Am
J Psychiatry
BRIEF
/36:2, February
COMMUNICATIONS
Lorazepam, of Anxiety: BY
/979
LAYTON
a New Benzodiazepine A Double-Blind Clinical MCCURDY,
HAS LONG been public and medical concern with the alleviation ofexcessive anxiety. This interest has resulted in extensive research to determine the causes of anxiety, design methods for evaluating it, and develop therapies for its treatment. Drugs, in particular the benzodiazepine derivatives, have proven to be a successful therapeutic modality. These compounds have been under continuing development and refinement since the l960s (1). Lorazepam, or 7-chloro-5-(o-chlorophenyl)-l ,3-dihydro-3-hydroxy-2H-l ,4-benzodiazepin-2-one one of the newer benzodiazepine compounds, is generally well tolerated, has a low biological toxicity (2), and produces few side effects (3-5). On a weight basis, loTHERE
,
March
Dr. McCurdy and Behavioral Ashley Ave.,
14,
1977;
is Professor Sciences, Charleston,
in the
Treatment
M.D.
Ninety-five adult outpatien ts sufferingfrom moderate to severe anxiety were randomly assigned to treatment with lorazepam or placebo in a double-blind four-week study. Patients were evaluated at pretreatment and after two andfour weeks oftreatment using three rating scales. Lorazepam, at an average daily dose of 3.2 mg tsvice daily, was high/v effective in relieving anxiety as documented by clinical/v and statistically significant differences overplacebo in most of the items on all rating scales at all rating periods. No serious adverse effects were reported, and there were no adverse interactions wit/i other medications, including digitalis and aspirin.
Received 1977.
Derivative, Evaluation
revised
June
22,
1977;
accepted
and Chairman, Department Medical University of South S.C. 29403.
The author wishes to thank J.W. Blanton, M.D., James Folk, M.D., and James Shecut, ton Area Mental Health Center, where much ducted.
Aug.
22,
of Psychiatry Carolina, 171
M.D., George Dunn, M.D., of the Charlesof the study was con-
0002-953X/79/02/0187/04/$00.45
© 1979
razepam is a more active anxiolytic than diazepam (1 mg versus 5 mg, respectively). While this drug is relatively new to the United States, it has been widely used in other parts of the world, particularly Europe. The following double-blind study was conducted to assess the efficacy and safety of lorazepam in treating anxiety.
METHOD
Ninety-five patients, 35 men and 60 women ranging in age from 18 to 65 years, participated in the study. These patients were referred from a community mental health center and an Alcoholics Anonymous group. They represented a broad range of socioeconomic backgrounds. Selection criteria required that all patients have ratings of at least moderately severe anxiety as well as three related symptoms on the Hamilton Anxiety Scale (6). They were also required to have a global rating of at least moderate illness. Patients excluded from the study consisted of those with signs of psychosis or a history of psychosis, acute or chronic brain syndrome, mental deficiency, acute reactive or involutional depression, suicidal tendencies, and drug addiction. Patients with a sensitivity to benzodiazepines were also excluded, as were pregnant patients and those with a history of myocardial infarction within 3 months of the study. Patients suffering from alcoholism were included in the study if they met the above criteria and had been sober for 60 days. Informed consent was obtained before patients were accepted into the study group. Patients were permitted no psychoactive medication for at least 4 days before the study began. The study design was fully randomized and was double-blind. The total duration of the study was 4 weeks; patients were evaluated at pretreatment and after 2 and 4 weeks of treatment. Patients received either
American
Psychiatric
Association
187
Am
LORAZEPAM
I-mg scored tablets oflorazepam or matching placebo, administered on a twice-daily schedule. All but 1 patient started on a regimen of 3 tablets per day, 1 in the morning and 2 at bedtime. If there was a need to reduce the dosage, the morning dose was eliminated first. After the first follow-up visit (at 2 weeks), the daily dosage was continued, reduced, or increased to a maximum of 6 tablets per day, maintaining the twicedaily regimen.
The
95 participants
were
randomly
divided
into
2
groups. Forty-seven patients received lorazepam and 48 received placebo. Efficacy and safety were evaluated after 2 and 4 weeks of treatment and at a final evaluation, which by protocol was defined as the last
evaluation for any patient who participated in the study for at least 4 days. Although 16 patients (5 in the lorazepam group and 1 1 in the placebo group) failed to complete the full 4-week course of treatment, 87 (43 in the lorazepam group and 44 in the placebo group) were available for final evaluation. The efficacy of medication was measured using a global
rating
scale,
the
ton Anxiety Lipman-Rickels
Rating
Scale 35-Item
global
assessment
physician-administered
of the
Hamil-
(6), and the self-administered Self-Rating Scale (7). severity
of
illness
used
The a 4-
point scale, while the degree of change since the start ofthe study wasjudged on a 7-point scale. The Hamilton Anxiety Rating Scale measured drug effectiveness through changes in total scores in 13 symptom categories, and in psychic and somatic clusters. Intensity of symptoms was rated on a 5-point scale (I =absent, 2=mild,
The
3=moderate,
Lipman-Rickels
apeutic
4=severe,
scale
was
and
used
5=very
severe).
to determine
ther-
effectiveness.
At each visit patients were asked whether there were any side effects and, if so, their nature and intensity. In order to avoid prompting the patients, the questions were asked without resort to a checklist. All adverse side effects were recorded regardless of the patient’s ultimate inclusion in or exclusion from the efficacy evaluation. One-way analysis of variance, chi-square test of independence,
and
Fisher
exact
probability
test
were
used to determine whether the 2 treatment groups were initially balanced and homogeneous in terms of severity of illness and demographic characteristics. Because of their subjective, ordinal nature the rating scale data were evaluated by means of nonparametric statistical
tests.
The
Kruskal-Wallis
scores from all three rating scales cacy between treatment groups. bility test was applied to changes after pretreatment to detect groups.
RESU
test
was
applied
to
to compare drug effiFisher’s exact probain the global ratings differences between
LTS
There were no significant differences between the 2 treatment groups in age, weight, race, sex, duration of 188
illness,
or initial
ilton,
severity
and self-rating were excluded
group tions
J Psychiatry
because
of illness
scales. from
rating
/36:2,
scale
February
on the
1979
global,
Ham-
Four patients from each the final efficacy evaluadata
obtained, leaving 43 in the the placebo group available
were
incomplete
lorazepam for final
or not
group and evaluation.
44 in
Dosage
Total daily dosages of lorazepam ranged from 2 to 5 mg, with a mean of 3.2 mg; the mean treatment period was 26.5 days. Dosages in the placebo group ranged from 3 to 6 tablets per day, with a mean of 3.4; the mean treatment period was 24.6 days. At the end of 4 weeks 38% of the patients were receiving an increased dosage oflorazepam (i.e., over 3 mg per day), and 51% required an increased dosage of placebo. Clinical
Efficacy
According
Ratios
to
psychotropic
published
drugs
(8),
standards a drug
can
for
evaluating
be regarded
as dem-
onstrating clinically significant efficacy if the percentage of patients improved with the drug divided by the percentage improved with placebo is at least 1 .5. Clinical
efficacy
ratios
the percent mean
may
be
of patients
scores
on
determined
improved,
rating
scales,
or
ratios were computed in this Table 1 presents the overall cent the cant
on
percent both.
the
of
Both
in
types
study. improvement
rates
of
(per-
of patients improved) for the three rating scales at final evaluation. There was a statistically signifidifference between lorazepam and placebo on all
three
scales.
similar scores
The
ratios
for patient
improvement
to the ratios for percent reduction on rating scales. The results of both
for measuring cacy
improvement
criteria
Global
outlined
Rating
therefore
severity
satisfied
the effi-
Scale
with
weeks
were in mean methods
above.
Intergroup analysis (Kruskal-Wallis test) that lorazepam was significantly more active cebo at all evaluation periods. Improvement lorazepam
was
significant
indicated than plain global at 2 and 4
(p
J Psychiatry
BRIEF
/36:2, February
COMMUNICATIONS
Lorazepam, of Anxiety: BY
/979
LAYTON
a New Benzodiazepine A Double-Blind Clinical MCCURDY,
HAS LONG been public and medical concern with the alleviation ofexcessive anxiety. This interest has resulted in extensive research to determine the causes of anxiety, design methods for evaluating it, and develop therapies for its treatment. Drugs, in particular the benzodiazepine derivatives, have proven to be a successful therapeutic modality. These compounds have been under continuing development and refinement since the l960s (1). Lorazepam, or 7-chloro-5-(o-chlorophenyl)-l ,3-dihydro-3-hydroxy-2H-l ,4-benzodiazepin-2-one one of the newer benzodiazepine compounds, is generally well tolerated, has a low biological toxicity (2), and produces few side effects (3-5). On a weight basis, loTHERE
,
March
Dr. McCurdy and Behavioral Ashley Ave.,
14,
1977;
is Professor Sciences, Charleston,
in the
Treatment
M.D.
Ninety-five adult outpatien ts sufferingfrom moderate to severe anxiety were randomly assigned to treatment with lorazepam or placebo in a double-blind four-week study. Patients were evaluated at pretreatment and after two andfour weeks oftreatment using three rating scales. Lorazepam, at an average daily dose of 3.2 mg tsvice daily, was high/v effective in relieving anxiety as documented by clinical/v and statistically significant differences overplacebo in most of the items on all rating scales at all rating periods. No serious adverse effects were reported, and there were no adverse interactions wit/i other medications, including digitalis and aspirin.
Received 1977.
Derivative, Evaluation
revised
June
22,
1977;
accepted
and Chairman, Department Medical University of South S.C. 29403.
The author wishes to thank J.W. Blanton, M.D., James Folk, M.D., and James Shecut, ton Area Mental Health Center, where much ducted.
Aug.
22,
of Psychiatry Carolina, 171
M.D., George Dunn, M.D., of the Charlesof the study was con-
0002-953X/79/02/0187/04/$00.45
© 1979
razepam is a more active anxiolytic than diazepam (1 mg versus 5 mg, respectively). While this drug is relatively new to the United States, it has been widely used in other parts of the world, particularly Europe. The following double-blind study was conducted to assess the efficacy and safety of lorazepam in treating anxiety.
METHOD
Ninety-five patients, 35 men and 60 women ranging in age from 18 to 65 years, participated in the study. These patients were referred from a community mental health center and an Alcoholics Anonymous group. They represented a broad range of socioeconomic backgrounds. Selection criteria required that all patients have ratings of at least moderately severe anxiety as well as three related symptoms on the Hamilton Anxiety Scale (6). They were also required to have a global rating of at least moderate illness. Patients excluded from the study consisted of those with signs of psychosis or a history of psychosis, acute or chronic brain syndrome, mental deficiency, acute reactive or involutional depression, suicidal tendencies, and drug addiction. Patients with a sensitivity to benzodiazepines were also excluded, as were pregnant patients and those with a history of myocardial infarction within 3 months of the study. Patients suffering from alcoholism were included in the study if they met the above criteria and had been sober for 60 days. Informed consent was obtained before patients were accepted into the study group. Patients were permitted no psychoactive medication for at least 4 days before the study began. The study design was fully randomized and was double-blind. The total duration of the study was 4 weeks; patients were evaluated at pretreatment and after 2 and 4 weeks of treatment. Patients received either
American
Psychiatric
Association
187
Am
LORAZEPAM
I-mg scored tablets oflorazepam or matching placebo, administered on a twice-daily schedule. All but 1 patient started on a regimen of 3 tablets per day, 1 in the morning and 2 at bedtime. If there was a need to reduce the dosage, the morning dose was eliminated first. After the first follow-up visit (at 2 weeks), the daily dosage was continued, reduced, or increased to a maximum of 6 tablets per day, maintaining the twicedaily regimen.
The
95 participants
were
randomly
divided
into
2
groups. Forty-seven patients received lorazepam and 48 received placebo. Efficacy and safety were evaluated after 2 and 4 weeks of treatment and at a final evaluation, which by protocol was defined as the last
evaluation for any patient who participated in the study for at least 4 days. Although 16 patients (5 in the lorazepam group and 1 1 in the placebo group) failed to complete the full 4-week course of treatment, 87 (43 in the lorazepam group and 44 in the placebo group) were available for final evaluation. The efficacy of medication was measured using a global
rating
scale,
the
ton Anxiety Lipman-Rickels
Rating
Scale 35-Item
global
assessment
physician-administered
of the
Hamil-
(6), and the self-administered Self-Rating Scale (7). severity
of
illness
used
The a 4-
point scale, while the degree of change since the start ofthe study wasjudged on a 7-point scale. The Hamilton Anxiety Rating Scale measured drug effectiveness through changes in total scores in 13 symptom categories, and in psychic and somatic clusters. Intensity of symptoms was rated on a 5-point scale (I =absent, 2=mild,
The
3=moderate,
Lipman-Rickels
apeutic
4=severe,
scale
was
and
used
5=very
severe).
to determine
ther-
effectiveness.
At each visit patients were asked whether there were any side effects and, if so, their nature and intensity. In order to avoid prompting the patients, the questions were asked without resort to a checklist. All adverse side effects were recorded regardless of the patient’s ultimate inclusion in or exclusion from the efficacy evaluation. One-way analysis of variance, chi-square test of independence,
and
Fisher
exact
probability
test
were
used to determine whether the 2 treatment groups were initially balanced and homogeneous in terms of severity of illness and demographic characteristics. Because of their subjective, ordinal nature the rating scale data were evaluated by means of nonparametric statistical
tests.
The
Kruskal-Wallis
scores from all three rating scales cacy between treatment groups. bility test was applied to changes after pretreatment to detect groups.
RESU
test
was
applied
to
to compare drug effiFisher’s exact probain the global ratings differences between
LTS
There were no significant differences between the 2 treatment groups in age, weight, race, sex, duration of 188
illness,
or initial
ilton,
severity
and self-rating were excluded
group tions
J Psychiatry
because
of illness
scales. from
rating
/36:2,
scale
February
on the
1979
global,
Ham-
Four patients from each the final efficacy evaluadata
obtained, leaving 43 in the the placebo group available
were
incomplete
lorazepam for final
or not
group and evaluation.
44 in
Dosage
Total daily dosages of lorazepam ranged from 2 to 5 mg, with a mean of 3.2 mg; the mean treatment period was 26.5 days. Dosages in the placebo group ranged from 3 to 6 tablets per day, with a mean of 3.4; the mean treatment period was 24.6 days. At the end of 4 weeks 38% of the patients were receiving an increased dosage oflorazepam (i.e., over 3 mg per day), and 51% required an increased dosage of placebo. Clinical
Efficacy
According
Ratios
to
psychotropic
published
drugs
(8),
standards a drug
can
for
evaluating
be regarded
as dem-
onstrating clinically significant efficacy if the percentage of patients improved with the drug divided by the percentage improved with placebo is at least 1 .5. Clinical
efficacy
ratios
the percent mean
may
be
of patients
scores
on
determined
improved,
rating
scales,
or
ratios were computed in this Table 1 presents the overall cent the cant
on
percent both.
the
of
Both
in
types
study. improvement
rates
of
(per-
of patients improved) for the three rating scales at final evaluation. There was a statistically signifidifference between lorazepam and placebo on all
three
scales.
similar scores
The
ratios
for patient
improvement
to the ratios for percent reduction on rating scales. The results of both
for measuring cacy
improvement
criteria
Global
outlined
Rating
therefore
severity
satisfied
the effi-
Scale
with
weeks
were in mean methods
above.
Intergroup analysis (Kruskal-Wallis test) that lorazepam was significantly more active cebo at all evaluation periods. Improvement lorazepam
was
significant
indicated than plain global at 2 and 4
(p
