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Neuroendocrine and hypothermic effects of intravenous injection of the selective 5-HT1A receptor agonist flesinoxan in humans
375 treatment with either paroxetine (20, 40 or 60 rag) or placebo, and finally 2 weeks placebo run-out. Dosages were adjusted according to efficacy and tolerance. Standardised cognitive therapy was given to all patients. Although 129 patients were screened for this trial, nine were withdrawn during the placebo run-in period and 120 were randomised to either paroxetine or placebo (paroxetine n = 6 0 , placebo n=60). All 120 patients entering the 12-week flexible dose period were eligible for inclusion in the intention to treat population. The two patient groups were comparable with respect to demographic data. The primary efficacy outcome was a reduction in the number of panic attacks. Analysis of the results showed statistically significant differences in favour of paroxetine between the two treatment groups in two out of three primary efficacy variables, i.e., 50% reduction in total number of panic attacks and the number of panic attacks reduced to one or less over the study period. For the third efficacy variable, the mean change in the total number of attacks from baseline, there was a positive trend in favour of paroxetine. Forty-six (77%) paroxetine patients and 33 (55%) placebo patients reported at least o n e emergent adverse event (Table 1).
Table 1. Emergent adverse events
Number of patients reporting at least one AE Number of frequent events Nausea Sweating Headache Dizziness
Paroxetine (n: 60)
Placebo (n 60)
46 (77%)
33 (55%)
14 (23%) 14 (23%) 13 (22%) 10 (17%)
7 (11%) 3 (5%) 14 (23%) 4 (7%)
The most common adverse events reported for paroxetine were class effects of serotonin re-uptake inhibitors; overall, treatment with paroxetine was well tolerated. In conclusion, paroxetine plus psychotherapy is significantly more effective than placebo plus psychotherapy in the treatment of panic disorder.
Neuroendocrine and hypothermic effects of intravenous injection of the selective 5-HTIA receptor agonist flesinoxan in humans C. Benkelfat a, P. Blier a, B. Seletti a, F. Gilbert b a n d C. de M o n t i g n y a "Neurobiological Psychiatry Unit, McGill University, Montreal. H3A 1A1 and Departement d'Endocrinologie, Hdpital Maisonneuve-Rosemont, Montreal, H1T 2M4, Canada Key words: Prolactin; Growth hormone; ACTH; Cortisol; Hypothermia; 5-HT]A; Receptors Several lines of pre-clinical and clinical evidence suggest that 5-HTIA receptors may be involved in the pathophysiology of anxiety and depressive disorders as well as in the mechanism of action of anxiolytic/antidepressant treatments. Flesinoxan is a p o t e n t and selective 5-HTIA receptor agonist which is presently under clinical investigation for the treatment of generalized anxiety and depressive disorders. In the rat hippocampus, flesinoxan, applied by microiontophoresis, is 17 times more potent than gepirone in suppressing the firing activity of pyramidal neurons. Unlike the azapirones buspirone, gepirone, tandospirone and ipsapirone, flesinoxan does not generate l-(2-pyrimidinyl)-piperazine, an ~2-adrenoceptor antagonist. The safety of the i.v. injection of flesinoxan has previously been established in studies carried out in hypertensive patients. These unique characteristics of flesinoxan therefore make it an ideal potential probe for assessing 5-HTtA receptor function in humans. The present studies consisted of measuring over a 2-h period the hypothermic and neuroendocrine responses (ACTH, cortisol, prolactin, and growth hormone) induced by the i.v. injection of flesinoxan over 10 min to healthy male volunteers. In the first study, saline and two doses of flesinoxan (7 and 14 Itg/kg) were given to 12 subjects under double-blind and randomized conditions, at least 1 week apart. Flesinoxan produced a dose-dependent hypothermia with a maximal effect after 2 h (7 ltg/kg: - 0 . 2 _+ 0.1C: 14/~g/kg: - 0 . 5 + 0.1 C). The low dose of flesinoxan induced modest effects on hormone levels, whereas the high dose consistently produced robust increases (prolactin: 22 + 5 ng/ml; growth hormone: 16 + 3 ng/ml; ACTH: 21 _+ I 0 ng/mk cortisol: 215 + 50 ng/ml). There were no significant effects on heart rate and blood pressure. The drug challenges were well tolerated and the side effects were mild and consisted of drowsiness, lightheadedness, and nausea.
376 In the second study, the ability of the 5-HTIA antagonist pindolol and of the 5-HTt : antagonist methysergide to block the effects of a fixed 1 mg dose of flesinoxan on the same hormones and on body temperature was assessed in 13 subjects. Pindolol (30 rag), methysergide (4 mg), or placebo were given orally under double-blind conditions 90 min prior to the i.v. injection of flesinoxan. The effects of flesinoxan on hypothermia and on hormone levels in the latter condition were similar to those obtained with the high dose in the first study. Methysergide by itself increased growth hormone and ACTH levels, suggesting a partial 5-HTI agonistic effect as it has previously been reported in paradigms assessing 5-HTt receptor function in animals. Pindolol completely blocked the increase in growth hormone but not in prolactin. Conversely, methysergide completely blocked the prolactin increase but not that of growth hormone. The hypothermic response was significantly reduced after 2 h by methysergide ( - 0 . 1 + 0.1 C versus - 0 . 3 ± 0.1 C in the control condition), but not by pindolol. These results indicate that the hypothermia and the increases in growth hormone and prolactin induced by flesinoxan can be blocked by drugs endowed with 5-HTt antagonistic properties. The inability of pindolol to antagonize the hypothermic and prolactin responses to the selective 5-HTIA agonist flesinoxan suggests that the 5-HTIA receptors which mediate these effects have different pharmacological properties than those mediating growth hormone secretion. In conclusion, the i.v. injection of flesinoxan represents a safe, sensitive, and reliable probe to study the responsiveness of 5HTIA receptors in humans.
Effects of litoxetine on psychomotor performance and cognitive function in healthy volunteers
A. Patat ~', I.
Hindmarch b and
V.H.
Curson ~
"S)'nthelabo Recherche (L.E.R.S.), 92225 Bagneu.v Cede.'< France, ]'Rot)ens Institute, University q( Surrey. Milford Hospital. Godalming. Surrey G U7 1UF, UK and ~Svnthelat)o Recherche. London W('I N 2ES, UK Key words. Litoxetine: Antidepressant; 5-HT reuptake inhibitor; Clinical pharmacology; Psychomotor perlbrmance: Cognitive functions Litoxetine, a new benzyloxypiperidine derivative, is a potent selective serotonin reuptake inhibitor. Previous clinical pharmacology studies carried out in healthy young volunteers demonstrated that the clinical and laboratory safety was satisfactory up to 100 mg (single dose) and up to 100 mg b.i.d. (repeated doses for 14 days). A dose-related reduction in platelet serotonin reuptake was observed from 5 mg b.i.d, and was still present after a 1-week treatment. Litoxetine also possesses a pharmaco-EEG profile of a non-sedative antidepressant after single and repeated doses (10 25 rag). Pharmacokinetics indicate that T,..... occurred 3~4 h post dosing and the elimination halt-life is approximately 9 11 11. This randomised, double-blind, 5-way, cross-over study was carried out in 19 healthy female volunteers aged between 20 and 57 years (mean 36.5). The objective was to assess the effects of acute and repeated oral doses of litoxetine 2.5 mg, 5 mg, 10 mg and 25 mg twice daily) or placebo on psychomotor performance and cognitive functions. Psychopharmacological testing was done on day 1 (acute) and day 4 (repeated administration) using a test battery which included critical flicker fusion (CFF), choice reaction time (CRT), simulated car driving test, Sternberg memory scanning test, Stroop test, linear analogue rating scales for sedation and Leeds sleep evaluation questionnaire. Statistical analysis was done using an ANOVA with repeated measures over time. There were no significant impairments on any test measures and a lack of any noticeable trends. Litoxetine 5, 10 and 25 mg b.i.d, induced a significant increase in CFF threshold of 1 1.5 Hz, mainly recorded 4- 12 h post dosing. In addition, litoxetine 5 mg b.i.d, improved memory scanning and matched Stroop test as indicated by a significant decrease in reaction time in comparison to placebo. Litoxetine 25 mg b.i.d, also improved reaction time in the simulated car driving task in comparison to placebo. Finally, litoxetine did not significantly change CRT and subjective evaluation. The lack of sedative side effects and associated cognitive impairment following a range of doses of litoxetine in healthy subjects indicates that the drug has little or no intrinsic potential to disrupt the integrity of performance, cognitive function or interfere with the activities of daily life and can therefore be used safely in ambulant depressed patients.
Table 1. Emergent adverse events
Number of patients reporting at least one AE Number of frequent events Nausea Sweating Headache Dizziness
Paroxetine (n: 60)
Placebo (n 60)
46 (77%)
33 (55%)
14 (23%) 14 (23%) 13 (22%) 10 (17%)
7 (11%) 3 (5%) 14 (23%) 4 (7%)
The most common adverse events reported for paroxetine were class effects of serotonin re-uptake inhibitors; overall, treatment with paroxetine was well tolerated. In conclusion, paroxetine plus psychotherapy is significantly more effective than placebo plus psychotherapy in the treatment of panic disorder.
Neuroendocrine and hypothermic effects of intravenous injection of the selective 5-HTIA receptor agonist flesinoxan in humans C. Benkelfat a, P. Blier a, B. Seletti a, F. Gilbert b a n d C. de M o n t i g n y a "Neurobiological Psychiatry Unit, McGill University, Montreal. H3A 1A1 and Departement d'Endocrinologie, Hdpital Maisonneuve-Rosemont, Montreal, H1T 2M4, Canada Key words: Prolactin; Growth hormone; ACTH; Cortisol; Hypothermia; 5-HT]A; Receptors Several lines of pre-clinical and clinical evidence suggest that 5-HTIA receptors may be involved in the pathophysiology of anxiety and depressive disorders as well as in the mechanism of action of anxiolytic/antidepressant treatments. Flesinoxan is a p o t e n t and selective 5-HTIA receptor agonist which is presently under clinical investigation for the treatment of generalized anxiety and depressive disorders. In the rat hippocampus, flesinoxan, applied by microiontophoresis, is 17 times more potent than gepirone in suppressing the firing activity of pyramidal neurons. Unlike the azapirones buspirone, gepirone, tandospirone and ipsapirone, flesinoxan does not generate l-(2-pyrimidinyl)-piperazine, an ~2-adrenoceptor antagonist. The safety of the i.v. injection of flesinoxan has previously been established in studies carried out in hypertensive patients. These unique characteristics of flesinoxan therefore make it an ideal potential probe for assessing 5-HTtA receptor function in humans. The present studies consisted of measuring over a 2-h period the hypothermic and neuroendocrine responses (ACTH, cortisol, prolactin, and growth hormone) induced by the i.v. injection of flesinoxan over 10 min to healthy male volunteers. In the first study, saline and two doses of flesinoxan (7 and 14 Itg/kg) were given to 12 subjects under double-blind and randomized conditions, at least 1 week apart. Flesinoxan produced a dose-dependent hypothermia with a maximal effect after 2 h (7 ltg/kg: - 0 . 2 _+ 0.1C: 14/~g/kg: - 0 . 5 + 0.1 C). The low dose of flesinoxan induced modest effects on hormone levels, whereas the high dose consistently produced robust increases (prolactin: 22 + 5 ng/ml; growth hormone: 16 + 3 ng/ml; ACTH: 21 _+ I 0 ng/mk cortisol: 215 + 50 ng/ml). There were no significant effects on heart rate and blood pressure. The drug challenges were well tolerated and the side effects were mild and consisted of drowsiness, lightheadedness, and nausea.
376 In the second study, the ability of the 5-HTIA antagonist pindolol and of the 5-HTt : antagonist methysergide to block the effects of a fixed 1 mg dose of flesinoxan on the same hormones and on body temperature was assessed in 13 subjects. Pindolol (30 rag), methysergide (4 mg), or placebo were given orally under double-blind conditions 90 min prior to the i.v. injection of flesinoxan. The effects of flesinoxan on hypothermia and on hormone levels in the latter condition were similar to those obtained with the high dose in the first study. Methysergide by itself increased growth hormone and ACTH levels, suggesting a partial 5-HTI agonistic effect as it has previously been reported in paradigms assessing 5-HTt receptor function in animals. Pindolol completely blocked the increase in growth hormone but not in prolactin. Conversely, methysergide completely blocked the prolactin increase but not that of growth hormone. The hypothermic response was significantly reduced after 2 h by methysergide ( - 0 . 1 + 0.1 C versus - 0 . 3 ± 0.1 C in the control condition), but not by pindolol. These results indicate that the hypothermia and the increases in growth hormone and prolactin induced by flesinoxan can be blocked by drugs endowed with 5-HTt antagonistic properties. The inability of pindolol to antagonize the hypothermic and prolactin responses to the selective 5-HTIA agonist flesinoxan suggests that the 5-HTIA receptors which mediate these effects have different pharmacological properties than those mediating growth hormone secretion. In conclusion, the i.v. injection of flesinoxan represents a safe, sensitive, and reliable probe to study the responsiveness of 5HTIA receptors in humans.
Effects of litoxetine on psychomotor performance and cognitive function in healthy volunteers
A. Patat ~', I.
Hindmarch b and
V.H.
Curson ~
"S)'nthelabo Recherche (L.E.R.S.), 92225 Bagneu.v Cede.'< France, ]'Rot)ens Institute, University q( Surrey. Milford Hospital. Godalming. Surrey G U7 1UF, UK and ~Svnthelat)o Recherche. London W('I N 2ES, UK Key words. Litoxetine: Antidepressant; 5-HT reuptake inhibitor; Clinical pharmacology; Psychomotor perlbrmance: Cognitive functions Litoxetine, a new benzyloxypiperidine derivative, is a potent selective serotonin reuptake inhibitor. Previous clinical pharmacology studies carried out in healthy young volunteers demonstrated that the clinical and laboratory safety was satisfactory up to 100 mg (single dose) and up to 100 mg b.i.d. (repeated doses for 14 days). A dose-related reduction in platelet serotonin reuptake was observed from 5 mg b.i.d, and was still present after a 1-week treatment. Litoxetine also possesses a pharmaco-EEG profile of a non-sedative antidepressant after single and repeated doses (10 25 rag). Pharmacokinetics indicate that T,..... occurred 3~4 h post dosing and the elimination halt-life is approximately 9 11 11. This randomised, double-blind, 5-way, cross-over study was carried out in 19 healthy female volunteers aged between 20 and 57 years (mean 36.5). The objective was to assess the effects of acute and repeated oral doses of litoxetine 2.5 mg, 5 mg, 10 mg and 25 mg twice daily) or placebo on psychomotor performance and cognitive functions. Psychopharmacological testing was done on day 1 (acute) and day 4 (repeated administration) using a test battery which included critical flicker fusion (CFF), choice reaction time (CRT), simulated car driving test, Sternberg memory scanning test, Stroop test, linear analogue rating scales for sedation and Leeds sleep evaluation questionnaire. Statistical analysis was done using an ANOVA with repeated measures over time. There were no significant impairments on any test measures and a lack of any noticeable trends. Litoxetine 5, 10 and 25 mg b.i.d, induced a significant increase in CFF threshold of 1 1.5 Hz, mainly recorded 4- 12 h post dosing. In addition, litoxetine 5 mg b.i.d, improved memory scanning and matched Stroop test as indicated by a significant decrease in reaction time in comparison to placebo. Litoxetine 25 mg b.i.d, also improved reaction time in the simulated car driving task in comparison to placebo. Finally, litoxetine did not significantly change CRT and subjective evaluation. The lack of sedative side effects and associated cognitive impairment following a range of doses of litoxetine in healthy subjects indicates that the drug has little or no intrinsic potential to disrupt the integrity of performance, cognitive function or interfere with the activities of daily life and can therefore be used safely in ambulant depressed patients.