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ORIGINAL RESEARCH |
From the Colorado Center for Reproductive Medicine, Englewood, Colorado; and Department of Obstetrics-Gynecology, Harvard University School of Medicine, Boston, Massachusetts.
Address reprint requests to: Eric S. Surrey, MD, Colorado Center for Reproductive Medicine, 799 East Hampden Avenue, Suite 300, Englewood, CO 80110; E-mail: esurrey{at}colocrm.com.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: This is a post-treatment follow-up analysis of a randomized, double-masked, placebo-controlled 52-week trial. All patients had received monthly leuprolide acetate and were randomized to one of four groups: A—daily placebo; B—daily norethindrone acetate 5 mg; C—daily norethindrone acetate 5 mg and conjugated equine estrogens 0.625 mg; and D—daily norethindrone acetate 5 mg and conjugated equine estrogens 1.25 mg. Of 201 patients enrolled in the initial trial, 123 completed at least 280 days of therapy and entered the follow-up period. Physical findings and symptoms were quantified, and lumbar spine bone mineral density was determined at intervals for up to 12 and 24 months post-therapy.
RESULTS: Symptom and pelvic examination scores remained significantly below baseline for at least 8 months after completion of therapy for all four groups (P < .05). Findings were not affected by endometriosis scores noted on screening laparoscopy. Mean bone mineral density values remained at or above baseline in all add-back groups. The significant mean loss in bone density in group A during therapy reversed slowly and had not returned to baseline at the final follow-up visit (P < .001).
CONCLUSION: GnRH agonist and norethindrone acetate alone or combined with low-dose conjugated equine estrogens administered to symptomatic endometriosis patients for 12 months provides extended pain relief and bone mineral density preservation after completion of therapy.
GnRH agonists have been shown to be effective in managing the symptoms and extent of endometriosis.1–3 Therapy with these agents has been generally restricted to a 6-month course because of concern for such secondary hypoestrogenic side effects as vasomotor symptoms and reversible bone mineral density loss, which could limit safety and compliance. A variety of steroidal and nonsteroidal agents have been employed with variable results as "add-back therapy" in an effort to maintain the therapeutic efficacy of the agonists while suppressing such side effects.4,5
A subset of patients with severe pelvic pain responds well to GnRH agonists but experiences rapid symptom recurrence and would benefit from prolongation of therapy. Given that several studies would suggest that recovery of bone density loss after a 6- month course trial may not be reversed for at least 6–12 months after completion of treatment, extension of therapy could lead to further and potentially clinically significant loss.6–9
In an effort to avoid this problem, a recent large-scale, prospective, randomized, double-masked, placebo-controlled, multicenter trial evaluated the effects on signs and symptoms of endometriosis of 1-year of treatment with GnRH agonist alone or in conjunction with three different add-back regimens.10 A total of 201 patients with symptomatic, surgically diagnosed endometriosis were administered a depot preparation of the GnRH agonist leuprolide acetate (Lupron Depot, TAP Pharmaceutical Products, Inc., Lake Forest, IL) 3.75 mg every 4 weeks for 52 weeks. Patients were randomized to one of four add-back groups and received either placebo for progestin and estrogen, or daily oral norethindrone acetate and placebo for estrogen, or daily norethindrone acetate in conjunction with one of two different doses of conjugated equine estrogens. During treatment, signs and symptoms of endometriosis were improved from baseline levels in all four groups. Vasomotor symptoms were suppressed in all three add-back groups as compared with the group receiving GnRH agonist alone. Progressive loss of lumbar spine bone mineral density as measured by serial dual energy x-ray absorptiometry scans was appreciated in patients receiving GnRH agonist alone. However, no clinically significant loss was appreciated in any of the add-back groups.
The results of this study showed that appropriate steroid add-back can sufficiently limit hypoestrogenic side effects to allow for 1 year of continuous GnRH agonist therapy in the appropriate endometriosis patient with severe pelvic pain. However, the long-term effects of these approaches have not been addressed. In the current investigation, we report the results of analysis of prolonged follow-up of those patients with symptomatic endometriosis who completed a prolonged treatment course of GnRH agonist with or without add-back therapy.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the initial trial, patients were assigned randomly to one of four treatment groups by permuted blocks of four at each of the treatment sites. Patients in all groups were to receive a depot preparation of the GnRH agonist leuprolide acetate 3.75 mg intramuscularly every 4 weeks for 52 weeks. Patients in group A (n = 51) received daily oral placebos for estrogen and progestin add-back. Those in group B (n = 55) received daily oral norethindrone acetate (Aygestin, Lederle, Wayne, NJ) 5 mg and placebo for estrogen. Patients in group C (n = 47) received oral norethindrone acetate 5 mg and conjugated equine estrogens (Premarin, Wyeth-Ayerst, Philadelphia, PA) 0.625 mg daily. Those in group D (n = 48) received oral norethindrone acetate 5 mg and conjugated equine estrogens 1.25 mg daily. All patients were to receive elemental calcium 1000 mg daily for the duration of the study. All patients provided written informed consent as approved by the Institutional Review Board of each study site. The details of monitoring symptoms, physical findings, bone density, as well as serum endocrine and metabolic parameters have been previously described.10
The initial sample size was chosen to ensure 80% power to detect a difference (
level = 0.05) in the reduction of pain between group A and any add-back regimenn if the expected mean difference in pain reduction between groups was a severity level of 0.51 with an assumed standard deviation of 0.9. This sample size also ensured an 80% power to detect a difference between any two dosing regimens with regard to mean percent bone loss, assuming an expected difference between treatments of 1.7% with an assumed standard deviation of 3%. It is important to note that a prospective power calculation was not performed to detect a difference regarding follow-up outcome measures. However, a post hoc calculation was performed as is discussed in the Results section of this manuscript.
The follow-up period began 29 days after the last leuprolide acetate injection and continued for up to 2 years. Patients included in the current follow-up investigation included those who had received at least 280 days of leuprolide acetate treatment. Patients included in the analyses of signs and symptoms had symptomatic improvement over baseline at the end of the treatment period, did not terminate the treatment protocol because of worsening symptoms, become pregnant, have surgical or medical intervention for endometriosis, or have non-endometriosis surgery that could have had an impact on pelvic pain during the treatment period. During follow-up, patients were seen monthly for the first 4 months and every 4 months thereafter for up to 24 months. At each visit during the first year of follow-up, a clinical evaluation was undertaken. Dysmenorrhea, nonmenstrual pelvic pain, and deep dyspareunia were evaluated, and a pelvic examination was performed with specific attention paid to pelvic tenderness and induration. Findings were quantified according to a modification of the Biberoglu and Behrman scale and rated from 1 to 4 (1 = no pain, 2 = mild pain, 3 = moderate pain, 4 = severe pain) by the examining clinician and by the coordinator using the patient’s symptom diaries.11 Serum was obtained for measurement of estradiol levels at the visit after the patient’s first post-treatment menstrual cycle. Additional fasting serum samples were obtained to assess circulating total cholesterol, cholesterol subfractions, and triglyceride levels. Samples were assayed at a central reference laboratory. Assays were repeated at successive visits until levels returned either to the normal range or to baseline if the baseline value(s) was abnormal.
Bone mineral density of the lumbar spine (L1–L4) was measured by dual energy x-ray absorptiometry during the initial study at baseline as well as week 24 and week 52 visits. These studies were repeated during the follow-up period at month 8 visit and every 4 months thereafter up to 24 months of follow-up after completion of therapy as necessary until the mean density returned to the baseline level. All measurements were performed in duplicate employing Hologic Quantitative Digital machines (Hologic MDM, Waltham, MA) and were read centrally in a blinded fashion. The coefficient of variation was 1%. All patients took oral elemental calcium 1000 mg daily throughout the 24-month follow-up period.
A patient was considered to have completed the first year of follow-up if she underwent a post-treatment month 12 pain evaluation and bone density evaluation. However, all patients with data collected 4 or more days after the end of treatment were considered to have entered the first year of follow-up. Similarly, all patients who underwent a post-treatment month 24 bone mineral density scan were considered to have completed the second year of follow-up. All patients with data collected 367 or more days after the end of treatment were considered to have entered the second year of follow-up.
Analyses of demographic data, serum estradiol levels, return of menses, bone mineral density, and lipid profiles were performed using all available data from all patients in the follow-up period who had received at least 280 days of GnRH agonist treatment. Signs and symptoms were analyzed for the subsets of patients described above. The following additional rules were applied for the analyses of return of symptoms or physical findings to baseline levels: 1) if a patient underwent surgical or medical therapy for endometriosis during the first year of follow-up but had not already returned to baseline severity levels, the month in which the intervention occurred was defined as the month of return to baseline severity; 2) if a patient terminated the first year of follow-up because of worsening of symptoms related to her disease and had not already returned to baseline levels, her month of return to baseline pain was defined to be the visit after that during which the patient’s last pain data were collected; 3) if during the first year of follow-up, a patient became pregnant or underwent surgery that was unrelated to endometriosis but could have an impact on pelvic pain, all pain data obtained for that patient after the intervention or after 6 weeks before the positive pregnancy test were excluded; 4) patients who had not returned to baseline severity levels after 12 months of follow-up were assumed to have returned to baseline at 16 months, which would have been the next scheduled visit had the follow-up period continued beyond 12 months.
A one-way analysis of variance with an effect for treatment was used to test for any differences among treatment groups with respect to baseline age, height, and weight. The proportion of patients having a prior pregnancy and prior treatment for endometriosis and the distributions of race and time since diagnosis were compared among treatment groups using Fisher exact tests. The distribution of severity of endometriosis at baseline was compared among treatment groups using a 
2 test.
The median number of months to the return of baseline pain levels in the post-treatment period and the median time to first post-treatment menses were estimated by Kaplan-Meier methods. The time interval to return to baseline pain or symptom scores was compared between groups using Cochran-Mantel-Haenszel methodology employing month of scheduled visit as the stratification variable and presence or absence of pain return as the response variable. Pair-wise comparisons between treatment groups for time to first post-treatment menses were made using log rank and Wilcoxon tests. For each sign and symptom, differences among the treatment groups at each follow-up visit were tested for significance using the Cochran-Mantel-Haenszel mean score test for ordered response categories with the baseline severity level as the stratification variable. Within groups, changes from baseline were tested for significance using the sign test. Although the primary objective of this investigation was to look at the effect of at least 280 days of therapy upon follow-up parameters, an intent-to-treat analysis was also performed using similar tests to evaluate time interval to return to baseline sign and symptom scores. Month 0 was used for symptom return for those patients included in the intent-to-treat analyses who had not improved from baseline at the final treatment visit or had additional surgical or medical treatment for endometriosis during therapy.
One-way analyses of covariance were used to analyze bone mineral density and lipid data. P values were calculated based upon two-tailed tests with a value < .05 deemed to be statistically significant. For the analyses of bone mineral density, comparisons between treatment groups were made only between group A and each of the add-back groups. Tests for significance of within-group changes and comparisons between groups were performed only for the final treatment, follow-up month 8, and final follow-up visits. Bonferroni adjustments for multiple comparisons were made at each of these time points, and P values < .017 were considered to be statistically significant. It is important to note that this subgroup analysis excludes those patients involved in the initial study who had completed less than 280 days of therapy. Performance of an intent-to-treat analysis would have an impact on P values and was performed separately regarding rates of return to baseline sign and symptom scores. Such patients were excluded from the overall follow-up investigation to eliminate the variable of the effects of shorter treatment duration on symptom recurrence and bone density.
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RESULTS |
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. The indications for dropout from the original study have been previously reported in detail.10 The median time for return of menses and mean circulating estradiol levels obtained after onset of first menses for each of the four treatment groups are displayed in Table 2. Note that patients who received either dose of conjugated equine estrogens as part of their add-back regimens experienced significantly more rapid return of menses than those receiving GnRH agonist alone or in conjunction with norethindrone acetate alone as add-back. Mean estradiol levels obtained at the first visit after return of menses were similar among the four groups. These visits were not scheduled based on a specific phase of menstrual cycle. The reasons for premature termination of follow-up before the end of the second post-treatment year are displayed in Table 3. The timing, incidence, and indications for dropout were similar among the four groups.
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–3, respectively. Decreases in symptom scores from baseline remained statistically significant through month 12 of follow-up for all groups with the exceptions of dysmenorrhea for groups A and D and deep dyspareunia for group D, which all remained suppressed through month 8 of follow-up. The only significant difference between groups regarding return to baseline scores occurred between groups A and D for dysmenorrhea, where group D patients returned to baseline levels sooner (Table 4).
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and 5, respectively). There were no significant differences between the groups with reference to time to return to baseline levels. The only significant differences among the four groups in changes from baseline occurred at month 4 for pelvic tenderness.
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An intent-to-treat analysis was performed on all patients. The results are also displayed in Table 4
. As would be expected, a more rapid return to baseline in comparison with successful completers was noted with regard to all parameters. There were three significant between-group differences. Group D had a more rapid return to baseline dysmenorrhea scores than groups A, B, or C, a more rapid return to baseline pelvic tenderness scores than groups B or C, and a more rapid return to baseline pelvic induration scores than group C.
The time to return of these five parameters to baseline for each of the four groups was reanalyzed based on the extent of endometriosis as documented at pretherapy laparoscopy (Table 4). There were no statistically significant differences between treatment groups when patients were stratified based on revised American Society for Reproductive Medicine endometriosis scores less than or equal to 15 (stages I, II) as compared with those with scores greater than 15 (stages III, IV) for any of the parameters assessed.12 Note, however, that the numbers of patients with higher endometriosis scores were extremely small in each treatment group.
Mean changes in lumbar spine bone mineral density from baseline during the follow-up period as well as at the end of 52 weeks of therapy for patients with follow-up data are displayed in Table 5. Patients in group A who had received GnRH agonist alone had been previously described to have progressive and significant loss of mean bone mineral density during therapy.10 Although a trend towards restoration was noted, this mean loss remained statistically significant in comparison with pretherapy values at both follow-up month 8 and at the overall final follow-up visit. No significant mean bone loss in comparison with baseline had been noted after completion of therapy for any of the three add-back groups.10 There were no further changes during the follow-up period for any of these groups (B, C, D). At the final follow-up visit, patients in group D receiving nor-ethindrone acetate and higher conjugated equine estrogen doses were noted to have a statistically significant mean increase from baseline. Mean changes in bone density were significantly different in the GnRH agonist-only group in comparison with each of the three add-back groups. This remained the case in comparison with group B through follow-up month 8, and in comparison with groups C and D through month 8 and at the final follow-up visit as well. These findings remained consistent when the data were recategorized into subgroups based on age. By follow-up month 16 visit, the number of patients having bone mineral density scans had greatly decreased in all groups, thus making it more difficult to detect significant differences between the treatment groups or within a treatment group after the first follow-up year. The mean number of days in follow-up at the time of the final bone scan was similar among the three groups (Table 5).
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DISCUSSION |
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The results of the current long-term analysis would suggest that patients administered any of the three add-back therapies employed in the initial study who then entered into the follow-up period after successfully completing at least 280 days of treatment in general experienced a similar rate of recurrence of symptoms and physical findings associated with endometriosis as those administered the agonist alone. There were no significant differences between any of the groups with regard to the time to return to baseline levels of symptoms and physical findings, with the exception of a significantly more rapid return of dysmenorrhea scores to baseline values in group D than in group A. This may have been a result of the more rapid return of menses noted in this group when compared with group A. As previously discussed, the number of dropouts may have masked more subtle differences between the groups as well.
The overall time to recurrence and the percent of women who remained improved from baseline with regard to physical findings and symptoms after 1 year of follow-up in the current investigation appears to be longer than that previously reported in investigations in which a 6-month GnRH agonist treatment course was employed. After completion of a 6-month course of therapy, Dlugi et al reported that, although 54% of patients with moderate-to-severe pelvic pain before initiation of therapy experienced a return by the third month after therapy, 37% remained improved at 1 year.2 These findings confirm those reported by others.13,14 In contrast, Vercellini et al reported that dysmenorrhea and nonmenstrual pain returned to baseline levels at the end of a 6-month follow-up period after completion of an initial 6-month GnRH agonist treatment course.15 In a large, multicenter, retrospective study, Miller et al reported that the median time to recurrence of pain after a similar course of therapy was 5.2 months.16 The results achieved in the current investigation were based upon a subset analysis of those who successfully completed at least 280 days of treatment. The reasons for dropout during the initial course of treatment have been discussed extensively elsewhere.10
An all-inclusive intent-to-treat analysis resulted in poorer long-term results with more rapid return of signs and symptoms. This would almost be expected given that a subset of those who did not complete the initial course of therapy may have dropped out because of persistent or recurrent pain. However, the point of the current investigation was to evaluate the long-term effects after completion of a prolonged course of GnRH agonist therapy. In comparing a 3-month with a 6-month course of GnRH agonist therapy, Hornstein et al demonstrated that patient- and physician-reported symptom scores returned toward baseline during a 12-month follow-up period but still remained significantly below baseline in both groups.17 As in the current investigation, the extent of symptom return was greater based on an intent-to-treat analysis in comparison with a group of successful completers.
These data would suggest that prolongation of GnRH agonist therapy beyond 6 months will not only result in the expected prolongation of pain relief during therapy but may also produce an impact on lengthening the interval to onset of symptom recurrence in the percentage who do recur. One important variable in this regard is the fact that patients who are candidates for a 12-month treatment course are those with more refractory pain and more likely to experience recurrence. In addition, the mean time to recurrence was artificially lowered in the current investigation by arbitrarily assuming that scores returned to baseline 16 months post-therapy in those who had not returned to baseline levels by 12 months. The smaller numbers of patients remaining for evaluation in the second year make more prolonged data analysis problematic. Moghissi et al performed a follow-up analysis of patients entered into a randomized initial 6-month trial of GnRH agonist estrogen replacement add-back (Moghissi K, Schlaff WD, Lemay A, Yuzpe AA, Pelty SR, Ferdonsi T. Abstract 0-116, 52nd Annual Meeting of the American Society for Reproductive Medicine, Boston, MA, November 1996). This group demonstrated that mean pelvic symptom scores remained approximately 25% below baseline through 48 weeks of follow-up in all treatment groups. To our knowledge, no comparative follow-up studies between 6-and 12-month treatment courses either with or without an add-back have been undertaken.
Data derived from each of the follow-up parameters reflecting either endometriosis symptoms or physical findings were re-evaluated based upon the severity of endometriosis appreciated at the screening laparoscopy. No differences were identified between any of the treatment groups for any of the parameters when patients with less extensive disease were analyzed separately from those with more extensive disease. The low numbers of patients with more extensive disease may somewhat obscure the comparisons such that these numbers may be too small to detect significant differences. However, the current investigation would support the results of previously published work suggesting that the severity of endometriosis correlated neither with severity of symptoms, response to GnRH agonist therapy, or time to recurrence after a 6-month treatment course with a 1-year follow-up period.18 In contrast, Waller and Shaw demonstrated that recurrence rates were lowest in patients with stage I endometriosis when assessed 5 years after an initial 6-month GnRH agonist therapeutic trial.19 Interestingly, in this trial, only minimal differences were appreciated between various stages of disease after the first year of follow-up.
We have previously demonstrated that the use of these three add-back regimens suppress the bone mineral density loss associated with the administration of GnRH agonist alone during a 12-month treatment course.10 The mean bone density remained stable in these three add-back groups during the follow-up period and in fact increased somewhat when higher doses of conjugated equine estrogens were employed. Subgroup analysis revealed no impact of patient age when either 28 or 35 years was used as a cutoff. One weakness in these analyses is the considerable number of dropouts during the second year of follow-up. However, the number of dropouts was much less significant at follow-up months 8 and 12. The initial sample size was chosen to ensure an 80% power to detect a difference between any two dosing regimens with regard to mean percent bone loss in the original trial as previously described. Calculation was not performed to take into account dropout during follow-up. This would have necessitated an impractical initial study sample size. Moghissi et al employed conjugated equine estrogens 0.3 and 0.625 mg in conjunction with medroxyprogesterone acetate 5 mg daily as add-back in a 6-month trial.20 Lumbar spine bone mineral density loss was significantly less than that noted with GnRH agonist alone, but did remain significantly lower than baseline. During a 48-week follow-up period, bone density returned to within 1% of baseline in all groups (Moghissi K, Schlaff WD, Lemay A, Yuzpe AA, Pelty SR, Ferdonsi T. Abstract 0-116, 52nd Annual Meeting of the American Society for Reproductive Medicine, Boston, MA, November 1996). The absence of statistically significant loss in the current study despite 12 months of GnRH agonist therapy may be due to the difference in progestational agents employed.
We have reported that significant and progressive bone mineral density loss was noted in patients receiving GnRH agonist alone as therapy was extended to 52 weeks.10 Although the mean level returned nearer to baseline, the time course was extremely protracted. Mean bone density at the final follow-up visit remained significantly lower than baseline values (Table 5). Only one other study has addressed this issue. Pierce et al evaluated lumbar spine bone density in follow-up endometriosis patients administered an agonist with and without add-back.21 Symptom recurrence was not evaluated in this study. These investigators noted that the add-back (daily oral estradiol 2 mg and norethindrone acetate 1 mg) had little impact on bone mineral loss preservation, which was not fully recovered 6 years after therapy. Unfortunately, in this study, the number of dropouts during follow-up was not described, add-back patients were treated for variable lengths of time (11.2 ± 4.3 months), and the dose of progestin administered may have been insufficient to prevent bone loss.4 Other studies demonstrating the value of add-back therapies during a 12-month treatment course did not assess bone density in follow-up.22
The potential recovery of bone density in women treated for a 6-month course with a GnRH agonist alone is somewhat controversial. Several investigators have demonstrated that although a trend towards normalization was appreciated, bone mineral density had not returned to baseline by 6 or even 12 months after completion of treatment.6–9 Paoletti et al noted that, although reduction in lumbar spine bone mineral density persisted 6 months post-therapy, values had returned to baseline within 24 months.23 Maillefort et al noted that men administered GnRH agonist as treatment for prostate carcinoma experienced progressive and accelerated bone loss at the lumbar spine and femoral neck over 18 months of therapy.24 However, these men may have had bone metastases, which would have served as a confounding variable. The potential return of bone to baseline after discontinuation of the agonist was not assessed in that trial. These data would suggest that GnRH agonist should not be administered in the absence of an appropriate add-back to endometriosis patients for more than a 6-month treatment course.
Although abnormal pertubations in lipid profiles were noted during therapy, a general return to baseline was appreciated during follow-up. The small number of patients with evaluable follow-up lipid samples may play a role in making data interpretation more difficult. It is difficult to explain these effects in patients receiving GnRH agonist alone. However, we are unaware of any other studies evaluating the effect of GnRH agonists alone on lipid parameters during 12 as opposed to 6 months of therapy. A greater adverse effect on lipid profiles of norethindrone acetate when used as an add-back in higher 10-mg daily doses for a 48-week treatment interval has been previously reported.22 However, a return to baseline within 8 weeks of completing therapy was demonstrated in that trial. The clinical significance of these changes is somewhat controversial.25 Indeed, Yin et al have demonstrated that the administration of estrogen plus norethindrone acetate as add-back to patients given GnRH agonists re-established impairment of endothelial reactivity induced by the agonist alone.26
In conclusion, symptomatic endometriosis can be effectively treated for 12 consecutive months with GnRH agonist in combination with norethindrone acetate administered alone or in combination with low-dose conjugated equine estrogens with minimization of hypoestrogenic symptoms. The pain relief achieved was maintained for a similar duration as patients receiving GnRH agonist alone with the exception of patients receiving higher doses of supplemental estrogens who experienced a more rapid return of dysmenorrhea. Bone mineral density was maintained at baseline levels in all add-back groups, whereas patients receiving GnRH agonist alone experienced protracted return of bone density to baseline. Thus, although extension of continuous GnRH agonist therapy alone beyond a 6-month treatment course may not be advisable, the addition of an appropriate add-back regimenn can afford safe prolongation of symptomatic relief in the appropriate patient. Confirmation of the safety of extending continuous add-back therapy beyond 1 year will await the results of future trials.
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Footnotes |
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The authors wish to express their gratitude to Linda Fredrick, MS, for her assistance with statistical analyses, and to Ron Arzaga, BA, for typing the manuscript.
Add-Back Study Group: Susan Ballagh, Marvin Bame, Richard Beyerlen, Eric Bieber, Vernie Bodden, Robert Browneller, Thomas Burwinkel, Michael Campion, Chong Chang, Richard Crane, Michael Doody, Roy Fleischman, Marc Fritz, Walter Gaman, Deborah Greenwall, John Harrington, W. Leroy Heinrichs, William Herzig, David Kmak, William Koltuh, Althea O’Shaugnessy, Roya Rakhshani, Joseph San Filippo, Vicki Schnell, Anthony Scialli, Barry Stewart, Dale Shadwall, Michael Thomas, and Stuart Weiss. 
Financial Disclosure
Drs. Surrey and Hornstein have received grant support and honoraria as members of the speaker’s bureau of TAP Pharmaceuticals. Dr. Surrey is also a member of the Medical Advisory Board of TAP Pharmaceuticals. Ms. Fredrick performed the statistical analysis and is an employee of Abbott Laboratories, a parent company of TAP Pharmaceuticals.
Received June 4, 2001. Received in revised form December 11, 2001. Accepted January 10, 2002.
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REFERENCES |
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