Regular Article

Clonazepam as a therapeutic adjunct to improve

the management of psychiatric disorders
SHIGERU MORISHITA MI), PhD,' SHOZO AOKI MI), PhD,' AND SHOSUKE WATANABE MD, phi?
of Psydiintry, Kaiimaki Medical School arid 'Kairvosnki U h m i r y
'Dq~rfritrrit 4Medirnl W'e@re, Kiwnsliiki, Japnri

Abstract Clonazepam, which is a benzodiazepine structurally related to chlordiazepoxide hydrochloride, diazepam and
nitrazepani, has been available for the treatment of seizure disorders in the USA since 1976 and in Japan since
1981. Increasingly, clonazepam has been used in the treatment of a variety of psychiatric disorders. Six repre-
sentative case studies are presented and specific guidelines for the use of clonazepam are discussed.

Key words akathisia, clonazepani, depression, mania, schizophrenia.

INTRODUCTION antidepressants, however they failed to respond to treatment of

Clonazepam, an anti-epileptic drug for the treatment of certain
types of seizures, is a benzodiazepine structurally related to
chlordiazepoxide hydrochloride, diazepam and nitrazepani.
Increasingly, it has been used in the treatment of a variety of
psychiatric disorders. In 1980 Lechin et al. observed that psy-
chiatric symptoms were reduced in nine schizoaffective patients
'
to whom clonazepam was administered. In 1983, Chouinard
et a/. reported that clonazepam was effective in the control of
manic agitation in combination with haloperidol.2 In 1985,
Frykholni reported that it was effective in suppressing psy-
chotic symptoms of atypical psychosi~.~ Freinhar and Alvarez
succeeded in the treatment of schizophrenic, borderline, and
mania, with clonazepani supplementation of psychotropic
drugs.4 Kishinioto rt nl. demonstrated the antidepressive effect
of clonazepam.'
These reports suggest that clonazepam can be employed as a
psychotherapeutic adjunct in the treatment of various psychi-
atric disorders. Over the preceding year we have been able to
successfully treat a minimum of 15 patients diagnosed as being
in a manic state or as having depression or other psychiatric
states, by supplementation of antipsychotics, lithium, antide-
pressants, and minor tranquilizers with clonazepam (Table 1).
The following case studies illustrate the adjunctive use of
clonazepam in these psychiatric states.
CASE REPORTS
Fifteen patients were diagnosed by DSM-IV criteria (Table I ) .
Cases 1 and 2 were bipolar I disorder, with the most recent
episode manic (mania). They were dramatically improved by
clonazepam supplementation. Cases 3-12 were patients ofmajor
depressive disorder (depression). They partially responded to
Correrpondrricc addrrn: Shigcni Morinhita. M I ) . i'hii. Ikpartmriit of hychiatry.
Kawaaaki Medical School. 377 Matsuchima. Kurarhiki 71114) 192. Japan.
Received 3 Fehnidry 1997: revised IH August 1997; accepted 21) September 1YLJ7.
depressive mood with antidepressants. Clonazepam supple-
mentation completely improved their prolonged depressive
mood within 2 weeks. Case 13 was a delusional disorder
(paraphrenia). Cases 14 and 15 were paranoid-type schizo-
phrenia. Clonazepam supplementation improved their anti-
psychotic drug-induced side effects. W e illustrate some case
studies.
Bipolar I disorder
Most receiif episode nianic
Case 1, a 25-year-old married woman, had a history of manic
episodes at 18 years old. When she was 23-years-old, she
suffered from systemic lupus erythematosus. She was brought
to Kawasaki Medical School Hospital by her family after an
episode of.wild behavior. Her symptoms included an expansive
and irritable mood, decreased sleep and reduced appetite,
motor overactivity, abusive language, and an act of violence.
She was admitted and initially received lithium 600 nig/day
and levoniepromazine 125 mg/day, which were ineffective in
controlling her syniptoms during the first 3 weeks. Haloperidol
2.25nig/day was added. However haloperidol could not be
continued due to side effects. Clonazepam 12mg/day was
added to the lithium and levomeproniazine. Within 4 days we
noted a dramatic improvement in her symptoms. Due to severe
drowsiness, the clonazepani and levomepromazine were im-
mediately decreased; clonazepani to 1.5 nig/day and lev-
omepromazine to 25 mg/day within 6 days. She did not have a
relapse in over 5 weeks and was subsequently discharged.
Case 2, a 62-year-old married man, suffered brain injury in a
traftic accident at 57-years-old, but his mental state was not
disturbed. H e presented to us with a 3-week history of irrita-
bility and impulsiveness. H e was angry, grandiose, and intru-
sive, with a moderate degree of hyperactivity and pressured
speech. H e was commenced on lithium 600 mg/day, zotepine
75 mglday, and chlorpromazine 25 nig/day. His manic state
76 S. Morishita and S. Watanabe

Table 1. Clonazepani as a psychopharmacologic adjunct

~~~

Case Age Sex Diagnosis @SM-IV) Other medication Reasons for clonazepam addition Clonazepam
(mdday) dosage (mg/day)
1 25 F Bipolar I disorder, manic Lithium 600 Haloperidol could not be used 112
Levomepromazine 125 by side effects
2 62 M Bipolar I disorder, manic Lithium 600 Manic symptoms unresponsive 8
Zotepine 75 lithium plus antipsychotics
Chlorproniazine 25 combination
3 69 M Major depression Maprotiline 75 Prolonged depressive mood 3
4 66 F Major depression M a p r o t h e 75 Prolonged depressive mood 3
5 62 F Major depression Maprotiline 30 Prolonged depressive mood 3
6 49 F Major depression Amoxapine 75 Prolonged depressive mood 3
Lithium 800
7 66 F Major depression Maprotiline 75 Prolonged depressive mood 3
n 58 F Major depression Amoxapine 75 Prolonged depressive mood 4.5
Trazodone 150
Normptyline 75
Amitriptyline 50
9 28 F Major depression Anioxapine 75 Prolonged depressive mood 3
Bromazepam 6
10 56 M Major depression Trazodone 150 Prolonged depressive mood 3
Dosulepine 75
11 54 M Major depression Amoxapine 75 Prolonged depressive mood 1.5
Alprazolam 1.2
12 27 M Major depression Maprotiline 75 Prolonged depressive mood 1.5
Mianserin 30
Sulpiride 150
13 63 Delusional disorder Thioridazine 10 Antipsychotics could not be 2
Biperiden 1 used by parkinsonism
14 36 Schizophrenia paranoid Haloperidol 2.25 Akathisia 3.5
Biperiden 3
15 33 Schzophrenia paranoid Risperidone 6 Akathisia 1.5
Chlorpromazine 12.5
Proniethazine 25

continued for 2 months. After improvement of his symptoms,
the regimen was continued for 2 months and then ceased. He
did not relapse for 4 months, but then the activity increased
again. He was commenced on the same regimen, but his manic
symptoms rapidly became worse within 1 week and so
clonazepam 8 mg/day was added. Within 7 days he showed
marked improvement in almost all his symptoms, but still re-
mained euphoric. Because of drowsiness, clonazepam was de-
creased to 2 mg/day. After a further 5 months of treatment he
no longer exhibited manic symptoms.
Major depressive disorder
Case 3, a 69-year-old married man, suffered from episodes of
depression. The first episode was marked by feelings of sadness,
insomnia, anxiety, irritability, and a reduction in appetite. He
was commenced on a regimen of an antidepressant, maproti-
line 75 mg/day, and a benzodiazepine, alprazolam 1.2 mglday.
Within 1 week he reported improvement and within 4 weeks
all his symptoms disappeared. Four months after his iniprove-
ment he decided to stop taking the medication. One month
later he reported a return of his symptoms. The same regimen
of medication was commenced but after 5 weeks there was
little improvement. Alprazolam was stopped and clonazepam
3 mg/day was added to the maprotiline 75 mg/day. Four days
later he reported that all his symptoms has disappeared. Since
then he has been functioning normally in his daily life.
Case 4, a 66-year-old married woman, had no history of
major depression. However, she underwent a gastrectoniy for
gastric cancer and after the operation, she became depressed
and agitated, and experienced insomnia and anxiety. She was
commenced on a regimen of an antidepressant, maprotiline
75 mg/day, and a benzodiazepine, alprazolam 1.2 nig/day.
During 4 months she reported little improvement, and her loss
of energy and insomnia continued. Treatment with clonaze-
pam 3mg/day was commenced and her other medication
stopped. However, 2 weeks later she reported little improve-
ment. Clonazepam was ceased and maprotiline 75 mg/day was
Clonazepani on psychiatric disorders
recommenced, but there was little improvement over a period
of 3 weeks. Clonazepam 3nig/day was added to the map-
rotiline. Within 2 weeks she was sleeping and eating well, and
her depressive mood had improved. After 1 month she was
almost functioning normally in her daily life. After 5 months'
treatment she no longer exhibited depressive mood.
Delirsiorial disorder
Case 13, a 63-year-old married woman, had a 2 year history of
paranoid delusions and affective disturbance. She had been
diagnosed as suffering &om paraphrenia. After haloperidol
2.25 mg/day and biperiden 3 mg/day for 2 months, she devel-
oped parkinsonism. When we met her, she was only taking a low
dose combination of thioridazine 10 mg/day, biperiden 1 mg/
day, and diazepam 2 nig/day because ofher parkinsonism, which
presented in the fomi ofa gait disturbance and tongue movement
disturbance. Paranoid delusion did not dominate, but she was
depressed and exhibited immaturity. Social functioning was in-
active. Clonazepam 2 mg/day was added to thioridazine 10 mg/
day and biperiden 1 mg/day. Within 1 week her mood lifted and
her affective lability improved. After several months she returned
to a normal mental condition.
Akatkisia
Case 14, a 36-year-old single woman, had a 4 year psychiatric
history with a diagnosis of paranoid schizophrenia and had
been treated for 1 year with haloperidol 2.25mg/day and
biperiden 3nigIday. She presented to us with complaints of
strong subjective discomfort. She felt that she had to get up and
walk or continuously move. The diagnosis was akathisia, and
clonazepam 3.5 mg/day was added to the haloperidol and the
biperiden. Within 7 days, the akathisia disappeared without a
decrease in haloperidol or increasing psychotic symptoms.
During treatment with clonazepam, there were no side effects.
After 3 months' treatment, she no longer exhibited akathisia.
DISCUSSION
Chouinard et a/. were the first to do a double-blind crossover
study comparing clonazepam to lithium for the treatment of
acute mania. Eleven patients with acute mania underwent a 10-
day trial of orally administered clonazepam (mean dose =
10.4mg/day) and lithium (mean dose = 1691 mg/day) in a
randomized, double-blind sequence. Clonazepam showed a
trend toward superiority in decreasing manic syniptonis but
reached statistical significance only on motor overactivity. Both
the clonazepam group and the lithium group required halo-
peridol to control behavioral disturbances. Victor et a/. reported
effective use of clonazepani in a 60-year-old woman with an
acute manic episode. Initially, she was treated with lithium and
trifluoperazine. Seven days later, clonazepam was added. O n
this regimen her manic symptoms were significantly decreased.
Freinhar and Alvarez also reported some cases in which
clonazepani as a psychopharniacologic adjunct proved useful in
treating acute Santos and Morton retrospectively
reviewed the use of clonazepani as an adjunct to antipsychotics
in 13 acutely manic patients.x They noted that clonazepani
77
reduced the manic symptoms as well as the daily dose of
antipsychotics required. Edwards et al.' and Gouliaev et al."'
conducted a controlled study of clonazepam as a psychophar-
macologic adjunct in the treatment of manic patients.
Clonazepam effectively controlled manic symptoms in com-
bination with other agents. Bradwejn et a / . , however, dem-
onstrated that clonazepam alone was not effective in
controlling the manic state in a double-blind controlled
study.' Twenty-four patients with acute mania received either
only clonazepam or only lorazepam for 14 days. Treatment
with lorazepam (mean dose = 13mg/day) produced marked
improvement but clonazepam (mean dose = 14.2 mglday)
failed to demonstrate a significant therapeutic effect.
These reports suggest clonazepam is a useful supplement in
the pharmacotherapy of manic states, but alone it cannot be
advocated as a therapeutic agent for treating manic states.
Clonazepani has been advocated as safe and as having a rapid
onset of action, but, in acute mania, such a high dose of
clonazepam may be needed that it causes drowsiness and
ataxia." O u r patients (Cases 1 and 2) needed a high dose of
clonazepam (8-1 2 mg/day) and experienced severe drowsiness.
Therefore, clonazepam should at this time be considered as a
therapeutic adjunct in manic patients nonresponsive to con-
ventional therapy. As clonazepam is an antiepileptic drug, we
suppose that clonazepam may by useful to psychiamc distur-
bance in organic conditions such as lupus o r brain injury.
The effect of clonazepam on depression was first reported by
Jones and Chouinard in 1985.13A patient with systemic lupus
erythematosus developed depression that did not respond to
conventional drug therapy. An additional 1.5 mg/day of
clonzepam relieved the depression. Zetin and Freedman re-
ported an effective combination of clonazepam (1 nig/day) and
imipramine (10 mg/day) in a case of prolonged depre~si0n.l~
Mas et a/. described a prolonged depressed patient with a head
injury who was responsive to a combination of clonazepam
(6 mglday) and carbamazepine (1400 mglday).I s In these cases
the regimen was reported to have had a rapid onset of action.
Kishimoto et al. conducted the first open trial to demonstrate
the antidepressive action of clonazepam as a treatment for
patients with depression."." Thirty-nine patients with pro-
longed depression who did not respond to conventional anti-
depressant therapy were supplemented with clonazepam at a
daily dose of 1-8mg (mean dose = 3.4mg). Twenty-five pa-
tients (64%) showed moderate to marked improvement within
1 week. Side effects occurred in 23 patients (58%), but most of
them were not severe. Svestka et al. also recently reported on
the effectiveness of clonazepani for 55 patients with depres-
sion.I7 The daily dose of clonazepani was 2.4-6.54mg and
complete remission was achieved in 60%.
W e presented 10 patients with prolonged depression
(Table 1). They did not respond to conventional antidepressant
therapy of at least 4 weeks duration. Clonazepam supple-
mentation improved depression within a few weeks. In Case 4,
clonazepam was administered alone with no improvement, but
after that, a combination of clonazepam (3 mg/day) and map-
rotiline (75 mglday) improved the symptoms. Therefore, we
encourage supplementation with a daily dose of 3 m g of
78
clonazepam in prolonged depression nonresponsive to con-
ventional therapy.
Although clonazepam alone has not been proved effective in
the treatment of chronic schizophrenia," several studies have
reported its usefulness as an adjunct in the treatment of schizo-
phrenia and atypical psychosis. 19-21 Clonazepam 2-4 mg/day
appears to be a particularly helpful adjunct to antipsychotic
medication and can be expected to improve character pathology
and intermittent and transient vulnerability to psychotic states.
However, Dorevitch reported a schizophrenic case who entered
a manic state after receiving a high dose of clonazepam (8 mg/
day)." Our Case 13 received 2mg/day of clonazepam with
other psychotropic drugs and showed improved behavior. Low
dose of clonazepam may be helpful for the management of
rambling behavior in schizophrenia.
Antipsychotic-induced akathisia is one of the most c o n m o n
and refractory side effects associated with antipsychotic ad-
ministration. It may manifest itself subjectively as anxiety or
depression or objectively as restlessness, pacing, or even un-
usual behavior. Several agents, including benzodiazepines, have
been used with varying degrees of success in the treatment of
akathisia. Several studies have reported the use of clonazepam
as an adjunct which significantly reduced antipsychotic-
induced akathisia at low daily doses (0.5-4 mg).'3-2' W e also
successfully treated antipsychotic-induced akathisia with low
doses of clonazepam in Cases 14 and 15.
Clonazepam is a high-potency benzodiazepine labeled as an
anticonvulsant. Its use in the treatment of a variety of psychi-
atric disorders has increased. However, the mechanism of its
psychiatric clinical action has not yet been established. With
high affinity for central benzodiazepine receptors, clonazepam
is a facilitator of the y-aminobutyric acid system3" and also
increases central synthesis of ~ e r o t o n i n , ~d' o p a n ~ i n e ,and
~~
norepinephrine,." a combination of effects that may offer
unique clinical characters. Clonazepam is a useful therapeutic
adjunct and the onset of its effects is rapid. W e cannot, how-
ever, advocate the use of only the therapeutic agent for ame-
lioration of any psychiatric condition. Clonazepam is a useful
supplement and has diverse optimum daily doses for a number
of psychiatric disorders. However, clonazepam should at this
time be considered as a therapeutic adjunct in psychiatric dis-
order patients who are nonresponsive to conventional therapy.
Since no placebo was used in the present case studies, it is
necessary to verifi the antipsychotic action of clonazepam
using stricter methods.
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