni E., Cadoni C., Tanda G. L., and Di Chiara G. (1989) Calcium-dependent, tetrodotoxin-sensitive stimulation of cortical serotonin release after a tryptophan load. J. Neurochem. 53, 976–978.
Invernizzi R., Belli S., and Samanin R. (1992) Citalopram’s ability to increase the extracellular concentrations of serotonin in the dorsal raphe prevents the drug’s effect in the frontal cortex. Brain Res. 584, 322–324.
Perry K. W. and Fuller R. W. (1992) Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum. Life Sci. 50, 1683–1690.
Hjorth S. (1993) Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study. J. Neurochem. 60, 776–779.
Adell A. and Artigas F. (1991) Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex. An in vivo brain microdialysis study. Naunyn Schmiedebergs Arch. Pharmacol. 343, 237–244.
Dawson L. A. and Nguyen H. Q. (2000) The role of 5-HT(1A) and 5-HT(1B/1D) receptors on the modulation of acute fluoxetine-induced changes in extracellular 5-HT: the mechanism of action of (+/−)pindolol. Neuropharmacology 39, 1044–1052.
Tao R., Ma Z. and Auerbach S. B. (2000) Differential effect of local infusion of serotonin reuptake inhibitors in the raphe versus forebrain and the role of depolarization-induced release in increased extracellular serotonin. J. Pharmacol. Exp. Ther. 294, 571–579.
Rutter J. J. and Auerbach S. B. (1993) Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J. Pharmacol. Exp. Ther. 265, 1319–1324.
Rutter J. J., Gundlah C., and Auerbach S. B. (1995) Systemic uptake inhibition decreases serotonin release via somatodendritic autoreceptor activation. Synapse 20, 225–233.
Kreiss D. S. and Lucki I. (1994) Differential regulation of serotonin (5-HT) release in the striatum and hippocampus by 5-HT1A autoreceptors of the dorsal and median raphe nuclei. J. Pharmacol. Exp. Ther. 269, 1268–1279.
Arborelius L., Nomikos G. G., Hertel P., Salmi P., Grillner P., Hook B. B., et al. (1996) The 5-HT1A receptor antagonist (S)-UH-301 augments the increase in extracellular concentrations of 5-HT in the frontal cortex produced by both acute and chronic treatment with citalopram. Naunyn Schmiedebergs Arch. Pharmacol. 353, 630–640.
Dreshfield L. J., Wong D. T., Perry K. W., and Engleman E. A. (1996) Enhancement of fluoxetine-dependent increase of extracellular serotonin (5-HT) levels by (−)-pindolol, an antagonist at 5-HT1A receptors. Neurochem. Res. 21, 557–562.
Malagie I., Trillat A. C., Douvier E., Anmella M. C., Dessalles M. C., Jacquot C., and Gardier A. M. (1996) Regional differences in the effect of the combined treatment of WAY 100635 and fluoxetine: an in vivo microdialysis study. Naunyn Schmiedebergs Arch. Pharmacol. 354, 785–790.
Romero L., Hervas I., and Artigas F. (1996) The 5-HT1A antagonist WAY-100635 selectively potentiates the presynaptic effects of serotonergic antidepressants in rat brain. Neurosci. Lett. 219, 123–126.
Rollema H., Clarke T., Sprouse J. S., and Schulz D. W. (1996) Combined administration of a 5-hydroxytryptamine (5-HT)1D antagonist and a 5-HT reuptake inhibitor synergistically increases 5-HT release in guinea pig hypothalamus in vivo. J. Neurochem. 67, 2204–2207.
Gobert A., Rivet J. M., Cistarelli L., and Millan M. J. (1997) Potentiation of the fluoxetine-induced increase in dialysate levels of serotonin (5-HT) in the frontal cortex of freely moving rats by combined blockade of 5-HT1A and 5-HT1B receptors with WAY 100,635 and GR 127,935. J. Neurochem. 68, 1159–1163.
Sharp T., Umbers V., and Gartside S. E. (1997) Effect of a selective 5-HT reuptake inhibitor in combination with 5-HT1A and 5-HT1B receptor antagonists on extracellular 5-HT in rat frontal cortex in vivo. Br. J. Pharmacol. 121, 941–946.
Dawson L. A., Nguyen H. Q., Smith D. I., and Schechter L. E. (2000) Effects of chronic fluoxetine treatment in the presence and absence of (+/−)pindolol: a microdialysis study. Br. J. Pharmacol. 130, 797–804.
Hoyer D., Clarke D. E., Fozard J. R., Hartig P. R., Martin G. R., Mylecharane E. J., et al. (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol. Rev. 46, 157–203.
Oksenberg D., Marsters S. A., O’Dowd B. F., Jin H., Havlik S., Peroutka S. J., and Ashkenazi A. (1992) A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT1B receptors. Nature 360, 161–163.
Parker E. M., Grisel D. A., Iben L. G., and Shapiro R. A. (1993) A single amino acid difference accounts for the pharmacological distinctions between the rat and human 5-hydroxytrypamine1B receptors. J. Neurochem. 60, 380–383.
Bel N. and Artigas F. (1993) Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse 15, 243–245.
Caccia S. (1998) Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications. Clin. Pharmacokinet. 34, 281–302.
Rutter J. J., Gundlah C., and Auerbach S. B. (1994) Increase in extracellular serotonin produced by uptake inhibitors is enhanced after chronic treatment with fluoxetine. Neurosci. Lett. 171, 183–186.
Kreiss D. S. and Lucki I. (1995) Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo. J. Pharmacol. Exp. Ther. 274, 866–876.
Invernizzi R., Bramante M., and Samanin R. (1996) Role of 5-HT1A receptors in the effects of acute chronic fluoxetine on extracellular serotonin in the frontal cortex. Pharmacol. Biochem. Behav. 54, 143–147.
Hutson P. H., Sarna G. S., O’Connell M. T., and Curzon G. (1989) Hippocampal 5-HT synthesis and release in vivo is decreased by infusion of 8-OHDPAT into the nucleus raphe dorsalis. Neurosci. Lett. 100, 276–280.
Sharp T., Bramwell S. R., Clark D., and Grahame Smith D. G. (1989) In vivo measurement of extracellular 5-hydroxytryptamine in hippocampus of the anaesthetized rat using microdialysis: changes in relation to 5-hydroxytryptaminergic neuronal activity. J. Neurochem. 53, 234–240.
Bosker F. J., Klompmakers A. A., and Westenberg H. G. (1995) Effects of single and repeated oral administration of fluvoxamine on extracellular serotonin in the median raphe nucleus and dorsal hippocampus of the rat. Neuropharmacology 34, 501–508.
Bosker F. J., van Esseveldt K. E., Klompmakers A. A., and Westenberg H. G. (1995) Chronic treatment with fluvoxamine by osmotic minipumps fails to induce persistent functional changes in central 5-HT1A and 5-HT1B receptors, as measured by in vivo microdialysis in dorsal hippocampus of conscious rats. Psychopharmacology 117, 358–363.
Invernizzi R., Bramante M. and Samanin R. (1995) Extracellular concentrations of serotonin in the dorsal hippocampus after acute and chronic treatment with citalopram. Brain Res. 696, 62–66.
Gur E., Dremencov E., Lerer B., and Newman M. E. (1999) Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in rat brain in vivo. Eur. J. Pharmacol. 372, 17–24.
Invernizzi R., Bramante M., and Samanin R. (1994) Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors. Eur. J. Pharmacol. 260, 243–246.
Gundlah C., Hjorth S., and Auerbach S. B. (1997) Autoreceptor antagonists enhance the effect of the reuptake inhibitor citalopram on extracellular 5-HT: this effect persists after repeated citalopram treatment. Neuropharmacology 36, 475–482.
Hjorth S. and Auerbach S. B. (1999) Autoreceptors remain functional after prolonged treatment with a serotonin reuptake inhibitor. Brain Res. 835, 224–228.
McAskill R., Mir S., and Taylor D. (1998) Pindolol augmentation of antidepressant therapy. Br. J. Psychiatry 173, 203–208.
Béïque J.-C., Blier P., de Montigny C., and Debonnel G. (2000) Potentiation by (−)pindolol of the activation of postsynaptic 5-HT(1A) receptors induced by venlafaxine. Neuropsychopharmacology 23, 294–306.
Schatzberg A. F. and Kraemer H. C. (2000) Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression. Biol. Psychiatry 47, 736–744.
Code of Federal Regulations (1985) 21CFR314.126.
United States Food and Drug Administration (1989) Supplementary advisory: Placebo-controlled and active controlled drug study designs, in The Ethics of Biomedical Research: An International Perspective, (Brody, B., ed.), Oxford University Press, New York, pp. 291, 292.
Berman R. M., Anand A., Cappiello A., Miller H. L., Hu X. S., Oren D. A., and Charney D. S. (1999) The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial. Biol. Psychiatry 45, 1170–1177.
Moreno F. A., Gelenberg A. J., Bachar K., and Delfado P. L. (1997) Pindolol augmentation of treatment-resistant depressed patients. J. Clin. Psychiatry 58, 437–439.
Maes M., Libbrecht I., van Hunsel F., Campens D., and Meltzer H. Y. (1999) Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance. J. Clin. Psychopharmacol. 19, 177–182.
Zanardi R., Artigas F., Franchini L., Sforzini L., Gasperini M., Smeraldi E., and Perez J. (1997) How long should pindolol be associated with paroxetine to improve the antidepressant response? J. Clin. Psychopharmacol. 17, 446–450.
Zanardi R., Franchini L., Gasperini M., Lucca A., Smeraldo E., and Perez J. (1998) Faster onset of action of fluvoxamine in combination with pindolol in the treatment of delusional depression: a controlled study. J. Clin. Psychopharmacol. 18, 441–446.
Bordet R., Thomas P., and Dupuis B. (1998) 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 155, 1346–1351.
Perez V., Gilaberte I., Faries D., Alvarez E., and Artigas F. (1997) Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 349, 1594–1597.
Tome M. B., Isaac M. T., Harte R., and Holland C. (1997) Paroxetine and pindolol: a randomized trial of serotonergic autoreceptor blockade in the reduction of antidepressant latency. Int. Clin. Psychopharmacol. 12, 81–89.
Perez V., Soler J., Puigdemont D., Alvarez E., and Artigas F. (1999) A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch. Gen. Psychiatry 56, 375–379.
Maes M., Vandoolaeghe E., and Desnyder R. (1996) Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J. Affect. Disord. 41, 201–210.
Cowen P. J., Anderson I. M., and Grahame-Smith D. G. (1990) Neuroendocrine effects of azapirones. J. Clin. Psychopharmacol. 10, 21S-25S.
Rabiner E. A., Gunn R. N., Castro M. E., Sargent P. A., Cowen P. J., Koepp M. J., et al. (2000) Beta-blocker binding to human 5-HT(1A) receptors in vivo and in vitro, implications for antidepressant therapy. Neuropsychopharmacology 23, 285–293.
Artigas F., Perez V., and Alvarez E. (1994) Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch. Gen. Psychiatry 51, 248–251.
Dinan T. G. and Scott L. V. (1996) Does pindolol induce a rapid improvement in depressed patients resistant to serotonin reuptake inhibitors? J. Serotonin Res. 3, 119–121.
Vinar O., Vinarová E., and Horácek J. (1996) Pindolol accelerates the therapeutic action of selective serotonin reuptake inhibitors (SSRI) in depression. Homeostasis 37, 93–95.
Bakish D., Hooper C. L., Thornton M. D., Wiens A., Miller C. A., and Thibaudeau C. A. (1997) Fast onset: an open study of the treatment of major depressive disorder with nefazodone and pindolol combination therapy. Int. Clin. Psychopharmacol. 12, 91–97.
Blier P., Bergeron R., and de Montigny C. (1997) Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response. Neuropsychopharmacology 16, 333–338.
Cardoni A. A. and Pisetsky M. (1997) Pindolol augmentation of antidepressant response in depressed psychiatric inpatients. Pharmacotherapy 17, 1100.
Erfurth A., Kammerer C., Ackenheil M., and Moller H.-J. (1997) Effect of pindolol in hastening response to serotoninergic antidepressants: an open study in severely depressed female in-patients. Pharmacopsychiatry 30, 164.
Erfurth A., Kammerer C., Grunze H., and Moeller H.-J. (1998) Does pindolol shorten the latency of action of serotoninergic antidepressives? An open study of severely depressed patients during stationary treatment. Nervenarzt 6, S108.
Shiah I.-S., Yatham L. N., Srisurapanont M., Lam R. W., Tam E. M., and Zis A. P. (1999) Pindolol addition accelerates antidepressant effects of ect in depression. Biol. Psychiatry 45, 70S.
Berman R. M., Darnell A. M., Miller H. L., Anand A., and Charney D. S. (1997) Effect of pindolol in hastening response to fluoxetine in the treatment of major depression: a double-blind, placebo-controlled trial. Am. J. Psychiatry 154, 37–43.
Tome M. B. and Isaac M. T. (1997) Cost-benefit and cost-effectiveness analysis of the rapid onset of selective serotonin reuptake inhibitors by augmentation. Int. J. Psychiatry Med. 27, 377–390.
Tome M. B., Cloninger C. R., Watson J. P., and Isaac M. T. (1997) Serotonergic autoreceptor blockade in the reduction of antidepressant latency: personality variables and response to paroxetine and pindolol. J. Affect. Disord. 44, 101–109.
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Kinney, G.G., Taber, M.T. & Gribkoff, V.K. The augementation hypothesis for improvement of antidepressant therapy. Mol Neurobiol 21, 137–152 (2000). https://doi.org/10.1385/MN:21:3:137
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DOI: https://doi.org/10.1385/MN:21:3:137