An open assessment of the acceptability, efficacy, and tolerance of venlafaxine in usual care settings

CURRENT THJZRAPEUTIC RESEARCH” VOL. 58, NO. 9, SEPTEMBER

1997

AN OPEN ASSESSMENT OF THE ACCEPTABILITY, EFFICACY, AND TOLERANCE OF VENLAFAXINE IN USUAL CARE SETTINGS ENRIQUE GONZALEZ RUELAS,’ ALEJANDRO DlAZ-MARTINEZ,’ RENE MARTINEZ RUIZ,3AND THE VENLAPAXINE-GLOBAL AWARENESS PROGRAM STUDY COLLABORATIVE GROUP* ‘Asociacion

Psiquiatrica

Mexicana, ‘Federation Mexicana de Sociedades and 3Wyeth, Mexico, Mexico City, Mexico

Pro-Salud

Mental,

ABSTRACT

An open-label study in 618 outpatients with major depression was performed by a collaborative group involving 105 psychiatrists in 22 cities in Mexico. The objectives of this study were to assess the tolerance and efacacy of venlafaxiue, a new antidepressive drug, in outpatients in usual care settings. The two largest psychiatric medical associations approved the proposed protocol, and their chairmen coordinated the study. Patients had to comply with the diagnostic criteria for maor depression as stated in the Diagnostic and Statistical Manual ofMental Disorders, 3rd edition, revised. The Hamilton Depression rating scale (21 items) and the Clinical Global Impressions (CGI) rating scale were used to assess a patient’s clinical response to drug, which was prescribed in different doses (37.6 to 75 mg, 100 to 150 mg, and 176 to 300 mg) according to a patient’s status at enrollment. Patients were followed for 6 weeks. A total of 436 patients (84% ) completed the study. After 7 days of treatment with venlafkxine, there was a statistically significant improvement in patients with mild-to-moderate depression-those in the 37.6- to 75mg group (mean CGI improvement, 3.8% to 38.2%) and iu the lOO- to 160~mggroup (mean CGI improvement, 1.3% to 16.7%)-d by day 14 in patients with severe depression-those in the 176- to 300~mg group (mean CGI improvement at day 14,1.8% to 20.0%). The efficacy of venlafaxine was assessed in all three groups by day 42, with statistically significant improvement observed after treatment with venlafaxine as compared with baseline. The adverse events most frequently associated with the use of venlafaxiue were nausea (36.13%) and headache (17.95%), which did not differ in nature and intensity from that reported by other investigators. A total of 93 patients withdrew from the study; 60 of these dropped out due to an adverse event. Although the study design weakened the conclusions drawn from this study, in this &week, open-label, uncontrolled trial, venlafaxine appeared to be an efficacious, well-tolerated antidepressant in patients with major depression, with improvement gen-

Address correspondence City, Mexico.

to: Rene A. Martinez, MD, Lazam Cardenas 475-504, Tlatelolco

06900, Mexico

Received for publication on May 28, 1997. F’rinted in the U.S.A. * See the Acknowledgments for a complete listing of the study group members. Reproduction in whole or part is not permitted.

609

0011-393x/97/$3.50

VENLAFAXINE

IN USUAL

CARE SETITNGS

era.lly detected in about 1 week. Keg words: venlafaxine, depres-

sion, antidepressants, multicenter.

INTRODUCTION Venlafaxine hydrochloride (l-[2-dimethylaminol-1-[(4-methoxyphenyl)ethyll cyclohexanol-HCl) (hereafter referred to as venlafaxine) is the first compound ever described of a new class of antidepressive substances: the phenylethylamines. These substances are unrelated to tricyclic antidepressants and other selective serotonin reuptake inhibitors. Preclinical data show that venlafaxine blocks the neuronal reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine in the central nervous system. Venlafaxine has no inhibitor activity over monoamine oxidase and shows slight or no affinity for muscarinic, cholinergic, histaminergic, or alpha,-adrenergic receptors. In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action, mainly due to a subsequent norepinephrine reuptake inhibition.lA Following oral administration, venlafaxine is well absorbed and reaches peak plasma levels in 2 hours. Venlafaxine is metabolized through hepatic pathways; renal excretion of venlafaxine and its metabolites is the primary route of elimination. 3 The main urinary metabolite of venlafaxine is 0-desmethylvenlafaxine (ODV), also an active compound that possesses the same reuptake inhibition properties as venlafaxine. When steady state is reached, the half-life of elimination of venlafaxine and ODV is 3 to 5 and 9 to 11 hours, respectively.5 The main (&SD) steady-state plasma clearance of venlafaxine and ODV is 1.3 f 1.6 and 0.4 f 0.2 L/h per kg, respectively, and the steady-state volume of distribution is 7.5 f 3.7 I.&g and 5.7 * 1.8 L/kg, respectively.3 In double-masked, randomized studies of venlafaxine versus imipramine, trazodone, and placebo in depressed outpatients, venlafaxine proved to be more effective than placebo in treating symptoms of depression and similar to or even better than comparative drugs.‘,2,6-8 The most common adverse events (AEls) associated with the use of venlafaxine in placebo-controlled clinical trials are: nausea (37%), headache (25%), somnolence (23%), dry mouth (22%), dizziness (19%), insomnia (18%), constipation (15%), nervousness (13%), abnormal ejaculation/ orgasm (l.l%), asthenia and sweating (12% each), and anorexia (11%L5 Seizures have been reported in some venlafaxine-treated patients. Most seizures occurred in patients receiving over 150 mg/d of venlafaxine. Hence, venlafaxine should be used cautiously in patients with a history of seizures. The objectives of this study were to assess the clinical acceptability of venlafaxine in usual care settings and to obtain data on physicians’ and patients’ assessments of improvement in symptoms of depression and of clinical tolerability to the drug. 610

E. G. RUELAS ET AL.

PATIENTS AND METHODS

Investigators

and Patients

This was an open-label, noncomparative, multicenter study. A total of 105 investigators participated in this project. Participating physicians were identified in 22 cities in Mexico (Table I). Each investigator had to enroll and manage 5 patients from the following categories as stated in the study’s protocol: @Mild-to-Moderate Depression: those patients with a score of less than 30 points on the Hamilton Depression (HAM-D) rating scaleg; 3 patients belonging to this category were to be enrolled by each investigator; and @Severe Depression: those patients with a HAM-D score of 30 points or more; investigators were to enroll 2 patients from this category (Figure 1). The entire study lasted 6 weeks. There was no follow-up evaluation. To be eligible for the study, patients had to be 18 years of age or older, outpatients, and need not be hospitalized at any time during the study, meet the criteria for a major depressive episode as stated in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised, have a nega-

Table I. Number of investigators and patients by city. Total No. 01 Patients tncluded City No.

City Name Acapulco Cd. Jukez Culiac&n Chihuahua Guadalajara ~~~~oslllo MBrida Mexicali Monterrey Aguascalientes MBxico, D.F. Morelia Puebla Quer&aro San Luis Potosi Tampico Tii&;; Torre6n Veracruz Villahermosa

n

fi)

2 10 7:

Total No. of Investigators n

0.8 1.0

1 1

1.; ‘1:;;

17

1

(“/.I

;

3.9 4.2 13.3 ‘1(El

1; 10 Ii 518

611

105

(iooj

VENLAFAXINE

O-

10

14

18

22

26

IN USUAL

CARE SETMNGS

34

30

38

42

48

50

54

58 -

HAM-D Score Figure 1. Frequency of distribution of Hamilton Depression (HAM-D) scores at baseline (n = 516).

tive urine pregnancy test at enrollment if a woman of childbearing potential, and provide written informed consent. Patients with the following were excluded from the study: a history of hypersensitivity to venlafaxine, clinically significant renal or hepatic disease, any other systemic disease that could affect the study’s progression, seizure disorders, a history of alcohol or drug abuse 2 years before study enrollment, a recent history of myocardial infarction or any unstable heart condition, known or suspected pregnancy, or suicidal ideation (in the opinion of the investigator). Patients were also excluded if they were breast feeding or had used other antidepressants before study enrollment. Table II. Premature discontinuation from the study. Venlafaxine No.ofPatients Pati;i;;e

n) 6 Completed Withdrawn Reasons for withdrawal Adverse event Other medical event Lost to follow-up Unsatisfactory response Protocol violation Death Other nonmedical event Requested by patient

518 435 83

612

w

E. G. RUNAS

ET AL.

A total of 535 patients were planned, but 518 enrolled. Of them, 435 (84%) completed the study, and 83 (16%) dropped out. Fifty patients (9.7%) withdrew prematurely from the study due to the occurrence of an AE (Table II). Dose of Venlclfcrxine

Venlafaxine 37.5-, 50-, and 75-mg tablets were available for the purposes of this study. Patients were treated according to their depression category as follows: (1) those who received 37.5 to 75 mg tie, mild depression: mean HAM-D score at enrollment, 26.5); (2) those who received 100 to 150 mg (ie, moderate depression: mean HAM-D score at enrollment, 30.6); and (3) those who received 175 to 300 mg tie, severe depression: mean HAM-D score at enrollment, 35.9). Once the desired clinical response had been reached, the dose was progressively decreased to a level compatible with maintenance of efficacy, that is, 37.5 mg twice daily, or kept the same, at the investigator’s discretion. Patients who received 150 mg/d or more at the end of the study period (6 weeks on treatment) had their dosage progressively tapered off over a l-week period. No other antidepressant drugs were allowed during the study. Depression

Rating Scales

The standard observer rating instrument for clinical depression,” the 21-item HAM-D,ll was used. A reliability coefficient of at least .80 is generally reported for this scale10,12;for assessments based on joint interviews (ie, a second physician evaluation), r = .88; for those based on separate interviews tie, patients evaluated separately by investigators), r = .86.13 Such data seem to indicate that good inter-rater agreement can be achieved with this scale, especially with well-trained observers. Another scale, the Clinical Global Impressions (CGI) scale,14 a recognized rating scale for global clinical judgment, was also used. The interrater reliability for this scale has been reported as 0.66 (for the severity of disease) and 0.51 (for the change of condition).15 The retest reliability for disease severity was found to be 0.65.15 Thus, the CGI scale, although useful, has a lower inter-rater reliability than the HAM-D scale, Investigators evaluated patients separately; there were no joint interviews planned in this study. Statistical Analysis

The statistical analysis was based on the pooled data from the individual study sites. The group of patients is described based on demo613

VENLAFAXINE

IN USUAL

CARE SETPINGS

graphic data, important medical history, and a physical examination pretreatment (mean * SD and range used for continuous variables). The reduction in HAM-D scores with respect to baseline and the severity of illness (CGI) scores with respect to baseline were both analyzed using Wilcoxon’s nonparametric statistical test for paired data. The same test was used for analysis of the HAM-D and CGI scores when the patients were placed into three dose groups (37.5 to 75 mg, 100 to 150 mg, or 175 to 300 mg> based on the final dose of study medication. The AEk were listed, including information on intensity, relationship to study medication, and onset of occurrence. Vital signs were assessed and graphed throughout the study and analyzed using Wilcoxon’s nonparametric test for paired data. A quantitative analysis of data on patients switched from another antidepressant to venlafaxine was also presented using descriptive statistics. Vital Signs Assessment

Investigators were requested to obtain vital signs (heart rate, respiratory rate, blood pressure) at each visit, according to their usual practices. No standardized methods to obtain vital signs were used in this study. Adverse Events Assessment

ADS were considered to be any negative clinical experience related to the use of venlafaxine that a patient would report to an investigator at any time during the study. Investigators reported each complaint on a special form (included in the case report forms) to be filled in during each patient visit to an outclinic. Whenever an investigator believed that a complaint reported by a patient could be an AE, this form was to be completed. These forms categorized AEk as mild, moderate, or severe, according to the investigator’s assessment. There were no formal definitions regarding the intensity of an AE given in this study’s protocol. Thus investigators classified the intensity of an AEJbased on their personal clinical experience. No observers other than investigators assessed AEs, and all reports of AEs were evaluated equally and considered for statistical analysis. Ethical Considerations

To comply with all ethical and legal regulations, the approved protocol was submitted to the Asociacion Psiaquiatrica Mexicana, Mexico City, Mexico, and the Federacidn Mexicana de Sociedades Pro-Salud Mental, 614

E. G. RUELAS

ET AL.

A.C., Mexico City, two large national psychiatric associations to which all participating physicians had memberships. Study coordinators were chosen from each of the involved parties-chairpersons from both associations, and the clinical trials manager from Wyeth, Mexico, Mexico City, Mexico. After clearance was obtained from the human ethics committees of both psychiatric associations, approval of the Ministry of Health was sought before starting the study. For all patients, particularly those markedly or severely ill, informed written consent was obtained in the presence of witnesses (generally, close relatives who took care of them) who were also required to sign the consent form. Study procedures were conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and the Mexican General Law of Health. RESULTS

Patients were scheduled to be evaluated during five visits with investigators via private consultation. At enrollment, a complete physical examination was done, and the 21-item HAM-D and CGI rating scales were administered. The HAM-D and CGI scales were also completed during each of the four other planned visits to obtain the patient’s and physician’s evaluations of drug efficacy and tolerability. Vital signs, including body weight, were recorded as safety variables. All patients were instructed to contact their attending physicians in the event that any problem regarding drug administration was observed. Demographic

and Background

Characteristics

A total of 518 patients were enrolled in this study by 105 investigators in 22 cities; the number of investigators included in each city is given in Table I. Demographic data were obtained for all patients (Table III). There were more women (67%) than men (32%). Their ages ranged from 18 to 92 years (mean, 41.9 years). On average, they were 164 cm tall and weighed 67 kg. The patients included in the efficacy analysis were those 435 patients who completed the study. All analyses were based on the nonmissing data values of the variables included in the corresponding analysis for these 435 patients. No data value was carried forward (even if a patient dropped out of the study), and no values were interpolated. The results of each analysis show exactly how many patients were involved.

VENLAFAXINE

IN USUAL

CARE SElTINGS

Table III. Patient baseline characteristics and Hamilton Depression (HAM-D) and Clinical Global Impressions (CGI) scores at baseline. Veniafaxine Variable

No. of Patients

Patients (n)

518

AgzlL f SD Range (min-max)

41.9il3.7 16-92 156

Sek$j *

%I&

487

Boi;;i$&(kg)

67*14 37-l 39 491

Range (min-max) HAL-D Mean f SD Range (min-max) if;resst

(100.0)

167 349

Female Height (cm Mean f 8 D Range (min-max)

Sekia;

W)

29.1 f 7.8

6-56 516

(CGI)

4.:-?o.go

Range (min-max) n

511

l n = 516 because information was not reported for two patients. t Scale for severity of illness (CGI : 0 = not assessed; 1 = normal, not at ail ill; 2 = borderline mental1 iii; 3 = mildly iii; 4 = moderately ill; A = markedly ill; 6 = severely iii; and 7 = among the most extremeyY. III patients.

Severity of Illness, Hamilton Depression Rating Scale, and Medical History at Baseline The mean severity of illness at baseline was 4.7 (range from 2 to 7) using the following scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill patients (Table III). Fifty-one percent of the patients had a medical history related to the digestive system, and 47% had a history of surgery. Medical histories related to other systems were reported by about 15% of the patients. According to the physical examinations conducted at baseline, the most fiequently detected abnormalities were in the abdomen (7%), head (6%), and skin (5%). Study Completion Status Four hundred thirty-five patients (84%) completed the treatment 616

E. G. RUEL4S

ET AL.

(Table II). Among those who discontinued, the most frequently reported reason was AEls (50 patients, 9.7%). Other reasons for withdrawal included: lost to follow-up (19 patients, 3.7%), unsatisfactory response (8 patients, 1.5%), patient request (3 patients, 0.6%), and protocol violation (1 patient, 0.2%). The group of 435 patients that completed the study was divided into three subgroups according to the final doses of venlafaxine reported by patients at day 42 of treatment. The number of patients for each subgroup is given in Table IV. Clinical Response

Both patients and investigators were requested to return report cards (given to them in advance) in which information regarding clinical improvement of symptoms of depression was requested. These cards were returned by 42 patients (149 responses) and 69 investigators (229 responses). The clinical response rate according to the patients’ report card was “I feel better” in 43.0% of patients, “I feel much better” in 43.6% of patients, and “I feel much much better” in 13.4% of patients; a similar result was reported by the investigators. The mean time to start to feel better was 10 days according to both patient and investigator report cards (Table V). Hamilton

Depression

Rating Scale

The trend in mean HAM-D over time is shown in Table VI. There was a marked decrease from baseline (mean, 29.4; range, 8 to 56) to day 42 (mean, 6.9; range, 0 to 38). This decrease was greatest during the first 2 weeks. The mean reduction in HAM-D scores at day 7 of treatment (9.4 units) was highly statistically significant P < 0.0001) according to Wilcoxon’s nonparametric statistical test for paired data. The corresponding reductions were 15.1 units at day 14, 19.3 units at day 28, and 22.5 units at day 42. All reductions were highly statistically significant (P < 0.0001). This mean reduction should be understood as the efficacy of the drug with

Table IV. Number of patients per subgroup according to the final doses of venlafaxine. Doses al Day 42 of Treatment (mg)

No. of Patients (%)

37.5-75

100-l50 175-300

Total

435(100)

617

VENLAFAXINE IN USUAL CARE SETTINGS

Table V. Patient and investigator report cards for each dose. Dose Variable

I feel Better Much better Much much better n Time to start to feel better Mean (d) SD Range n Patiefeeels Much better Much much better Tin!e to start to feel better Mean (d) SD Range n

37.5-15 mg

100-150 mg

175-300 mg

Patient Report Card

69

26

a.8

6.4 l-31 53 Investigator Report Card

10.2 7.5 l-32 36

55 50.9% 5.6%) ’ 476 I43.5% 108 E 2-30 39

13.9 10.7 2-42 14

34 10.8 7.4 2-28 31

13.1 9.6 2-35 12

regard to patients’ symptoms of depression in terms of well-being over time. The trend in HAM-D scores over time for each dose is presented in Figure 2. For the 37.5 to 75mg doses, the average value of HAM-D was 26.5 at baseline, and at day 42 this value was reduced to 4.9. For the lOOto 150-mg doses, the average value of HAM-D was reduced from 30.6 to 7.8 at day 42 of treatment. In addition, for the 175- to 300-mg doses, the average value of HAM-D was reduced from 35.9 to 11.0 at day 42 of treatment (Table VI). Trends were very similar for all three dose groups (Figure 2). As expected in this type of titration trial, the patients who finished the trial in the highest dose group (175 to 300 mg) typically were those who were more severely ill at baseline (mean HAM-D, 35.9). In the same fashion, the patients who finished in the lowest dose group were typically those who were the least ill at baseline (mean HAM-D, 26.5). For the three dose groups, the mean reduction in HAM-D scores at day 7 of treatment was statistically significant (P c 0.0001) according to Wilcoxon’s nonparametric statistical test for paired data (Table VII). Severity of Illness (Clinical Global Impressions)

A total of 391 (97.4%) patients were moderately ill or worse on admission, and at day 42 of treatment, only 41 (10.5%) patients re618

E. G. RUEIAS

Table VI. Trend in mean Hamilton

Day of Treatment Baseline Mean &SD Range Da" ;a;f;r$ment x1 Dai,,;;rtrnent Range Da" LZ?nof;~tment Ll Range

Dai;G&of ytment Range n

Depression

ET AL.

(HAM-D) scores over time for each dose.

Dose

HAM-D (All groups)

37.5-75 mg

29.4 i 7.9 8-56 431

26.5i6.5 8-56 205

3oi-+5i.’ 35iEli.7

20.0f 9.0 O-51 431

16.7i8.2* O-51 205

21.4i8.3' 4-44 165

27.3* 8.7* 7-51 61

14.3i8.4 O-42 431

11.1f 7.4' O-35 205

15.6i7.4* O-39 165

22 *8.5* 2-42 61

10.1f.7.2 O-41 431

7E~o* 205

10.8i6.6* O-41 165

17.1f 7.6* 3-34 61

6.9* 6.0 O-38 431

4.9i4.7' O-25 205

7.8* 6* O-38 165

11.0*7.5* O-34 61

10&150

mg

175-300 mg

165

61

* PC 0.0001versusbaseline.

mained moderately ill or worse (Table VIII; Figure 3). The severity of illness was significantly reduced (P c 0.0001) from day 7 of treatment and onward. For the 37.5 to 75mg group, 96.2% of patients were moderately ill or

1.6

175-300 mg

\

100-150

/

0

mg

'7.1

’ 0

Figure 2. Hamilton

7

14 Depression

(HAM-D)

21

28

Day of Treatment

35

scores for each dose versus time. 619

42

49

VENLAFAXINElNUSUALCARESETTINGS

Table VII. Mean reduction in Hamilton Depression (HAM-D) scores between visits for each dose.

Variable HAM-D Mean*SD Ranoe n ”

P

HAM-D MeankSD Range n

P

MeanReduction

Baseline (Day0)

Day7

Day28

Day42

19.0* 7.2 -1-38 205 0.0001

21.6in6.6 O-44 205 0.0001

19.8+ 9.3

22ci~.g

Day14

Dose:37.5-75mg 9.8i7.5 -10-33 205 0.0001

26c5E.5 205

’“E3~~’ 205 0.0001

Dose: DO-150 mg

’%Y

"Z." 165

""E5Y 165

-7-42 165 0.0001

165 0.0001

0.0001

165 0.0001

Dose: 75-300 mg

HAM-D

Meant SD Range n

35iEt69'7 61

P

8.5k7.6

18.7klO.0 -5-39 61 0.0001

'"",;"," 61 0.0001

s:-28 0.0001

‘“%:” 61 0.0001

worse on admission, and this value was reduced to 4.8% at day 42. For the lOO- to 150-mg group, 98.2% of patients were moderately ill or worse at baseline, and this value was reduced to 10.7% at day 42. For the 175 to 300-mg group, 98.7% of patients were moderately ill or worse at baseline, and this value was reduced to 29.1% at day 42 (Table Ix, Figure 4). For the two 37.5 to 75mg and lOO- to 150-mg groups, the severity of illness was significantly reduced (P c 0.0001) from day 7 of treatment. However, for Table VIII. Severity of illness (Clinical Global Impressions): Baseline versus 42 days of treatment (n = 391). Dayof Treatment 0

Varlabla

3 4 5 6 7 P

= = = = =

Mildly ill Moderately ill Markedly III Severelv ill Among-the most extremely ill patients

n

a

7

(%)

n

(2.0)

2

14

(%)

(0.5) 0.0001

n

0

(%)

(0.0) 0.0001

42

28

n

0

(%)

(0.0) 0.0001

n

0

W)

(0.0) 0.0001

E. 0 RUELAS ET AL.

9,

100.0%

E

30 90.0% 5j 80.0% fY 70.0% a 3 80.0% ?1 8 50.0% 3 40.0% s 5 30.0% 'S B 20.0% b .@

10.0%

0

7

14

21

28

Day of Treatment

35

42

49

Figure 3. Severity of illness (Clinical Global Impressions) versus time.

the 175 to 300-mg group, the reduction in severity of illness was not statistically significant until after day 14 of treatment. Figure 4 shows that the rate of reduction of severity of illness is much greater in the first 14 days for the 37.5- to 75-mg group than for the other two dose groups. Global Improvement (Clinical Global Impressions) Of the 435 patients who completed the trial, 407 had complete CGI data. At day 7 of treatment, 39.8% of patients reported “very much improved” or “much improved” and this percentage increased to 94.1% (383 of 407 patients) at day 42 of treatment (Tables VIII through XI; Figures 3 through 6). Of these 383 patients, 280 (73.1%) reported “very much improved,” whereas 103 (26.9%) reported “much improved.” Fourteen (3.4%) of the 407 patients reported “m~im~ly improved,” and 6 (1.5%) reported “no change.” Only 4 (1.0%) patients reported “minimally worse.” Of the 407 patients who completed the trial and had complete CGI data, none reported “much worse” or “very much worse.” The global improvement value for each dose at each visit is reported in Table XI. In Figure 6, one can see that the global improvement for the 37.S to 75mg group is much greater than for the other two dose groups. Patient and Investigator Report Cards For the group of patients receiving doses of 37.5 to 75 mg, the general condition (according to the patients’ report cards) was “I feel better” in 621

VENL4FAXlNE

IN USUAL CARE SETTINGS

Table IX. Severity of illness (Clinical Global Impressions)

for each dose versus time (n = 55).

Day ofTreatment 0 n

Variable Severity of illness Mildly ill or belter Moderately ill or worse

n

(%)

;;i

(8@

P

Severity of illness Mildly ill or belter Moderately ill or worse n

1;;

2

(1.3 (98.2

P

Severity of illness Mildly ill or ,better pderately III or worse

d

14

7

n

;i

(%)

n

Dose: 37.5-75

mg

42

20 (%)

186 0.0001 0.0001 Dose: lOC-150 mg

25 125 150 0.0001 0.0001 Dose: 175-300 mg

n

(%)

n

186 0.0001

188 0.0001

0.0001

0.0001

W)

(fS

44.9%, “much better” in 42.0%, and “much much better” in 13.0%. The percentage distribution of the general condition of patients in the other dose groups and for the investigators’ report cards was very similar to the preceding results (Table V). The mean time to start to feel better (according to the patients’ report cards) was 8.8 days for the 37.6 to 75mg group, 10.2 days for the lOO- to

175-300

mg

29.1%

3

*

0

37.5-75

mg

10.7%

10.0%

0.0%

,4.8%

’ 0

7

14

21

28

35

42

Day of Treatment Figure 4. Severity of illness (Clinical Global Impressions) 622

for each dose versus time.

49

E. G. RIJELAS

ET AL.

Table X. Global imurovement (Clinical Global Impressions) versus time (II = 407). Dayof Treatment 7 n

Variable

(%)

n

42

28

14

(%)

(%)

n

n

(%)

Global Improvement 1 = Very much improved 2 = Much improved 3 = Minimally improved 4 = No change 5 = Minimally worse 6 = Much worse 7 = Very much worse Global Improvement: Summary Very much improved or much improved Minimally improved or worse

150-mg group, and 13.9 days for the 175 to 300-mg group. Results according to the investigators’ report cards were very similar. These findings most likely reflect that those patients who ended treatment in the highest dose group (175 to 300 mg) were the ones most severely ill or the ones who did not respond to the lower doses administered when admitted to the study and, hence, took longer (13.9 days) to feel better. Patients with Resistant

Depression and Relapse Rates

For patients with resistant depression, that is, patients who switched Table XI. Global improvement (Clinical Global Impressions) for each dose versus time. Day of Treatment 14

7 Variable Global Improvement Very much improved or much improved Mirumally improved or worse n Global Improvement Very much improved or much improved Minimally improved or worse n Global Improvement Very much improved or much improved Minimally improved or worse n

623

26

42

VENLAFAXlNEINUSUALCARESElTlNGS

Table XII. Antidepressant

treatment

used previously

Medication (Generic Name)

by patients with resistant depression.

No. of Patients

1 lmipramine 2 Fluoxetine 3 Amitriptyline 4 Paroxetine 5 6 Chlorimipramine Butriptyhne 7 Maprotiline 8 Desi ramine 9 Mot Pobemide 10 Nortriptyiine 11 Lithium Carbonate 12 Ademetionine 13 Sertraline Total

another antidepressant medication to the study drug, an additional page in the case report form was completed. Sixty-four patients completed this form, and the information on previous antidepressant therapy used is presented in Table XII. There were no clinical observations made after day 42 of treatment; therefore, a relapse rate is not available.

from

TOLERABILITY

All 518 patients treated were evaluated for tolerability. All analyses were

E ; =

b c 2 H

80.0% 70.0% 60.0%

6 >

50.0%

.g 9

40.0%

Venlafaxine

lu 2 30.0% 0

21

28

35

Day of Treatment Figure 5. Global improvement

(Clinical Global Impressions) 624

versus time.

42

49

E. G. RUELAS ET AL.

based on the nonmissing data values of the variables included in the corresponding analysis. No data value was carried forward (even if a patient dropped out of the study), and no values were interpolated. The results of each analysis show exactly how many patients were involved. Adverse

Experiences

In Table XIII, a summary of patients with AEA is given. Table XIV contains data on patients who dropped out of the study due to an AE. There were 50 premature discontinuations due to AEs. Investigators were required to follow-up all patients who dropped out due to an AEl. No suicidal attempts were reported afterward, and investigators were free to start psychotherapy, another antidepressant, or both, in accordance with their usual practices. Table XV displays the frequency of distribution of the number of patients with at least one AE and the number of patients with at least one AE with at least a possible relationship to the trial medication. There were 318 patients (61.4%) with at least one AE with at least a possible relationship to the trial medication. The AEs associated with treatment with an incidence greater than 5% among the 518 patients included the following: nausea reported by 35.13% of patients, headache by 17.95%, dizziness by 12.35%, insomnia by 15.44%, dryness of the mouth by 7.72%, somnolence by 7.9%, constipation by 6.94%, anxiety by 7.5%, vomiting by 6.2%, and shaking by 5.0%. A& were most frequently noted during the first week of drug administration in those patients who experienced 100.0% -S! g 90.0% h ,E

80.0%

5 = H

70.0%

2

60.0%

2 I

50.0%

5 >" 40.0% 2 .G 30.0% iii !g 20.0% 0

7

Figure 6. Global improvement

14

21

Dayof

Tre$nent

(Clinical Global Impressions) 625

35

42

for each dose versus time.

49

VEMAFAXINE

IN USUAL CARE SElTINGS

Table XIII. Summary of the most frequently reported adverse events.* Adverse Event

Nemerofft (“W

Frequency

Nausea Headache Somnolence Dry mouth insomnia Dizziness Anxiety Constipation Abnormal ejaculation Asthenia * n = 518 patients. T Nemeroff CB. Evolutionary trends in the pharmacotherapeutic management of depression. J C/in try.1994;55(Suppl 12):3-15.

Psychia-

them. Moreover, there was a clear trend toward decrement in the intensity of the AEk as the study progressed. Serious Adverse Experiences and Premature Discontinuations Adverse Experiences

Due to

No deaths were reported during the trial. There were no serious AEIs Table XIV. Most frequently reported adverse events associated with patients who dropped out of the study (n = 50). Adverse Event

Frequency

Nausea Headache Insomnia Shaking Anxiety Vomiting Dizziness Uneasiness Suicidal thought Agitation Angioneurotic edema Anorexia Cramps Dermatosis l!!$astric pain Gastritis Hypertension Irritability Loss of appetite Mental clumsiness Psychic anxiety Somatic anxiety Tinnitus Unmotivated fear

626

E. G. RUELAS

ET AL.

reported during this study. The principal reason for discontinuation from the study for 50 patients was the occurrence of mild-to-moderate AEs. Investigators evaluated and reported such AEs according to their clinical criteria. Safety Monitoring of Vital Signs

Blood pressure, heart rate, and respiratory rate were documented at each visit during treatment. There were no standardized methods for assessment of vital signs in this study. There were no clinically nor statistically significant detectable differences in vital signs. DISCUSSION

Venlafaxine proved to be a very efficacious antidepressant drug in this large clinical trial with outpatients. As previously reported, a rapid onset of action was evident during the first 14 days of active treatment in all patient subgroups, starting from day 7; above all, patients with mild-to-moderate depression (ie, those starting with 37.5 to 75 mg/d of venlafaxine) experienced a remarkable improvement in their symptoms of depression by day 14. As with other groups, they showed a continuous trend toward clinical improvement, which could also be documented by means of the HAM-D and CGI scales. There was a marked decrease in the mean HAM-D scores over time (29.4 at baseline vs 6.9 after 42 days of treatment). The mean reduction was statistically significant at all intermediate points in time. At the end of treatment, only 10.5% of all patients enrolled remained either moderately ill or worse, as compared with 97.4% at admission. For the two lower-dose groups, the severity of illness was significantly reduced starting at day 7 of treatment according to the HAM-D and CGI rating scales. For the higher-dose group, the reduction was significant at day 7 Table XV. Frequency of distribution of patients with at least one adverse event (AEI)*associated with treatment. Venlafaxine

Count per patient No. of patients treated No. of patients with at least one AE No. of patients with at least one AE associated with study medication

n

(%I

518 356

cl,:sl:Y

318

(61.4)

* Note: An AE is defined as being associated with treatment when, by investigator judgment, it is considered to be possibly, probably, or definitely related to treatment. 627

VENLAFAXINE

IN USUAL

CAR?3 SElWNGS

according to the HAM-D scale (reduction of 8.5 points) but not according to the CGI scale until day 14. Based on CGI data, the percentage of patients who reported “very much or much improved” increased from 39.8% to 94.1% between days 7 and 42 of treatment. Global improvement was greater for the lower-dose group (97.4% vs about 90.2% for the higher-dose group). In this open-label, noncomparative trial, investigators reported every complaint made by patients and rated the intensity of the event based on their clinical criteria. As such, these data are presented here without further assessment from other observers. There were 50 premature discontinuations due to AEs. There were no fatal or serious AEs reported. Relapse among patients treated with antidepressants is a well-known phenomenon-there are reports of relapse rates of 22% for patients on active drugs versus 50% for those on placebo.16 The criteria to define relapse vary among the authors,17-1g but it seems clear that the longer a patient stays within a certain treatment, the better. Measurement of the rate of relapse was not among this study’s objectives. CONCLUSION

Although the study design weakened the conclusions that can be drawn from the study, in this g-week, open-label, uncontrolled trial, venlafaxine appeared to be an efficacious, well-tolerated antidepressant with improvement generally detected within 1 week. Acknowledgments

The Venlafaxine-Global Awareness Program Study Collaborative Group included the following investigators: J. N. Acosta, J. Aguayo, R. Aguilar, G. Aguilera, J. L. Alamilla, G. Amara, J. M. Araquistain, J. Arriaga, A. Barrera, V. Berlanga, J. Bermeo, F. Buendia, R. Caballero, A. Calatayud, C. A. Camacho, J. M. Cano, G. Cantu, C. Cardenas, R. Castro, L. Cavazos, A. Celis, L. F. Cerdan, C. Cerecedo, J. R. Comas, R. Cordiba, A. Costilla, F. De La Garza, J. Escotto, J. Espinoza, M. Fierro, M. C. Flores, L. Garay, H. Garcia, J. J. Garza, B. Gaxiola, A. Geiger, R. Gomez, E. Gonzalez, H. J. Gonzalez, J. G. Gonzalez, J. M. Hernandez, R. Hijar, A. Hinojosa, M. Huerta, A. Ibarra, 0. Kawas, E. Landa, J. J. Langarica, R. Ledezma, J. Lopez, M. R. Lopez, A. Magaiia, L. M. Martinez, F. Matsumoto, J. Mendez, R. Miranda, M. Molina, A. Nieto, M. A. Olaiz, M. A. Olivares, J. Olvera, H. A. Ortega, M. Ortiz, A. Palma, F. Perez, H. H. Perez, J. Perez, L. E. Perez, M. Perez, S. Perez, M. Ponzio, G. Pruneda, M. R. Quezada, E. Reyes, A. Rish, H. S. Rivas, H. Rocha, J. E. Rodriguez, A. Romero, J. C. Rueda, I. Ruiz, S. Sanchez, J. Saucedo, R. Secin, R. Sepulveda, A. Silva, M. P. So-

E. G. RUELAS ET AL.

mohano, A. A. Suarez, S. Suarez, G. Tapia, G. C. Teran, A. Torre, M. A. Trava, F. Trejo, L. F. Urias, J. Urquiaga, E. Valle, A. Vazquez, C. Vazquez, J. L. Vazquez, J. C. Villa, H. Villalobos, J. F. Ville, M. Zapata, R. Zapata. This study was sponsored by Wyeth-Ayerst International, Philadelphia, Pennsylvania, and Wyeth, Mexico, Mexico City. We are grateful to CT Consultoria Farmaceutica, Mexico City, for their involvement in the monitoring procedures and to Estadisticos Asociados, S.C., Mexico City, and Mrs. Imelda Batos for their technical assistance. References: 1. Scweizer E, Weise C, Clary C, et al. Placebo-controlled trial for the treatment of major depression. J Clin Psychophurmacol. 1991;11:233-236. 2. Scweizer E, Feighner J, Mandos L, et al. Comparison of venlafazine and imipramine in the acute treatment of major depression in outpatients. J Clin Psychiatry. 1994;55:104108. 3. Klamerus KI, Maloney R, Rudolph RL, et al. Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active o-desmethyl metabolite. J Clin Pharmacol. 1992;32:716-724. 4. Troy SM, Parker VD, Fruncillo RJ, Chiang ST. The pharmacokinetics of venlafaxine when given in a twice-daily regimen. J Clin Pharmacol. 1995;35:404409. 5. Nemeroff CB. Evolutionary trends in the pharmacotherapeutic management of depression. J CZin Psychiatry. 1994;55(Suppl 121:3-15. 6. Montgomery SA. Venlafaxine: A new dimension in antidepressant pharmacotherapy [Academic Highlights]. J Clin Psychiatry. 1993;54:119-127. 7. Khan A, Fabre LF, Rudolph RL, et al. Venlafaxine in depressed outpatients. Psychophurmacol Bull. 1991;27:141-144. 8. Shrivastava RR, Cohn C, Crowder J, et al. Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression. J CZin Psychopharmacol. 1994;14:322-329. 9. Carroll BJ, Fielding JM, Blashki TG. Depression rating scales. A critical review. Arch Gen Psychiatry. 1973;28:361-366. 10. Hedlund JL, Viewing BW. The Hamilton rating scale for depression: A comprehensive overview. J Oper Psychiatry. 1979;10:149-165. 11. Hamilton M. A rating scale for depression. J Neural Neurosurg Psychiatry. 62.

1960;23:53-

12. Fuglum EF, Rosenberg C, Dam&o N, et al. Danish University Antidepressive Group. Screening and treating depressed patients. A comparison of two controlled citalopram trials across treatment settings: Hospitalized patients vs. patients treated by their family doctors. Acta Psychiatr &and. 1996;94:18-25. 13. Beth P, Gram LF, Dein E, et al. Quantitative rating of depressive states: Correlation between clinical assessment, Beck’s self-rating scale and Hamilton’s scale. Acta Psychiatr &and. 1975;51:161-170.

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IN USUAL CARE SETllNGS

14. Guy W. ECDEU Assessment manual for psychopharmacology, revised. DHEW Pub. No. (ADM) 76-338, Rockville, MD; National Institutes of Mental Health, 1976. 15. Dahlke F, Lohaus A, Gutzmann H. Reliability and clinical concepts underlying global judgements in dementia: Implications for clinical research. Psychopharmacol Bull. 1992; 2k425-432. 16. Montgomery SA, Roberts A, Pate AG. Placebo controlled efficacy of antidepressants in continuation treatment. Znt Clin Psychopharmacol. 1994;9(Suppl 1):49-53. 17. Kupfer DJ, Frank E. Relapse in recurrent unipolar depression. Am J Psychiatry. 144:86-B&

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18. Georgotas A, McCue R. Relapse of depressed patients after effective continuation therapy. J Affect Disord. 1989;17:159-164. 19. Belsher G, Costello C. Relapse at&r recovery from unipolar depression: A critical review. Psycho1 Bull. 1988;104:84-96.

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