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The long-term efficacy and safety of paroxetine in panic disorder
0-25
207
Neuroendocrine
hibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are effective in the treatment of panic disorder (PD). In this study the SSRI fluvoxamine (Fluv) was compared to the selective and reversible MAO-A-I brofaromine (Brof). Thirty patients suffering from PD with or without Agoraphobia were treated with either Fluv or Brof (150 mg daily) in a double-blind design. After 12 weeks of treatment 93% of the Brof group and 87% of the Fluv group considered themselves as much or very much improved. After an increase in anxiety in the first week, which was slightly more severe in the Fluv group than in the Brof group, a clinically relevant decrease in anxiety and reduction in panic attacks and avoidance behaviour was observed. There were no significant differences between both treatment groups. During a double-blind follow-up period of another 12 weeks a further improvement was found in both treatment groups, without significant differences between the two groups. (1.Clin. Psychopharmacology, 1996)
10-24-91 The Long-Term Efficacy and Safetyof Paroxetine in PanicDisorder R. Judge I, M. Steiner 2. I SmithKline Beecham Pharmaceuticals, New Frontiers Science Park; Harlow, Essex, UK; 2 SmithKline Beecham Pharmaceuticals, Four Falls Corporate Center, King of Prussia, USA
This is the only published study to assess the role of a selective serotonin reuptake inhibitor (SSRI) in relapse prevention in a double-blind fashion. One hundred and thirty-eight responders from a short-term, double-blind, placebo-controlled study in patients with DSM-III-R panic disorder [I] were entered into a 6-month extension study to evaluate the long-term efficacy and safety of paroxetine in panic disorder. In phase I of the study, patients were maintained on current medication for 3 months, while in phase II, responders were re-randornized, in a double-blind fashion, to either their current treatment or to placebo for a further 3 months. The primary efficacy outcome was the percentage of patients who relapsed during phase II and the time to relapse. Of the 138 responders who entered phase I (30 placebo, 34 paroxetine 10 mg, 34 paroxetine 20 mg, 40 paroxetine 40 mg), 76% (105 patients) continued to phase II (62 placebo, 43 paroxetine combined). Thirty per cent (11137) of patients crossing over from paroxetine to placebo relapsed during phase II, while only 5% (2/43) of patients continuing on paroxetine treatment relapsed (p 0.002; Chi-square test). The median time to relapse after crossing over to placebo was 14 days and for the two patients in the paroxetine group was 14 and 28 days. Paroxetine treatment for up to 6 months demonstrated continuing therapeutic efficacy, and during phase I was associated with a generally lower incidence of adverse events compared with the initial short-term study. In phase II, the incidence of most common adverse events was not appreciably different between the placebo and combined paroxetine groups. In conclusion, therapeutic efficacy was maintained during long term paroxetine treatment for up to 6 months and importantly, paroxetine was effective in the prevention of relapse. Furthermore, good tolerability for paroxetine was evident with a lower incidence of adverse events compared with the short-term study.
=
Methods - We assessed central 5-HT activity and depressive symptomatology in hypothyroidism before and after thyroxine replacement therapy, and compared this to control subjects. Twenty subjects entered the study: 10 drug free hypothyroid patients and 10 age, sex, weight and menstrual cycle matched controls. Patients were diagnosed as being depressed using DSM-IIIR criteria and rated using the Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BOI). Cortisol and prolactin responses to dexfenfluramine, a centrally acting 5-HT releasing agent, were used as an index of central 5-HT responsivity. Results - Both cortisol and prolactin responses were reduced in the hypothyroid relative to the control group. After thyroxine replacement, cortisol responses were significantly higher, but prolactin responses were not, perhaps due to pre-treatment responses being elevated by direct stimulatory effects of hypothyroidism itself on pituitary prolactin secretion. Cortisol responses were inversely correlated to TSH levels, while TSH levels were positively correlated with HAM-D and BOI scores. 4/10 patients were clinically depressed, while depressive symptomatology was reduced with thyroxine in all patients. Conclusions - These findings support animal work suggesting that hypothyroidism reduces central 5-HT activity. This reduced activity is related to increased depressive symptomatology, and is reversible with thyroxine replacement therapy.
I
0-25-2 1 Effects of Nefazodone and Paroxetine on S-Hydroxytryptamlne 1A Receptor Sensitivity
P. Cowen, D. Williamson, P. Sargent, G. Pearson, 1. Odontiades. University Department ofPsychiatry, Littlemore Hospital, Oxford, UK We studied the effect of the 5-Hydroxytryptamine lA (5-HT 1A ) receptor agonist Gepirone given orally, on a group of 37 healthy male volunteer subjects who were randomly allocated to receive either Placebo, Paroxetine, or Nefazodone, before and after 17 days treatment. Paroxetine significantly attenuated the hypothermic response to Gepirone, markedly attenuated the Growth Hormone and Cortisol response, and reduced subjective ratings of nausea, lightheadedness, and dizziness. Nefazodone also mildly attenuated the hypothermic response to Gepirone, but significantly increased the Growth Hormone and Cortisol response, and increased subjective ratings of nausea, lightheadedness and dizziness. In animal studies the hypothermic response to 5-HT IA receptor agonists is attenuated by depletion of 5-HT with repeated administration of parachlorophenylalanine, or destruction of 5-HT neurons by injection of 5,7-dihydroxytryptamine, while the endocrine and behavioural responses to 5-HT 1A receptor agonists are not, suggesting a pre-synaptic location of the 5-HT IA receptors mediating hypothermia and post-synaptic location of 5-HT 1A receptors mediating the endocrine and behavioural responses. The results suggest that longterm Paroxetine treatment causes reduced sensitivity of pre-synaptic 5-HT 1A receptors and reduced sensitivity of post-synaptic 5-HT 1A receptors in the hypothalamus, and that long-term Nefazodone treatent causes reduced sensitivity of pre-synaptic 5-HT 1Apreceptors and increased sensitivity of post-synaptic receptors in the hypothalamus.
[I] Dunbar G, et aJ. Eur Neuropsychophannacol 1995; 5: 361
10-25-31 The Combined Dexamethasone/CRH-Test in Rats: Characterization of the HPA AxisActivity in Aging
10-251 Neuroendocrine I0-25-1 I 5-HT Mediated Endocrine Responses to
D-Fenfluramine In Hypothyroidism before and after Treatment
A.J. Cleare, A.M. McGregor, V. O'Keane. Departments of Psychological Medicine and Medicine, Institute of Psychiatry and Kings College Hospital, London, England Objective - The incidence of depression in those with hypothyroidism is increased compared to healthy populations, though the mechanism for this is unclear. We tested the hypothesis that reduced 5-HT function might be responsible.
M. Hatzinger, R. Landgraf, F. Holsboer, I. Neumann. Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany In human aging the hypothalamo-pituitary-adrenocortical (HPA) system becomes gradually disinhibited as reflected by basal hypercortisolemia and dexamethasone (DEX) non-suppression. To further explore the mechanisms underlying these neuroendocrine phenomena in an animal model, the combined DEXlCRH-test was established in young male Wistar rats (YR: 350-400 g; 3 months) and then used in aged rats (AR: 400-1100 g, 24 months). Five days before testing, the jugular vein of 7 YR and 7 AR (kept under standard conditions with 12 h light-dark cycle, lights on at 0600h) was catheterized under halothane anesthesia for subsequent blood sampling. On the day of experiment, DEX (30 fLlkg) and CRH (0.05 /lglkg) were given at 1200h and 2000h, respectively. After DEX treatment, basal ACTH levels were significantly higher in AR than in YR (77.6 ± 23.2 vs 19.9 ± 0.9 pg/ml; p < 0.01) indicating resistance of the
207
Neuroendocrine
hibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are effective in the treatment of panic disorder (PD). In this study the SSRI fluvoxamine (Fluv) was compared to the selective and reversible MAO-A-I brofaromine (Brof). Thirty patients suffering from PD with or without Agoraphobia were treated with either Fluv or Brof (150 mg daily) in a double-blind design. After 12 weeks of treatment 93% of the Brof group and 87% of the Fluv group considered themselves as much or very much improved. After an increase in anxiety in the first week, which was slightly more severe in the Fluv group than in the Brof group, a clinically relevant decrease in anxiety and reduction in panic attacks and avoidance behaviour was observed. There were no significant differences between both treatment groups. During a double-blind follow-up period of another 12 weeks a further improvement was found in both treatment groups, without significant differences between the two groups. (1.Clin. Psychopharmacology, 1996)
10-24-91 The Long-Term Efficacy and Safetyof Paroxetine in PanicDisorder R. Judge I, M. Steiner 2. I SmithKline Beecham Pharmaceuticals, New Frontiers Science Park; Harlow, Essex, UK; 2 SmithKline Beecham Pharmaceuticals, Four Falls Corporate Center, King of Prussia, USA
This is the only published study to assess the role of a selective serotonin reuptake inhibitor (SSRI) in relapse prevention in a double-blind fashion. One hundred and thirty-eight responders from a short-term, double-blind, placebo-controlled study in patients with DSM-III-R panic disorder [I] were entered into a 6-month extension study to evaluate the long-term efficacy and safety of paroxetine in panic disorder. In phase I of the study, patients were maintained on current medication for 3 months, while in phase II, responders were re-randornized, in a double-blind fashion, to either their current treatment or to placebo for a further 3 months. The primary efficacy outcome was the percentage of patients who relapsed during phase II and the time to relapse. Of the 138 responders who entered phase I (30 placebo, 34 paroxetine 10 mg, 34 paroxetine 20 mg, 40 paroxetine 40 mg), 76% (105 patients) continued to phase II (62 placebo, 43 paroxetine combined). Thirty per cent (11137) of patients crossing over from paroxetine to placebo relapsed during phase II, while only 5% (2/43) of patients continuing on paroxetine treatment relapsed (p 0.002; Chi-square test). The median time to relapse after crossing over to placebo was 14 days and for the two patients in the paroxetine group was 14 and 28 days. Paroxetine treatment for up to 6 months demonstrated continuing therapeutic efficacy, and during phase I was associated with a generally lower incidence of adverse events compared with the initial short-term study. In phase II, the incidence of most common adverse events was not appreciably different between the placebo and combined paroxetine groups. In conclusion, therapeutic efficacy was maintained during long term paroxetine treatment for up to 6 months and importantly, paroxetine was effective in the prevention of relapse. Furthermore, good tolerability for paroxetine was evident with a lower incidence of adverse events compared with the short-term study.
=
Methods - We assessed central 5-HT activity and depressive symptomatology in hypothyroidism before and after thyroxine replacement therapy, and compared this to control subjects. Twenty subjects entered the study: 10 drug free hypothyroid patients and 10 age, sex, weight and menstrual cycle matched controls. Patients were diagnosed as being depressed using DSM-IIIR criteria and rated using the Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BOI). Cortisol and prolactin responses to dexfenfluramine, a centrally acting 5-HT releasing agent, were used as an index of central 5-HT responsivity. Results - Both cortisol and prolactin responses were reduced in the hypothyroid relative to the control group. After thyroxine replacement, cortisol responses were significantly higher, but prolactin responses were not, perhaps due to pre-treatment responses being elevated by direct stimulatory effects of hypothyroidism itself on pituitary prolactin secretion. Cortisol responses were inversely correlated to TSH levels, while TSH levels were positively correlated with HAM-D and BOI scores. 4/10 patients were clinically depressed, while depressive symptomatology was reduced with thyroxine in all patients. Conclusions - These findings support animal work suggesting that hypothyroidism reduces central 5-HT activity. This reduced activity is related to increased depressive symptomatology, and is reversible with thyroxine replacement therapy.
I
0-25-2 1 Effects of Nefazodone and Paroxetine on S-Hydroxytryptamlne 1A Receptor Sensitivity
P. Cowen, D. Williamson, P. Sargent, G. Pearson, 1. Odontiades. University Department ofPsychiatry, Littlemore Hospital, Oxford, UK We studied the effect of the 5-Hydroxytryptamine lA (5-HT 1A ) receptor agonist Gepirone given orally, on a group of 37 healthy male volunteer subjects who were randomly allocated to receive either Placebo, Paroxetine, or Nefazodone, before and after 17 days treatment. Paroxetine significantly attenuated the hypothermic response to Gepirone, markedly attenuated the Growth Hormone and Cortisol response, and reduced subjective ratings of nausea, lightheadedness, and dizziness. Nefazodone also mildly attenuated the hypothermic response to Gepirone, but significantly increased the Growth Hormone and Cortisol response, and increased subjective ratings of nausea, lightheadedness and dizziness. In animal studies the hypothermic response to 5-HT IA receptor agonists is attenuated by depletion of 5-HT with repeated administration of parachlorophenylalanine, or destruction of 5-HT neurons by injection of 5,7-dihydroxytryptamine, while the endocrine and behavioural responses to 5-HT 1A receptor agonists are not, suggesting a pre-synaptic location of the 5-HT IA receptors mediating hypothermia and post-synaptic location of 5-HT 1A receptors mediating the endocrine and behavioural responses. The results suggest that longterm Paroxetine treatment causes reduced sensitivity of pre-synaptic 5-HT 1A receptors and reduced sensitivity of post-synaptic 5-HT 1A receptors in the hypothalamus, and that long-term Nefazodone treatent causes reduced sensitivity of pre-synaptic 5-HT 1Apreceptors and increased sensitivity of post-synaptic receptors in the hypothalamus.
[I] Dunbar G, et aJ. Eur Neuropsychophannacol 1995; 5: 361
10-25-31 The Combined Dexamethasone/CRH-Test in Rats: Characterization of the HPA AxisActivity in Aging
10-251 Neuroendocrine I0-25-1 I 5-HT Mediated Endocrine Responses to
D-Fenfluramine In Hypothyroidism before and after Treatment
A.J. Cleare, A.M. McGregor, V. O'Keane. Departments of Psychological Medicine and Medicine, Institute of Psychiatry and Kings College Hospital, London, England Objective - The incidence of depression in those with hypothyroidism is increased compared to healthy populations, though the mechanism for this is unclear. We tested the hypothesis that reduced 5-HT function might be responsible.
M. Hatzinger, R. Landgraf, F. Holsboer, I. Neumann. Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany In human aging the hypothalamo-pituitary-adrenocortical (HPA) system becomes gradually disinhibited as reflected by basal hypercortisolemia and dexamethasone (DEX) non-suppression. To further explore the mechanisms underlying these neuroendocrine phenomena in an animal model, the combined DEXlCRH-test was established in young male Wistar rats (YR: 350-400 g; 3 months) and then used in aged rats (AR: 400-1100 g, 24 months). Five days before testing, the jugular vein of 7 YR and 7 AR (kept under standard conditions with 12 h light-dark cycle, lights on at 0600h) was catheterized under halothane anesthesia for subsequent blood sampling. On the day of experiment, DEX (30 fLlkg) and CRH (0.05 /lglkg) were given at 1200h and 2000h, respectively. After DEX treatment, basal ACTH levels were significantly higher in AR than in YR (77.6 ± 23.2 vs 19.9 ± 0.9 pg/ml; p < 0.01) indicating resistance of the