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Gender Differences in Treatment Response to Sertraline
Versus Imipramine in Chronic Depression
Susan G. Kornstein, M.D.
Objective: The authors examined gender
study. Gender differences in time to re- differences in treatment response to ser- sponse were seen with imipramine, with Alan F. Schatzberg, M.D.
traline, a selective serotonin reuptake in- women responding significantly more hibitor (SSRI), and to imipramine, a tricy- slowly than men. Comparison of treat- clic antidepressant, in chronic depression.
Michael E. Thase, M.D.
ment response rates by menopausal sta- Method: A total of 235 male and 400 fe-
tus showed that premenopausal women Kimberly A. Yonkers, M.D.
male outpatients with DSM-III-R chronic responded significantly better to sertra- major depression or double depression line than to imipramine and that post- (i.e., major depression superimposed on James P. McCullough, Ph.D.
menopausal women had similar rates of dysthymia) were randomly assigned to 12 response to the two medications.
weeks of double-blind treatment with ser- Gabor I. Keitner, M.D.
traline or with imipramine after placebo Conclusions: M e n a n d w o m e n w i t h
chronic depression show differential re- Alan J. Gelenberg, M.D.
sponsivity to and tolerability of SSRIs and Results: Women were significantly more
tricyclic antidepressants. The differing re- likely to show a favorable response to ser- Sonia M. Davis, Dr.P.H.
sponse rates between the drug classes in traline than to imipramine, and men women was observed primarily in pre- were significantly more likely to show a Wilma M. Harrison, M.D.
favorable response to imipramine than to menopausal women. Thus, female sex sertraline. Gender and type of medication hormones may enhance response to SSRIs Martin B. Keller, M.D.
were also significantly related to dropout or inhibit response to tricyclics. Both gen- rates; women who were taking imipra- der and menopausal status should be mine and men who were taking sertraline considered when choosing an appropriate were more likely to withdraw from the antidepressant for a depressed patient.
(Am J Psychiatry 2000; 157:1445–1452)
Although the gender difference in the prevalence of recent years because of their underdiagnosis and under- unipolar depression has been well established (1–3), little treatment and the morbidity and costs associated with attention has been paid to gender differences in treatment these disorders (8, 9). We previously reported gender dif- response to antidepressant medications. Possible sex dif- ferences in the presentation of chronic depression in a ferences in response to imipramine were first noted sev- large clinical sample of men and women with DSM-III-R eral decades ago (4, 5). In a recent meta-analysis of 35 chronic major depression or double depression (major de- studies published between 1957 and 1991 that reported pression superimposed on dysthymia) (10, 11). In this ar- imipramine response rates separately by gender, men re- ticle, we examine gender-specific differences in treatment sponded more favorably to imipramine than did women response to sertraline, a newer SSRI, and to imipramine, arepresentative tricyclic antidepressant, in this same clini- (6). A study comparing tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) found that inpatients with atypical depression and associated panicattacks, women showed a more favorable response to MAOIs and men to tricyclic antidepressants (7). These dif- Subjects were 235 men and 400 women who participated in a ferential response patterns suggest that gender should be multicenter, double-blind, randomized, parallel-group compara- considered when making treatment decisions.
tive trial of sertraline and imipramine in the treatment of chronicmajor depression and double depression. The study rationale, de- However, to our knowledge, no published studies have sign, methods, and inclusion/exclusion criteria have been de- examined gender differences in response to selective sero- tailed in manuscripts by Rush et al. (12) and Keller et al. (13). Indi- tonin reuptake inhibitors (SSRIs), currently the most viduals age 21–65 years who met DSM-III-R criteria for chronic widely used class of antidepressants. In addition, we could major depression (i.e., major depression of at least 2 years' dura- find no studies of gender differences in treatment re- tion without antecedent dysthymia) or double depression (i.e.,major depression superimposed on dysthymia) were recruited sponse among chronically depressed patients. Chronic through advertisement or medical referral to one of 10 university- depressive disorders have received increasing attention in affiliated medical centers or two clinical research centers. After a Am J Psychiatry 157:9, September 2000 GENDER AND RESPONSE TO ANTIDEPRESSANTS
TABLE 1. Baseline Characteristics of Men and Women With Chronic Depression in a 12-Week Double-Blind Study of Sertra-
line and Imipramine

Experiencing a recurrent episode of major depression Meets criteria for dysthymia Affective disorder in first-degree relative Previously treated with psychotropic medication Previously treated with psychotherapy Age at onset of major depression (years) Duration of index episode of major depression (years) Age at onset of dysthymia (years) Duration of dysthymia (years) Measure of depression severity Hamilton depression scale score CGI severity scale score Beck Depression Inventory score a Data on some characteristics were not available for all subjects.
complete description of the study was given to the subjects, writ- of other parameters and subgroups were of secondary interest ten informed consent was obtained.
and were performed to help describe and support the main re- A 24-item Hamilton Depression Rating Scale (14) score of ≥18 sults. To control for type I error in multiple comparisons, the Bon- and a Clinical Global Impression (CGI) (15) severity scale score of ferroni correction was applied. The p values from the two primary ≥3 after 1 week of placebo washout were required for study entry.
tests of interaction were evaluated for significance relative to Subjects were randomly assigned to 12 weeks of double-blind p<0.05÷2=0.025. Unadjusted significance levels of p<0.05 were treatment with sertraline or imipramine in a 2:1 ratio. (The 2:1 ra- applied to all supportive and descriptive evaluations.
tio was used because of a second random assignment of patients Men and women were compared for baseline characteristics by who received sertraline during the maintenance phase of the using Mantel-Haenszel chi-square tests for categorical variables study, which is not described here.) The starting dose of both and analysis of variance (ANOVA) for continuous variables. All medications was 50 mg/day. The dose of imipramine was titrated analyses adjusted for treatment group (sertraline or imipramine), by 50 mg/day each week, according to clinical response and the depression type, and investigator site.
absence of dose-limiting side effects, to a maximum of 300 mg/ Gender and treatment groups were compared at endpoint for day. Because sertraline is effective for some patients at the start- attrition and response rates by using Mantel-Haenszel chi-square ing dose, the first opportunity to titrate the medication was at the tests, as just described. The pair-wise interactions between gen- end of week 3, at which point the dose could be increased by 50 der, treatment, and depression type were evaluated for statistical mg/day per week to a maximum of 200 mg/day. The mean sertra- significance by using a logistic regression model that adjusted for line dose at endpoint was 139.6 mg/day (SD=59.7) in women and143.2 mg/day (SD=58.8) in men. The mean imipramine dose at investigator site. Changes from baseline to endpoint in continu- endpoint was 196.3 mg/day (SD=81.6) for women and 207.5 mg/ ous variables (e.g., Hamilton depression scale scores) were exam- day (SD=83.2) for men. The endpoint for each subject was de- ined by using analysis of covariance (ANCOVA) with effects for fined as the last study visit attended, with the last observation car- baseline score, treatment group, gender, depression type, and in- ried forward.
vestigator site. Interactions between gender, treatment, and de-pression type were also evaluated for inclusion in the model. Me- Patient visits were scheduled at weekly intervals after initiation of medication for the first 6 weeks and biweekly thereafter. At dian time to discontinuation and time to response were each visit, the following rating scales were administered: the 24- estimated by using Kaplan-Meier survival methods. Patient item Hamilton depression scale, the CGI severity and improve- groups were compared by using an unadjusted log rank test. The ment scales, and the Beck Depression Inventory (16). Adverse interactions between gender, treatment, and depression type events, either reported by the patient or observed by the clinician, were evaluated by using a Cox proportional hazards regression were recorded at each visit. Medication compliance was deter- model that adjusted for investigator site.
mined by pill counts.
The frequency of treatment-emergent adverse events in men Satisfactory therapeutic response was defined as a 50% de- and women was compared by using chi-square tests with Yates's crease in the Hamilton depression scale score, a Hamilton de- correction, or Fisher's exact test for small samples. Treatment- pression scale score ≤15, a CGI severity scale score ≤3, and a CGI emergent adverse events were those that either began or in- improvement scale score of 1 or 2 (corresponding to "very much" creased in severity after initiation of treatment.
or "much improved").
Subgroups defined by characteristics other than gender (e.g., We focused on two primary research questions: Do the genders pre- versus postmenopausal women) were evaluated by using differ in their response to sertraline versus imipramine in terms of similar methods. Actual sample sizes varied slightly by parameter.
1) response rate at study endpoint or 2) dropout rate? Evaluations All tests used two-tailed probability values.
Am J Psychiatry 157:9, September 2000 KORNSTEIN, SCHATZBERG, THASE, ET AL.
TABLE 2. Reasons for Withdrawal From a 12-Week Study of Sertraline and Imipramine by Men and Women With Chronic
Depression

Sertraline (N=264) Imipramine (N=136) Sertraline (N=162) Imipramine (N=73) Reason for Withdrawal From the Study sufficient clinical response Intercurrent illness Lost to follow-up Protocol deviation ormality on ECG or la a Significant difference between women taking imipramine and women taking sertraline (Mantel-Haenszel χ2=5.20, df=1, p=0.02).
b Includes withdrawal of consent, patient relocation, and scheduling conflicts.
c Significant interaction of gender and treatment (logistic regression Wald χ2=6.80, df=1, p=0.009).
d Significant difference between women taking imipramine and women taking sertraline (Mantel-Haenszel χ2=9.27, df=1, p=0.002).
FIGURE 1. Rates of Response to Sertraline and Imipramine
at Endpoint Among Men and Women With Chronic Depres-

Differences at Baseline
sion in a 12-Week Double-Blind Treatment Studya
Comparisons by gender at baseline have been pre- sented and discussed in detail in a separate article (11).
The findings are summarized in Table 1. Briefly, women were significantly younger than men. Men were signifi- cantly more likely to be married and to have a college de- gree, yet they were more likely to be unemployed (i.e., not employed outside the home, retired, or a student). Menand women were not significantly different in race.
Compared with men, women had significantly higher baseline severity ratings on the Hamilton depression scale, the CGI severity scale, and the Beck Depression In- ventory. Women were significantly younger than men at a Endpoint was the subject's last study visit, with the last observation the onset of their major depressive disorder. Men were sig- carried forward. Satisfactory therapeutic response was indicated by nificantly more likely to have dysthymia in addition to ma- a 50% decrease in the Hamilton depression scale score, a Hamiltondepression scale score ≤15, a Clinical Global Impression (CGI) sever- jor depressive disorder. Women were significantly more ity scale score ≤3, and a CGI improvement scale score of 1 or 2 (cor- likely to have received previous treatment for depression, responding to "very much" or "much improved"). including pharmacotherapy and psychotherapy, and to Significant interaction of gender and treatment (logistic regressionWald χ2=10.47, df=1, p=0.001).
report a family history of affective disorder.
c Significantly higher response rate for sertraline than for imi- pramine (Mantel-Haenszel χ2=5.34, df=1, p=0.02).
d Significantly higher response rate for imipramine than for sertra- line (Mantel-Haenszel χ2=4.12, df=1, p=0.04).
As Table 2 shows, a statistically significant interaction of gender and treatment was found for dropout rates.
Women who were taking imipramine and men who were taking sertraline were more likely to withdraw from the Response analysis using an intent-to-treat approach study. Women who were taking imipramine were signifi- showed a statistically significant interaction of gender and cantly more likely to drop out than women who were tak- treatment, with the highest response rates at endpoint ing sertraline; 36 (26%) of 136 women randomly assigned (last study visit) seen in women who took sertraline and to receive imipramine withdrew from the study, compared men who took imipramine (Figure 1). Women were signif- to 37 (14%) of 264 women randomly assigned to receive icantly more likely to respond to sertraline than to imi- sertraline. In contrast, the dropout rates for men were 14 pramine (147 [57%] of 260 versus 61 [46%] of 133), and (19%) of 73 who took imipramine and 39 (24%) of 162 whotook sertraline; this difference was not statistically signifi- men were significantly more likely to respond to imi- cant (Mantel-Haenszel χ2=0.78, df=1, p=0.38). Analyses of pramine than to sertraline (43 [62%] of 69 versus 73 [45%] time to discontinuation from the study showed similar re- of 161). A response analysis of subjects who completed the sults. The most common reason for dropout was adverse 12-week trial also showed a statistically significant inter- events, which accounted for nearly half of the patients action of gender and treatment (Wald χ2=4.82, df=1, p= who withdrew from the study.
0.03), with women more likely to respond to sertraline Am J Psychiatry 157:9, September 2000 GENDER AND RESPONSE TO ANTIDEPRESSANTS
TABLE 3. Depression Severity Scores at Baseline, Weeks 4 and 12, and Endpointa of Women and Men Receiving Sertraline
or Imipramine for Chronic Depression

Sertraline (N=264) Imipramine (N=136) Sertraline (N=162) Imipramine (N=73) Hamilton depression scale score Change from baseline Clinical Global Impression (CGI) severity scale score Change from baseline CGI improvement scale score Beck Depression Inventory score Change from baseline a Endpoint for each assessment was the subject's last study visit, with the last observation carried forward.
b Significant interaction of gender and treatment (ANCOVA F=3.95, df=1, 609, p=0.05).
c Significant interaction of gender and treatment (ANCOVA F=5.03, df=1, 495, p=0.03).
d Significant difference between women taking sertraline and women taking imipramine (ANCOVA F=6.42, df=1, 382, p=0.01).
e Significant interaction of gender and treatment (ANCOVA F=6.23, df=1, 611, p=0.01).
f Significant interaction of gender and treatment (ANCOVA F=4.03, df=1, 494, p=0.05).
g Significant interaction of gender and treatment (ANCOVA F=5.06, df=1, 562, p=0.03).
than to imipramine and men more likely to respond to im- ipramine than to sertraline.
Men and women taking either sertraline or imipramine There was also a statistically significant interaction of showed no significant gender differences in overall fre- gender and treatment for time to response (Cox propor- quency of treatment-emergent adverse events or in re- tional hazards regression model, χ2=7.56, df=1, p=0.006).
ports of severe adverse events (Table 4). However, women Men responded significantly more rapidly than women to who were taking imipramine were significantly more likely imipramine, with a median time to response of 8 weeks in to withdraw from the study because of adverse events men compared to 10 weeks in women (log rank χ2=4.17, than women who were taking sertraline (18 [13%] of 136 df=1, p=0.04). Women tended to respond more rapidly versus 17 [6%] of 264; Mantel-Haenszel χ2=5.20, df=1, p= than men to sertraline (10 versus 12 weeks median time to 0.02). Discontinuation rates due to adverse events for men response), although this difference was not significant (log who took imipramine and sertraline were 7 (10%) of 73and 10 (6%) of 162, respectively; this difference was not rank χ2=2.60, df=1, p=0.11).
significant (Mantel-Haenszel χ2=0.83, df=1, p=0.36).
Analyses based on scores on the Hamilton depression As shown in Table 4, there were several statistically sig- scale, CGI, and Beck Depression Inventory showed similar nificant gender differences in types of adverse events with results, with women tending to respond better to sertra- frequencies of occurrence of ≥10% in men or women.
line and men to imipramine (Table 3). There was a statisti- Among those taking sertraline, women were significantly cally significant interaction of gender and treatment for more likely to report nausea and dizziness, and men were the change in Hamilton depression scale score from base- significantly more likely to report dyspepsia, sexual dys- line to endpoint, as well as for the changes in CGI severity function, and urinary frequency. Among those taking imi- scale score and Beck Depression Inventory score. The in- pramine, women were significantly more likely than men teraction of gender and treatment for the CGI improve- to report nausea and were more likely, but not signifi- ment scale score at endpoint approached, but did not cantly so, to report constipation and nervousness. Men reach, statistical significance.
taking imipramine were significantly more likely than Am J Psychiatry 157:9, September 2000 KORNSTEIN, SCHATZBERG, THASE, ET AL.
TABLE 4. Treatment-Emergent Adverse Events During a 12-Week Study of Sertraline and Imipramine Among Women and
Men With Chronic Depression

Any adverse event Adverse events with >10% frequency Increased sweating Sexual dysfunctione,f Urinary frequencyg,h Other urinary disorder Postural dizziness Any severe adverse event a Significant difference between women and men taking sertraline (χ2=5.19, df=1, p=0.02, with Yates's correction).
b Significant difference between women and men taking sertraline (χ2=4.67, df=1, p=0.03, with Yates's correction).
c Significant difference between women and men taking sertraline (χ2=10.97, df=1, p=0.001, with Yates's correction).
d Significant difference between women and men taking imipramine (χ2=10.84, df=1, p=0.001,with Yates's correction).
e Significant difference between women and men taking sertraline (χ2=27.51, df=1, p=0.001, with Yates's correction).
f Significant difference between women and men taking imipramine (χ2=15.41, df=1, p=0.001, with Yates's correction).
g Significant difference between women and men taking sertraline (χ2=4.70, df=1, p=0.03, with Yates's correction).
h Significant difference between women and men taking imipramine (p=0.03, Fisher's exact test).
women to complain of urinary frequency and sexual dys- (115 [57%] of 201 versus 41 [43%] of 96; Mantel-Haenszel function. In addition, men taking imipramine were more χ2=6.31, df=1, p=0.01), whereas response rates to sertra- likely to complain of other urinary disorders, but the gen- line and imipramine in postmenopausal women were der difference was not significant.
similar (27 [57%] of 47 versus 14 [56%] of 25; Mantel-Haen-szel χ2=0.02, df=1, p=0.88). The interaction between Effect of Menopausal Status
menopausal status and treatment was not significant Of the 400 women in the study, 301 (203 taking sertraline (Wald χ2=0.88, df=1, p=0.35).
and 98 taking imipramine) were premenopausal and 74 When we used change in Hamilton depression scale (49 taking sertraline and 25 taking imipramine) were post- score at endpoint as a measure of treatment response, pre- menopausal; for the remaining 25 women, menopausal menopausal women again responded significantly better status either could not be determined or the data were to sertraline than to imipramine (t test of ANOVA least squares means, t=2.65, df=360, p=0.008). Among post- A significant interaction was found between treatment menopausal women, there were no significant differences and menopausal status for dropout rates (Wald χ2=7.41, in change in Hamilton depression scale scores between df=1, p=0.007). Premenopausal women taking imipramine those taking sertraline and those taking imipramine (t test were significantly more likely to withdraw from the study of ANOVA least squares means, t=0.69, df=360, p=0.49). The than postmenopausal women taking imipramine (28 interaction between menopausal status and treatment ap- [29%] of 98 versus 2 [8%] of 25; Mantel-Haenszel χ2=5.24, proached significance (ANCOVA F=3.24, df=1, 360, p=0.07).
df=1, p=0.02). Among women taking sertraline, a greater Examination of the effects of oral contraceptives and hor- number of postmenopausal women withdrew from the mone replacement therapy on response rates in premeno- study compared with premenopausal women (11 [22%] of pausal and postmenopausal women was attempted, but 49 versus 26 [13%] of 201), but the difference was not statis- the group sizes were too small to allow statistical analysis.
tically significant (Mantel-Haenszel χ2=2.50, df=1, p=0.11).
Responder analysis at endpoint by menopausal status Response Rates by Age and Gender
showed that premenopausal women were significantly The men and women in the sample were divided by age more likely to respond to sertraline than to imipramine into subgroups of those <40 years, 40–50 years, and >50 Am J Psychiatry 157:9, September 2000 GENDER AND RESPONSE TO ANTIDEPRESSANTS
years. For men, imipramine response rates were found to Our data also showed gender differences in time to re- be consistently higher than sertraline response rates sponse, with men who took imipramine responding sig- across all age groups, but the differences did not reach sta- nificantly more rapidly than women who took imi- tistical significance. For the women, response rates to ser- pramine. These results are consistent with the study by traline and imipramine were nearly identical in the 40–50 Frank et al. (19), who reported that women were slower and >50 age groups, whereas response rates to sertraline than men to respond to combination treatment with imi- and imipramine in the <40 age group were 79 (61%) of 129 pramine plus interpersonal psychotherapy. This latter and 26 (40%) of 65, respectively, and the difference was finding is even more compelling if one considers that in- statistically significant (Mantel-Haenszel χ2=7.94, df=1, p= terpersonal psychotherapy is an effective treatment for 0.005). It is noteworthy that 186 (96%) of the women age depression, in and of itself (Klerman et al. [20], Elkin et al.
<40 years were premenopausal.
[21], Thase et al. [22]), which would tend to blunt the gen-der difference in response rates to imipramine.
Several significant gender differences in types of ad- verse events were also noted in our study. Among subjects This study is the first that we are aware of to report gen- who took sertraline, women were more likely to report der differences in treatment response to tricyclic antide- nausea and dizziness, and men tended to report dyspep- pressants compared with SSRIs in patients with chronic sia, sexual dysfunction, and urinary frequency. Gender depression. We found a significant interaction of gender differences in adverse events due to imipramine were and treatment for both response rates and dropout rates, manifested in similar patterns, with women more likely to with the highest response rates and the lowest dropout report nausea and men more likely to report urinary diffi- rates occurring in women taking sertraline and in men culties and sexual dysfunction. The tendency for men to taking imipramine. The intent-to-treat response rate for report more sexual side effects while taking antidepres- women taking sertraline was 57%, compared to only 46% sants has been noted previously (23). Sociocultural factors for women taking imipramine. In contrast, men re- may contribute to this disparity, as women may be morereluctant to discuss sexual complaints.
sponded significantly better to imipramine than to sertra-line, with response rates of 62% and 45%, respectively. Sig- Differences were also shown in response and dropout nificant differences in dropout rates were also found; rates in pre- versus postmenopausal women. Premeno-pausal women responded significantly better to sertraline women taking imipramine were significantly more likely than to imipramine, whereas response rates to the two to withdraw from the study than women taking sertraline.
drugs in postmenopausal women were similar. Among Because a significant interaction of gender and treatment those taking imipramine, premenopausal women were was found by using both intent-to-treat and completer significantly more likely to discontinue treatment than analyses, we did not conclude that the differences in re- postmenopausal women. These findings suggest that the sponse rates were due merely to differences in tolerability.
gender differences in imipramine response found in our Even women who were able to tolerate imipramine study were due primarily to poor response and tolerability throughout the 12-week trial showed poorer response in premenopausal women.
rates, compared with women who took sertraline. In addi- Previous studies have not specifically examined re- tion, the time-to-response analysis, which appropriately sponse by stratifying the data by subjects' menopausal sta- adjusts for dropouts by using available data for each sub- tus; however, a poor response to imipramine in younger ject up until the time of dropout and then censors the sub- versus older women has been noted. In a study by Raskin ject, also supported this conclusion.
(4), imipramine response in women differed by age group, Our finding that women respond poorly to imipramine although men responded favorably to the drug regardless is consistent with other results reported in the literature of age. Imipramine was no more effective than placebo for (4–6). That women may respond better to an SSRI than a women under age 40, who responded preferentially to tricyclic has not been previously reported, although data phenelzine, whereas older women were as responsive as presented by Steiner et al. (17) showed that women re- men to imipramine. Similarly, Thase et al. (24) reported no sponded better to paroxetine than to imipramine. In con- difference between response to psychotherapy alone and trast, Lewis-Hall et al. (18) noted that fluoxetine was better combined treatment with a tricyclic plus psychotherapy tolerated but no more effective than tricyclics in de- for women under age 40, whereas men showed a more pressed women. It should be mentioned that no compari- favorable response to combined treatment across all age son data were given for men or for placebo in the latter groups. The response to combined treatment among study; an important point: the possible interactive effect women over age 50 was comparable to that in men. The of menopausal status was not taken into account. In pa- poorer results in younger women in the latter study may be tients with dysthymia, the superior response of women, explained by the use of tricyclics in the combined regimen.
compared with men, to sertraline has also been noted by Such differences in imipramine response by age among Yonkers et al. (unpublished data).
women but not men also emerged in our study when we di- Am J Psychiatry 157:9, September 2000 KORNSTEIN, SCHATZBERG, THASE, ET AL.
vided the men and women into <40 years, 40–50 years, and the generalizability of our findings to patients with chronic >50 years age groups. Women showed a significantly higher depression in the general population may be compro- response rate to sertraline than to imipramine in the <40 mised. Similarly, the restriction of our study group to pa- age group, whereas response rates to sertraline and imi- tients with chronic major depression or double depression pramine were nearly identical in the other two age groups.
may limit the applicability of these findings to patients with These findings strongly suggest that the differences in re- other types of depressive disorders, such as acute or epi- sponse by menopausal status noted in our study were not sodic depression. Finally, we did not have the statistical attributable simply to age-dependent differences.
power needed to address the effects of oral contraceptives The underlying mechanism of these gender differences and hormone replacement therapy on response rates in in treatment response is unclear. One explanation is that premenopausal and postmenopausal women; these effects the serotonergic potency of sertraline may be important should be examined in future work.
for young women. Serotonergic agents have demon-strated efficacy in depressive disorders unique to this age group, such as premenstrual dysphoric disorder (25). Sec-ond, it may be that depressive subtype (i.e., typical versus The study results provide evidence of gender-specific dif- atypical depression) is the critical determinant of re- ferences in the efficacy and tolerability of antidepressant sponse differences, as suggested by Thase et al. (26).
medications in the treatment of chronic depression. Specif- Women are more likely to present with atypical depressive ically, women in our study responded significantly better to symptoms (27), which have been shown to respond pref- sertraline than to imipramine, whereas men responded sig- erentially to SSRIs or MAOIs (28, 29); men, on the other nificantly better to imipramine than to sertraline. Women hand, often have more classic neurovegetative features of also had more tolerability problems with imipramine, aswell as a slower response time to that medication. On the depression, which are responsive to tricyclics.
basis of analyses of the effect of age and menopausal status A third explanation for gender differences in treatment on response rates, it appears that the gender difference was response is that female sex hormones may have an effect predominantly determined by differential responsivity to in determining response. Specifically, female gonadal hor- the two medications in premenopausal women. In clinical mones may play a permissive or inhibitory role in antide- practice, both gender and menopausal status should be pressant activity, e.g., enhancing response to SSRIs or in- considered in the decision about which antidepressant to hibiting response to tricyclic antidepressants. Several use for a depressed patient. Whether these gender differ- studies have shown that estrogen enhances serotonergic ences in acute treatment response will be associated with activity (30, 31), and preliminary studies have suggested differences in subsequent relapse or recurrence rates will be that estrogen augments SSRI response in postmenopausal examined in future reports.
women (32). Further research is clearly needed to deter-mine the exact mechanisms of these differential antide- Received Dec. 23, 1998; revision received Feb. 8, 2000; accepted pressant effects.
Mar. 13, 2000. From the Medical College of Virginia, Virginia Com- On the basis of our results, consideration should be monwealth University; Stanford University School of Medicine, Stan-ford, Calif.; the University of Pittsburgh and Western Psychiatric Insti- given to both gender and menopausal status in selecting tute, Pittsburgh; the Yale University School of Medicine, New Haven, an antidepressant for a given patient with depression. Pre- Conn.; the Department of Psychology, Virginia Commonwealth Uni- menopausal women should be treated preferentially with versity; Brown University, Providence, R.I.; the University of Arizona,Tucson; Quintiles, Inc., Research Triangle Park, N.C.; Pfizer, Inc., New SSRIs; men, on the other hand, may respond better to tri- York; and the College of Physicians and Surgeons, Columbia Univer- cyclics. However, concerns about side effect profiles and sity School of Medicine, New York. Address reprint requests to Dr. Ko- lethality of overdose must also be considered. Postmeno- rnstein, Department of Psychiatry, Medical College of Virginia, Vir-ginia Commonwealth University, P.O. Box 980710, Richmond, VA pausal women appear to respond equally well to either 23298-0710; skornstein@hsc.vcu.edu (e-mail).
class of medication.
This study was completed under contracts from Pfizer Pharmaceuti- A major limitation of this study is the lack of a placebo cals to the following investigators: Martin B. Keller, M.D. (Program Di-rector), Gabor I. Keitner, M.D., and Ivan W. Miller, Ph.D., Brown Univer- control group. The inclusion of a placebo condition may sity; James H. Kocsis, M.D., and John C. Markowitz, M.D., Cornell have altered the interpretation of our results by uncoupling University; Daniel N. Klein, Ph.D., Fritz Henn, M.D., and David Schlager, specific and nonspecific elements of therapeutic response M.D., State University of New York at Stony Brook; James P. Mc-Cullough, Ph.D., and Susan G. Kornstein, M.D., Virginia Common- (26). Our decision not to use a placebo group has been ex- wealth University; Robert M.A. Hirschfeld, M.D., and James Russell, plained in detail elsewhere (12) and was based primarily on M.D., University of Texas, Galveston; Michael E. Thase, M.D., and Rob- ethical considerations, demonstrated low placebo response ert Howland, M.D., University of Pittsburgh; John S. Carman, M.D., psy-chiatry and research, Atlanta; A. John Rush, M.D., and George Trapp, rates among chronically depressed adults (33), and the fact M.D., University of Texas Southwestern; Alan F. Schatzberg, M.D., and that the primary aim of the study was to test the relative ef- Lorrin Koran, M.D., Stanford University; Alan J. Gelenberg, M.D., andPedro Delgado, M.D., University of Arizona; John Feighner, M.D., Feigh- ficacy of the newer agent, sertraline, against a standard ner Research Institute; and Jan A. Fawcett, M.D., and John Zajecka, comparator. Other limitations must be noted. Because of M.D., Rush Institute for Mental Well-Being.
the inclusion/exclusion criteria used in this clinical trial, Am J Psychiatry 157:9, September 2000 GENDER AND RESPONSE TO ANTIDEPRESSANTS
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Global Optimization of Clusters, Crystals, and Biomolecules David J. Wales1* and Harold A. Scheraga2 crystals, and biomolecules. We focus on the Finding the optimal solution to a complex optimization problem is of great impor- PES, rather than the free energy, to avoid the tance in many fields, ranging from protein structure prediction to the design of additional complications arising from finite