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ORIGINAL RESEARCH |
From the Departments of Obstetrics/Gynecology and Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas (now at Yale University, New Haven, Connecticut); and Wyeth-Ayerst Research, Radnor, Pennsylvania.
Address reprint requests to: Ellen W. Freeman, PhD, Department of Obstetrics/Gynecology, 2 Dulles/Mudd Suite, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; E-mail: freemane{at}mail.med.upenn.edu.
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ABSTRACT |
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METHOD: We conducted a randomized, double-blind, placebo-controlled, parallel-group, flexible-dose trial. After three screening cycles, including a single-blind placebo cycle, 164 women were randomly assigned to double-blind treatment with venlafaxine (50–200 mg/day) or placebo for four menstrual cycles. Primary outcome measures were the total premenstrual symptom scores as assessed by a daily symptom report (DSR) and the Hamilton Rating Scale for Depression.
RESULTS: Venlafaxine was significantly more effective than placebo in reducing PMDD symptoms as assessed by DSR scores (P <.001 for last observation carried forward and observed analyses). Sixty percent of venlafaxine versus 35% of placebo subjects improved >50% (P = .003). Forty-three percent of venlafaxine subjects versus 25% of placebo subjects experienced symptom remission, defined as reduction of DSR scores to the postmenstrual level (P = .034). Venlafaxine treatment was significantly better than placebo for all statistically derived DSR factors (mood, function, pain, and physical symptoms). Improvement was relatively swift, with approximately 80% symptom reduction in the first treatment cycle. Mean venlafaxine doses ranged from 50 mg/day in the first treatment cycle to 130 mg/day in the fourth treatment cycle. Adverse events such as nausea, insomnia, and dizziness were mild and transient.
CONCLUSIONS: Venlafaxine is significantly more efficacious than placebo for PMDD treatment. Response to treatment can occur in the first treatment cycle, and venlafaxine is well tolerated. Further studies are needed to evaluate the potential of intermittent (luteal phase) dosing for this cyclic disorder and the efficacy of long-term maintenance treatment with venlafaxine.
Symptoms from premenstrual syndrome (PMS) are commonly reported by menstruating women. About 3–5% of reproductive age women experience sufficient distress and functional impairment to meet the criteria for a severe form of PMS, which is termed premenstrual dysphoric disorder (PMDD) and defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).1
Abnormalities in central serotonergic activities are postulated to have a role in the pathophysiology of PMDD because of the alterations in mood, behavior, and appetite that are experienced with this disorder. Altered serotonergic activity during the luteal phase in women with premenstrual symptoms is also inferred from empiric observations, including a reduced platelet uptake of serotonin2 and decreased serotonin levels in peripheral blood premenstrually.3
Antidepressants with serotonin reuptake–inhibiting properties have been consistently efficacious for PMDD in randomized, double-blind, placebo-controlled trials.4–10 Whereas approximately half to two-thirds of PMDD study subjects respond well to serotonergic antidepressants, a sizeable number do not respond to such treatments for unknown reasons. It was therefore hypothesized that venlafaxine—a new-generation antidepressant that selectively inhibits the reuptake of both serotonin and norepinephrine—might significantly alleviate premenstrual symptoms in women with PMDD. The objective of this study was to evaluate the efficacy and safety of venlafaxine compared with placebo for the treatment of PMDD.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Inclusion criteria were age 18–45 years; regular menstrual cycles of 22–35 days for the last 6 months (and documented in the DSRs throughout the study); evidence of probable ovulation as tested in the screening period; meeting criteria for PMDD (outlined below); general good health as determined by medical history, physical exam, and laboratory screens; and no current major psychiatric illness as determined by SCID interview.
Study exclusions included use of psychopharmacologic medications that could not be discontinued for the duration of the study; all prescription or nonprescription medications or treatments for PMDD; pregnancy, breast feeding, hysterectomy, symptomatic endometriosis, irregular menstrual cycles, not using medically approved nonhormonal contraception; serious health problems; any major Axis 1 psychiatric diagnosis, including any major depressive episode within the last 6 months; risk of suicide; and alcohol or drug dependence within the last 2 years as defined by DSM-III-R criteria.
PMDD symptoms were assessed at screen visit 1 in a structured interview based on DSM-III-R diagnostic criteria for late luteal phase dysphoric disorder11 (renamed PMDD in the DSM-IV1). The reported symptoms were then confirmed by the subjects’ prospective daily symptom ratings for the two qualifying cycles using the DSR.13 The DSR listed 17 common premenstrual symptoms, including the symptoms for PMDD: depression, feeling hopeless or guilty, anxiety/tension, mood swings, irritability/persistent anger, decreased interest, concentration difficulties, fatigue, food cravings/increased appetite, insomnia/hypersomnia, feeling out of control/overwhelmed, poor coordination, headache, aches, swelling/bloating/weight gain, cramps, and breast tenderness. Subjects rated each symptom daily on a five-point scale (0, none to 4, extreme) with descriptors provided for each point. Scores were calculated by adding the ratings of cycle days 5–10 for the postmenstrual scores (day 1 was the first day of menses) and the ratings of the 6 days before the menses for the premenstrual scores. The study criteria required that the subjects had at least one mood and four other PMDD symptoms rated as severe premenstrually and mild or absent postmenstrually, with a total premenstrual DSR score of 80 or more and with at least a 50% increase over the postmenstrual score in each qualifying cycle. In addition, the postmenstrual Ham-D-21 score could not exceed 16 in either qualifying cycle.
This was a randomized, double-blind, parallel-group, placebo-controlled, flexible-dose trial of venlafaxine, a new-generation antidepressant that selectively inhibits the reuptake of serotonin and norepinephrine. The screening phase consisted of an initial screening visit followed by two menstrual cycles of daily symptom ratings, with single-blind placebo medication in the second qualifying cycle. Women who met the entrance criteria at the end of the single-blind placebo pretreatment cycle were randomly assigned to one of two treatment groups.
The treatment phase consisted of four menstrual cycles, followed by a 2-week taper. Visits were scheduled for the postmenstrual and premenstrual weeks in each cycle throughout the study. Random assignment and maintenance of blinded treatment were conducted as follows. The study medications for the double-blind treatment cycles were code labeled by the sponsor according to a computer-generated randomization schedule. Randomization numbers were assigned in blocks of four. The sponsor assigned specific patient randomization numbers to each study center. At each center, a woman eligible to enter the double-blind phase was assigned the next available randomization number (and the accompanying treatment supplies) from the number list assigned to the center. Tablets for venlafaxine and placebo were identical in appearance, individually packaged in identical bottles and code labeled for each subject by the sponsor. Subjects received medication bottles with the same code number assigned at randomization throughout the double-blind treatment.
The dose of venlafaxine ranged from 50 to 200 mg/day, administered in 25-mg tablets and taken twice daily orally with food. During the first treatment cycle, starting on day 1 of the menstrual cycle and continuing through the entire cycle, subjects received one tablet twice daily (50 mg/day of venlafaxine or placebo). In the absence of clear improvement, at the discretion of the clinician and in agreement with the subject, the dose could be increased by 50 mg/day at the beginning of each subsequent menstrual cycle. The mean (plus or minus standard deviation [SD]) doses of venlafaxine remained at the low end of the dose range: 84 (±23) mg/day in cycle 2; 115 (±37) mg/day in cycle 3; and 130 (±52) mg/day in cycle 4. In cycle 4, the placebo group took an average of six tablets per day, the mean dose equivalent of 156 (±46) mg/day.
The primary outcome measures were the subject-rated premenstrual DSR scores (sum of the 6 days before menses) and the Ham-D-21 scores, rated by the clinician for the premenstrual week. In addition to the total scores of each measure, the statistically derived DSR factors (emotion, function, pain, physical symptoms, and the appetite item) and four symptom clusters of the Ham-D-21 (anxiety/somatization, cognitive disturbance, retardation, and sleep disturbance) were evaluated. Clinician ratings of symptom severity and improvement were obtained at each visit using the Clinical Global Impressions (CGI) Scale.14
Sample size estimates were calculated before initiation of the study. The estimates were based on the proportion of responders (improvement from baseline of at least 50%) using the premenstrual DSR score, which was a primary efficacy parameter, with a placebo response rate of 10% and a venlafaxine response rate of 35%. A between-group difference of this magnitude would represent a clinically meaningful advantage for venlafaxine. Based on these hypothesized response rates, 60 subjects per group would be sufficient for 90% power with P = .05.
The primary analysis of outcome as defined in the protocol before initiating the study was the last observation for DSR (ie, analysis of cycle 4 with last observation carried forward [LOCF]). Additional efficacy analyses were conducted for treatment over all cycles using repeated-measures analyses of covariance (ANCOVA). The final models included treatment, cycle and treatment by cycle interaction, and baseline scores as the covariate. The repeated-measures models retained all available observations from all subjects randomly assigned to double-blind treatment (observed-case analysis). Response rates in the observed-case analyses were nearly identical to those from the more conservative LOCF analyses. The treatment by investigator interaction was not significant and was not included in the final models. Tests of categorical distributions used the 
2 statistic, Fisher’s exact test, or Cochran-Mantel-Haenszel statistics. Statistical results with P 
.05 for a two-tailed interpretation were considered statistically significant. The statistical software package was SAS (SAS Institute Inc., Cary, NC).15
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RESULTS |
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). This difference appeared to be a chance result, which was controlled in the data analyses by using the baseline premenstrual DSR scores as a covariate with treatment outcome.
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Adverse events were reported by the subjects in response to general questioning by a clinician at each visit. There were no serious adverse events during the study. Twelve women (seven venlafaxine, five placebo) who experienced adverse events reported these as the primary reason for discontinuation. The most frequently reported adverse events are shown in Table 2. Nausea, insomnia, dizziness, and decreased libido were adverse events reported for the venlafaxine group with a significantly greater frequency than for the placebo group.
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). Venlafaxine treatment was significantly more effective than the placebo in reducing PMDD symptoms in the first treatment cycle (P < .001), with a decrease of 42% in the venlafaxine group compared with 14% in the placebo group in the mean DSR scores. Improvement increased further in the second treatment cycle and then leveled off, decreasing from baseline 57% in the venlafaxine group versus 31% in the placebo group (LOCF). Venlafaxine remained significantly more efficacious than placebo in all four double-blind cycles (P < .001). The DSR postmenstrual scores remained low with no significant difference between the venlafaxine and placebo groups throughout treatment (Figure 1).
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). Only appetite (a single item) showed no drug–placebo difference at endpoint.
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). At treatment endpoint, the mean (standard error of the mean [SEM]) Ham-D-21 scores were 8.1 (1.6) and 12.3 (1.7) for the venlafaxine and placebo groups, respectively (P < .001, LOCF). Further examination of the Ham-D-21 factor scores indicated significantly greater reduction from baseline for the venlafaxine group compared with the placebo group for anxiety/somatization (P = .005), cognitive disturbance (P = .002), retardation (P = .007), and sleep disturbance (P = .043).
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Symptom remission, defined as a reduction in premenstrual DSR scores at endpoint to less than or equal to 10 (the postmenstrual mean of the sample), was observed in 43% of the venlafaxine group and 25% of the placebo group (P = .034). Symptom remission, defined as a Ham-D-17 score at treatment endpoint of 7 or less, was reported by 44% of the venlafaxine and 27% of the placebo groups (P = .035).
The results of the clinician-rated CGI were consistent with the DSR and Ham-D results. CGI improvement was significantly greater in the venlafaxine group (endpoint mean of 2.1, median 2.0, signifying "much improved" compared with the placebo group mean of 2.9, median 3.0, signifying "minimally improved") (P < .001 for the mean and the median treatment differences).17,21
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DISCUSSION |
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Although between-trial comparisons are limited by differences in design and measurement, other trials of serotonergic antidepressants that used continuous dosing for PMDD or severe PMS, including sertraline,7,10 fluoxetine,4 paroxetine,9 citalopram,16 and clomipramine,17 likewise demonstrated significant drug improvement. Response rates ranged from 52% to 69% with treatment with serotonergic antidepressants and from 15% to 34% with placebo treatment in these trials.
Improvement with venlafaxine was relatively rapid. Approximately 80% of the decrease in total premenstrual DSR scores at endpoint occurred in the first treatment cycle, when daily doses were low (50 mg/day). Venlafaxine maintained a statistically significant advantage over placebo throughout the entire treatment phase. Results of recent preliminary studies indicate that SSRIs may be efficacious even when administered during only the symptomatic premenstrual phase.8,16,18–21 Evidence suggests that such intermittent dosing may avoid the development of drug tolerance in PMDD treatment.
Venlafaxine was well tolerated. There were no serious adverse events requiring medical withdrawal from the study. The overall attrition was nearly identical in the drug (35%) and placebo (36%) treatments, and only 12 subjects who discontinued the study reported adverse events as the primary or secondary reason for discontinuing (9% of the venlafaxine group and 6% of the placebo group). The cumulative frequency of the most commonly reported adverse effects (nausea, insomnia, dizziness) was nearly identical to the frequencies reported for these in a meta-analysis of SSRI treatments for PMDD.21 Most importantly, these adverse effects appeared to be transient, with the highest incidence reported in the first treatment cycle and rapidly decreasing thereafter. Subjects who experienced them initially and continued in the study typically adapted to them over time. For example, the most common adverse effect, nausea, was reported by 36% on the venlafaxine group in the first treatment cycle; this decreased to 15% in the second cycle and to 12% by the fourth treatment cycle. A similar pattern was observed for the other side effects reported with treatment onset, particularly insomnia and dysmenorrhea. It is worth noting that the immediate-release formulation of venlafaxine used in this study was subsequently superseded by an extended-release formulation; this formulation showed a statistically significant benefit-to-risk ratio of at least 2:1 for the most frequent adverse effects, nausea and dizziness, indicating the possible superiority of the extended-release formulation for reducing these adverse effects.23
The reports of decreased libido appeared to be relatively low and showed little change across the four treatment cycles, ranging from 12% to 9% in the first and fourth treatment cycles, respectively. Because sexual functioning was not systematically assessed before or during treatment, it is not possible to determine the actual extent of disturbance in sexual functioning resulting from the antidepressant medication in this study. Kennedy et al found that the frequency of venlafaxine-induced sexual dysfunction was 21–24% in women with major depression, which was less than paroxetine and sertraline, but more than moclobemide.24 Kennedy et al also noted that there is little information on venlafaxine-related sexual dysfunction but suggested that there may be a potential benefit of its noradrenergic activity.24 An alternative possibility is that the low doses at which PMDD subjects responded to the antidepressant may limit sexual adverse effects. It is also possible that comparisons of the frequency of sexual adverse effects in women with PMDD to women with major depressive disorders and other diagnoses may not be valid. For those subjects who do experience sexual dysfunction with venlafaxine, a number of recently reviewed management strategies could be considered.25
The question of whether nonresponders would improve if treated with higher doses of venlafaxine, at which the drug maximally inhibits both serotonin and norepinephrine reuptake, is important for further study. The study design intentionally excluded women who did not meet the criteria for the DSM-III-R diagnosis of late luteal phase dysphoric disorder (renamed PMDD in DSM-IV), which is estimated to include about 5% of women at the severe end of a spectrum of premenstrual distress,26 and therefore does not answer the questions about response to venlafaxine in the broader spectrum of PMS. Other important questions for further study include the effectiveness of long-term treatment and the occurrence of relapse if the medication is discontinued.
In conclusion, venlafaxine is effective for the treatment of PMDD. Response to treatment is rapid, observed during the first treatment cycle at a relatively low dose, and treatment is well tolerated overall. Further studies are needed to evaluate whether venlafaxine dosing only in the symptomatic luteal phase is effective for this cyclic disorder, whether nonresponders to lower doses of venlafaxine improve with higher doses, and whether long-term maintenance with venlafaxine is effective for this disorder.
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Footnotes |
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Received January 23, 2001. Received in revised form May 14, 2001. Accepted June 15, 2001.
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REFERENCES |
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2. Taylor DL, Matthew RJ, Beng TH. Serotonin levels and platelet uptake during premenstrual tension. Neuropsychobiology 1984;12:16–8.[Medline]
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5. Pearlstein TB, Stone AB, Lund SA, Scheft H, Zlotnick C, Brown WA. Comparison of fluoxetine, bupropion and placebo in the treatment of premenstrual dysphoric disorder. J Clin Psychopharmacol 1997;17:261–6.[Medline]
6. Diegoli MSC, da Fonseca AM, Diegoli CA, Pinotti JA. A double-blind trial of four medications to treat severe premenstrual syndrome. Int J Gynaecol Obstet 1998;62:63–7.[Medline]
7. Yonkers KA, Halbreich U, Freeman EW, Brown C, Endicott J, Frank E, et al. Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment: A randomized controlled trial. JAMA 1997;278:983–8.[Abstract]
8. Halbreich U, Smoller J. Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome. J Clin Psychiatry 1997;58:399–402.[Medline]
9. Eriksson E, Hedberg MA, Andersch B, Sundblad C. The serotonin reuptake inhibitor paroxetine is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome: A placebo-controlled trial. Neuropsychopharmacology 1995;12(2):167–76.[Medline]
10. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: A randomized controlled trial. Arch Gen Psychiatry 1999; 56:932–9.
11. Spitzer RL, Williams JBW, Gibbon M, First MB. Instruction manual for the structured clinical interview for DSM-III-R (SCID). New York: Biometrics Research, 1988.
12. Hamilton M. A rating scale for depression. J Neurol Neurosurg 1960;23:56–62.
13. Freeman EW, DeRubeis RJ, Rickels K. Reliability and validity of a daily diary for premenstrual syndrome. Psychiatry Res 1996;65:97–106.[Medline]
14. Guy W. ECDEU assessment manual for psychopharmacology. Revised 1st ed. Rockville, MD: US Dept of Health, Education and Welfare, 1976.
15. SAS user’s guide, statistics version 6 edition. Cary, NC: SAS Institute Inc., 1990.
16. Wikander I, Sundblad C, Andersch B, Dagnell I, Zylberstein D, Bengtsson F, et al. Citalopram in premenstrual dysphoria: Is intermittent treatment during luteal phases more effective than continuous medication throughout the menstrual cycle? J Clin Psychopharmacol 1998;18:390–8.[Medline]
17. Sundblad C, Modigh K, Andersch B, Eriksson E. Clomipramine effectively reduces premenstrual irritability and dysphoria: A placebo-controlled trial. Acta Psychiatr Scand 1992;85:39–47.[Medline]
18. Young SA, Hurt PH, Benedek DM, Howard RS. Treatment of premenstrual dysphoric disorder with sertraline during the luteal phase: A randomized, double-blind, placebo-controlled crossover trial. J Clin Psychiatry 1998;59: 76–80.[Medline]
19. Sundblad C, Hedberg MA, Eriksson E. Clomipramine administered during the luteal phase reduces the symptoms of premenstrual syndrome: A placebo-controlled trial. Neuropsychopharmacology 1993;9:133–45.[Medline]
20. Freeman EW, Rickels K, Arredondo F, Kao L-C, Pollack SE, Sondheimer SJ. Full- or half-cycle treatment of severe premenstrual syndrome with a serotonergic antidepressant. J Clin Psychopharmacol 1999;19:3–8.[Medline]
21. Jermain DM, Preece CK, Sykes RL, Kuehl TJ, Sulak PJ. Luteal phase sertraline treatment for premenstrual dysphoric disorder: Results of a double-blind, placebo-controlled, crossover study. Arch Fam Med 1999;8:328–32.
22. Dimmock PW, Wyatt KM, Jones PW, O’Brien PMS. Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: A systematic review. Lancet 2000; 356:1131–6.[Medline]
23. Entsuah R, Chitra R. A benefit-risk analysis of once-daily venlafaxine extended release (XR) and venlafaxine immediate release (IR) in outpatients with major depression. Psychopharm Bull 1997;33:671–6.[Medline]
24. Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline and venlafaxine. J Clin Psychiatry 2000;61:276–81.[Medline]
25. Rothschild AJ. Sexual side effects of antidepressants. J Clin Psychiatry 2000;61:28–36.
26. Steiner M. Premenstrual syndromes. Annu Rev Med 1997;48:447–55.[Medline]
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luteal phase placebo (n = 75); 
luteal phase venlafaxine (n = 68); 
follicular phase placebo (n = 75); 
follicular phase venlafaxine (n = 68). *P 
venlafaxine (N = 68) and 
50% decrease in premenstrual scores from pretreatment baseline.