Sertraline safety and efficacy in major depression: A double-blind fixed-dose comparison with placebo

Sertraline Safety and Efficacy in Major Depression: A Double-Blind Fixed-Dose Comparison with Placebo

Louis F. Fabre, F.S. Abuzzahab, M. Amin, J.L. Claghorn, J. Mendels,

William M. Petrie, S. Dub6, and Joyce G. Small

In a 6-week, randomized, double-blind, multicenter trial, sertraline 50 mg, IO0 mg, or 200 mg, or placebo, wa~ administered once daily to 369 patients with DSM-lll-defined major depression. Efficacy variables included changes from baseline scores for total Hamilton Rating Scale for Depression (HAMD). HAMD Bech Depression Cluster, Clinical Global Impressions (CGI) Severity, CGI Improvement, and Profile of Mood States Depression/ Dejection Factor. For the evaluable-patients analysis, all sertraline groups showed significantly (p < 0.05 or better) greater improvements in all efficacy variables except one when compared with the placebo group. For the all-patients analysis, all efficacy variables in the 50 mg group were statistically signi[icantly (p < 0.05) better than placebo. Side effects increased with increasing dosage but were usually mild and well tolerated. The results of this study show that sertraline 50 mg once daily is as effective as higher dosages Cbr the treatment of major depression with )ewer side effects and therapy discontinuations.

Key Words: Major depression, selective serotonin reuptake inhibitor, sertraline

BIOL PsvcrnArr'~ 1995:38:592-602

Introduction Neurotransmission is influenced by the rate of neurotransmitter synthesis, neurotransmitter concentration in the synapse, rates of neurotransmitter reuptake and break- down, and number and affinity of target postsynaptic receptors to which a particular neurotransmitter can bind (Richelson 1988). Research findings suggest depression may be associated with decreased functional neurotransmission that results from depletion of the availability ofaminergic neurotransmitters--dopamine, norepineph-

From the Fabre Research Clinics Inc.. Hl~ush,n, Texas, Address reprint requests to Louis F Fabre. MD. Phi), Fabrc Research Clinics Inc.

5503 Crawford, Houston, TX 77111)4. Received May 23, 1994; revised October 21, 19¢14

rine, serotonin--in the vesicles at the presynaptic nerve endings (Garver and Davis 1979).

The new antidepressant drugs known as selective serotonin reuptake inhibitors (SSRIs) have molecular struc- tures distinctly different from those of the standard tricy- clics or monoamine oxidase inhibitors and biochemical effects that are different from those customarily observed with the older classes of antidepressant agents. These new compounds make more serotonin functionally available [or receptor stimulation (Shopsin et al 19811, and their efficacy is equivalent to that of other drugs used to treat depressive disorders (Mendels 1987). The SSRIs, which include sertraline, fluoxetine, fluvoxamine, citalopram, and paroxetine (Lemberger et al 1985; Tulloch and John- son 1992), also exhibit fewer anticholinergic and cardio-

© 1995 Society of Biological Psvchiatr~ 0006-3223/95/$09.50 SSDI 0006-3223(95)00178-J

Sertraline for Major Depression BIOL PSYCHIATRY 593 1995;38:592-602

toxic side effects and, therefore, may be the preferred treatment in a variety of patients (Mendels 1987).

Sertraline hydrochloride (C 17 H ~ 7 N CI 2HC1) is a structur- ally unique and highly selective serotonin reuptake inhibitor. Of the SSRIs approved for use in the United States, sertraline is the most selective agent with respect to blocking reuptake of serotonin over norepinephrine (Bolden-Watson and Richelson 1993). It is also one of the most potent inhibitors of serotonin reuptake, being 20 times more potent than amitriptyline, 10 times more potent than fluvoxamine, and 5 times more potent than fluoxetine (Koe et al 1983). Sertraline is 200 times less active than desipramine against norepinephrine reuptake, is weakly active against dopamine reuptake, and has no inhibitory effect on monoamine oxidase (Koe et al 1983). Sertraline has a low affinity for muscarinic receptors--60 times less than amitriptyline--and, therefore, has markedly lower anticholinergic activity. The major metabolite, desmethyl- sertraline, is over 20 times less potent than the parent compound in blocking serotonin reuptake and is considered inactive as an antidepressant (Bolden-Watson and Richelson 1993).

In the open field test, an animal model of depression considered predictive of efficacy for antidepressant drugs, administration of sertraline attenuated the behavioral effects of stress in rats (Kennett et al 1987). Sertraline exerts its antidepressant effects through a variety of mechanisms, including facilitation of serotonergic activity and induc- tion of downregulation of beta-adrenoreceptor systems (Koe et al 1987).

The average half-life of sertraline in healthy volunteers is 26 hours, with peak plasma concentrations occurring 5-8 hours after an oral dose. Single- and multiple-dose studies have shown linear pharmacokinetics, indicating consistent bioavailability over the recommended dose range (50-200 mg daily) (Fouda et al 1987).

The purpose of this study was to identify the dosage of sertraline that is most useful in clinical practice. The effectiveness, tolerability, and safety of three fixed dosage levels of sertraline (50, 100, 200 mg) given once a day for 6 weeks were compared to placebo. A portion of the data contained herein has been presented in poster format (Fabre 1991a) and as an abstract (Fabre 1991b); in addition, data from one of the eight centers have been published previously (Amin et al 1989).

Subjects and Methods

Subject Description A total of 369 patients (both symptomatic volunteers and patients already undergoing treatment) with major depressive disorder were entered into this 6-week, eight-center

study. The patient population consisted of 172 men and 197 women between the ages of 18 and 65 years. The women were postmenopausal, surgically sterile, or prac- ticing an adequate method of contraception. All subjects were required to meet the DSM-III (American Psychiatric Association 1980) criteria for major depressive disorder and to have a minimum score of 22 on the 17-item Hamilton Rating Scale for Depression (HAMD; Hamilton 1960) following an antidepressant drug washout period of 4-14 days; however, 11 patients entered double-blind treatment with HAMD scores less than 22, primarily because their symptoms improved between screening and baseline.

Excluded from the study were (1) pregnant or lactating women; (2) anyone taking concomitant psychotherapeutic medications or certain other concomitant medications; (3) those with a history of serious intolerance or resistance to any antidepressant drug or use of any other investigational drug in the 4 weeks preceding this study; (4) persons with a history of schizophrenia, schizoaffective disorders, or significant medical disease, including convulsive disorders; and (5) persons with continuous alcohol and/or drug abuse, including those experiencing recent symptoms of withdrawal.

Study Design This study was conducted in compliance with institutional review board and informed consent regulations, and all centers followed an identical protocol. Participants who had been previously receiving monoamine oxidase inhibitors were required to undergo a single-blind placebo washout period of 2 weeks. Those previously receiving other psychoactive drugs or who had been receiving a monoamine oxidase inhibitor and had deteriorated clinically underwent a washout period of 1 week. All others went through a washout period of 4-14 days. The length of the washout period was determined based on the investigator's judgment.

Patients were randomly assigned to one of four groups of equal size and were placed on a regimen of placebo or sertraline, the latter in a fixed dosage of 50 mg, 100 rag, or 200 m g a day, without any period of upward titration. In the event of the occurrence of a clinically unacceptable reaction in which the patient's intolerance to study medication was more than transient, study drug was discontinued. Those patients who discontinued before 2 weeks of active drug therapy because of inadequate response, inter- current medical problems, or unacceptable concomitant medications were replaced. All drug and placebo doses were prepared in identical capsules and administered once daily. If sleep-inducing medication was needed, patients were permitted only intermittent chloral hydrate, with the

594 BIOL PSYCHIATRY L.F. Fabre et al 1905"38:592-602

exception of the nights before psychiatric scale testing, when chloral hydrate was not allowed.

Data Collection

In order to assess efficacy, the HAMD scale, Clinical Global Impressions (CGI; Guy 1976) scale, and Profile of Mood States (POMS; McNair et al 1980) were administered at screening, baseline, and each week thereafter during the 6-week trial. Safety evaluations included investigator observations and laboratory parameters. Electrocar- diography was performed, and temperature, supine and standing blood pressures, pulse rate, and weight were recorded at each visit. Laboratory tests, conducted at screening, baseline, and every 2 weeks during the study, included a complete blood count with differential, platelet count, serum chemistry (lactate dehydrogenase, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, total bilirubin, creatinine, blood urea nitrogen (BUN), glucose, and electrolytes), and a routine urinalysis. A physical examination was performed at baseline and at termination of the study.

Statistical Analysis

Efficacy variables included the change in total 17-item HAMD score from baseline to the last visit, the percentage change in total 17-item HAMD score from baseline to the last visit, the change in CGI Severity score from baseline to the last visit, the CGI Improvement score at the last visit, and the change in the POMS Depression/Dejection Factor score from baseline to the last visit. Scores were also calculated for the Bech Depression Cluster (Bech et al 1975), a 6-item subscale of the HAMD (items 1-depressed mood; 2-guilt; 7-work and interests; 8-retardation; 10- anxiety, psychic; and 13-somatic symptoms, general).

For safety data, formal statistical analyses were performed on vital signs data, body weights, and the compar- ative incidence of side effects for all side effects that occurred with an incidence of at least 3% in any of the sertraline dosing groups.

Two descriptive analyses of laboratory test results were also performed for each dosing group: the incidence of patients with clinically significant laboratory abnormalities and the mean change from baseline (pre-double- blind) to the final visit for each laboratory parameter.

Statistical analyses on efficacy variables were performed for both an evaluable-patients group and an all- patients group. Evaluable patients were classified as those who took study medication on or after the 1 lth day of the double-blind phase, who had efficacy assessments on or after study day 11, and who were not major protocol

violators. The all-patients group included those who took at least one dose of double-blind medication and had at least one double-blind efficacy assessment.

All safety evaluations, including descriptive statistics of laboratory test results and formal analyses of vital signs, body weights, and side effects incidence, were performed for an all-patients group that included all patients who took at least one dose of double-blind medication and had at least one relevant double-blind safety-related observa- tion.

HAMD and POMS variables were tested in a two-way analysis-of-variance (ANOVA) framework with PROC GLM of SAS followed by t tests on the least squares means via the ESTIMATE option (SAS Institute 1985). The CGI variables were analyzed nonparametrically with a Wilcoxon Rank Sum test blocked on center (Hollander and Wolfe 1973). The contrasts of interest were sertraline (both individual dosing level groups and all doses combined) versus placebo, and were assessed with two-sided significance. No adjustment of p values was made for multiple comparisons. The HAMD total scores at last visit were also analyzed in an analysis of covariance (AN- COVA) framework using the baseline HAMD total scores as covariates.

For the safety analyses, vital signs and body weight analyses were performed with a one-way ANOVA, while comparisons of side-effects incidence were performed with Fisher's Exact Test. For safety analyses, the quoted p values are two-sided.

Results

Patients

The demographic characteristics of the patients randomly assigned to a treatment group are shown in Table 1. Although depressive illness is diagnosed in twice as many women as men (American Psychiatric Association 1980), women made up only 53% of the study population. (Women of childbearing potential became eligible for entry about midway through the study.) Most patients were relatively young, with a mean age of 37.6 years. The mean weight for men was 80.2 kg; for women, 64.3. The racial composition of the trial population was 91% white, 7% black, and 2% other.

The largest segment (38%) of the patient population had a depressive illness for more than 10 years (Table 1), followed in order of incidence by 31% with 1-5 years' duration, 15% with 5-10 years' duration, and 14% with less than 1 year's duration. The average duration of depressive illness was 9.5 years.

The majority (64%) of patients (Table 1) were diagnosed as having major depression, recurrent, with or


Table 1. D e m o g r a p h i c Character is t ics , Depress ive History, and Pr imary Psychia t r ic D iagnos i s for All Patients Enter ing Doub le -Bl ind The rapy

Sertraline

50 mg 100 mg 200 mg Placebo Parameter (n = 95) (n ~: 92) (n = 91) (n = t~l)

Sex Male 47 411 34 51 Female 48 52 5 7 4( I

Age (yr) 18-44 74 72 68 ~7 45- 64 2(I 20 23 24 >65 1 0 0 i) Mean age (yr) 37.3 37.1 38.6 37.3

Mean weight (kg) Male 77.t~ 82.4 77.3 83. I Female 63.t~ 64.4 64.7 64.2

Race White 91 85 81 7~ Black 2 6 7 11 Other 2 1 3 2

Duration of depressive history (yr)

< 1 21) N 8 15 1 5 22 31 3O 31 5-10 15 14 14 14 >10 34 38 38 3(I Not specified 4 I 1 1 Mean duration (yr) S.6 10.6 1(I.3 8.¢~

DSM-II1 classification Bipolar disorder, 1 _~, _ ~ .a

depressed Major depression. 36 2~ 27 33

single episode: With melancholia 7 7 5 8 Without melancholia 16 13 13 15 Unspecified as to 13 6 9 1 I)

melancholia Major depression, 58 f~3 62 55

recurrent: With psychotic II II [) 1

features With melancholia 21 I f~ 16 15 Without melancholia 26 3(I 28 21 Unspecified as to I 1 17 18 18

melancholia

without melancholic features. Fewer (33%) were diagnosed as having major depression, single episode, and only 2% were diagnosed as having bipolar disorder, depressed. The distribution of those diagnoses did not vary appreciably among the four treatment groups.

The number of patients that entered double-blind treatment was 95 in the sertraline 50 rag/day group, 92 in the 100 rag/day group, 91 in the 200 rag/day group, and 91 in the placebo group. A total of 191 patients (52%) completed the study (Table 2). Of the 369 patients randomly assigned to double-blind treatment, a total of 289 (78%)

Table 2. Completion and Discontinuation Rates for Patients Entering Double-Blind Therapy

No. of Patients (%)

Sertraline

50 mg 100 mg 200 mg Placebo (n = 95) (n = 92) (n = 91) (n = 9U

Cornpleters 59 (62) 47 (51) 39 (43) 46 (51) Evaluable patients" 82 (86) 75 (82) 56 (62) 76 (84) Discontinued 36 (38) 45 (49) 52 (57) 45 (49)

Lack of efficacy 14 (15) 18 (20) 9 (10) 25 (27) Side effects 10 (11) 15 (16) 33 (36) 4 (4) Laboratory - - - - - - 1 abnormalities Non-study- 12 (13) 10 (11) 10 (11) 15 (16)

medication-related t'

" Defined as patients who took study medication on or after the llth day of the double*blind phase, who had efficacy assessments on or after study day 11, and who were not major protocol violators.

J' Primarily patient default.

remained to be included in the evaluable-patients efficacy analysis.

Twenty-two patients had at least one dose of double- blind medication, but no double-blind efficacy assessments: 5 in the sertraline 50 mg/day group, 3 in 100 rag/day group, 9 in the 200 mg/day group, and 5 in the placebo group. These patients were excluded from the all-patients (intention-to-treat) efficacy analyses.

A total of 178 patients (48%) discontinued prematurely from this study (Table 2). Side effects and lack of efficacy were the most frequently cited reasons for discontinuation. The number of patients in each group who discontinued because of side effects prior to study day 11 and who were thus excluded from the evaluable-patients efficacy analysis was 4 (4%) in the sertraline 50 rag/day group, 10 (11%) in the 100 rag/day group, 23 (25%) in the 200 mg/day group, and 2 (2%) in the placebo group.

The mean duration of double-blind therapy was 33, 30, and 24 days in the sertraline 50 mg/day, 100 mg/day, and 200 rag/day groups, respectively, and 31 days in the placebo group. Thus, the shortest mean duration of therapy was in the 200 rag/day group, with 33 patients (36%) discontinuing within the first 10 days, indicating that in the absence of dose titration, the drug was better tolerated at the 50 mg/day and 100 rag/day doses.

The final dosages of double-blind sertraline did not differ substantially from the treatment dosages originally assigned. The mean final daily dose was 50 mg for the 50 rag/day group, 98 mg for the 100 mg/day group, and 190 nag for the 200 mg/day group.

Efficacy In the evaluable-patients analysis, there was significantly (p <- 0.05) greater improvement from baseline in the

596 BIOL PSYCHIATRY L.F. Fabre et al 1995;38:592-602

26

2 4 -

2 2 -

20- 2 8 o~ 18-

o 16-

-1- 14-

12-

10- " " " ' " l

Baseline 1 2 3 4 5 6

Week

Sertraline 50 mg/day - I ! - (N=82)*

Sertraline 100 mg/ --O-- day (N-74)*

Sertraline 200 mg/ '"'&'"' day (N=56)'1"

Sertraline Combined - • - (N=212)t

-C3,- Placebo (N=76)

*p < 0.05 compared with placebo at last visit

l"p< 0.01 compared with placebo at last visit

Figure 1. Hamilton Rating Scale for Depression (HAMD) total score by treatment group and visit (evaluable patients).

HAMD Total (Figure 1), HAMD Bech Depression Clus- ter, CGI Improvement, and POMS Depression/Dejection Factor scores for all dosage levels of sertraline (50, 100, and 200 mg/day) and for the combined sertraline dosage group compared with placebo (Table 3). The percentage of responders, as measured by a CGI Improvement score of 1 or 2 at the last visit, is shown in Figure 2. Results of the ANCOVA analysis also demonstrated a significant treatment effect for all three sertraline dosage groups and for the combined sertraline dosage group versus placebo (Table 4).

In the intention-to-treat efficacy analyses (all patients), significant (p <- 0.05) improvement in all parameters compared with placebo was observed in the sertraline 50 mg/day and combined sertraline dosage groups (Table 5). In the sertraline 100 mg/day group, significant improvement compared with placebo was noted in all parameters except the HAMD Total and CGI Severity scores, and in the 200 mg/day group, significant improvement was observed in all but the HAMD Total and CGI Improvement scores (Table 5). The efficacy of sertraline 50 rag/day was at least equivalent to that of 100 mg/day and 200 mg/day.

An analysis of the 191 patients who completed the study, stratified by severity of depression, revealed even greater response in each treatment group in severely depressed patients than was seen in the moderately de-

pressed patients (Table 6); however, the differences were not significant.

Safety The number of patients with at least one treatment-related side effect was 43 (47%) in the placebo group, 65 (68%) in the sertraline 50 mg/day group, 68 (75%) in the 100 mg/day group, and 79 (87%) in the 200 rag/day group; however, the number of patients who discontinued because of side effects was much lower in all groups (Table 2). Nausea and tremor were the most common side effects causing discontinuation in sertraline-treated patients.

Table 7 presents a comparison of incidence of treatment-related side effects for all side effects experienced by at least 5% of any one sertraline dosing group. The incidence of side effects increased with increasing drug dosage: The number of side effects with an incidence in the sertraline group significantly greater (p ----- 0.05) than in the placebo group was one (1%) in the 50 mg/day group, three (3%) in the 100 mg/day group, and 10 (11%) in the 200 rag/day group.

At any dosage level, sertraline had no statistically significant effect on ECGs, laboratory parameters, or vital signs. The number of ECGs recorded during the study that were judged to be more abnormal than at screening was


T a b l e 3. M e a n E f f i c a c y P a r a m e t e r s ( _ + S D ) at L a s t V i s i t in E v a l u a b l e - P a t i e n t s G r o u p s "

Sertral ine

50 m g l d a y 100 rag/day 200 m g / d a y C o m b i n e d P lacebo

Pa ram e te r (n = 7 9 - 8 2 ) (n = 7 1 - 7 5 ) (n = 5 4 - 5 6 ) (n = 2 0 4 - 2 1 2 ) (n = 7 3 - 7 6 )

H A M D total

Basel ine score 24.~ + 3.0 24.9 ~: 3.1 25.9 ± 3.5 25.1 -+ 3.2 25.1 ± 2.6

Change f rom basel ine I 1.3 _+ 8 .7 ' I 1.4 ~ 8.7 ~ 12.5 + 7 .0 t - 1 1 . 7 --_ 8.2 f - 8 . 6 -+ 7.8

% change f rom base l ine ~' - 4 5 . 5 + 34.7 - 4 5 . 9 + 35.1 50.1 -+ 28.9 - 4 6 . 8 -+ 33.3 - 3 4 . 6 _+ 30.9

H A M D Bech Depress ion

C lus t e r '

Basel ine score 12.3 ~ 1.9 12.4 - _. ~ I 12.9 _+ 1.6 12.5 _ + 1.9 12.7 _ + 1.5

Change f rom base l ine - 5 . 5 -+ 4.Y" - 5 . 7 ~ 4.9" - 6 . 7 ± 3.8 ~ - 5 . 9 ± 4.4 g - 3 . 9 + 4.2

C G I Sever i ty

Basel ine score 4.,. ~ I).6 4.3 ~ 0.5 4.4 ± 0 .6 4.3 ± 0.6 4.2 ± 0.5

Change f rom base l ine 1.2 -~ 1.3 .... 1.3 + 1.3 '~ - 1 . 6 ± 1.0 g 1.3 ± 1.2 r - 0 . 8 ± 1.1

C G I I m p r o v e m e n t Score" 2.4 ~ 14 ' 2.4 + 1.5 ̀~ 2.2 ± 1.2 f 2 .4 _+ 1.4 r 2.9 ± 1.4

P O M S Depress ion /De jec t ion

Factor

Basel ine score 2.7 ± 1.1 2.6 : 1.0 2.5 + 1.0 2.6 _+ 1.0 2.6 ___ 1.1

C h a n g e f rom basel ine - 1).5 _+ 1.1 i - -0 .5 ~ 1.0" - 0 . 5 + 0.7 e - 0 : 5 -+ 1.0 t - 0 . 1 ± 0.7

The significance levels given for individual items are for comparison of that sertraline group (individual sertraline dosing groups or the combined sertraline group) vs. placebo for the parameter in question.

" Ranges are given for n values because data tot all parameters were not a'~ailable for all patients. ~' Statistical comparisons by individual sertralinc dosing groups (50, 100. 2()1] rag/day) vs. the placebo dosing group were not done for % change from baseline. ' Items I (depressed mood), 2 (guilt), 7 (work and interest), 8 (retardation/, 10 (anxiety, psychic), and 13 (somatic symptoms, general) of the HAMD. a Smaller positive values for this variable indicate greater improvement; scores are given only at assessments after the start of double-blind therapy, and only positive

values are given. For all other variables in the lablc, larger negative scnres indicate greater improvement. p -< 0.05 compared with placebo.

S p < 0.01 compared with placebo ,e p < 0.001 compared with placebo. HAMD - Hamilton Rating Scale h~r Depression: C(il Clinical Global hrTprcssions; POMS ;: Profile of Mood States.

not greater for any sertraline group than for the placebo group.

None of the 278 sertraline-treated patients discontinued prematurely because of a treatment-related laboratory abnormality, as compared with one of the 91 placebo- treated patients. Except for random blood glucose and triglycerides, the incidence of clinically significant laboratory abnormalities was low (<4%) and similar in all four treatment groups. Clinically significant abnormal random blood glucose values were noted in 3.6% of the sertraline 50 mg/day group, 5.5% of the 100 rag/day group, and 11.1% of the 200 mg/day group, however, the incidence rate in the placebo group (6.3%) was greater than in all but the 200 rag/day sertraline group, suggesting that these findings are not of clinical relevance. For triglycerides, the placebo group had the greatest incidence (9.0%) of clinically significant abnormalities. Again, this finding is of doubtful clinical relevance.

The mean changes from baseline to the final visit for all laboratory parameters in all treatment groups were not statistically significant, with mean changes in the placebo group generally of comparable magnitude to changes in the individual sertraline dosing groups. Within the three

sertraline groups, the mean changes for all but two laboratory parameters--uric acid and random glucose-- fluctuated around a mean change of 0, with no evidence of dosage-related effects.

For uric acid, the mean changes in the sertraline 50 rag/day, 100 mg/day, and 200 mg/day groups were -0 .10 mg/dL, -0 .33 mg/dL, and -0 .42 mg/dL, respectively. These changes in uric acid are consistent with a slight hypouricemic effect of sertraline. For random glucose, the mean changes in the sertraline 50 mg/day, 100 mg/day, and 200 rag/day groups were - 1.45 mg/dL, -0 .69 mg/dL, and -0 .04 mg/dL, respectively. It is of note that these changes are inversely related to dosage and are all negative in direction. These negative changes in mean glucose further suggest that the elevations in glucose were of no clinical relevance.

Thus, the data for discontinuations for laboratory abnormalities, for incidence rates of clinically significant abnormalities, and for mean changes in laboratory parameters from baseline to the final visit all suggest that in this study, sertraline had no clinically relevant effects on laboratory values.

Body weight, however, was significantly affected by

598 BIOL PSYCHIATRY L.F, Fabre et al 1995;38:592-602

70

60

50

-~ 40

~: 30

20

10

Sertraline Sertraline Sertraline Sertraline 50 rng/day 100 mg/day 200 mg/day Combined

(N=82) (N=75) (N=56) (N=213)

*p < 0.05 compared with placebo

Placebo (N=76)

Figure 2. Percentage of responders at last visit as measured by Clinical Global Im- pressions (CGI) Improvement Score of 1 or 2 (evaluable patients).

sertraline. The mean weight loss from baseline to the last visit in the combined sertraline groups was 0.58 kg, whereas a mean weight gain of 0.29 kg was observed in the placebo group. Sertraline-associated weight loss, which was significantly different from placebo effect at the p <-- 0.001 level for the combined sertraline group, appeared to be dose-related, with the greatest mean weight loss, 1.3 kg, observed in the 200 mg/day dosing group.

Discussion

Comparing different fixed dosage levels of a drug is considered the best method for determining relationships between dosage and efficacy, tolerability, and other safety

Table 4. Analysis of Covariance (ANCOVA) Results at Last Visit

variables. In the present study, all dosages of sertraline (50, 100, and 200 mg/day) were substantially more effective than placebo in treating major depression; however, small differences in dose-response relationships were noted with the intention-to-treat and evaluable-patients analyses. By the intention-to-treat analysis, sertraline 50 mg/day demonstrated a trend for superiority in efficacy to the higher dosage levels on most parameters, while the evaluable-patients analysis showed a similar trend in favor of the 200 rag/day dosage. Nonetheless, the differences in efficacy were not markedly different among the sertraline dosage groups.

Several factors may have contributed to the difference in results of the two types of analyses. SSRIs have been

in Evaluable-Patients Groups

Sertraline

50 nag/day 100 nag/day 200 mg/day Combined Placebo

(n = 82) (n = 74) (n = 56) (n = 212) (n = 76)

H A M D total score:

Mean 13.34 13.49 13.38 13.40 16.51

Least squares mean 14.45 14.37 13.21 14.01 17.31 Treatment effect vs. placebo - 2.87 ~ - 2.94 a - 4. l0 b - 3.30 t' - -

° 0.01 < p -< 0.05 compared with placebo. b 0 .001 < p "~ 0.01 compared with placebo. HAMD ~ Hamilton Rating Scale for Depression.


Table 5. Mean Efficacy, Parameters (_+SD) at Last Visit in All-Patients Groups

Parameter

Sertraline

5(1 mg/day l(t0 mg/da 5, 200 mg/day Combined Placebo (n = 9(1) (,7 = 89) (n = 82) (n = 261) (n = 86)

HAMD total Baseline score 24.8 +_: 3.0 24. t) : 3.0 25.7 ± 3.2 25.1 ± 3.1 25.3 + 2.9 Change from baseline 10.6 + 8.6 J - 9.8 ~ 8.9 -9.2 -+ 8.2 9.9 ± 8.6 a -7 .6 ± 7.5 % change from baseline" 42.6 2 34.4 39.3 ~ 30.1 --36.9 +- 33.4 --39.7 ± 34.6 -30.7 + 30.2

HAMD Bech Depression Cluster b

Baseline score 12.4 ~ 1.8 12.4 ~ 2.0 12.9 ± 1.5 12.5 _+ 1.8 12.8 + 1.5 Change from baseline - 5 2 + 4.3 '~ - 5.0 ~. 4.8 '~ -5.:l + 4.3 J 5.1 + 4.5 ~ -3.5 ± 4.0

CGI Severity Baseline score 4.3 :: 0.6 4.3 ~ 0.5 4.3 ± 0.6 4.3 -+ 0.5 4.2 ± 0.5 Change from baseline I.l ~ 1.3 J 1.1 ~: 1.3 l.l ± 1.2 '~ -1.1 + 1.2 a -0 .7 + 1.1

CGI Improvement Score' 2.5 + 1.4 J 2.(~ ~: 1.5 a 2.8 ± 1.6 2.7 ± 1.5 a 3.1 ± 1.4 POMS Depression/Dejection

Factor Baseline score 2.8 + 1.1 2.7 '~ 1.0 2.5 +- 1.0 2.7 ± 1.1 2.6 + 1.1 Change from baseline 0.5 ~ 1.1' (I.5 :. 1.1" 0.4 +- 0.7 J (1.5 ± 1.~ -0.1 + 0.7

The significance levels given for individual items are tk~r comparison ot lhal sertraline group (individual senraline dosing groups or the combined sertraline group) vs. placebo for the parameter in question.

Statistical comparisons by individual sertraline dosing groups (511. 1110, and 2(10 mg/day/vs, the placebo group were not done for % change from baseline. ~' Items 1 (depressed mood), 2 (guilt), 7 (work and interest), g (retardation). 1(1 (anxiety, psychic), and 13 (somatic symptoms, general) of the HAMD. ' Smaller positive values for this variable indicate greater improvement: scores are given only at assessments after the start of double-blind therapy, and only positive

values are given. For all other variables in the table, larger negative scores indicate greater improvement. ,l p ~ 0.05 compared with placebo.

p < 0.01 compared with placebo. fp --< 0.00l compared with placebo. HAMD = Hamilton Rating Score tot Depression: CGI - Clinical (;lgbai Impressions: PCMS " Profile of Mood States.

r epo r t ed to s h o w fiat d o s e - r e s p o n s e curves : I n c r e a s i n g

d o s a g e d o e s not m a r k e d l y inc rease t h e r a p e u t i c r e s p o n s e

bu t does i nc rease the inc idence o f s ide e f fec t s (R icke l s and

S c h w e i z e r 1990). A c o m m o n f ind ing w i t h m a n y ant ide-

p r e s s a n t d r u g s is that s ide e f fec t s o c c u r m o r e f r equen t ly

w h e n t he r apy is ini t ia ted w i th d o s e s at the h igh end o f the

t h e r a p e u t i c r a n g e ra the r than t i t ra t ing f r o m a l o w to a h igh

dose . In addi t ion , the r e s p o n s e to a n t i d e p r e s s a n t d r u g

the rapy , i n c l u d i n g t he r apy wi th S S R I s , o c c u r s in two

phase s . T h e benef ic i a l e f fec t s are not o b s e r v e d imrned i -

a t e l y - - 2 - 3 w e e k s m a y be r e qu i r e d be f o r e an i m p r o v e m e n t

in s y m p t o m s is o b s e r v e d - - w h i l e s ide e f fec t s re la ted to

a n t i d e p r e s s a n t d r u g t he r apy are e x p e r i e n c e d w i t h i n seve ra l

d a y s o f s t a r t ing t r e a t m e n t ( K a r a s u 1989).

In this s tudy , the in t en t ion - to - t r ea t a na ly s i s i nc lud ed all

pa t i en t s en t e red in the s tudy w h o had at leas t o n e e f f i cacy

a s s e s s m e n t d u r i n g the d o u b l e - b l i n d t r e a t m e n t pha s e . O f

note, h o w e v e r , is that the n u m b e r o f p r e m a t u r e d i s c o n t i n u -

a t ions i nc reased wi th i n c r e a s i n g dosa ge ; the 6 - w e e k treat-

m e n t p h a s e w a s no t c o m p l e t e d by 36 ( 38% ) , 45 (4 9 %) ,

Table 6. Mean HAMD Scores ( ± S D ) at Last Visit by Severity, of Depression in Patients Who Completed the Study

Nertraline

50 mg, da~, 100 rag/day 200 rag/day Combined Placebo Parameter (~ = 59) (it .... 46l (n = 38) (n = 143) (n = 48)

Moderately depressed" HAMD Total:

Baseline score 22.6 + 0.3 22.7 + 0.2 22.9 ± 0.2 22.7 ± 0.1 23.0 + 0.2 Change from baseline 12.9 ± 1.3 15.4 +_ l.(I -15.0 ± 1.1 -14.3 ± 0.7 -11.9 +- 1.0 % change from baseline -56.6 _+ 6.0 ~8.3 + 4.6 --65.6 ± 4.8 62.8 ± 3.1 -52.0 ± 4.4

Severely depressed" HAMD Total:

Baseline score 26.7 ~ 0.4 20.8 + (I.4 27.2 _+ 0.5 26.9 ± 0.3 27.0 ± 0.5 Change from baseline 14.3 + 1.4 16.8 ± 1.3 16.1 -+ 1.5 15.6 ± 0.8 -12.8 ± 1.4 % change from baseline 53.8 -+ 4.8 62.7 ± 4.5 -59.7 ± 5.8 -58.2 ± 2.9 -42.0 ± 5.2

Moderately depressed indicates a HAMD score at baseline of 17-24: severely depressed indicates a HAMD score at baseline ->25. HAMD = Hamilton Rating Scale for Depression.

600 BIOL PSYCHIATRY L.F. Fabre et al 1995;38:592 602

Table 7. Incidence of Treatment-Related Side Effects by Organ System (All Patients)

System Side effect

No. of Patients (%)

Sertraline

50 100 mg/day mg/day

(n 95) (n = 92)

200 mg/day Placebo

(n = 91) (n : 911

Psychiatric disorders Somnolence '4 (9.5) Agitation 9 (9.51 Insomnia 9 (9.5) Sexual dysfunction-male ~' 4 (8.5)

Central and peripheral nervous systems Headache 14 (14.7) Tremor 6 (6.3) Dizziness 6 (6.3)

Autonomic nervous system Dry mouth 9 Increased sweating 2

Gastrointestinal system Nausea 21 Diarrhea/loose stools 2(1 Anorexia 5 Vomiting (l Constipation 5 Flatulence 5 Dyspepsia I

Special senses Vision abnormality 5 (including blurred vision)

Cardiovascular system Palpitations 7 ( 7.4 )

General Fatigue 11 ( 11.6)

12{13.01 17 (18.7)" 7(7.7) 9 (9.8) 18 (19.81 8 (8,8) 8{8.7) 16(17.6) 8(8.8) 3 (7.5) 7 (20.6)" (}

20(21.7) 19(20.91 12 (13.21 6 (6.5) 26 (28.6)" 2 (2.2) 5(5.4) 17(18.7)" 6(6.6)

(9.5) (~ (9.81 15 (1~,51 ~ (9.9) (2.1) 3(3.3) 7(7.7)" (t

(22.11 33 (21.1)" 21 (5.3) 9

5 (5.3) 2 (5.3) 5 ( I .1) 3

(35.9)" 40(44,01" t4(15.41 (22.8)" 19 (20,9)" 8 (8.8) (9.8)" 10 (11.0) ~ (5.4) 12 (13.2)" 3(3.3) (2.2) 5 (5.5) It (5.4) 1 I 1.1 ) 2 (2.2) (3.3) 5 (5.5) 3 (3.3)

(5.3) 7 (7,6) t) (9.9) 3 (3.3)

2(2.2) 6(6.6) 1 (1.1)

7 (7.t~) 14 (15.4)" 5 (5.5)

"p -< 0.05 compared with placebo. b Incidence was calculated using the number of male patients in each group

and 52 (57%) of patients in the 50 mg, 100 mg, and 20(1 mg dosage groups, respectively. Many of these patients had insufficient exposure to sertraline to achieve therapeutic benefit. In contrast, the evaluable-patients analysis included only those patients who were still taking study medication on or after day 11 of the double-blind treatment phase. Therefore, by this analysis, patients were more likely to have had adequate exposure to sertraline to demonstrate a therapeutic response.

The results of this study supported early occurrence of side effects and higher discontinuation rates due to side effects with increasing sertraline dosages. In the 200 mg/day group, 25% of patients discontinued therapy before day 11 because of side effects, compared with 4q,~ in the 50 rag/day group. In addition, the total side-effect discontinuation rate of 11% in the 50 mg/day group was approximately half that of the combined sertraline group (21%). Thus, the present study demonstrated that sertra-

line 50 mg/day is an effective dosage for the treatment of major depression and is better tolerated than higher dosages.

In fixed-dose studies evaluating other SSRls, a similar lack of dose-response curves has been noted. Lower dosages (20 rag/day) of fluoxetine have been found to be as effective and better tolerated than dosages of 40 mg/day (Wemicke et al 1987) or 60 mg/day (Fabre and Putman 1987) in outpatients with major depression. Similarly, dosing studies of paroxetine (Dunner and Dunbar 1992) show a relatively flat dose-response curve across the range of 20-40 nag and an increase in discontinuation due to side effects associated with increasing dosage,

A large dose-titration study (Reimherr et al 1990) comparing the efficacy of sertraline, amitriptyline, and placebo in patients with major depression provides further evidence for the efficacy and tolerability of sertraline. It also provides support for the hypothesis that in a fixed- dosage design early discontinuations because of side effects can be expected in the high-dosage group. This can result in a discrepancy in results for the evaluable- and all-patients analyses; however, the results of the evaluable- patients and all-patients analyses in the Reimherr et al study (1990) were similar, in that both analyses showed significant improvements in all primary efficacy parameters for the sertraline group that were greater than for placebo and comparable to amitriptyline. In addition, the higher sertraline dosage was well tolerated: the overall discontinuation rate due to side effects was 17% in sertraline-treated patients, 61% of whom were titrated to a dosage of 200 mg/day. This discontinuation rate is much lower than the 36% rate for the 200 mg/day group in the present study, and somewhat lower than the 21% discontinuation rate for the combined sertraline group.

Other studies also support the findings of the present study that lower sertraline dosages are effective and well tolerated. In a small, fixed-dose study, lower dosages of sertraline--50 mg/day and 100 mg/day--were better tolerated than dosages of 200 rag/day or higher (Guy et al 1986). Recent data from a large, open study of 2,053 general practice patients with major depression also indi- cated that sertraline dosages of 50 mg/day and 100 rag/day are effective and well tolerated (Thompson et al 1993). Using a flexible dose-titration design, patients were started on sertraline 50 rag; if response was inadequate after a minimum of 2 weeks, the dosage was increased gradually to a maximum of 200 mg. The majority (58%) of patients received a final sertraline dose of 50 mg, and 32% received a final dose of 100 mg. Only 12% of patients withdrew from the study because of adverse events. Thus, it would appear that the majority of depressed patients will be treated effectively with sertraline 50 mg/day, and, if


higher dosages are required, they will be better tolerated if achieved through dose titration.

In the present study, most of the commonly reported side effects were dose related. The principal side effects of sertraline were related to the gastrointestinal tract--nausea, vomiting, and diarrhea~and are commonly reported with other SSRIs. The 21% incidence of male sexual dysfunction, mainly transient or intermittent ejaculation disturbance, in the sertraline 200-mg/day group in this study is similar to that reported with imipramine treatment (Harrison et al 1986) and other SSRIs (Herman et al 1990; Mendels 1987; Musher 1990; Zajecka et al 1991; Preskorn 1994).

Unlike tricyclic antidepressants, which promote an increase in appetite, carbohydrate craving, and weight gain, sertraline caused a small but significant weight loss in this study. Drugs with a serotonergic effect, such as the SSRIs that selectively inhibit serotonin reuptake, are more likely to promote weight loss, whereas serotonin antagonists are more likely to stimulate weight gain (Bernstein 1988). The literature suggests that weight gain is a major reason for premature discontinuation of tricyclic antidepressant therapy; therefore, patient compliance may be improved with sertraline treatment.

Summary The results of this study show that sertraline 50 ms/day is as effective as dosages of 100 ms/day and 200 ms/day for the treatment of major depression. The 50 ms/day dosage was associated with fewer side effects and premature discontinuations of thcrapy. This study confirmed the flat dose-response curve previously reported with other SSRIs: Increasing doses of scrtraline were not associated with marked increases in therapeutic benefit but were associated with an increased occurrence of side effects. These data corroborate previous findings that the 50 mg dose of sertraline, the lowest recommended dose, appears to be cffectivc for the majority of depressed patients.

Supported by a grant from Pfizer Inc. From Fabre Research Clinics, Inc., Houston, TX (LFF); Clinical Psychopharmacology Consultants, P.A., Minneapolis, MN (FSA); Lakeshore General Hospital, Pointe Claire, Quebec, Canada (MA); Clinical Research Associates, Inc., Houston, TX (JLC); Therapeutics, Inc., Philadelphia, PA (JM); Psychiatric Consult- ants, P.C., Nashville, TN (WMP); Wayne State University (Lafayette Clinic), Detroit, MI (SD); and Larue D. Carter Memorial Hospital, Indianapolis, IN (JGS).

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Sertraline safety and efficacy in major depression: A double-blind fixed-dose comparison with placebo