Acute treatment of moderate to severe depression with hypericum extrac
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《英国医生杂志》
1 Charité-Universit?tsmedizin Berlin, Campus Benjamin Franklin, Department of Psychiatry and Psychotherapy, Eschenallee 3, 14050 Berlin, Germany, 2 Institute for Medical Research Management and Biometrics GmbH, Scheurlstra?e 21, 90478 Nürnberg, Germany, 3 Dr Willmar Schwabe Pharmaceuticals, PO Box 410925, 76209 Karlsruhe, Germany
Correspondence to: M Kieser meinhard.kieser@schwabe.de
Extract of Hypericum perforatum (St John's wort) is more effective than placebo in the treatment of mild to moderate major depression1 and as effective as several tricyclic antidepressants2-5 or fluoxetine.6 In patients with more severe depression, however, the antidepressant efficacy of hypericum extract is disputed. In a comparison of 1800 mg/day hypericum extract (LI 160) and 150 mg/day imipramine the effect of both drugs was comparable during six weeks of acute treatment.4 That study, however, was not sufficiently powered to demonstrate non-inferiority of the herbal extract.
In clinical practice, hypericum extract is better tolerated than synthetic antidepressants.7 It may be particularly helpful in severe depression with its high risk of chronicity.8 We compared the efficacy and safety of hypericum extract with paroxetine in patients with moderate to severe depression.
Hypericum extract WS 5570 at a dose of 300 mg three times a day has been shown to be more effective than placebo in patients with mild to moderate major depression treated for six weeks.9 Paroxetine, on the other hand, is a potent selective serotonin reuptake inhibitor with proved efficacy in patients with depression of any severity10 and has a more favourable safety profile than tricyclic antidepressants.11 In major depression, daily doses between 20 mg and 50 mg have been recommended12 and are commonly used in clinical trials and in daily practice.
In accordance with Kupfer's model of acute therapy and subsequent prophylactic treatment of unipolar depression,13 our study included a six week acute phase after which responders undergo four months of prophylactic continuation treatment (to prevent relapse or recurrence, or both).
Methods
Participants
Between May 2000 and July 2003, we assessed 301 white patients and randomised and treated 251 (125 to hypericum and 126 to paroxetine). Figure 1 shows reasons for non-randomisation, premature termination, or exclusion. We did not exclude any patients because we thought they were at increased risk of suicide. Among the patients who were not randomised, two were withdrawn because they responded to placebo during the run-in period. All decisions regarding patient eligibility were made before code breaking.
Fig 1 Flow of patients and datasets for analysis
Baseline demographic and clinical measures were comparable in both groups (table 1). Mean age and average duration of the current episode, however, were higher in the hypericum group. The baseline total depression scores ranged from 22 (minimum required) to 34 in both groups. In each group more than half of the patients had a total score 25 and were thus severely depressed.20
Table 1 Demographic and clinical characteristics at baseline (intention to treat analysis; figures are means (SD); medians unless stated otherwise)
Investigational treatment
After two weeks of randomised treatment, 69/122 patients in the hypericum group (57%) and 58/122 in the paroxetine group (48%) were switched to the higher doses. We assessed compliance with treatment by counting tablets; it was 96% (SD 7%) for hypericum and 98% (SD 10%) for paroxetine.
Figure 2 shows the total Hamilton depression scores over time. Between baseline and day 42 scores decreased by an average of 14.4 (SD 8.8) points (corresponding to 57% (SD 34%) of the baseline value) for hypericum and by 11.4 (SD 8.6) points (45% (SD 34%)) for paroxetine (lower one sided repeated 97.5% confidence limit adjusted for the interim analysis18 for the difference hypericum-paroxetine was 1.5 points). In the per protocol analysis the decreases in scores during treatment were 14.6 (SD 9.0) points for hypericum and 12.0 (SD 8.5) points for paroxetine (lower confidence limit 0.7 points). Hence, the lower confidence limits not only exceeded the non-inferiority margin of -2.5 points but also the value 0, showing that hypericum is statistically superior to paroxetine at the one sided 2.5% level.
Fig 2 Total Hamilton depression scores over time (intention to treat analysis, means and 95% confidence intervals)
According to mean change in depression score from baseline, hypericum was descriptively superior to paroxetine in 11 of those 13 centres that had two or more patients in each group. At the end of the acute treatment phase 86/122 patients (71%) in the hypericum group and 73/122 (60%) in the paroxetine group responded to treatment (P = 0.08; 2 test), and 61/122 (50%) and 43/122 patients (35%) showed remission (P = 0.02).
A subgroup analysis showed that patients who were switched to 1800 mg/day hypericum or 40 mg/day paroxetine because of lack of efficacy during the first two weeks of randomised treatment showed marked decreases in total depression score during weeks three to six. By the end of the double blind treatment period (day 42) we observed a substantial amelioration of symptoms compared with baseline in patients with or without an increase in drug dose in both treatment groups (mean (SD) decrease in total score from baseline to day 42: hypericum 900 mg/day 16.6 (7.5) points, hypericum 1800 mg/day 12.6 (9.3) points, paroxetine 20 mg/day 11.0 (8.9) points, paroxetine 40 mg/day 11.8 (8.1) points).
Table 2 shows the main results for selected secondary measures. For all standardised psychiatric scales we found differences between treatment groups in favour of hypericum, confirming our previous results.
Table 2 Secondary measures (intention to treat analysis; figures are numbers (percentages) unless stated otherwise)
Safety and tolerability
During the acute treatment phase 69/125 patients randomised to hypericum (55%) reported 172 adverse events and 96/126 treated with paroxetine (76%) reported 269 adverse events. The incidences were 0.035 adverse events per day of exposure (0.029 at 900 mg/day and 0.039 at 1800 mg/day) for hypericum and 0.060 (0.062 at 20 mg/day and 0.059 at 40 mg/day) for paroxetine. Based on the rate ratio, the incidence of adverse events in the paroxetine group was 1.72 (95% confidence interval21 1.42 to 2.10) of the rate observed for hypericum. The highest incidence was found for gastrointestinal disorders (59 events in 42 patients in the hypericum group and 106 events in 67 patients in the paroxetine group), followed by nervous system disorders (35 events in 29 patients and 61 events in 43 patients, respectively). Table 3 shows adverse events that occurred in at least 10 patients in one group. Two serious adverse events occurred in the hypericum group (psychic decompensation attributable to social problems; hypertensive crisis); both were thought to be unrelated to hypericum—that is, a cause other than the administration of hypericum was evident.
Table 3 Adverse events that occurred in at least 10 patients in one group (safety analysis set; figures are numbers (percentages) of patients
Discussion
Linde K, Mulrow CD. St John's wort for depression. Cochrane Database Syst Rev 2004;(4): CD000448.
Harrer G, Hübner WD, Podzuweit H. Effectiveness and tolerance of the hypericum extract LI 160 compared to maprotiline: a multicenter double-blind study. J Geriatric Psychiatry Neurol 1994;7(suppl 1): S24-8.
Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ 1999;319: 1534-8.
Vorbach EU, Hübner WD, Arnoldt KH. Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. J Geriatric Psychiatry Neurol 1994;7(suppl 1): S19-23.
Wheatley D. LI 160, an extract of St. John's wort, versus amitriptyline in mildly to moderately depressed outpatients—a controlled 6-week clinical trial. Pharmacopsychiatry 1997;30(suppl 2): 77-80.
Harrer G, Schmidt U, Kuhn U, Biller A. ?quivalenzvergleich Johanniskrautextrakt LoHyp-57 versus Fluoxetin. Arzneimittel-Forschung 1998;49: 3-10.
Izzo AA. Drug interactions with St. John's Wort (Hypericum perforatum): a review of the clinical evidence. Int J Clin Pharmacol Ther 2004;42: 139-48.
Winkler D, Tauscher J, Kasper S. Maintenance treatment in depression. The role of pharmacological and psychological treatment. Curr Opin Psychiatry 2002;15: 63-8.
Lecrubier Y, Clerc G, Didi R, Kieser M. Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. Am J Psychiatry 2002;159: 1361-6.
Bourin M, Chue P, Guillon Y. Paroxetine: a review. CNS Drug Rev 2001;7: 25-47.
Preskorn SH. Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry 1995;56(suppl 6): 12-21.
Dunner DL, Dunbar GC. Optimal dose regimen for paroxetine. J Clin Psychiatry 1992;53(suppl): 21-6.
Kupfer DJ. Lessons to be learned from long-term treatment of affective disorders: potential utility in panic disorder. J Clin Psychiatry 1991;52(suppl); 12-7.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The miniinternational neuropsychiatric interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(suppl 20): S22-33.
Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996;313: 36-9.
Montgomery SA. Clinically relevant effect sizes in depression. Eur Neuropsychopharmacology 1994;4: 283-4.
Bauer P, K?hne K. Evaluation of experiments with adaptive interim analyses. Biometrics 1994;50: 1029-41.
Brannath W, Posch M, Bauer P. Recursive combination tests. J Am Stat Assoc 2002;97: 236-44.
Committee for Proprietary Medicinal Products. Points to consider on switching between superiority and non-inferiority. London: European Agency for the Evaluation of Medicinal Products, 2000.
Paykel ES. The classification of depression. Br J Clin Pharmacol 1983;15(suppl 2): 155-9S.
Ederer F, Mantel N. Confidence limits on the ratio of two Poisson variables. Am J Epidemiol 1974;100: 165-7.
Golsch S, Vocks E, Rakoski J, Brockow K, Ring J. Reversible Erh?hung der Photosensitivit?t im UV-B-Bereich durch Johanniskrautextrakt-Pr?parate. Hautarzt 1996;48: 249-52.
Schulz V. Incidence and clinical relevance of the interactions and side effects of Hypericum preparations. Phytomedicine 2001;8: 152-60.
Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John's wort) in major depressive disorder. JAMA 2002;287: 1807-14.(A Szegedi, managing senior physician1, R)
Correspondence to: M Kieser meinhard.kieser@schwabe.de
Extract of Hypericum perforatum (St John's wort) is more effective than placebo in the treatment of mild to moderate major depression1 and as effective as several tricyclic antidepressants2-5 or fluoxetine.6 In patients with more severe depression, however, the antidepressant efficacy of hypericum extract is disputed. In a comparison of 1800 mg/day hypericum extract (LI 160) and 150 mg/day imipramine the effect of both drugs was comparable during six weeks of acute treatment.4 That study, however, was not sufficiently powered to demonstrate non-inferiority of the herbal extract.
In clinical practice, hypericum extract is better tolerated than synthetic antidepressants.7 It may be particularly helpful in severe depression with its high risk of chronicity.8 We compared the efficacy and safety of hypericum extract with paroxetine in patients with moderate to severe depression.
Hypericum extract WS 5570 at a dose of 300 mg three times a day has been shown to be more effective than placebo in patients with mild to moderate major depression treated for six weeks.9 Paroxetine, on the other hand, is a potent selective serotonin reuptake inhibitor with proved efficacy in patients with depression of any severity10 and has a more favourable safety profile than tricyclic antidepressants.11 In major depression, daily doses between 20 mg and 50 mg have been recommended12 and are commonly used in clinical trials and in daily practice.
In accordance with Kupfer's model of acute therapy and subsequent prophylactic treatment of unipolar depression,13 our study included a six week acute phase after which responders undergo four months of prophylactic continuation treatment (to prevent relapse or recurrence, or both).
Methods
Participants
Between May 2000 and July 2003, we assessed 301 white patients and randomised and treated 251 (125 to hypericum and 126 to paroxetine). Figure 1 shows reasons for non-randomisation, premature termination, or exclusion. We did not exclude any patients because we thought they were at increased risk of suicide. Among the patients who were not randomised, two were withdrawn because they responded to placebo during the run-in period. All decisions regarding patient eligibility were made before code breaking.
Fig 1 Flow of patients and datasets for analysis
Baseline demographic and clinical measures were comparable in both groups (table 1). Mean age and average duration of the current episode, however, were higher in the hypericum group. The baseline total depression scores ranged from 22 (minimum required) to 34 in both groups. In each group more than half of the patients had a total score 25 and were thus severely depressed.20
Table 1 Demographic and clinical characteristics at baseline (intention to treat analysis; figures are means (SD); medians unless stated otherwise)
Investigational treatment
After two weeks of randomised treatment, 69/122 patients in the hypericum group (57%) and 58/122 in the paroxetine group (48%) were switched to the higher doses. We assessed compliance with treatment by counting tablets; it was 96% (SD 7%) for hypericum and 98% (SD 10%) for paroxetine.
Figure 2 shows the total Hamilton depression scores over time. Between baseline and day 42 scores decreased by an average of 14.4 (SD 8.8) points (corresponding to 57% (SD 34%) of the baseline value) for hypericum and by 11.4 (SD 8.6) points (45% (SD 34%)) for paroxetine (lower one sided repeated 97.5% confidence limit adjusted for the interim analysis18 for the difference hypericum-paroxetine was 1.5 points). In the per protocol analysis the decreases in scores during treatment were 14.6 (SD 9.0) points for hypericum and 12.0 (SD 8.5) points for paroxetine (lower confidence limit 0.7 points). Hence, the lower confidence limits not only exceeded the non-inferiority margin of -2.5 points but also the value 0, showing that hypericum is statistically superior to paroxetine at the one sided 2.5% level.
Fig 2 Total Hamilton depression scores over time (intention to treat analysis, means and 95% confidence intervals)
According to mean change in depression score from baseline, hypericum was descriptively superior to paroxetine in 11 of those 13 centres that had two or more patients in each group. At the end of the acute treatment phase 86/122 patients (71%) in the hypericum group and 73/122 (60%) in the paroxetine group responded to treatment (P = 0.08; 2 test), and 61/122 (50%) and 43/122 patients (35%) showed remission (P = 0.02).
A subgroup analysis showed that patients who were switched to 1800 mg/day hypericum or 40 mg/day paroxetine because of lack of efficacy during the first two weeks of randomised treatment showed marked decreases in total depression score during weeks three to six. By the end of the double blind treatment period (day 42) we observed a substantial amelioration of symptoms compared with baseline in patients with or without an increase in drug dose in both treatment groups (mean (SD) decrease in total score from baseline to day 42: hypericum 900 mg/day 16.6 (7.5) points, hypericum 1800 mg/day 12.6 (9.3) points, paroxetine 20 mg/day 11.0 (8.9) points, paroxetine 40 mg/day 11.8 (8.1) points).
Table 2 shows the main results for selected secondary measures. For all standardised psychiatric scales we found differences between treatment groups in favour of hypericum, confirming our previous results.
Table 2 Secondary measures (intention to treat analysis; figures are numbers (percentages) unless stated otherwise)
Safety and tolerability
During the acute treatment phase 69/125 patients randomised to hypericum (55%) reported 172 adverse events and 96/126 treated with paroxetine (76%) reported 269 adverse events. The incidences were 0.035 adverse events per day of exposure (0.029 at 900 mg/day and 0.039 at 1800 mg/day) for hypericum and 0.060 (0.062 at 20 mg/day and 0.059 at 40 mg/day) for paroxetine. Based on the rate ratio, the incidence of adverse events in the paroxetine group was 1.72 (95% confidence interval21 1.42 to 2.10) of the rate observed for hypericum. The highest incidence was found for gastrointestinal disorders (59 events in 42 patients in the hypericum group and 106 events in 67 patients in the paroxetine group), followed by nervous system disorders (35 events in 29 patients and 61 events in 43 patients, respectively). Table 3 shows adverse events that occurred in at least 10 patients in one group. Two serious adverse events occurred in the hypericum group (psychic decompensation attributable to social problems; hypertensive crisis); both were thought to be unrelated to hypericum—that is, a cause other than the administration of hypericum was evident.
Table 3 Adverse events that occurred in at least 10 patients in one group (safety analysis set; figures are numbers (percentages) of patients
Discussion
Linde K, Mulrow CD. St John's wort for depression. Cochrane Database Syst Rev 2004;(4): CD000448.
Harrer G, Hübner WD, Podzuweit H. Effectiveness and tolerance of the hypericum extract LI 160 compared to maprotiline: a multicenter double-blind study. J Geriatric Psychiatry Neurol 1994;7(suppl 1): S24-8.
Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ 1999;319: 1534-8.
Vorbach EU, Hübner WD, Arnoldt KH. Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. J Geriatric Psychiatry Neurol 1994;7(suppl 1): S19-23.
Wheatley D. LI 160, an extract of St. John's wort, versus amitriptyline in mildly to moderately depressed outpatients—a controlled 6-week clinical trial. Pharmacopsychiatry 1997;30(suppl 2): 77-80.
Harrer G, Schmidt U, Kuhn U, Biller A. ?quivalenzvergleich Johanniskrautextrakt LoHyp-57 versus Fluoxetin. Arzneimittel-Forschung 1998;49: 3-10.
Izzo AA. Drug interactions with St. John's Wort (Hypericum perforatum): a review of the clinical evidence. Int J Clin Pharmacol Ther 2004;42: 139-48.
Winkler D, Tauscher J, Kasper S. Maintenance treatment in depression. The role of pharmacological and psychological treatment. Curr Opin Psychiatry 2002;15: 63-8.
Lecrubier Y, Clerc G, Didi R, Kieser M. Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. Am J Psychiatry 2002;159: 1361-6.
Bourin M, Chue P, Guillon Y. Paroxetine: a review. CNS Drug Rev 2001;7: 25-47.
Preskorn SH. Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry 1995;56(suppl 6): 12-21.
Dunner DL, Dunbar GC. Optimal dose regimen for paroxetine. J Clin Psychiatry 1992;53(suppl): 21-6.
Kupfer DJ. Lessons to be learned from long-term treatment of affective disorders: potential utility in panic disorder. J Clin Psychiatry 1991;52(suppl); 12-7.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The miniinternational neuropsychiatric interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(suppl 20): S22-33.
Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996;313: 36-9.
Montgomery SA. Clinically relevant effect sizes in depression. Eur Neuropsychopharmacology 1994;4: 283-4.
Bauer P, K?hne K. Evaluation of experiments with adaptive interim analyses. Biometrics 1994;50: 1029-41.
Brannath W, Posch M, Bauer P. Recursive combination tests. J Am Stat Assoc 2002;97: 236-44.
Committee for Proprietary Medicinal Products. Points to consider on switching between superiority and non-inferiority. London: European Agency for the Evaluation of Medicinal Products, 2000.
Paykel ES. The classification of depression. Br J Clin Pharmacol 1983;15(suppl 2): 155-9S.
Ederer F, Mantel N. Confidence limits on the ratio of two Poisson variables. Am J Epidemiol 1974;100: 165-7.
Golsch S, Vocks E, Rakoski J, Brockow K, Ring J. Reversible Erh?hung der Photosensitivit?t im UV-B-Bereich durch Johanniskrautextrakt-Pr?parate. Hautarzt 1996;48: 249-52.
Schulz V. Incidence and clinical relevance of the interactions and side effects of Hypericum preparations. Phytomedicine 2001;8: 152-60.
Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John's wort) in major depressive disorder. JAMA 2002;287: 1807-14.(A Szegedi, managing senior physician1, R)