Double-blind dose determination study of a new antidepressant—sertraline

Drug Development Research 9:267-272 (1986)

Double-Blind Dose Determination Study of a New Antidepressant-Sertraline William Guy, Gregory Manov, and William H. Wilson

Vanderbilt University and Tennesse Neuropsychiatric Institute

ABSTRACT

Guy, W., G. Manov, and W.H. Wilson: Double-blind dose determination study of a new antidepressant-sertraline. Drug Dev. Res. 9:267-272, 1986.

As part of a multicenter dose determination study designed to evaluate the safety and therapeutic activity of four fixed dose levels of sertraline-a new antidepressant with biochemical characteristics different from tricyclics--17 patients with diagnoses of major depressive disorder were treated with active medication under double-blind conditions for 4 weeks following a 1-week washout period. Patients receiving the two higher dose levels of sertraline exhibited almost no symptomatic improvement and manifested more adverse events than patients receiving the two lower dose levels. No statistically significant differ- ences between the low-dose groups and the placebo group were found. Thus, the efficacy of sertraline could not be demonstrated under these design constraints, although differential dose level effects were indicated. Dosage levels up to 100 mglday would appear to be more clinically appropriate than higher dosage levels.

Key words: dose range, adverse effects, therapeutic effect

INTRODUCTION

Sertraline (d-cis-4-(3,4-dichloropheny)- 1,2,3,4-tetrahydro-N-methyl- 1 -naphthalenamine hydroch1oride)is a structurally novel antidepressant with biochemical and behavioral characteristics distinct from those of tricyclic antidepressants. It selectively inhibits synaptosomal serotonin (5HT) uptake in vitro and markedly blocks 5HT uptake in vitro at doses which do not elicit significant psychostimulant and anticholinergic activity in animals-potentiating pharmacological effects dependent on serotoninergic activity without enhancing those involving catecholamines. Sertraline does not affect brain monoamine levels or inhibit monoamine oxidase and was well tolerated in rodents and dogs with no untoward cardiovascular effects. Biologically, sertraline is similar to other prototypical 5HT uptake blockers; e.g., fluvoxamine, with recently reported antidepressant activity [van Praag, 1980; Wilson et al., 1983; Guy et al., 19841. Early studies with human volunteers have shown it to be well tolerated in doses up

Received final version November 19, 1985; accepted April 7, 1986. Address reprint requests to William Guy, Ph.D., 242 Medical Arts Bldg., 1211 21st Ave. S . , Nashville, TN 37212.

0 1986 Alan R. Liss, Inc.

268 Guy, Manov, and Wilson

to 400 mg/day. The most frequent side effects in both single- and multiple-dose studies have been gastrointestinal in nature, i.e., diarrhea, cramps, nausea, and vomiting at dose levels of 125 mgiday and up [ Investigator’s Reference Manual, 19821.

DESIGN

The present trial was one part of a multicenter study designed to evaluate the safety and therapeutic activity of sertraline under different fixed dose levels. Following a I-week drug- free washout period, four dose levels of sertraline (50, 100, 200, 400 mg/day) were compared under double-blind conditions with placebo (PBO) over a 4-week treatment period in patients with DSM-111 diagnoses of major depressive disorder. Male and postmenopausal or surgically sterile female patients between the ages of 18 and 65 years without significant systemic illness or drugialcohol abuse and with an end of washout minimum total Hamilton Depression Scale (HAMD) score of 18 on the first 17 items were acceptable for the study. All patients signed an informed consent form after the nature and purpose of the study was explained to them. While all patients were on inpatient status during the washout period and first week of treatment, patients could continue in the trial on an outpatient basis for the remaining 3 weeks of treatment if their condition warranted it.

Major psychiatric assessments consisting of HAMD, Clinical Global Impressions (CGI), and Profile of Mood States (POMS) were conducted pre- and post- washout and on days 4, 7, 14, 21, and 28 [Guy, 19751. All psychiatric assessments for a given patient were conducted by the same rater. Laboratory parameters, electrocardiograms, and assessment of adverse effects were conducted at pretreatment and weekly thereafter. Vital signs were taken daily for inpatients and weekly for outpatients.

RESULTS

The analytic cohort consisted of 17 patients; and, therefore, the interpretation of results should be viewed in the light of the small sample size. Following the completion of data collection and early in the analytic phase, it became apparent that the outcome patterns for both therapeutic effect and safety of the two low-dose groups (50 and 100 mg/day) were virtually indistinguishable from each other as were the patterns for the two high-dose groups (200 and 400 mg/day). For these reasons and in an effort to increase treatment cell size, subsequent analyses were conducted employing a PBO group, a combined LO-dose group, and a combined HI-dose group.

The major demographic characteristics of the sample are presented in Table 1. Equally distributed by sex, the sample can be generally described as one in its mid-thirties with one previous episode of depression, with precipitating stress, and with a family history of psychiatric illness in approximately one-third of the patients. The majority of the sample were smokers and coffee drinkers; and approximately 60% used alcohol but not at a level which was considered abusive.

Table 2 presents the status of patients at termination as measured by the CGI Global Improvement item along with reasons for termination. While just over 50% of the total sample were judged to have improved, this proportion was not reflected equally among the three treatment groups. In the HI-dose group, 71 % of the patients were judged “unimproved”- twice as many as in the PBO and LO-dose groups combined (30%). Three of HI-dose patients were judged “worse,” i .e., deteriorated from pretreatment status.

To qualify for the analytic cohort, all patients had to receive at least 14 days of treatment-exclusive of the washout period. The mean duration of treatment for the sample as a whole was 23.3 days. Treatment duration was shortest in the HI-dose group (20.3 days) and longest in the LO-dose group (25.3 days). With the exception of four patients (three in the HI- dose group, one in the LO-dose group), all patients underwent at least 21 days of treatment.

Sertraline: A New Antidepressant 269

TABLE 1. Demographic Data (No. [%I of Patients)

Variable

Age Mean SD

Sex M F

Mean No. previous episodes Family history-depression Family history-other psychiatric

illnesses Precipitating stress present Drug usage

Tobacco Alcohol Coffee Marijuana

Major depressive-single Major depressive-recurrent

DSM-I11 diagnoses

PBO = 4 LO-dose = 6 HI-dose = 7 Total = 17

31.7 37.5 34.7 34.9 7.2 10.3 12.7 10.1

-

TABLE 2. Global Improvement at Termination (No. [%] of Patients)


Level 1-Very much improved 2(50) 3(50) 1(14) 6(35) 2-Much improved - 1(17) 1(14) 2(12) 3-Minimally improved 1(25) 2(28) 5(29)

1(6) 2(33)

4-Unchanged 1(25) 5-Minimally worse -

- 2(28) 2(12) 7-Very much worse - - Total improved (1 f 2 + 3) 3(75) 4(67) 2(29) 9(53) Total unimproved (4 + 5 + 6 + 7) ~ 2 5 ) 3(33) 5(71) 8(47)

Mean days in treatment 24.5 25.3 20.3 23.3 Completed protocol ~ ( 5 0 ) 4(66) 2(29) 8(47)

2(12) Patient withdrawal 1(25) 1(17) 1(17) 4(57) 6(35) - l(14) l(6)

Inadequate response 1(25) Adverse reaction -

- -

- - - 6-Much worse -

1(14) 1(6)

Reason for termination

-

Of the 47% of the patients who completed the protocol, three-fourths were in the PBO and LO-dose groups. Conversely, two-thirds of the patients prematurely terminated for inadequate response were in the HI-dose groups. Two patients (one PBO; one LO-dose) withdrew from the study after approximately 3 weeks of treatment for fear of losing their jobs. Both of these patients were judged to be improved at termination. One patient receiving 200 mg/day (HI-dose group) was discontinued after 3 weeks of treatment because of abnormal liver findings (elevated SGOT, SGPT, LDH). Following referral to a gastrointestinal clinic for evaluation, the laboratory values fell to within normal limits within a few days and the patient was considered recovered without sequelae.

The major indices of therapeutic activity were the HAMD, the POMS, and the Severity of Illness item of the CGI. Employing analysis of variance-repeated measures, the treatment


groups were not significantly different at pretreatment. The most prevalent findings were significant PERIOD effects (P > .05), reflecting improvement at termination for the population as a whole. These PERIOD effects were obtained on the HAMD factors of Cognitive Disturbance, Sleep Disturbance, Retardation; and on the POMS factors of Anger-Hostility, Fatigue, Confusion-Bewilderment; as well as on HAMD and POMS total scores.

Statistically significant interactions (P > .05) were obtained on the HAMD total score and CGI-Severity of Illness, reflecting a lack of improvement at termination in the HI-dose group in comparison to the LO-dose and PBO groups (Fig. 1). A similar significant interaction was also obtained on the HAMD factor of Retardation. While these findings differentiate the HI-dose from the other two groups, it shoud be emphasized that there were no significant findings which differentiated the LO-dose from the PBO group with regard to outcome.

Table 3 presents the most frequently cited treatment-emergent symptoms for the three treatment groups. A treatment-emergent symptom is defined as one which was not present at pretreatment but was subsequently cited under treatment conditions. The manner in which the treatment emergent symptoms are distributed provide much information concerning the effects of the various dose levels. It is readily apparent that the frequency of adverse events (62%) is greater in the HIdose group than in the other two groups combined. Gastrointestinal symptoms, in particular, are more prevalent in the HI-dose group and appear to be dose-related- 70% of all citations occurring in this group. Constipation occurs only in the PBO group instead of the diarrhrea, which is cited under both HI and LO-drug conditions. On the other hand,

C G I SEVERITY OF ILLNESS 6 , O

2.04

30 -1 0 4

WEEK (Terminat ion)

H I DOSE LO DOSE HAMD TOTAL SCORE .--.-- P B O

- ---

0 4 EEK ( T e r m inot ion I

Fig. 1. Mean score changes across time in three treatment groups.

Sertraline: A New Antidepressant 271

TABLE 3. Most Frequently Cited Treatment-Emergent Symptoms (No. [%I of Patients)


Symptom 1(17) 3 (43) 5 (29)

2 (29) 2 (12) Vomiting -

Diarrhea - 2 (29) 3 (18) 2 (12)

1(17)

3 (43) 5 (29) Constipation 2 (50) Headache 2 (50)

Insomnia - 1(17) 2 (29) 3 (18) 2 (29) 2 (12) Dry mouth - - 2 (29) 2 (12) Loss of appetite - -

1(14) 1 (6) Dose reduction - -

3 (50) 7 (100) 14 (82) - l(14) 1 (6)

Remedial medication 3 (75) Discontinuation -

- Nausea 1(25)

- - -

Agitation/excitment 1 (25) 2 (33) 2 (29) 5 (29)

Action taken

headache is present in both the HI-dose and PBO groups and does not appear to differentiate between drug and PBO. Symptoms such as insomnia, dry mouth, agitation, and loss of appetite, which may also be somatic symptoms of depression, are much more frequent in the HI-dose group and may explain why most of these patients were prematurely terminated for “ineffectiveness” rather than for “adverse reactions. ”

Actions undertaken as a consequence of an adverse event were primarily the use of remedial medications (chloral hydrate, acetominophen, kaopectate). All HI-dose patients required at least one type of remedial medication and one HI-dose patient required a dose reduction as a consequence of nausea and diarrhea. For the most part, contraactive medications enabled patients to tolerate the adverse symptoms, which, in most instances, were transient in duration and mild in intensity. With the exception of the previously mentioned HI-dose patient with abnormal liver findings, no other clinically abnormal laboratory findings were reported. Similarly, no abnormal electrocardiogram (EKG) or other cardiovascular effects-e.g . , ortho- static hypertension-were reported.

CONCLUSIONS

While the primary purposes of dose range studies are to determine therapeutic and safe dose levels, they can often provide clinical information important for subsequent drug development. Clearly, caution must be used in the interpretation of the results of trials at this phase of drug development because of the relatively small sample sizes and because the matching of dose level to patient is a random-rather than a clinical procedure.

In the present study, differential findings were obtained despite the small sample size. Patients receiving the two higher dose levels exhibited almost no symptomatic improvement across the treatment period and, at the same time, were observed to manifest more adverse events than either the LO-dose or PBO groups. There were no statistically significant differ- ences between the LO-dose group and the PBO group in the degree of improvement across time. Under these design constraints, then, the efficacy of sertraline over PBO could not be demonstrated, but differential effects between the LO- and HI-dose levels were indicated. Dosage levels of sertraline up to 100 mg/day would appear to be more clinically appropriate than the higher dosage levels. The next phase of drug development-comparative designs employing a flexible dosage schedule in which dose is clinically titrated to meet the needs of the individual patient-should provide a more adequate and definitive test of the efficacy of sertraline.


ACKNOWLEDGMENTS

Drugs for this study were provided by Pfizer-Groton. The project was supported in part under an agreement with the Tennessee Department of Mental Health and Mental Retardation and, in part, by a grant in aid from Pfizer-Groton. We also wish to acknowledge the assistance of Olaf Fjetland and Glynda Miller in the collection and analyses of data.

REFERENCES

Guy, W.: “ECDEU Assessment Manual for Psychopharmacology .” DHEW Pub. No. (ADM) 76-338, Washington, DC, 1975.

Guy, W., Wilson W.H., Ban, T.A. King, D.L., Manov, G. and Fjetland, 0.: A double-blind clinical tiral of fluvoxamine and imipramine in patients with primary depression. Drug Dev. Res. 4:2, 143-148, 1984.

Investigator’s Reference Manual: Pfizer Inc. Department of Clinical Research, Groton, CT 1982. van Praag, H.M.: Central monoamine metabolism in depressions. 1. Serotonin and related compunds.

Wilson, W.H., Higano, H., Papadatos, J., Kelwala, S. and Ban, TA.: Autonomic effects of fluxovamine Comp. Psychiatry 21:30-43, 1980.

vs amitriptyline, doxepin and placebo. Psychopharmacol. Bull. 19 (1):111-112, 1983.

Double-blind dose determination study of a new antidepressant—sertraline

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