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’