sertraline in ocd

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Article

88 Am J Psychiatry 159:1, January 2002

Efficacy of Sertraline in the Long-Term Treatmentof Obsessive-Compulsive Disorder

Lorrin M. Koran, M.D.

Elizabeth Hackett, Ph.D.

Arkady Rubin, Ph.D.

Robert Wolkow, M.D.

Delbert Robinson, M.D.

Objective: Obsessive-compulsive disor-

der (OCD) typically begins early in life andhas a chronic course. Despite the need for

long-term treatment, the authors found

no placebo-controlled studies that have

examined the relapse-prevention efficacy

of maintenance therapy.

Method: Patients who met criteria for re-

sponse after 16 and 52 weeks of a single-

blind trial of sertraline were randomly as-

signed to a 28-week double-blind trial of

50–200 mg/day of sertraline or placebo.

Primary outcomes after the double-blind

trial were full relapse, dropout due to re-

lapse or insufficient response, or acute ex-

acerbation of OCD symptoms.Results: Of 649 patients at baseline, 232

completed 52 weeks of the single-blind

trial and met response criteria. Among the

223 patients in the double-blind phase of

the study, sertraline had significantly

greater efficacy than placebo on two of

three primary outcomes: dropout due to

relapse or insufficient clinical response (9%versus 24%, respectively) and acute exacer-

bation of symptoms (12% versus 35%). Ser-

traline resulted in improvement in quality

of life during the initial 52-week trial and

continued improvement, significantly su-

perior to placebo, during the subsequent

28-week double-blind trial. Long-term

treatment with sertraline was well toler-

ated. Over the entire study period, less

than 20% of the patients stopped treat-

ment because of adverse events.

Conclusions: Sertraline demonstrated

sustained efficacy among patients re-

sponding to treatment and was generallywell tolerated during the 80-week study.

During the study’s last 28 weeks, sertra-

line demonstrated greater efficacy than

placebo in preventing dropout due to re-

lapse or insufficient clinical response and

acute exacerbation of OCD symptoms.

(Am J Psychiatry 2002; 159:88–95)

One-year prevalence estimates for obsessive-compul-

sive disorder (OCD), based on community surveys, have

been reported to range from 0.4% to 2.3% (1), with lifetimeprevalence estimates ranging as high as 2.6% (2). OCD typ-

ically has an early age at onset, with a course of illness that

is among the most chronic of the psychiatric disorders. In

a study of 560 patients (3), 85% reported a continuous

course of illness, 10%, a deteriorating course, and only 2%,

an episodic course marked by full remissions lasting 6

months or more. Surveys of both community and treat-

ment populations (4–6) found the diagnosis of OCD to be

associated with significant impairment in perceived func-

tioning and quality of life.

A substantial body of placebo-controlled studies has es-

tablished the safety and efficacy of selective serotonin re-

uptake inhibitor (SSRI) antidepressants for the acute

treatment of OCD, although only slightly more than 30%–

60% of the subjects who participated in the controlled tri-

als met response criteria (7–12). Moreover, although SSRIs

are usually well tolerated, a minority of patients stop treat-

ment because of gastrointestinal, sexual, or other side ef-

fects (7–12). Given the early onset of OCD, it is important

to note that sertraline, fluvoxamine, and fluoxetine have

demonstrated significant efficacy in the treatment of OCD

in children and adolescents (13–15). Few placebo-con-

trolled studies, however, have investigated the usefulness

of SSRIs, once a short-term response has been achieved, in

preventing exacerbation of obsessive-compulsive symp-toms or relapse of the illness.

The ability of sertraline to maintain improvement in

OCD patients after short-term treatment has been dem-

onstrated in a double-blind placebo-controlled study (16)

in which responders to 12 weeks of fixed doses (50, 100, or

200 mg/day) of sertraline or placebo were assigned to a

double-blind fixed-dose trial for an additional 40 weeks.

At the 52-week endpoint, mean scores on all four primary

outcome measures—the Yale-Brown Obsessive Compul-

sive Scale, the National Institute of Mental Health (NIMH)

Global Obsessive Compulsive Scale, and the Clinical Glo-

bal Impression (CGI) severity-of-illness and improve-ment scales—revealed significantly greater improvement

(p<0.005) for the pooled sertraline group than for the pla-

cebo group.

Fifty-one of the patients who originally participated in

the double-blind trial of sertraline or placebo continued to

receive open-label sertraline treatment for up to a total of

2 years (17). The Yale-Brown Obsessive Compulsive Scale

scores of these patients decreased by a mean of 11.4 dur-

ing the first year and by a mean of 3.2 during the second



Am J Psychiatry 159:1, January 2002 89

KORAN, HACKETT, RUBIN, ET AL.

year, which suggests that efficacy was not only maintained

but that modest additional improvement occurred.

The present study augments the results of that long-

term treatment study with a design intended to assess the

efficacy of sertraline in preventing patient relapse during a

28-week double-blind trial of sertraline or placebo in pa-

tients who had achieved a sustained response during 52

weeks of single-blind sertraline therapy.

Method

Study Design

This was an 80-week study conducted at 21 sites in the United

States. The subjects were outpatients 18 years of age and older

who had a DSM-III-R-defined diagnosis of OCD. At study entry,

the patients completed a 1-week drug-free washout period. If

they continued to meet study criteria at the end of the washout

period (baseline), they entered 16 weeks of single-blind treatment

with flexible doses of sertral ine. All medication admi nistered

throughout the 80-week study period was administered from blis-

ter packs holding 50-mg tablets of sertraline (or identical placebo

tablets). The patients took 50 mg/day of sertraline during weeks 1

through 4. Patients who failed to respond satisfactorily to treat-

ment could have their dose titrated up to 100 mg/day during

weeks 5 and 6 in the absence of dose-limiting adverse events, to

150 mg/day during weeks 7 and 8, and to the maximum dose of

200 mg/day after 8 weeks. In the presence of dose-limiting ad-

verse events, the dose could be reduced in 50-mg/day decre-

ments to a minimum of 50 mg/day. Patients who failed to meet

response criteria by the end of 16 weeks of sertraline treatment

were withdrawn from the study.

Patients who met the response criteria at the end of week 16

continued with the same dose of single-blind sertraline treatment

for an additional 36 weeks; assessments were performed every 4

weeks. For the patients who were not taking the maximum per-

missible daily dose, an increase in dose was permitted if the in-

vestigator thought it might improve the patient’s response. Pa-

tients who met relapse criteria on any one of these assessments were scheduled for an assessment 2 weeks later. If they continued

to meet the relapse criteria by the 2-week visit, they were sched-

uled for a third relapse assessment after an additional 2 weeks; if

they still met the relapse criteria, they were dropped from the

study.

The patients who continued to meet the response criteria at

the end of week 52 were randomly assigned to a 28-week double-

blind trial with either sertraline or matching placebo. For the pa-

tients randomly assigned to sertraline treatment, their daily dose

of sertraline as of week 52 was maintained. Until the end of week

56, the patients randomly assigned to placebo took the same

number of tablets daily as they had during week 52, but the sertra-

line dose was blindly decreased by 50 mg/day every 3 days by use

of planned substitution of placebo tablets into the blister packs at

weeks 53 and 54. Thus, from the end of week 54, these patientstook only placebo tablets.

Study Patients

The study patients were recruited by means of newspaper and

radio advertisements and from the clinical practices of the inves-

tigators. We included male and female outpatients 18 years of age

and older who met DSM-III-R criteria for obsessive-compulsive

disorder as determined by the Structured Clinical Interview for

DSM-III-R (SCID-P) (18). At baseline, the patients had to have a

minimum total score of 20 on the Yale-Brown Obsessive Compul-

sive Scale (19, 20) and a score of at least 7 on the NIMH Global Ob-

sessive Compulsive Scale (21). Patients were excluded from study

entry for the following reasons:

1. Having a total score on the 24-item Hamilton Depression

Rating Scale (22) of 17 or higher.

2. Being a woman who was currently pregnant or lactating or of

childbearing potential and not using a medically accepted form

of contraception.

3. Having a current diagnosis of organic mental disorder, major

depression, bipolar disorder, Tourette’s syndrome, or a severe axis

II personality disorder or a principle diagnosis of trichotilloma-nia, somatoform disorder, panic disorder, social phobia, or gener-

alized anxiety disorder.

4. Having a current or verified past diagnosis of schizophrenia,

delusional disorder, or other psychosis.

5. Having a DSM-III-R-defined diagnosis of alcohol or sub-

stance abuse and/or dependence in the past 6 months

6. Having a positive urine drug screening test.

7. Having any medical contraindications to treatment with ser-

traline.

8. Having a history or evidence of malignancy other than ex-

cised basal cell carcinoma.

9. Having an acute or unstable medical illness.

10. Participating in an investigational drug study within 28 days

before entering the study.

11. Taking sertraline within 2 months of study entry, not re-sponding to an adequate trial of sertraline in the past, or partici-

pating in an investigational study of sertraline.

12. Concomitantly using any psychotropic medication (other

than chloral hydrate for sleep).

13. Receiving concurrent behavior therapy for OCD.

14. Receiving treatment with an monoamine oxidase inhibitor

within 2 weeks, a depot neuroleptic within 6 months, fluoxetine

within 5 weeks, or a neuroleptic, anxiolytic, or antidepressant on

a daily basis in the 2 weeks before the first administration of ser-

traline.

15. Having a test of liver function showing a level at more than

twice the upper limit of normal on the first day of the washout

period.

16. Being illiterate, or, in the investigator’s judgment, unable or

unlikely to follow the study protocol for the full 80 weeks.The study protocol and forms giving the patients’ informed

consent were approved by the institutional review board at each

study site. Before study entry, written informed consent was ob-

tained from each subject.

Efficacy Measures

The patients were evaluated at baseline and at subsequent

study visits, which occurred weekly for the first 4 weeks and then

biweekly until the end of week 16. From week 16 on, the patients

were seen and evaluated every 4 weeks unless they met the re-

lapse criteria, in which case an additional assessment was sched-

uled in 2 weeks. The investigator completed at baseline and at

each study visit the Yale-Brown Obsessive Compulsive Scale, the

NIMH Global Obsessive Compulsive Scale, the CGI (23) severity-

of-illness scale, and, after the baseline trial, the CGI improvementscale. A patient rating, the Quality of Life Enjoyment and Satisfac-

tion Questionnaire (24), a scale assessing 16 aspects of quality of

life and functioning, was completed at study entry and at study

assessments after 16, 52, and 80 weeks of the trial or at study

dropout. The investigators specified and agreed to the following

definitions during protocol development:

Response. A “response” was defined as occurring when pa-

tients’ total scores decreased 25% or more from their baseline (at

entry into the single-blind trial) levels on the Yale-Brown Obses-

sive Compulsive Scale and their CGI improvement scale score

was 3 or lower (at least “minimal” improvement). (Although a de-




SERTRALINE FOR OCD

crease in score of 25% or more would not be accepted as a “re-

sponse” criterion in studies involving diabetes, this criterion in

commonly used in trials of OCD pharmacotherapy. Its accep-

tance is testimony to the need for better OCD treatments.) The

patients had to meet response criteria by the end of week 16 tocontinue in the single-blind trial and by the end of week 52 to be

randomly assigned to the double-blind phase of the study.

Relapse. After week 16, “relapse” required that a patient meet

three criteria during three consecutive visits at 2-week intervals (a

period of 1 month):

1. Have an increase in score of 5 points or more (from the week-

16 score) on the Yale-Brown Obsessive Compulsive Scale.

2. Have a total score on the Yale-Brown Obsessive Compulsive

Scale of 20 or more.

3. And at least a 1-point increase in score on the CGI improve-

ment scale.

We elected to require 1 m onth of substa ntial worsening be-

cause OCD patients often experience fluctuations in the intensity

of their symptoms. In addition, changes in a patient ’s environ-

ment may exacerbate their symptoms; e.g., a patient with a fear of

germs may have more symptoms if a friend with an acute infec-

tion visits his or her home. To differentiate routine oscillations in

clinical status from relapse, we used repeated evaluations over a

1-month interval. The patients whose symptoms resolved contin-

ued in the study; the patients whose symptoms continued to

meet the relapse criteria were classified as relapsed and were au-tomatically removed from the study. The patients could also be

removed from the study before completing the 1-month observa-

tion period if the investigator believed that it was in the patient ’s

best interest.

During the double-blind study phase, the definition of relapse

was based on the same numeric change in score on the Yale-

Brown Obsessive Compulsive Scale and the same change in score

on the CGI improvement scale from the end of the single-blind

trial (week 52). In many cases the strict protocol definition of re-

lapse was not satisfied because the patient (or investigator) de-

cided, as a result of insufficient clinical response, to drop out of

(or drop the patient from) the study immediately at a regular as-

sessment and, consequently, before the three relapse-defining

visits.

Acute exacerbation of OCD. In order to describe on a finerscale the outcomes during the double-blind study phase, the in-

vestigators wished to have a less stringent, more acute criterion of

symptom worsening than the criteria that defined relapse. This

endpoint was termed “acute exacerbation of OCD” and used as its

reference point the patients’ scores at the end of week 52, which

was the baseline for the double-blind phase. Acute exacerbation

of OCD was defined as an increase in score of 5 points or more to

a minimum of a score of 20 on the Yale-Brown Obsessive Compul-

sive Scale or an increase in score of at least 2 points on the CGI im-

provement scale. The patients who met criteria for acute exacer-

bation of OCD were not automatically released from the study for

this reason.

Safety Assessments

A medical history and physical examination were performedon the patients at study entry; a physical examination was re-

peated at weeks 52 and 80 or when a patient dropped out of the

study. Blood pressure, heart rate, and weight were obtained at

each study visit.

Both observed and volunteered adverse events were recorded,

including date of onset of symptoms, duration, severity, causality,

and outcome. ECG testing was performed at study entry and at

the end of treatment weeks 2, 10, 16, 32, 52, and 80 (or at study

dropout). Laboratory testing was performed at a central labora-

tory, and blood samples were obtained at each study site at study

entry (day 1 of washout) and at the end of treatment weeks 2, 10,

16, 32, 52, 64, and 80 (or at study dropout). Laboratory tests con-

sisted of standard hematology and blood chemistry panels, a uri-

nalysis, and beta human chorionic gonadotropin pregnancy test-

ing for all women of child-bearing potential. Blood samples for T3

uptake and T4 level and urine for a drug screening were obtained

only at day 1 of the drug washout.

Statistical Analysis

A Kaplan- Meier surviva l anal ysis was used to estimate the

probability of relapse, study discontinuation due to relapse or in-

sufficient clinical response, or acute exacerbation of OCD as a

function of time in the presence of censored observations. Time

to relapse, time to dropout due to relapse or insufficient clinical

response, and time to acute exacerbation of OCD were compared

between groups by use of the log-rank test. Observed rates of re-

lapse, dropout due to relapse or insufficient clinical response, and

FIGURE 1. Stages in Single- and Double-Blind Trials of Sertraline or Placebo Over 80 Weeks for Patients WithObsessive-Compulsive Disorder (OCD)

a Efficacy evaluable subjects: N=108.b Efficacy evaluable subjects: N=113.

Entered double-blindsertraline

trial (N=109)a

Completed double-blindsertraline

trial (N=76);

dropped out (N=33)

Completed double-blindplacebo

trial (N=55);

dropped out (N=59)

Entered double-blind

placebotrial (N=114)b

Completed week 52

of single-blindtrial (N=232)

(responders, N=227)

Entered weeks 17–52of single-blindtrial (N=348)

Responders randomlyassigned to

double-blind

trial (N=223)

Completed week 16of single-blindtrial (N=460)

(responders, N=348)

Evaluated for drugefficacy (N=621)

Patients with OCDenrolled in

single-blind trial (N=649)





acute exacerbation of OCD were also evaluated as rates by divid-

ing the number of patients experiencing the event by the total

number of patients who took the study drug and provided effi-

cacy data. These rates were compared between groups by using

continuity-adjusted chi-square tests. Treatment comparisons of

changes in efficacy scores from baseline to endpoint (with the last

observation carried forward) were performed by using the Wil-

coxon rank-sum test (normal approximation with a continuity

correction of 0.5). Quality of Life Enjoyment and Satisfaction

Questionnaire scores were calculated as a percent of the maxi-mum score of 70 for the first 14 items of the scale. All tests of hy-

potheses were based on the SAS NPAR1WAY procedure. Statistical

tests were two-tailed and were conducted at the 0.05 significance

level.

Results

Patient Group and Disposition

Figure 1 shows the disposition of the 649 patients who

enrolled in the study during the course of the single-blind

and double-blind trials. The patients were nearly equally

divided by gender at study baseline; at entry into the dou-

ble-blind phase, men slightly outnumbered women in

both groups (Table 1). At study entry, all the patients re-

ported that their OCD was chronic (mean=21 years, SD=

12), with a moderate or greater degree of illness severity, as

reflected in their scores on the Yale-Brown Obsessive

Compulsive Scale and the NIMH Global Obsessive Com-

pulsive Scale. At the end of week 52 (baseline of the dou-

ble-blind phase), there were no significant descriptive

differences between the patients who were randomly as-

signed to treatment with sertraline and those who were as-

signed to placebo.

By the end of 16 weeks of the single-blind sertraline trial,

301 of the patients (46%) had stopped participating for a

variety of reasons (Table 2). Among them, 98 patients (15%

of those who entered the study) were dropped as per pro-

tocol because of failure to meet response criteria. When

patients in the 52-week, single-blind sertraline trial were

analyzed, adverse events were the most common reason

for study discontinuation (N=120, 18%), followed by ineli-

gibility to continue (did not meet response criteria, N=101,

16%), and withdrawal of consent (N=57, 9%).

During the 28-week double-blind trial, more patients tak-

ing placebo (N=27, 24%) than taking sertraline (N=10, 9%)

stopped participating because of relapse or insufficient

clinical response (χ2=7.47, df=1, p=0.006) (Table 2). In thedouble-blind phase, there were no statistically significant

differences between the two groups regarding study dis-

continuation for adverse events (placebo: N=12, 10.5%; ser-

traline: N=5, 4.6%), being lost to follow-up (placebo: N=5,

4.4%; sertraline: N=9, 8.3%), and withdrawal of consent

(placebo: N=10, 8.8%; sertraline: N=3, 2.8%) (Table 2).

Seven patients receiving sertraline and 16 patients receiving

placebo met relapse criteria at one visit and were dropped

from the study at that visit for insufficient clinical response.

Clinical Response

Single-blind trial. There was consistent and progressive

improvement in all four investigator-rated efficacy mea-

surements (Table 3) throughout the 52 weeks of the single-

blind sertraline trial. This was due in part to some patients

dropping out for lack of efficacy. This symptomatic im-

provement was associated with improved quality of life, as

measured by the patient-rated Quality of Life Enjoymentand Satisfaction Questionnaire (higher scores reflect bet-

ter quality of life) (Table 3).

Double-blind trial. Sertraline demonstrated a signifi-

cant advantage over placebo (Figure 2) according to two of

the three primary outcome endpoints: study discontinua-

tion due to relapse or insufficient clinical response (sertra-

line: N=10, 9%, versus placebo: N=27, 24%) and acute ex-

acerbation of OCD symptoms (sertraline, N=13, 12%,

versus placebo, N=40, 35%).

Figure 3 shows the Kaplan-Meier survival probability es-

timate of the cumulative probability of not dropping out

of the study because of relapse or insufficient clinical re-

sponse for patients receiving sertraline or placebo over the

28-week double-blind trial. The difference significantly fa-

vored the patients taking sertraline. Analogous Kaplan-

Meier estimates for an acute exacerbation of OCD symp-

toms provided a difference that significantly favored ser-

traline (log-rank test, χ2=18.95, df=1, p=0.0001).

The third outcome criterion, the cumulative probability

of remaining relapse-free, was higher for patients receiv-

ing sertraline (N=105, 97%) than for patients receiving pla-

cebo (N=108, 96%). The small number of patients who met

the stringent relapse criteria (three visits, including the

first visit and subsequent visits at 2-week intervals, in

which patients met the criteria for scores on the Yale-Brown Obsessive Compulsive Scale and the CGI scale)

(three of 108 patients taking sertraline and five of 113 pa-

tients receiving placebo) resulted in a finding of no signif-

icant difference between groups (log-rank test, χ2=0.90,

df=1, p=0.34).

Sertraline was associated with sustained symptom im-

provement during the double-blind study phase, com-

pared to the patients at the end of the 52-week single-

blind phase. In an analysis of patients in the last-observa-

tion-carried-forward group at endpoint (Table 3), the ser-

traline group experienced a significantly smaller adjusted

mean increase in scores on the Yale-Brown Obsessive

Compulsive Scale from the baseline of the double-blind

trial (adjusted for scores at week 52) than did the placebo

group. Similar results, statistically significantly favoring

sertraline over placebo, were also found on analysis of

scores of the last-observation-carried-forward group at

endpoint on the NIMH Global Obsessive Compulsive

Scale and the CGI severity-of-illness and improvement

scales.

During the double-blind trial, sertraline provided a

modest but significant advantage over placebo in the as-




SERTRALINE FOR OCD

sociated score on the Quality of Life Enjoyment and Satis-

faction Questionnaire. On average, patients had improve-

ment in their quality of life scores during the 52-week

single-blind study phase. During the 28-week double-

blind trial, the patients who were randomly assigned to

sertraline continued to show gains in their mean score,

while those who were randomly assigned to placebo had a

decrease in their mean quality-of-life rating. For change in

score on the Quality of Life Enjoyment and Satisfaction

Questionnaire from baseline to endpoint of the double-

blind trial, the difference between groups was statistically

significant ( Wilcoxon rank-sum test, z=2.58, p=0.007). The

difference favoring sertraline was also statistically signifi-

cant on the score on item 16 of Quality of Life Enjoyment

and Satisfaction Questionnaire, the patient’s overall satis-

faction (Wilcoxon rank-sum test, z=3.82, p<0.001).

Tolerability. The mean dose of sertraline at the double-

blind baseline (week 52) was 183 mg/day. At week 56, after

we tapered the placebo group’s sertraline at the rate of 50

mg/day every 3 days until those patients stopped taking it,

the mean doses of sertraline were 189 mg/day for the ser-

traline group and 177 mg/day of placebo equivalent for

the placebo group. At the study endpoint, the sertraline

dose was 187 mg/day, and the placebo equivalent was 174

mg/day. Sertraline treatment was well tolerated at these

doses. Among the patients who completed the trial, the

prevalence of ongoing adverse effects and the incidence of

new adverse effects diminished during the course of the

single-blind sertraline trial. During the first 16 weeks of

the study, the most frequently reported (incidence of 20%

or more) adverse events were insomnia, headache, nau-

sea, ejaculatory failure (male patients only), somnolence,

and diarrhea. From weeks 17 through 52, diarrhea, head-

ache, and upper respiratory infection only occurred in

20% or more of the patients. During the double-blind

phase, the only adverse events that occurred with an inci-

dence of 10% or more in the sertraline-treated patients

were upper respiratory infection, headache, and malaise.

The only notable difference in the rates of adverse events

was the increase in dizziness and depression reported in

the patients receiving placebo.

Sertraline was generally well tolerated during the 80

weeks of treatment. Over this interval, less than 20% of the

patients stopped participating in the study because of ad-

verse events. During the 28-week double-blind phase,

dropouts due to adverse events occurred at a higher rate

among the patients who had been randomly assigned to

receive placebo (N=12, 10.5%) than among those receiving

sertraline (N=5, 4.6%) (Table 2). No patient was dropped

from the study at any point because of laboratory test ab-

TABLE 1. Demographic and Clinical Characteristics of Patients With Obsessive-Compulsive Disorder Who Participated inSingle- and Double-Blind Trials of Sertraline or Placebo Over 80 Weeks

CharacteristicSingle-Blind Sertraline Trial

(Weeks 1–52) (N=649)

Double-Blind Trial (Weeks 53–80)

Sertral ine (N=109) Placebo (N=114)

N % N % N %

SexMale 330 51 61 56 63 55Female 319 49 48 44 51 45

Mean SD Mean SD Mean SD

Age (years) 38.6 11.9 39.2 11.5 39.5 10.8Duration of illness (years) 21.4 12.4 21.9 13.1 22.4 12.2Scores on symptom measures Yale-Brown Obsessive Compulsive Scale 26.1 4.2 10.2 6.0 10.1 5.4NIMH Global Obsessive Compulsive Scale 9.2 1.5 4.4 2.1 4.4 2.0CGI severity-of-illness scale 4.8 0.7 2.7 1.0 2.7 1.0

TABLE 2. Reasons for Study Dropout of Patients With Obsessive-Compulsive Disorder Who Participated in Single- andDouble-Blind Trials of Sertraline or Placebo Over 80 Weeks

Reason for Dropout

Single-Blind Sertraline Trial Double-Blind Trial (Weeks 53–80)

Weeks 1–16 (N=649) Weeks 17–52 (N=348) Sertraline (N=109) Placebo (N=114)

N % N % N % N %

Total dropouts 301 46.4 125 35.9 33 30.3 59 51.8

Reasons for dropping outRelapse 0 0.0 6 1.7 3 2.8 5 4.4Insufficient clinical response 15 2.3 13 3.7 7 6.4 22 19.3Not eligible to continue 98 15.1 3 0.9Adverse events 84 12.9 36 10.3 5 4.6 12 10.5Abnormal laboratory values 11 1.7 1 0.3 0 0.0 0 0.0Protocol violation 24 3.7 11 3.2 4 3.7 2 1.8Withdrawal of consent 25 3.9 32 9.2 3 2.8 10 8.8Lost to follow-up 25 3.9 17 4.9 9 8.3 5 4.4Other 19 2.9 6 1.7 2 1.8 3a 2.6

a Including one patient who died of a myocardial infarction 12 days after taking last verifiable dose.





normalities, nor was there a statistically significant differ-

ence between the sertraline and placebo groups in the in-

cidence of any treatment-emergent abnormalities in

ECGs, vital signs, or laboratory test results or in clinically

significant changes in weight.

Discussion

The results of this study clearly demonstrate the efficacy

of a 28-week, double-blind sertraline trial in maintaining

the clinical benefits achieved during a 52-week single-

blind trial in outpatients suffering from chronic OCD with

symptoms of moderate to marked severity. Furthermore,

during the double-blind phase, sertraline was significantly

more effective than placebo at two of the three endpoints

for judging clinical outcomes: study discontinuation due

to relapse or insufficient clinical response and acute exac-

erbation of OCD symptoms. Sertraline and placebo

groups did not differ significantly on the third outcome in-

dicator, a strictly defined relapse, probably because of its

very low incidence (<5% overall) during the 28-week dou-

ble-blind phase. This low relapse rate may be partly due to

our having required that relapse criteria be met at three

consecutive visits over a 4-week period. The low relapse

rate may also reflect a sustained benefit of 52 weeks of

therapy with sertraline, even after drug discontinuation,

although uncontrolled studies (25, 26) have suggested

rates of relapse in the range of 40%–60% after 1 year for pa-

tients who dropped out of clomipramine or SSRI treat-

ment. These studies, however, were marked by a much

shorter duration of treatment before drug discontinuation

than in the present study.

The fact that only about one-third of the patients

treated with placebo experienced an acute exacerbation of OCD symptoms within the 28-week double-blind study

period is notable. Again, this may reflect the sustained

benefit of 52 weeks of drug therapy. Alternately, since we

did not make regular inquiries, some placebo patients,

sensing the onset of worsened symptoms, may have en-

gaged in self-designed behavior therapy guided by one the

many self-help books available. Finally, the study ’s limit of

6 months of observation for the placebo patients means

that additional research is needed to determine the rates

at which OCD symptom exacerbation occurs during

longer periods of treatment with effective medication.

In addition to the investigator-rated efficacy measures,

the patients’ self-rated quality of life, as measured by the

Quality of Life Enjoyment and Satisfaction Questionnaire,

improved significantly during the single-blind phase of

the study. From the baseline of the double-blind trial, the

patients randomly assigned to receive sertraline reported

a small but measurable increase in quality of life scores

over 28 weeks, while the patients randomly assigned to re-

ceive placebo reported a loss from their previous gain in

scores, resulting in a statistically significant difference be-

tween the two groups. Thus, continued sertraline treat-

TABLE 3. Efficacy Scores for Patients With Obsessive-Compulsive Disorder Who Participated in Single- and Double-BlindTrials of Sertraline or Placebo Over 80 Weeks

Measure and Time of Assessment

Score

Yale-BrownObsessive

CompulsiveScalea

NIMH GlobalObsessive

CompulsiveScaleb

CGISeverity-of-

Illness Scalec

CGIImprovement

Scaled

Quality of LifeEnjoyment and

SatisfactionQuestionnaire (%)e

Mean SD Mean SD Mean SD Mean SD Mean SD

Pretreatment baseline (N=620) 26.1 4.2 9.2 1.5 4.8 0.7 60.0 17.9

Single-blind sertraline trialEnd of week 16 (N=459) 15.9 7.3 6.4 2.3 3.5 1.1 2.3 1.0 73.7 16.3End of week 52 (N=232) 10.3 5.8 4.5 2.1 2.7 1.0 1.6 0.7 78.2 15.1

Double-blind trial (efficacy evaluable subjects)Sertraline (N=108)

Baseline 10.1 6.1 4.4 2.1 2.6 1.0 1.6 0.6 75.1 12.8Last-observation-carried-forward endpointf 11.4 7.5 4.8 2.6 2.8 1.2 1.9 1.1 77.3 16.1Completer endpoint 9.6 6.0 4.2 2.3 2.6 1.0 1.6 0.7 77.3 11.4

Placebo (N=113)Baseline 10.1 5.4 4.3 2.0 2.6 1.0 1.6 0.7 74.4 12.8Last-observation-carried-forward endpointf 14.2 7.7 5.7 2.7 3.3 1.2 2.3 1.3 67.5 20.3Completer endpoint 10.3 6.2 4.4 2.2 2.7 1.0 1.7 0.8 75.5 14.8

a Significant difference between sertraline and placebo from baseline of double-blind trial to last-observation-carried-forward endpoint (Wil-coxon rank-sum test, z= – 3.21, p=0.001).

b Significant difference between sertraline and placebo from baseline of double-blind trial to last-observation-carried-forward endpoint (Wil-coxon rank-sum test, z= – 3.71, p=0.001).

c Significant difference between sertraline and placebo from baseline of double-blind trial to last-observation-carried-forward endpoint (Wil-coxon rank-sum test, z= – 3.23, p=0.001).

d Score is relative to that at pretreatment baseline. Significant difference between sertraline and placebo from baseline of double-blind trialto last-observation-carried-forward endpoint (Wilcoxon rank-sum test, z= – 3.56, p=0.001).

e Baseline of single-blind trial, N=608; week 16, N=439; week 52, N=225. Last-observation-carried-forward endpoint: sertraline group, N=106; placebo group, N=109. Score expressed as percent of maximum score of 70; higher scores reflect better quality of life. Significant dif-ference between sertraline and placebo from baseline of double-blind trial to last-observation-carried-forward endpoint (Wilcoxon rank-sumtest, z=2.71, p=0.007).

f Last assessment during double-blind trial.




SERTRALINE FOR OCD

ment was associated with diminished effects of OCD

symptoms on patients’ everyday lives.Sertraline was generally well tolerated during the 80

weeks of treatment. Less than 20% of the patients with-

drew from the study because of adverse events. There was

a progressive reduction in the frequency of reported ad-

verse events over the course of the single-blind trial, al-

though some of this decrease was due to study discontin-

uation by patients who were intolerant of sertraline. Most

adverse events occurring during the double-blind phase

were mild to moderate in intensity, despite a mean sertra-

line dose of 187 mg/day at study endpoint. Given the chro-

nicity of OCD and the need for long-term therapy in the

majority of patients, the tolerability of sertraline is clini-cally important. A favorable side effect profile is especially

important for patients with OCD, since as many as 20% of

patients refuse study medication because of fears of possi-

ble side effects (25).

Although this study demonstrated positive results re-

garding the efficacy of sertraline, alterations in the study

design could benefit future investigations. The most obvi-

ous is the protocol definition of “relapse.” It was important

to differentiate a true relapse from routine oscillations in

clinical status. However, our requirement of three visits

and a total of 4 weeks’ participation to confirm relapse was

probably too conservative. A confirmatory evaluation af-

ter a patient meets relapse criteria at a single visit is desir-able, but one additional visit at a 1- or 2-week interval

might be adequate. If the patient did not meet relapse cri-

teria at the confirmatory visit, he or she would be retained

in the study.

Although the length of the 1-year single-blind portion of

the study undoubtedly contributed to patient attrition for

reasons other than worsening of OCD symptoms, a design

incorporating a shorter single-blind study phase would

not have told us whether a 1-year trial is of adequate dura-

tion to assess SSRI treatment of OCD. A 1-year, open-label

initiation period is a study design alternative that might

promote greater retention of patients and would accu-

rately reflect what occurs in clinical practice. Future re-

search should investigate how long maintenance treat-

ment should continue, the optimal dose of medication to

prevent relapse, and the role of supplementary behavior

therapy in preventing relapse.

In conclusion, the current study examined the effects

over 6 months of double-blind placebo-controlled medi-

cation maintenance after 12 months of single-blind ser-

traline treatment. The results confirm the clinical efficacy

of sertraline in achieving and sustaining response over 18

months. The results also demonstrate the lack of promi-

nent discontinuation symptoms after sertraline cessation

and confirm its effectiveness in preventing acute exacer-

bation of OCD symptoms and treatment discontinuation

due to relapse or insufficient clinical response.

Presented in part at the 152nd annual meeting of the American

Psychiatric Association, Washington, D.C., May 15–20, 1999, and at

the 39th annual meeting of the New Clinical Drug Evaluation Units,

Boca Raton, Fla., June 1–4, 1999. Received Aug. 8, 2000; revision re-

ceived June 11, 2001; accepted July 31, 2001. From the Department

of Psychiatry, Stanford University; the Research Department, Hillside

Hospital, Glen Oaks, NY; and the Department of Psychiatry, Albert

Einstein College of Medicine, Bronx, N.Y. Address reprint requests to

Dr. Koran, OCD Clinic, Rm. 2363, Department of Psychiatry, 401

Quarry Rd., Stanford, CA 94305; [email protected] (e-mail).

Supported by a grant from Pfizer, Inc.

The authors thank the following investigators for their help: Jeffrey

T. Apter, M.D., Robert J. Bielski, M.D., Jonathan Davidson, M.D., Brian

B. Doyle, M.D., Robert L. DuPont, M.D., James Ferguson, M.D., Wayne

Goodman, M.D., Carl Houck, M.D., Ari Kiev, M.D., Peter D. Londborg,

M.D., R. Bruce Lydiard, Ph.D., M.D., Dennis Munjack, M.D., Bharat

Nakra, M.D., Philip Ninan, M.D., Steven Rasmussen, M.D., Jeffrey Si-

mon, M.D., Ward Smith, M.D., Stephen Stahl, M.D., Ph.D., and John

Zajecka, M.D.

FIGURE 2. Rates of Poor Clinical Response Among PatientsWith Obsessive-Compulsive Disorder (OCD) During a 28-Week Double-Blind Trial of Sertraline and Placebo

a Significant difference between groups (χ2=7.47, df=1, p=0.006).b Significant difference between groups (χ2=15.27, df=1, p=0.001).

50

40

30

20

10

0

P e r c

e n t

Relapsed Dropped OutBecause of Relapse

or InsufficientClinical Response

ExperiencedAcute

Exacerbation of OCD Symptoms

OCD patients receiving placebo (N=114)(efficacy evaluable: N=113)

OCD patients receiving sertraline (N=109)(efficacy evaluable: N=108)

a

b

FIGURE 3. Time to Dropout Due to Relapse or InsufficientClinical Response for Patients With Obsessive-CompulsiveDisorder (OCD) During a 28-Week Double-Blind Trial of Sertraline and Placebo

a Kaplan-Meier survival probability.b Significant difference between groups (log-rank test, χ2=10.87, df=

1, p=0.001).

1.0

0.8

0.6

0.4

0.2

0.00 4 8 12 16 20 24 28

P r o p o r t i o n

o f P a t i e n t s N o t

D r o p p i n g O u t B e c a u s e o f R e l a p s e

o r I n s u f f i c i e n t C l i n i c a l R e s p o n s e a

Week

OCD patients receivingplacebo (N=113)

OCD patients receivingsertraline (N=108)

b





References

1. Koran LM: Obsessive-Compulsive and Related Disorders in

Adults: A Comprehensive Clinical Guide. Cambridge, UK, Cam-

bridge University Press, 1999, p 49

2. Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Lee

CK, Newman SC, Oakley-Browne MA, Rubio-Stipec M, Wickra-

maratne PJ, Wittchen HU, Yeh EK (The Cross National Collabo-

rative Group): The cross national epidemiology of obsessive

compulsive disorder. J Clin Psychiatry 1994; 55(suppl 3):5 – 10

3. Rasmussen SA, Eisen JL: The epidemiology and clinical features

of obsessive compulsive disorder. Psychiatr Clin North Am

1992; 15:743 – 758

4. Koran LM, Thienemann ML, Davenport R: Quality of life for pa-

tients with obsessive-compulsive disorder. Am J Psychiatry

1996; 153:783 – 788

5. Hollander E, Kwon JH, Stein DJ, Broatch J, Rowland CT,

Himelein CA: Obsessive-compulsive and spectrum disorders:

overview and quality of life issues. J Clin Psychiatry 1996;

57(suppl 8):3 – 6

6. A Gallup Study of Obsessive-Compulsive Disorder Sufferers.

Princeton, NJ, Gallup Organization, 1990

7. Greist J, Chouinard G, DuBoff E, Halaris A, Kim SW, Koran L, Lie-

bowitz M, Lydiard RB, Rasmussen S, White K, Sikes C: Double-

blind parallel comparison of three dosages of sertraline and

placebo in outpatients with obsessive-compulsive disorder.

Arch Gen Psychiatry 1995; 52:289 – 295

8. Bisserbe J-C, Lane RM, Flament MF (Franco-Belgian OCD Study

Group): A double-blind comparison of sertraline in outpatients

with obsessive-compulsive disorder. Eur Psychiatry 1997; 12:

82 – 93

9. Zohar J, Judge R: Paroxetine versus clomipramine in the treat-

ment of obsessive-compulsive disorder. Br J Psychiatry 1996;

169:468 – 474

10. Koran LM, McElroy SL, Davidson JRT, Rasmussen SA, Hollander

E, Jenike M: Fluvoxamine versus clomipramine for obsessive-

compulsive disorder: a double-blind comparison. J Clin Psy-

chopharmacol 1996; 16:121 – 129

11. Tollefson GD, Rampey AH, Potvin JH, Jenike MA, Rush AJ,

Dominguez RA, Koran LM, Shear K, Goodman W, Genduso LA:

A multicenter investigation of fixed-dose fluoxetine in thetreatment of obsessive-compulsive disorder. Arch Gen Psychia-

try 1994; 51:559 – 567

12. Goodman WK, Price LH, Delgado PL, Palumbo J, Krystal JH,

Nagy LM, Rasmussen SA, Heninger GR, Charney DS: Specificity

of serotonin reuptake inhibitors in the treatment of obsessive-

compulsive disorder: comparison of fluvoxamine and de-

sipramine. Arch Gen Psychiatry 1990; 47:577 – 585

13. March JS, Biederman J, Wolkow R, Safferman A, Mardekian J,

Cook EH, Cutler NR, Dominguez R, Ferguson J, Muller B, Riesen-

berg R, Rosenthal M, Sallee FR, Wagner KD: Sertraline in chil-

dren and adolescents with obsessive-compulsive disorder: a

multicenter randomized controlled trial. JAMA 1998; 280:

1752 – 1756

14. Riddle MA, Claghorn J, Gaffney G: A controlled trial of fluvox-

amine for OCD in children and adolescents (abstract). Biol Psy-

chiatry 1996; 39:568

15. Riddle MA, Scahill L, King RA, Hardin MT, Anderson GM, Ort SJ,

Smith JC, Leckman JF, Cohen DJ: Double-blind trial of fluoxe-

tine and placebo in children and adolescents with obsessive-

compulsive disorder. J Am Acad Child Adolesc Psychiatry 1992;31:1062 – 1069

16. Greist JH, Jefferson JW, Kobak KA, Chouinard G, DuBoff E,

Halaris A, Kim SW, Koran LM, Liebowitz MR, Lydiard RB, McEl-

roy S, Mendels J, Rasmussen S, White K, Flicker C: A 1 year dou-

ble-blind placebo-controlled fixed dose study of sertraline in

the treatment of obsessive-compulsive disorder. Int Clin Psy-

chopharmacol 1995; 10:57 – 65

17. Rasmussen SA, Hackett E, DuBoff E, Greist JH, Halaris A, Koran

LM, Liebowitz M, Lydiard RB, McElroy S, Mendels J, O’Connor K:

A 2-year study of sertraline in the treatment of obsessive-com-

pulsive disorder. Int Clin Psychopharmacol 1997; 12:309 – 316

18. Spitzer RL, Williams JBW, Gibbon M, First MB: Structured Clini-

cal Interview for DSM-III-R — Patient Version 1.0 (SCID-P). Wash-

ington, DC, American Psychiatric Press, 1990

19. Goodman WK, Price LH, Rasmussen SA, Mazure C, FleischmannRL, Hill CL, Heninger GR, Charney DS: The Yale-Brown Obses-

sive Compulsive Scale, I: development, use, and reliability.

Arch Gen Psychiatry 1989; 46:1006 – 1011

20. Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P,

Heninger GR, Charney DS: The Yale-Brown Obsessive Compul-

sive Scale, II: validity. Arch Gen Psychiatry 1989; 46:1012 – 1016

21. Murphy DL, Pickar D, Alterman IS: Methods for the quantitative

assessment of depressive and manic behavior, in The Behavior

of Psychiatric Patients. Edited by Burdock EL, Sudilovsky A, Ger-

shon S. New York, Marcel Dekker, 1982, pp 355 – 392

22. Hamilton M: Development of a rating scale for primary depres-

sive illness. Br J Soc Clin Psychol 1967; 6:278 – 296

23. Guy W (ed): ECDEU Assessment Manual for Psychopharmacol-

ogy: Publication ADM 76-338. Washington, DC, US Department

of Health, Education, and Welfare, 1976, pp 218 – 22224. Endicott J, Nee J, Harrison W, Blumenthal R: Quality of Life En-

joyment and Satisfaction Questionnaire: a new measure. Psy-

chopharmacol Bull 1993; 29:321 – 326

25. Rasmussen SA, Eisen JL, Pato MT: Current issues in the pharma-

cologic management of obsessive-compulsive disorder. J Clin

Psychiatry 1993; 54(suppl 6):4 – 9

26. Ravizza I, Barzega G, Bellino S, Borgetto F, Maina G: Drug treat-

ment of obsessive-compulsive disorder (OCD): long-term trial

with clomipramine and selective serotonin reuptake inhibitors

(SSRIs). Psychopharmacol Bull 1996; 32:167 – 173

sertraline in ocd

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