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November 1995, Vol 52, No. 11 >
Article | November 1995

Pindolol, 5-Hydroxytryptamine, and Antidepressant Augmentation

Francesc Artigas, PhD
Arch Gen Psychiatry. 1995;52(11):969-971. doi:10.1001/archpsyc.1995.03950230083012
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References
Comments

I read with interest the letter by Howland1 in the February issue of the Archives on the use of pindolol to augment antidepressant effects.2 Howland argues that pindolol could be acting through β-adrenergic receptors to potentiate the effects of 5-hydroxytryptamine (5-HT) reuptake inhibitors and monoamine oxidase inhibitors. Based on the augmentation of antidepressant effects induced by buspirone hydrochloride,3 a partial 5-HT1A agonist, he also found it difficult to reconcile the fact that agonists and antagonists of the same receptors may produce the same effect. It is important to clarify this issue because it may be critical to understanding the mode of action of pindolol and other Potentially useful 5-HT1A antagonists.

The 5-HT1A receptors are anatomically and pharmacologically heterogeneous. They are localized on the soma and dendrites of serotonergic neurons in the raphe nuclei (presynaptic or somatodendritic location) or on other cell types, in limbic

REFERENCES

1 +
Howland RH.  Biochemical effects of antidepressant augmentation . Arch Gen Psychiatry . 1995;;52:156.
2 +
Artigas F, Perez V, Alvarez E.  Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors . Arch Gen Psychiatry . 1994;;51:248-251.
3 +
Jacobsen FM.  Possible augmentation of antidepressant response by buspirone . J Clin Psychiatry . 1993;;54:269-271.
4 +
Pazos A, Palacios JM.  Quantitative autoradiographic mapping of serotonin receptors in the rat brain, I: serotonin-1 receptors . Brain Res . 1985;;346:205-230.
5 +
Vergé D, Daval G, Marcinkiewicz M, Patey A, El Mestikawy S, Gozlan H, Hamon M.  Quantitative autoradiography of multiple 5-HT receptor subtypes in the brain of control and 5,7-dihydroxytryptamine-treated rats . J Neurosci . 1986;;6:3474-3482.
6 +
Sotelo C, Cholley B, El Mestikawy SE, Gozlan H, Hamon M.  Direct immunohistochemical evidence of the existence of 5-HT autoreceptors on serotonergic neurons in the midbrain raphe nuclei . Eur J Neurosci . 1990;;2:1144-1154.
7 +
Pompeiano M, Palacios JM, Mengod G.  Distribution and cellular localization of mRNA coding for 5-HT1A, receptor in the rat brain: correlation with receptor binding . J Neurosci . 1992;;12:440-453.
8 +
Sprouse JS, Aghajanian GK.  Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: a comparative study with dorsal raphe neurons . Neuropharmacology . 1988;;27:707-715.
9 +
Hjorth S, Sharp T.  Mixed agonist/antagonist properties of NAN-190 at 5-HT1A receptors: behavioural and in vivo brain microdialysis studies . Life Sci . 1990;;46:955-963.
10 +
Sharp T, Backus LI, Hjorth S, Bramwell SR, Grahame-Smith DG.  Further investigation of the in vivo pharmacological properties of the putative 5-HT1A antagonist, BMY 7378 . Eur J Pharmacol . 1990;;176:331-340.
11 +
Sharp T, Mcquade R, Fozard JR, Hoyer D.  The novel 5-HT(1A)—receptor antagonist, SDZ 216-525, decreases 5-HT release in rat hippocampus in vivo . Br J Pharmacol . 1993;;109:699-702.
12 +
Blier P, Lista A, de Montigny C.  Differential properties of presynaptic and postsynaptic 5-hydroxytryptamine(1A) receptors in the dorsal raphe and hippocampus, I: effect of spiperone . J Pharmacol Exp Ther . 1993;;265:7-15.
13 +
Meller E, Goldstein M, Bohmaker K.  Receptor reserve for 5-hydroxytryptamine-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytriptamine agonists . Mol Pharmacol 1990;;37:231-237.
14 +
Cox RF, Meller E, Waszczak BL.  Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT(1A) agonists . Synapse . 1993;;14:297-304.
15 +
Scott PA, Chou JM, Tang H, Frazer A.  Differential induction of 5-HT(1A)—mediated responses in vivo by three chemically dissimilar 5-HT(1A) agonists . J Pharmacol Exp Ther . 1994;;270:198-208.
16 +
Albert PR, Zhou QY, Van Tol HHM, Bunzow JR, Civelli O.  Cloning, functional expression, and mRNA tissue distribution of the rat 5-hydroxytryptamine1A receptor gene . J Biol Chem . 1990;;265:5825-5832.
17 +
Lesch KP, Mayer S, Disselkamp Tietze J, Hoh A, Schoellnhammer G, Schulte HM.  Subsensitivity of the 5-hydroxytryptamine, (5-HT1A) receptor-mediated hypothermic response to ipsapirone in unipolar depression . Life Sci . 1990;;46:1271-1277.
18 +
Cowen PJ, Power AC, Ware CJ, Anderson IM.  5-HT1A receptor sensitivity in major depression: a neuroendocrine study with buspirone . Br J Psychiatry . 1994;;164:372-379.
19 +
Blier P, Seletti B, Young SN, Benkelfat C, De Montigny C.  Serotonin1A receptor activation and hypothermia: evidence for a postsynaptic mechanism in humans . Neuropsychopharmacology . 1994;;10( (suppl 3) ):92S.
20 +
Artigas F, Bel N, Ferrer A, Cortés R.  Increased cortical extracellular 5-HT after repeated, but not acute, treatment with low doses of antidepressants: reduction after tryptophan depletion . Soc Neurosci Abstr . 1993;;19:297. Abstract.
21 +
Green AR, Goodwin GM.  The pharmacology of the hypothermic response of rodents to 8-OH-DPAT administration and the effects of psychotropic drug administration on this response . In: Dourish CT, Ahlenius S, Hutson PH, eds. Brain 5-HT1A Receptors . Chichester, England: Ellis Horwood Ltd; 1987;:161-176.
22 +
Hutson PH, Donohoe TP, Curzon G.  Hypothermia induced by the putative 5-HT1A agonists LY 165163 and 8-OH-DPAT is not prevented by 5-HT depletion . Eur J Pharmacol . 1987;;143:221-228.
23 +
O'Connell MT, Sarna GS, Curzon G.  Evidence for postsynaptic mediation of the hypothermic effect of 5-HT, receptor activation . Br J Pharmacol 1992;;106:603-609.
24 +
Bill DJ, Knight M, Forster EA, Fletcher A.  Direct evidence for an important species difference in the mechanism of 8-OH-DPAT-induced hypothermia . Br J Pharmacol . 1991;;103:1857-1864.
25 +
Artigas F, Romero L, Celada P, Bel N.  5-HT1A antagonists and terminal 5-HT release: effects of the combined treatment with 5-HT uptake inhibitors . Soc Neurosci Abstr . 1994;;20:1541. Abstract.
26 +
Blier P, Seletti B, Bouchard C, Artigas F, De Montigny C.  Functional evidence for the differential responsiveness of pre- and postsynaptic 5-HT1A receptors in the rat brain . Soc Neurosci Abstr . 1994;;20:1540. Abstract.
27 +
Aulakh CS, Wozniak KM, Haas M, Hill JL, Zohar J, Murphy DL.  Food intake, neuroendocrine and temperature effects of 8-OHDPAT in the rat . Eur J Pharmacol . 1988;;146:253-259.
28 +
Bel N, Romero L, Celada P, De Montigny C, Blier P, Artigas F. Neurobiological basis for the potentiation of the antidepressant effect of 5-HT reuptake inhibitors by the 5-HT1A antagonist pindolol. In: Louilot A, Durkin T, Spampinato U, Cador M, eds. Monitoring Molecules in Neuroscience: Proceedings of the 6th International Conference of In Vivo Methods. Bordeaux, France: University of Bordeaux; 1994:209-210.
29 +
Wong DT, Dreshfield LJ, Perry KW, Engleman EA. Augmentation of fluoxetine-induced elevation of extracellular 5-HT levels by pindolol, an antagonist at 5-HT1A receptors. In: The 33rd Annual Meeting of the American College of Neuropsychopharmacology. Nashville, Tenn: ACNP Secretariat; 1994;102.
30 +
Blier P, De Montigny C.  Current advances and trends in the treatment of depression . Trends Pharmacol Sci . 1994;;15:220-226.
31 +
Palacios JM, Pazos A, Hoyer D.  Characterization and mapping of 5-HT1A sites in the brain of animals and man . In: Dourish CT, Ahlenius S, Hutson PH, eds. Brain 5-HT1A Receptors . Chichester, England: Ellis Horwood Ltd; 1987;:67-81.
32 +
Pazos A, Gonzalez-Gil J, Castillo MJ. Increased affinity of beta-blockers for 5-HT1A receptors in the human brain: an autoradiographic study. IUPHAR Satellite Meeting Serotonin. 1994;3:99.
33 +
Hoyer D, Engel G, Kalkman HO.  Characterization of the 5-HT1B recognition site in rat brain: binding studies with (-)(125I)iodocyanopindolol . Eur J Pharmacol . 1985;;118:1-12.
34 +
Martindale. The Extra Pharmacopoeia . 30th ed. London, England: Pharmaceutical Press; 1993;.
35 +
Blier P, Bergeron R.  Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression . J Clin Psychopharmacol . 1995;;15:217-221.
36 +
Avorn J, Everitt DE, Weiss D.  Increased antidepressant use in patients prescribed β-blockers . JAMA . 1986;;255:357-360.
37 +
Sulser F, Vetulani J, Mobley PL.  Mode of action of antidepressant drugs . Biochem Pharmacol . 1978;;27:257-261.
38 +
Assie MB, Charvern M, Palmier C, Puozzo C, Moret C, Briley M.  Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat . Neuropharmacology . 1992;;31:149-155.
39 +
Dechant KL, Clissold SP.  Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness . Drugs . 1991;;41:225-253.
40 +
Hyttel J, Overo KF, Arnt J.  Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor, citalopram . Psychopharmacology (Berl) . 1984;;83:20-27.
41 +
Nalepa I, Vetulani J.  Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram . J Neurochem . 1993;;60:2029-2035.
42 +
Palvimaki EP, Laakso A, Kuoppamaki M, Syvalahti E, Hietala J.  Upregulation of beta(1)-adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments . Psychopharmacology (Berl) . 1994;;115:543-546.
43 +
Peroutka SJ, Snyder SH.  Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding . Science . 1980;;210:88-90.
44 +
Byerley WF, McConnell EJ, McCabe RT, Dawson TM, Grosser BI, Wamsley JK.  Decreased beta-adrenergic receptors in rat brain after chronic administration of the selective serotonin uptake inhibitor fluoxetine . Psychopharmacology . 1988;;94:141-143.
45 +
Nelson JC, Mazure CM, Bowers MB, Jatlow PI.  A preliminary open study of the combination of fluoxetine and desipramine for rapid treatment of major depression . Arch Gen Psychiatry . 1991;;48:303-307.
46 +
Danish University Antidepressant Group.  Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance but weaker antidepressant effect than clomipramine in a controlled multicenter study . J Affect Disord . 1990;;18:289-299.
47 +
Bel N, Artigas F. Acute and chronic effects of imipramine on serotonergic function: microdialysis studies in conscious rats. In: Eighth Congress of the European College of Neuropsychopharmacology. October 1995; Venice, Italy. In press.

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Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Howland RH.  Biochemical effects of antidepressant augmentation . Arch Gen Psychiatry . 1995;;52:156.
2 +
Artigas F, Perez V, Alvarez E.  Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors . Arch Gen Psychiatry . 1994;;51:248-251.
3 +
Jacobsen FM.  Possible augmentation of antidepressant response by buspirone . J Clin Psychiatry . 1993;;54:269-271.
4 +
Pazos A, Palacios JM.  Quantitative autoradiographic mapping of serotonin receptors in the rat brain, I: serotonin-1 receptors . Brain Res . 1985;;346:205-230.
5 +
Vergé D, Daval G, Marcinkiewicz M, Patey A, El Mestikawy S, Gozlan H, Hamon M.  Quantitative autoradiography of multiple 5-HT receptor subtypes in the brain of control and 5,7-dihydroxytryptamine-treated rats . J Neurosci . 1986;;6:3474-3482.
6 +
Sotelo C, Cholley B, El Mestikawy SE, Gozlan H, Hamon M.  Direct immunohistochemical evidence of the existence of 5-HT autoreceptors on serotonergic neurons in the midbrain raphe nuclei . Eur J Neurosci . 1990;;2:1144-1154.
7 +
Pompeiano M, Palacios JM, Mengod G.  Distribution and cellular localization of mRNA coding for 5-HT1A, receptor in the rat brain: correlation with receptor binding . J Neurosci . 1992;;12:440-453.
8 +
Sprouse JS, Aghajanian GK.  Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: a comparative study with dorsal raphe neurons . Neuropharmacology . 1988;;27:707-715.
9 +
Hjorth S, Sharp T.  Mixed agonist/antagonist properties of NAN-190 at 5-HT1A receptors: behavioural and in vivo brain microdialysis studies . Life Sci . 1990;;46:955-963.
10 +
Sharp T, Backus LI, Hjorth S, Bramwell SR, Grahame-Smith DG.  Further investigation of the in vivo pharmacological properties of the putative 5-HT1A antagonist, BMY 7378 . Eur J Pharmacol . 1990;;176:331-340.
11 +
Sharp T, Mcquade R, Fozard JR, Hoyer D.  The novel 5-HT(1A)—receptor antagonist, SDZ 216-525, decreases 5-HT release in rat hippocampus in vivo . Br J Pharmacol . 1993;;109:699-702.
12 +
Blier P, Lista A, de Montigny C.  Differential properties of presynaptic and postsynaptic 5-hydroxytryptamine(1A) receptors in the dorsal raphe and hippocampus, I: effect of spiperone . J Pharmacol Exp Ther . 1993;;265:7-15.
13 +
Meller E, Goldstein M, Bohmaker K.  Receptor reserve for 5-hydroxytryptamine-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytriptamine agonists . Mol Pharmacol 1990;;37:231-237.
14 +
Cox RF, Meller E, Waszczak BL.  Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT(1A) agonists . Synapse . 1993;;14:297-304.
15 +
Scott PA, Chou JM, Tang H, Frazer A.  Differential induction of 5-HT(1A)—mediated responses in vivo by three chemically dissimilar 5-HT(1A) agonists . J Pharmacol Exp Ther . 1994;;270:198-208.
16 +
Albert PR, Zhou QY, Van Tol HHM, Bunzow JR, Civelli O.  Cloning, functional expression, and mRNA tissue distribution of the rat 5-hydroxytryptamine1A receptor gene . J Biol Chem . 1990;;265:5825-5832.
17 +
Lesch KP, Mayer S, Disselkamp Tietze J, Hoh A, Schoellnhammer G, Schulte HM.  Subsensitivity of the 5-hydroxytryptamine, (5-HT1A) receptor-mediated hypothermic response to ipsapirone in unipolar depression . Life Sci . 1990;;46:1271-1277.
18 +
Cowen PJ, Power AC, Ware CJ, Anderson IM.  5-HT1A receptor sensitivity in major depression: a neuroendocrine study with buspirone . Br J Psychiatry . 1994;;164:372-379.
19 +
Blier P, Seletti B, Young SN, Benkelfat C, De Montigny C.  Serotonin1A receptor activation and hypothermia: evidence for a postsynaptic mechanism in humans . Neuropsychopharmacology . 1994;;10( (suppl 3) ):92S.
20 +
Artigas F, Bel N, Ferrer A, Cortés R.  Increased cortical extracellular 5-HT after repeated, but not acute, treatment with low doses of antidepressants: reduction after tryptophan depletion . Soc Neurosci Abstr . 1993;;19:297. Abstract.
21 +
Green AR, Goodwin GM.  The pharmacology of the hypothermic response of rodents to 8-OH-DPAT administration and the effects of psychotropic drug administration on this response . In: Dourish CT, Ahlenius S, Hutson PH, eds. Brain 5-HT1A Receptors . Chichester, England: Ellis Horwood Ltd; 1987;:161-176.
22 +
Hutson PH, Donohoe TP, Curzon G.  Hypothermia induced by the putative 5-HT1A agonists LY 165163 and 8-OH-DPAT is not prevented by 5-HT depletion . Eur J Pharmacol . 1987;;143:221-228.
23 +
O'Connell MT, Sarna GS, Curzon G.  Evidence for postsynaptic mediation of the hypothermic effect of 5-HT, receptor activation . Br J Pharmacol 1992;;106:603-609.
24 +
Bill DJ, Knight M, Forster EA, Fletcher A.  Direct evidence for an important species difference in the mechanism of 8-OH-DPAT-induced hypothermia . Br J Pharmacol . 1991;;103:1857-1864.
25 +
Artigas F, Romero L, Celada P, Bel N.  5-HT1A antagonists and terminal 5-HT release: effects of the combined treatment with 5-HT uptake inhibitors . Soc Neurosci Abstr . 1994;;20:1541. Abstract.
26 +
Blier P, Seletti B, Bouchard C, Artigas F, De Montigny C.  Functional evidence for the differential responsiveness of pre- and postsynaptic 5-HT1A receptors in the rat brain . Soc Neurosci Abstr . 1994;;20:1540. Abstract.
27 +
Aulakh CS, Wozniak KM, Haas M, Hill JL, Zohar J, Murphy DL.  Food intake, neuroendocrine and temperature effects of 8-OHDPAT in the rat . Eur J Pharmacol . 1988;;146:253-259.
28 +
Bel N, Romero L, Celada P, De Montigny C, Blier P, Artigas F. Neurobiological basis for the potentiation of the antidepressant effect of 5-HT reuptake inhibitors by the 5-HT1A antagonist pindolol. In: Louilot A, Durkin T, Spampinato U, Cador M, eds. Monitoring Molecules in Neuroscience: Proceedings of the 6th International Conference of In Vivo Methods. Bordeaux, France: University of Bordeaux; 1994:209-210.
29 +
Wong DT, Dreshfield LJ, Perry KW, Engleman EA. Augmentation of fluoxetine-induced elevation of extracellular 5-HT levels by pindolol, an antagonist at 5-HT1A receptors. In: The 33rd Annual Meeting of the American College of Neuropsychopharmacology. Nashville, Tenn: ACNP Secretariat; 1994;102.
30 +
Blier P, De Montigny C.  Current advances and trends in the treatment of depression . Trends Pharmacol Sci . 1994;;15:220-226.
31 +
Palacios JM, Pazos A, Hoyer D.  Characterization and mapping of 5-HT1A sites in the brain of animals and man . In: Dourish CT, Ahlenius S, Hutson PH, eds. Brain 5-HT1A Receptors . Chichester, England: Ellis Horwood Ltd; 1987;:67-81.
32 +
Pazos A, Gonzalez-Gil J, Castillo MJ. Increased affinity of beta-blockers for 5-HT1A receptors in the human brain: an autoradiographic study. IUPHAR Satellite Meeting Serotonin. 1994;3:99.
33 +
Hoyer D, Engel G, Kalkman HO.  Characterization of the 5-HT1B recognition site in rat brain: binding studies with (-)(125I)iodocyanopindolol . Eur J Pharmacol . 1985;;118:1-12.
34 +
Martindale. The Extra Pharmacopoeia . 30th ed. London, England: Pharmaceutical Press; 1993;.
35 +
Blier P, Bergeron R.  Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression . J Clin Psychopharmacol . 1995;;15:217-221.
36 +
Avorn J, Everitt DE, Weiss D.  Increased antidepressant use in patients prescribed β-blockers . JAMA . 1986;;255:357-360.
37 +
Sulser F, Vetulani J, Mobley PL.  Mode of action of antidepressant drugs . Biochem Pharmacol . 1978;;27:257-261.
38 +
Assie MB, Charvern M, Palmier C, Puozzo C, Moret C, Briley M.  Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat . Neuropharmacology . 1992;;31:149-155.
39 +
Dechant KL, Clissold SP.  Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness . Drugs . 1991;;41:225-253.
40 +
Hyttel J, Overo KF, Arnt J.  Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor, citalopram . Psychopharmacology (Berl) . 1984;;83:20-27.
41 +
Nalepa I, Vetulani J.  Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram . J Neurochem . 1993;;60:2029-2035.
42 +
Palvimaki EP, Laakso A, Kuoppamaki M, Syvalahti E, Hietala J.  Upregulation of beta(1)-adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments . Psychopharmacology (Berl) . 1994;;115:543-546.
43 +
Peroutka SJ, Snyder SH.  Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding . Science . 1980;;210:88-90.
44 +
Byerley WF, McConnell EJ, McCabe RT, Dawson TM, Grosser BI, Wamsley JK.  Decreased beta-adrenergic receptors in rat brain after chronic administration of the selective serotonin uptake inhibitor fluoxetine . Psychopharmacology . 1988;;94:141-143.
45 +
Nelson JC, Mazure CM, Bowers MB, Jatlow PI.  A preliminary open study of the combination of fluoxetine and desipramine for rapid treatment of major depression . Arch Gen Psychiatry . 1991;;48:303-307.
46 +
Danish University Antidepressant Group.  Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance but weaker antidepressant effect than clomipramine in a controlled multicenter study . J Affect Disord . 1990;;18:289-299.
47 +
Bel N, Artigas F. Acute and chronic effects of imipramine on serotonergic function: microdialysis studies in conscious rats. In: Eighth Congress of the European College of Neuropsychopharmacology. October 1995; Venice, Italy. In press.

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