Am

TOFISOPAM

Comparative BY

HAROLD

Efficacy L. GOLDBERG,

of Tofisopam M.D.,

AND

and

RICHARD

is a new

TOFISOPAM

agent

developed

by

activity

profile that sets it apart currently in use in the

Tofisopam

has

been

from United

investigated

tran-

in approximately

1,200 patients in 29 trials in Europe. The European investigators found that tofisopam has the therapeutic characteristics of a minor tranquilizer and also has a mild stimulatory effect. It produced no substantial

muscle tigue,

relaxation, or drowsiness.

France

and

ataxia, loss of concentration, It is currently on the market

fain

Hungary.

Szobor’s open study of 20 patients (1) found that best results were obtained in vegetative neuroses, depression, and anxiety. According to a 1971 report by Danel in the files of Diamant Laboratories in France, in an open study of 47 patients with anxiety and depression a rapid marked anxiolytic effect was found in 23 patients given a daily dose of 200-300 mg/day of

tofisopam. psychosomatic

These

patients complaints.

also

showed

Danel

an open study by Fouks tofisopam tients for 6 months. The patients

ReceivedJuly

11, I977;revisedOct.

also

a reduction reported

that

in in

was given to 61 pawho had hyper-

31, l977;acceptedian.

6, 1978.

Dr. Goldberg is Director and Dr. Finnerty is Co-Director, WestRos-Park Mental Health Center, Boston, Mass. Dr. Goldberg is also Clinical Professor of Psychiatry, Tufts University Medical School, Boston, Mass. Address reprint requests to Dr. Goldberg at 26 Central Ave., Hyde Park, Mass. 02136.

196

0002-953X/79/02/0l96/04/$00.45

/979

and

anxiety

particularly

with

psychosomatic

well

disturbances

to the drug.

Danel

also

re-

ported that Herbeuval found that 29 of4l patients with psychoneurotic disturbances such as anxiety and diifuse neurovegetative symptoms responded favorably in an open study to 100 mg/day of tofisopam in 3-4 days. Patients with anxiety accompanied by neurovegetative symptoms responded best. Finally, Juhasz and Tringer (2) evaluated 32 patients with various forms of chronic neuroses and neurotic personality disorders given 150 mg/day of tofisopam. Clinical observation using the Symptom Distress Checklist (HSCL) (3) revealed that patients with somatic symptoms responded best to the drug. Normalization of diminished sexual drive occurred in 5 of these 32 patients.

a European

the minor States.

February

PH.D.

responded

pharmaceutical firm. It bears a structural resemblance to diazepam (Valium) and oxazepam (Serax). Although clinically a benzodiazepine, tofisopam differs from the diazepam-like minor tranquilizers in the position ofthe nitrogen atoms (see figure 1). This structural difference manifests itself in a pharmacological and clinical quilizers

/36:2,

Placebo

J. FINNERTY,

Tofisopam is a new agent marketed in Europe as a minor tranquilizer. The authors conducted a 4-week double-blind trial ofthis drug compared with placebo in 57 outpatients with anxiety and depression. They found that according to physician ratings and patient self-ratings tofisopam was an effective anxiolytic agentfor subjects with anxiety and depression. Twenty-one percent of the patients receiving tofisopam and 10% ofthose receiving placebo reported side effects. The drug was especially effective in the treatment ofsomatic difficulties.

J Psychiatry

© 1979

METHOD

Study

Design

The study the anxiolytic and placebo

reported here was and antidepressant in the treatment

undertaken to evaluate effects of tofisopam of patients with con-

current symptoms of anxiety and depression. Subjects satisfying the selection criteria were given either tofisopam or a similar-appearing placebo on a doubleblind basis. Evaluations were conducted before treatment and potentially at 1 2, and 4 weeks after initia,

tion

of the

study.

the study for patient care: ciated need side effects, consent was jects.

Subjects

could

be terminated

from

reasons consistent with high standards of lack oftherapeutic response and the assofor intervention, emergence of substantial and remission of symptoms. Informed obtained from all of the participating sub-

Population

A total of57 outpatients were admitted to the study. All of the patients were at least moderately ill: 42.1% were moderately ill, 38.6% were moderately severely ill, 15.8% severely

were severely ill, and 3.5% were extremely ill. Twenty-one percent of the patients were 79% women. The average age was 37 years.

men and Subjects were admitted to the study if their scores on the depression scale of Raskin and associates (4) and the Covi Rating Scale for Anxiety (5) were greater than 13 and neither score was less than 5. The mean total for the depression scale was 9.7, and the anxiety mean was 1 1 .2. Subjects were also required to have total Hamilton Anxiety Scale (6) scores greater than American

Psychiatric

Association

Am

J Psychiatry /36:2, February

FIGURE Structure

RESU

1 of Diazepam C H2

HAROLD

1979

C2H

0

CH3

H3CO

i.:0:..i

N Tofisoparii

pretreatment

Hamilton

a depression

anxiety

checklist,

patient

groups

that

were

total

and

fam-

produced

two

distinguishable

from

patient each

ness with severely

measurement period subject on a global seven categories ill. Measures of

very

much

the treating physician scale of severity of ill-

from not therapeutic

improved

to very

ill to extremely effect ranged

much

tients rated their experience on a similar tients who failed to complete the 4-week assigned a final rating from either the final schedule or the previous rating depending stances and the opportunity for physician

The

sam-

other.

Measures

At each rated each

from

clearly not

Experimental

Hamilton

Rating

Scale

for

worse.

Pa-

scale. Pastudy were disposition on circuminterview.

Depression

(8) was

administered at intake and at week 4 ofthe study. Unfortunately, patients who failed to complete the 4 weeks could not be consistently interviewed to obtain final ratings, and posttreatment scores are available only for completers. The Hamilton Anxiety Scale (6) and Symptom Check List (SCL-56) (3) were administered before treatment and at 1 2, and 4 weeks on medication. Endpoint ratings were assigned to subjects who did not complete the 4 weeks of study. The ,

SCL-56

was

scored

to produce

the eight

composite

rat-

ings suggested by the assessment manual of NIMH’s New Clinical Drug Evaluation Unit (NCDEU) (9): somatic complaints, cognitive difficulties, irritabilityhostility depression, fear-anxiety, hostility, imtability-sensitivity, anxiety. ,

Subject

Seven placebo

Attrition

patients recipients

FINNERTY

receiving active were terminated

fore the 4-week completion showed enough improvement cused from treatment.

medication from the

of the

patients

receiving

tofiso-

of

dizziness, did

not from

syncope,

excitement,

moderate the study.

after 7 days. The other

and

con-

This patient patient who

dropped out of the study because of side effects had more moderate levels of difficulty, but the side effects (blurred vision and dry mouth) persisted for nearly 2

ily history inventory, and the Klein procedure for the diagnosis of endogenomorphic depression (7) were completed by the physician at intake. Baseline analysis of background characteristics revealed that the randomization of the total patient population into the two ples

percent

fusion that was excused OC H3

treatment

J.

reported

gence

I

In addition,

RICHARD

the emergence ofside effects during drug treatment; 10% ofthe placebo recipients also indicated some difficulties. The total number of complaints was nearly equal across treatment groups. One patient receiving tofisopam had an immediate and severe emer-

CH7 C N

18. The mean score was 24.48.

AND

LTS

Twenty-one pam

-

Diazepani

GOLDBERG

and Tofisopam

N-C

CI

L.

and 12 study be-

date. Only 3 subjects to justify their being ex-

weeks. After the first week of treatment no patients had dropped out of the study and no difference was observed between tofisopam and placebo. By week 2 tofisopam was more effective than placebo, but 9 patients had left the study. By week 4, 13 placebo subjects had dropped out of the study. Most of these dropouts were nonresponders, and the week 4 distribution of ratings is greatly influenced by their elimination. The final global illness ratings, not confounded by subject attrition, showed tofisopam to be significantly

more effective than placebo (see table 1). Both the physicians’ and the patients’ therapeutic

treatment was

effect

were

groups

accepted

not

(chi-square as

ratings

significantly

analysis

significant).

of

different

for

was used;

However,

a

p=.05 consid-

eration of the total distribution indicates that if ratings of a little improvement were combined with ratings of nonimprovement, the distributions would be equal to the global illness ratings listed in table 1 and would show tofisopam significantly more effective than placebo. Analyses of outcome measures rated at each of the time intervals may have been confounded by subject attrition. At week 1 the sample was still complete and the analyses were not biased by the dropout of subjects. At week 2 the subjects with negative responses

to tofisopam, as well as some had dropped out ofthe study, were definitely biased in favor

placebo nonresponders, but the ratings at week oftofisopam. By week

2 4

a large number of placebo recipients had dropped out because of a worsening of illness due to the absence of active medication. Most ofthe remaining placebo subjects were placebo responders or placebo recipients

who

had

intervention. placebo.

measures

not

become

Our

The week presentation

will focus

sufficiently

more

on week

1 and

lections to avoid the confounding attrition. Although an exhaustive analysis

variables groups,

ill to warrant

4 data were biased and discussion

in favor of of outcome

endpoint

data

of results

by

of the

pretreatment

col-

sample

revealed no differences between treatment in all of the analyses reported below the postscores have been adjusted for pretreatment

treatment level. The Hamilton

depression

scale

scores

were

ob197

Am

TOFISOPAM TABLE 1 Physicians’

Global

Rating

only

before

Week

1

Tofisopam

Placebo

Tofisopam

8 20 28

8 21 29

17 6 23

No illness to mildly ill Moderately to severely ill Total aThe difference between tofisopam fourth week it was nonsignificant

tamed

and

placebo

treatment

first week

in the

(x2=2.94). At

endpoint

was

it was

and at week

The Hamilton nificantly less

nonsignificant

4. The

insomnia,

somatic

ratings; (p’

Comparative efficacy of tofisopam and placebo.

Am TOFISOPAM Comparative BY HAROLD Efficacy L. GOLDBERG, of Tofisopam M.D., AND and RICHARD is a new TOFISOPAM agent developed by activi...
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