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Serotonin 5-HT1a Receptor Agonists as Antidepressants

Pharmacological Rationale and Evidence for Efficacy

  • Pharmacology and Pathophysiology
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Abstract

Although typically considered anxiolytics, for 20 years serotonin 5-HT1A receptor agonists have been evaluated for effectiveness in treating depressive disorders and depressive symptoms occurring in a range of diagnostic categories, including major and minor depression, mixed states of anxiety and depression, and mixed syndromes of depression and alcohol dependence. 5-HT1A agonists have also been studied as adjuncts to standard antidepressant therapy. Most of the work has been done with the widely marketed azapirone, buspirone. A limited amount has been done with other, unmarketed azapirones, including gepirone, ipsapirone, tandospirone and zalospirone. Nonazapirone 5-HT1A receptor agonists have also been studied, and one, flesinoxan, is continuing in clinical trials for the treatment of depression and anxiety.

As a whole, the results have shown antidepressant effects for all compounds, though neither consistently nor robustly. The compounds appear to be well tolerated but adverse effects such as dizziness and nausea are common, and the short half-life of these drugs makes twice or 3 times daily administration necessary. Tolerability and adverse effect problems have been attributed to a metabolite of the azapirones, 1-pyrimidinyl-piperazine (1-PP), which is not a metabolite of the nonazapirone flesinoxan. The short half-life issue has been addressed by extended release oral preparations and transdermal administration via a once-daily skin patch. One study was of 6 months’ duration; the remaining studies have lasted 10 weeks or less. We cannot recommend buspirone, the only currently marketed 5-HT1A receptor agonist, as a first-line treatment for depression, but it is reasonable to consider its use as an adjunct to standard antidepressant drug therapy or in mixed states of anxiety and depression.

The combined results have greatly contributed to our understanding of the role of the 5-HT1A receptor in a range of clinical forms of depression. They have also been useful in understanding the mechanisms of actions of other antidepressants and have guided the development of new medications.

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References

  1. Pecknold JC. Serotonin 5-HT1a agonists: a comparative review. CNS Drugs 1994 Sep; 2: 234–51

    Article  CAS  Google Scholar 

  2. Schweitzer I, Tuckwell V, Johnson G. A review of the use of augmentation therapy for the treatment of resistant depression: implications for the clinician. Aust NZ J Psychiatry 1997 Jun; 31(3): 340–52

    Article  CAS  Google Scholar 

  3. Borne RF. Serotonin: the neurotransmitter for the 90’s. Drug Topics 1994 Oct; 138(19): 108–17

    Google Scholar 

  4. Fulton B, Brogden RN. Buspirone: an updated review of its clinical pharmacology and therapeutic applications. CNS Drugs 1997 Jan; 7(1): 68–88

    Article  CAS  Google Scholar 

  5. Dubovsky SL. Approaches to developing new anxiolytics and antidepressants. J Clin Psychiatry 1993 May; 5Suppl. 54: 75–83

    Google Scholar 

  6. Eison MS. Azapirones: mechanism of action in anxiety and depression. Drug Ther 1990 Aug; 20 Suppl.: 3–8

    Google Scholar 

  7. Keichel JR, Gammans RE. Pharmacocinétique de la buspirone. Psychol Med 1989; 21: 19–31

    Google Scholar 

  8. Cohn JB, Wilcox CS. Buspirone: effectiveness, safety and mechanisms of action. IM —Internal Medicine for the Specialist 1987 Jan; 8(1): 216–24

    Google Scholar 

  9. Gower AJ, Tricklebank MD. Alpha2-adrenoceptor antagonist activity may account for the effects of buspirone in an anti-conflict test in the rat. Eur J Pharmacol 1988; 155: 129–37

    Article  PubMed  CAS  Google Scholar 

  10. DeVry J, Glaser T, Schurman T, et al. 5-HT1a receptors in anxiety. In: Briley M, File SE, editors. New concepts in anxiety. London: Macmillan Press, 1991: 94–129

    Google Scholar 

  11. McIvor RJ, Sinanan K. Buspirone-induced mania [letter]. Br J Psychiatry 1991 Jan; 158: 136–7

    Article  PubMed  CAS  Google Scholar 

  12. Feighner JP, Boyer WF. Buspirone in the treatment of depression. Drug Ther 1990 Aug; 20 Suppl.: 9–17

    Google Scholar 

  13. Robinson DS, Rickels K, Feighner J, et al. Clinical effects of the 5-HT1a partial agonists in depression: a composite analysis of buspirone in the treatment of depression. J Clin Psychopharmacol 1990 Jun; 10Suppl. 3: 67S–76S

    Article  PubMed  CAS  Google Scholar 

  14. Cohn JB, Wilcox CS, Bowden CL, et al. Double-blind comparison of buspirone and clorazepate in anxious outpatients with and without depressive symptoms. Psychopathology 1992; Suppl. 1: 10-21

  15. Tollefson GD, Lancaster SP, Montague-Clouse J. The association of buspirone and its metabolite 1-pyrimidinylpiperazine in the remission of comorbid anxiety with depressive features and alcohol dependency. Psychopharmacol Bull 1991; 27(2): 163–70

    PubMed  CAS  Google Scholar 

  16. Gammans RE, Stringfellow JC, Hvizdos AJ, et al. Use of buspirone in patients with generalized anxiety disorder and coexisting depressive symptoms: a meta-analysis of eight randomized, controlled studies. Neuropsychobiology 1992; 25(4): 193–201

    Article  PubMed  CAS  Google Scholar 

  17. Schweizer E, Rickels K, Hassman H. A double-blind, placebo-controlled comparison of imipramine and buspirone in the treatment of major depression in the elderly in the community [abstract]. Psychopharmacol Bull 1994; 30(4): 639

    Google Scholar 

  18. Jenkins SW, Robinson DS, Fabre LF, et al. Gepirone in the treatment of major depression. J Clin Psychopharmacol 1990 Jun; 10(3 Suppl.): 77S–85S

    Article  PubMed  CAS  Google Scholar 

  19. Fitton A, Benfield P. Gepirone in depression and anxiety disorders: an initial appraisal of its clinical potential. CNS Drugs 1994; 1(5): 388–98

    Article  Google Scholar 

  20. McGrath PJ, Stewart JW, Quitkin FM, et al. Gepirone treatment of atypical depression: preliminary evidence of serotonergic involvement. J Clin Psychopharmacol 1994 Oct; 14: 347–52

    Article  PubMed  CAS  Google Scholar 

  21. Feiger AD. A double-blind comparison of gepirone extended release, imipramine, and placebo in the treatment of outpatient major depression. Psychopharmacol Bull 1996; 32(4): 659–65

    PubMed  CAS  Google Scholar 

  22. Wilcox CS, Ferguson JM, Dale JL, et al. A double-blind trial of low- and high-dose ranges of gepirone-ER compared with placebo in the treatment of depressed outpatients. Psychopharmacol Bull 1996; 32(3): 335–42

    PubMed  CAS  Google Scholar 

  23. Heller AH, Beneke M, Kuemmel B, et al. Ipsapirone: evidence for efficacy in depression. Psychopharmacol Bull 1990; 26: 219–22

    PubMed  CAS  Google Scholar 

  24. Rickels K, Derivan A, Kunz N, et al. Zalospirone in major depression: a placebo-controlled multicenter study. J Clin Psychopharmacol 1996 Jun; 16: 212–7

    Article  PubMed  CAS  Google Scholar 

  25. Hamilton MA. Rating for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62

    Article  PubMed  CAS  Google Scholar 

  26. Hamilton MA. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32: 50–5

    Article  PubMed  CAS  Google Scholar 

  27. McNair DM, Lorr M, Droppleman LF. Profile of mood states (manual). San Diego: Educational and Industrial Testing Services, 1981

    Google Scholar 

  28. Rickels K, Schweizer E. The treatment of generalized anxiety disorder in patients with depressive symptomatology. J Clin Psychiatry 1993 Jan; 54 Suppl.: 20–3

    PubMed  Google Scholar 

  29. Grof P, Joffe P, Kennedy S, et al. An open study of oral flesinoxan, a 5-HT1A receptor agonist, in treatment-resistant depression. Int Clin Psychopharmacol 1993 Fall; 8(3): 167–72

    Article  PubMed  CAS  Google Scholar 

  30. Dimitriou E. Discussant presentation: serotonin partial agonists in the treatment of depression. J Clin Psychiatry 1990 Sep; 9 Suppl. 51: 65–6

    Google Scholar 

  31. Bech P, Gram LF, Dein E, et al. Quantitative rating of depressive states. Acta Psychiatr Scand 1975; 51: 161–70

    Article  PubMed  CAS  Google Scholar 

  32. American Psychiatric Association. Diagnostic statistical manual of mental disorders. 3rd ed (rev). Washington, DC: American Psychiatric Association, 1987: 251–3

    Google Scholar 

  33. American Psychiatric Association. Diagnostic statistical manual of mental disorders. 4th ed. Washington,DC: American Psychiatric Association, 1994: 432–6

    Google Scholar 

  34. Cohen A. The evaluation of the pharmacokinetics of buspirone and its major metabolites from a buspirone transdermal system and buspirone oral tablets in healthy volunteers: a multiple dose study. SANO Corporation, final study report; 1995 May; P512-O494

  35. Sussman N. How to manage anxious patients who are depressed. J Clin Psychiatry 1993 May; Suppl. 54(5): 8–16; discussion 17-20

    PubMed  Google Scholar 

  36. Liebowitz MR. Antidepressants in panic disorders. Br J Psychiatry 1989; 155Suppl. 6: 46–52

    Google Scholar 

  37. DeVry J. 5-HT1a receptor agonists: recent developments and controversial issues. Psychopharmacology 1995; 129(1): 1–26

    Article  Google Scholar 

  38. Stahl SM. 5-HT1a receptors and pharmacotherapy: is serotonin down-regulation linked to the mechanism of action of antide-pressant drugs? Psychopharmacol Bull 1994; 30(1): 39–43

    PubMed  CAS  Google Scholar 

  39. Yocca FD. Neurochemistry and neurophysiology of buspirone and gepirone: interactions at presynaptic and postsynaptic 5-HT1A receptors. J Clin Psychopharmacol 1990; 10(3 Suppl.): 6s–12s

    Article  PubMed  CAS  Google Scholar 

  40. Modell JG. The high cost of buspirone. J Clin Psychiatry 1995 Aug; 56: 375–6

    PubMed  CAS  Google Scholar 

  41. Bristol-Myers Squibb Co. Buspar® (buspirone Acl, USP). Physicians’ desk reference. 52nd ed. Montvale, NJ: Medical Economics Co, Inc, 1998: 782

    Google Scholar 

  42. Borsini F, Giraldo E, Monferini E, et al. BTMT 17, a 5-HT2A receptor antagonist and 5-HT1a receptor full agonist in rat cerebral cortex. Naunyn-Schmiedebergs Arch Pharmacol 1995; 352: 276–82

    PubMed  CAS  Google Scholar 

  43. Peroutka SJ. Molecular biology of serotonin (5-HT) receptors. Synapse 1994; 18(3): 241–60

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Pharmacology Research Institute, 1000 Dove Street, Suite 200, Newport Beach, California, 92660-2814, USA.

    Jon F. Heiser & Charles S. Wilcox

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  1. Jon F. Heiser
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  2. Charles S. Wilcox
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Correspondence to Jon F. Heiser.

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Heiser, J.F., Wilcox, C.S. Serotonin 5-HT1a Receptor Agonists as Antidepressants. Mol Diag Ther 10, 343–353 (1998). https://doi.org/10.2165/00023210-199810050-00004

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