Psychopharmacology

, Volume 127, Issue 1–2, pp 174–180 | Cite as

Effects of the 5-HT1A receptor agonist flesinoxan in panic disorder

  • Irene M. van Vliet
  • Herman G. M. Westenberg
  • Johan A. den Boer
Original Investigation

Abstract

The effects of flesinoxan, a potent and selective 5-HT1A agonist, were studied in two pilot studies in panic disorder patients to explore the role of 5-HT1A receptors in the mechanism of action of antipanic agents. This paper reports on the results of these two studies with flesinoxan. In study I, using a single-blind crossover design, five patients were treated for 1 week with placebo, 4 weeks with flesinoxan (up to 2.4 mg per day), and 2 weeks with placebo. In study II, 15 patients were enrolled in a double-blind, three-armed study with placebo and two dosages of flesinoxan. After a single-blind placebo run-in phase of 1 week, patients were treated for 8 weeks with placebo, 0.6 or 1.2 mg/day flesinoxan. In pilot study I patients’ condition worsened during the 4-week flesinoxan treatment period. Anxiety was frequently reported as an adverse event. Symptoms returned to the pre-treatment level during the 2-week placebo washout period. In pilot study II, no treatment effects in either group were observed. Anxiety as an adverse event was less prominent than in the first pilot study. A lowering of mood was seen in some patients. The sample sizes of these two pilot studies are too small to draw firm conclusions on the efficacy of flesinoxan in panic disorder, but the present data are not encouraging in this respect. The worsening of symptoms seen with the highest dose of flesinoxan is intriguing and might give a clue to the understanding of the mechanism underlying similar effects seen with antidepressants in panic disorder patients.

Key words

Panic disorder Agoraphobia Anxiety Flesinoxan 5-HT1A agonist Human studies 

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References

  1. American Psychiatric Association (1987) Diagnostic and statistic manual of mental disorders. 3rd edn. revised. Washington APA, DCGoogle Scholar
  2. Bel N, Artigas F (1991) Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: in vivo microdialysis study. Eur J Pharmacol 229:101–103CrossRefGoogle Scholar
  3. Borison RL, Albrecht JW, Diamond BI (1990) Efficacy and safety of a putative anxiolytic agent: ipsapirone. Psychopharmacol Bull 26:207–210PubMedGoogle Scholar
  4. Bradford LD, Stevens G (1994) Double-blind placebo controlled fixed does studies of flesinoxan in generalized anxiety disorders. Abstract of the American College of Neuropsychopharmacology, Puerto Rico, p 167Google Scholar
  5. Briley M, Chopin P, Moret C (1991) The role of serotonin in anxiety: behavioural approaches. In: Briley M, File SE (eds) New concepts in anxiety. MacMillan, London, pp 56–73Google Scholar
  6. Chaput Y, Blier P, de Montigny C (1988) Acute and long-term effects of antidepressant serotonin (5-HT) uptake blockers on the efficacy of 5-HT neurotransmission. Electrophysiological studies in the rat. Adv Biol Psychiatry 17:1–17Google Scholar
  7. Chaput Y, de Montigny C, Blier P (1991) Presynaptic and postsynaptic modifications of the serotonergic system by long-term administration of antidepressant treatments. Neuropsychopharmacology 5:219–229PubMedGoogle Scholar
  8. De Montigny C, Blier P (1992) Electrophysical properties of 5-HT-1A receptors and 5-HT-1A agonists. In: Stahl S, Gastpar M, Keppel Hesselink JM et al. (eds) Sorotonin 1A receptors in depression and anxiety. Raven Press, New York, pp 83–98Google Scholar
  9. Den Boer JA, Westenberg HGM (1988) Effects of a serotonin and noradrenaline uptake inhibitor in panic disorder: a double-blind comparative study with fluvoxamine and maprotiline. Int Clin Pshchopharmacol 3:59–74CrossRefGoogle Scholar
  10. Den Boer JA, Westenberg HGM (1990) Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Psychopharmacology 102:85–94CrossRefGoogle Scholar
  11. Den Boer JA, Westenberg HGM, Kamerbeek WDJ, Verhoeven WMA, Kahn RS (1987) Effect of serotonin uptake inhibitors in anxiety disorders; a double-blind comparison of clomipramine and fluvoxamine. Int Clin Psychopharmacol 2:21–32CrossRefGoogle Scholar
  12. De Vry J (1995) 5-HT1A receptor agonists: recent developments and controversial issues. Psychopharmacology 121:1–26PubMedCrossRefGoogle Scholar
  13. Frazer GA, Lapierre YD (1987) The effect of buspirone on panic disorder: a case report. J Clin Psychopharmacol 7:118–119PubMedGoogle Scholar
  14. Fux M, Taub M, Zohar J (1993) Emergence of depressive symptoms during treatment for panic disorder with specific 5-hydroxytryptophan reuptake inhibitors. Acta Psychiatr. Scand 88: 235–237PubMedCrossRefGoogle Scholar
  15. Grof P, Joffe R, Kennedy S, Persad E, Syrotiuk J, Bradford D (1993) An open study of oral flesinoxan, a 5-HT-1A receptor agonist, in treatment-resistant depression. Int Clin Psychopharmacol 8:167–172PubMedCrossRefGoogle Scholar
  16. Guy W (1976) ECDEU Assessment manual for psychopharmacology. US Dept of Health, Education and Welfar, Rockville, Maryland, pp 337–340Google Scholar
  17. Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:50–55PubMedGoogle Scholar
  18. Harto NF, Branconnier RJ, Spera KF (1988) Clinical profile of gepirone: a non-benzodiazepine anxiolytic. Psychopharmacol Bull 24:154–160PubMedGoogle Scholar
  19. Invernizzi R, Belli S, Samamanti R (1991) Citalopram’s ability to increase the extracellular concentration of serotonin in the dorsal raphe prevents the drug’s effect in the frontal cortex. Brain Res 584:322–325CrossRefGoogle Scholar
  20. Invernizzi R, Bramante M, Samamanti 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 260:243–246PubMedCrossRefGoogle Scholar
  21. Johnston DG, Troyer IE, Whitstett SF (1988) Clomipramine in the treatment of agoraphobic woman: Biol Psychiatry 25:101Google Scholar
  22. Kahn RS, Westenberg HGM, Verhoeven WMA, Gispen-De Wied CC (1987) Effects of a serotonin precursor and uptake inhibitor in anxiety disorders: a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Int Clin Psychopharmacol 2:23–45CrossRefGoogle Scholar
  23. Kahn RS, Wetzler S, Van Praag HM, Asnis GM (1988a) Behavioral indications of serotonin receptor hypersensitivity in patients with panic disorder. Psychiatry Res 25:101–104PubMedCrossRefGoogle Scholar
  24. Kahn RS, Wetzler S, Van Praag HM, Asnis GM (1988b) Neuroendocrine evidence for serotonin receptor hypersensitivity in patients with panic disorder. Psychopharmacology 96:360–364PubMedCrossRefGoogle Scholar
  25. Klein E, Zohar J, Geraci MF, Murphy DL, Uhde TW (1991) Anxiogenic effects ofm-CPP in patients with panie disorder—comparison to caffeïne’s anxiogenic effects. Biol Psychiatry 30: 973–984PubMedCrossRefGoogle Scholar
  26. Lesch KP, Wiesmann M, Hoh A, Muller T, Disselkamp-Tietze J, Osterheider M, Schulte HM (1992) 5-HT1A receptor-effector system responsivity in panic disorder. Psychopharmacology 106:111–117PubMedCrossRefGoogle Scholar
  27. Mavissakalian M (1986) The fear questionnaire: a validity study. Behav Res Ther 24:83–85PubMedCrossRefGoogle Scholar
  28. Montgomery SA, Åsberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 34:382–389Google Scholar
  29. Pecknold JC (1994) Serotonin 5-HT-1A agonists: a comparative review. CNS Drugs 2 [3]:234–251CrossRefGoogle Scholar
  30. Pecknold JC, Matas M, Howarth BG (1989) Evaluation of buspirone as an antianxiety agent: buspirone and diazepam versus placebo. Can J Psychiatry 34:766–774PubMedGoogle Scholar
  31. Pecknold JC, Luthe L, Scott-Fleury MH, Jenkins S (1993) Gepirone in the treatment of panic disorder: an open study. J Clin Psychopharmacol 13[2]:145–149PubMedCrossRefGoogle Scholar
  32. Pohl R, Balon R, Yeragani VK, Gershon S (1989) Serotonergic anxiolytics in the treatment of panic disorder: a controlled study with buspirone. Psychopathology 22 [suppl. 1]:60–67PubMedCrossRefGoogle Scholar
  33. Rickels K, Weisman K, Norstad N (1989) Buspirone and diazepam in anxiety: a controlled study. J Clin Psychiatry 43:81–86Google Scholar
  34. Robinson DS, Shrotriya RC, Alms DR, Messina M, Andary J (1989) Treatment of panic disorder: nonbenzodiazepine anxiolytics, including buspirone. Psychopharmacol Bull 25[1]: 21–26PubMedGoogle Scholar
  35. Schipper J, Tulp MTM, Berkelmans B, Mos J, Van der Heijden JAM, Olivier B (1991). Preclinical pharmacology of flesinoxan: a potential anxiolytic and antidepressant drug. Hum Psychopharmacol 6:53–61CrossRefGoogle Scholar
  36. Schweizer E, Rickels K (1988) Buspirone in the treatment of panic disorder: a controlled pilot comparison with clorazepate. J Clin Psychopharmacol 8:303PubMedCrossRefGoogle Scholar
  37. Sharp T, Bramwell SR, Grahame-Smith DG (1991). 5-HT1 agonists reduce 5-HT release in rat hippocampus in vivo as determined by brain microdialysis. Br J Pharmacol 96:283–290Google Scholar
  38. Sheehan D, Raj AB, Harnett Sheehan K, Soto S (1988) The relative efficacy of buspirone, imipramine and placebo in panic disorder: a preliminary report. Pharmacol Biochem Behav 29:815–817PubMedCrossRefGoogle Scholar
  39. Sheehan D, Raj A, Sheehan K, Soto S (1990) Is buspirone effective for panic disorder? J Clin Psychopharmacol 10:3–11PubMedCrossRefGoogle Scholar
  40. Sheehan D, Raj A, Harnett Sheehan K, Soto S, Knapp E (1993) The relative efficacy of high-dose buspirone and alprazolam in the treatment of panic disorder: a double-blind placebo-controlled study. Acta Psychiatr. Scand 88:1–11PubMedCrossRefGoogle Scholar
  41. Snaith RP, Baugh SJ, Clayden AD, Husain A, Sipple MA (1982) The clinical anxiety scale: an instrument derived from the Hamilton Anxiety Scale. Br J Psychiatry 141:518–523PubMedCrossRefGoogle Scholar
  42. Targum SD, Marshall LE (1989) Fenfluramine provocation of anxiety in patients with panic disorder. Psychiatry Res 28:295–306PubMedCrossRefGoogle Scholar
  43. Westenberg HGM, Den Boer JA (1994) The neuropharmacology of anxiety; a review on the role of serotonin. In: Den Boer JA, Sitsen JMA (eds) Handbook of depression and anxiety; a biological approach. Marcel Dekker. New York, Basel, Hong Kong, pp 405–446Google Scholar
  44. Zitrin C, Klein D, Woerner M, Ross D (1983) Treatment of phobias. Comparison of imipramine hydrochloride and placebo. Arch Gen Psychiatry 40:125–138PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Irene M. van Vliet
    • 1
  • Herman G. M. Westenberg
    • 1
  • Johan A. den Boer
    • 1
  1. 1.Rudolf Magnus Institute for Neurosciences. Department of PsychiatryUniversity Hospital UtrechtUtrechtThe Netherlands

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