Department of Psychiatry, Heinrich Neina University, D-4000 Duesseldorf, Germany
Cantents 1.
21
2.2
3. 3.1 3*2 4. 4.1 4.2 5. 5*2 5.2 f:
Abstract
135
Introduction Study NO 1 Methods Results Study NO 2 Methods
136 137 137 137 138 138 138 238 138 139 3.39 139 146 140 141 142
RC%TlUltS study
NC+ 3
FIethods RewfLS
Study NO 4 ~~~~~~S RWSU2.t.S
General Discussion Conclusions References
Beinrbz!h,Kurt and Erla Lehmarm: Low Rose Neur~la~tanx~~~~~~s in Anxiety States. Prog. Neuro-Psychopharmacol. & Biai. Psychiat. 1992, 16f21 : 135-143. order to prove that neuroleptanxioiysis represents a therapeutical alternative in the treatment of patients suffering from anxiety we conducted four investigations. In the first study it was experimentally proved with 45 outpatients suffering from anxiety that fluspirilene (1.5 mg per week) is superior to br5ma~e~am (6 mg/da~~~ especially in patients with a high degree 5f somatic anxiety. Xn the second study the tolerance of fluspfrilsne (J-5 mg per week) was investigated In 1261 patients with anxiety states and psychoreactive disorders under controlled and apen conditions for a period of six weeks, Side effects were found in 11.5% of the patients. All side effects had in common that they occurred already within the first few weeks of treatment. In the third study investigating the dose-effect relationship 106 patients received either 0.5, 1.0, or 1.5 mg Eluspirilene per week for a periad af 6 weeks. The main result of this study was the verification of a clear dose-effect relationship. The fourth study compared IS5 patients who had received fongterm treatment with fluspirilene fmax 1.5 ma/week1 and 121 patients with long-term benaodiazepine trea~ment..N~ differences were found with regard to the frequency and intensity of extra-pyramidal disturbances. The therapeutical relevance of the findings wss emphasized in the general discussion, In
K.HeinrlchandE.Lehmann
136
anxiety, benzodiazepine
Keywords:
fluphenazine,
neuroleptanxiolysis.
Abbreviations: extrapyramidal symptoms scale abnormal (EPS), involuntary movements (AIM), acathisia scale (AKA), Hamilton anxiety scale (HAMA). Introduction
1.
Patients suffering or psychoreactive psychotherapy treatment
disorders such
of
use
due
benzodiazepines
of
approx.
6
%
anxiolytics
administered
The
nearly
range
psychiatrists
most fre-
and efficacy.
exponentially
majority
and or
in
the
benzodiazepine
of
general physicians by
therapy
type are widely used.
increased
given by
are
only
of
for the
psychopharmacological
wide therapeutic
1982).
complaints
partners. The combination therapy is necessary
In
to the
to their
(Hoffmeister,
prescriptions lists,
belong
worldwide
70ties
patients.
of the benzodiazepine
Benzodiazepines The
anxiety, psychosomatic
are difficult
and psychopharmacological
tranquilizers
quently
from abnormal
internal specia-
psychotherapeutists
(Ladewig, 1982). Especially of
the risks of addiction
such a wide, uncritical
recent
years
anxiety syndromes In 1960
with low
gation
and
dose
positive
majority
of
neuroleptics
judgement
increasingly
therefore in
the treatment of
by general
psychiatrists requires
as
of an
the treatment of
anxiety paThe investi-
is Fluphenazine.
fluspirilene important
in
the
treatment of
contribution
to
neuro-
et al., 1990). But, since most benzodiazepines
(Lehmann
administered
reported on
neuroleptics
furnished
syndromes
leptanxiolysis are
are
alternative
warnings
During the
(Lehmann et al., 1984).
Proctor already
tients
of benzodiazepines.
neuroleptics
as a pharmacotherapeutical
discussed
anxiety
dose
low
gave rise to appropriate
application
physicians is
expert
of
(Ladewig, 1982) opinion
the
application
by
a
and since the
that
the
use
psychiatrist,
of this
treatment concept gained ground rather slowly. The
clinical benefits
observed groups
of fluspirilene
in 1973 (Path et al. of
probands
confirmed
in anxiolysis
were already
1973). Later investigations these
first
reports
with larger
(Lehmann et
al.
1984). As an treatment
advantage with
of
the therapeutic
benzodiazepines
it
was
procedure pointed out
as
opposed to
that
a
within the
frame of
neuroleptic therapv no disturbing sedation and no development
of addiction must be apprehended. The risk of extrapyramidal, vegetative and endocrinological side effects under antipsychotic dosage was insignificant under low dose neuroleptanxiolytic dosage. The author's group carried out a series of systematic investigations with fluspirilene in outpatients with anxiety syndromes DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, third edition, revised, Washington, D.C., APA, 1987). We would like to present here some studies and their practical significance. 2. Study No 1 2.1
Methods In an experimental study of a total of 45 out-door anxiety patients complaints and psychoreactive from organic functional suffering disorders, the effect of six weeks' treatment with 1.5 mg fluspirilene per week was compared with 6 mg bromazepam daily. The drugs were administered in a double-blind, double-dry technique. To objectify diagnosis, the Minnesota Multiphasic the Personality Inventory (Greene, 1980) and a life history questionnaire (Lazarus, 1983) were used. At the beginning of the study, as well as after 14, 28, and 42 days the Hamilton Anxiety Scale (Hamilton, 1976) was applied. In addition, a global assessment of therapeutic effectiveness was made. 2.2 Results It was demonstrated that fluspirilene in six weeks of treatment was therapeutically superior to bromazepam (Table 1). Fluspirilene was particularly advantageous in patients with anxiety, while there was no difference as psychic anxiety (Hassel, 1985).
a high degree of somatic regards the influence on
Table 1 Global Therapeutic Improvement after 42 Days
markedly improved slightly improved and improved unchanged and impaired BROMAZEPAM FLUSPIRXLENE TOTAL
8 16 24
ChiL = 6.51;
p < 0.02
15 6 21
23 22 45
138
K.HeinrichandE.I.ehmann
3. 3.1
Study No 2
Methods The tolerance
study.
1261
of fluspirilene
patients with
ceived 1.5 mg
fluspirilene
open conditions. and
the subject of
psychoreactive
a separate
disorders
re-
per week for six weeks under controlled
and
particular
The
was made
anxiety and
aim of this study was to evaluate type
incidence of side effects. For
this purpose informal side effects
reports by the patients were recorded in weekly intervals. 3.2
Results
The total
number of
patients complaining
of side effects
at some
time during treatment was 145 = 11.5 %. Table 2 shows the frequencies side effects had few
weeks of treatment.
fluspirilene deserves
had
to be
to be emphasized
the
effects that we observed. All
In these cases the weighed against
decision not
(Heinrich and Lehmann,
to continue
therapeutic
its side
that we found a
effects and therapeutic
between side to
of side
in common that they occurred already within the first usefulness
effects.
of
The fact
distinct negative relation
effectiveness,
treatment when
which again points effects occur
side
1988). Table 2
Side Effects in 1261 Patients under Fluspirilene
Incidence
Percentage
74 48 42 17 10 9 7 4 4 11
5.87 3.81 3.33 1.35 0.79 0.71 0.56 0.32 0.32 0.87
weight gain tiredness extrapyramidal alsoLders dryness of the mouth perspiration vertiqo circulatory disorders gastrointestinal symptoms visual defects unspecific reactions
4. 4.1
Study No 3
Methods The
dosage-effect
patients, with
and 1.5
abnormal
disorders
mq
relations
mg (35
patients),
1.0
mg (35
(36 patients) fluspirilene in 106 out-patients complaints or psychoreacitve psychosomatic
anxiety,
were investigated.
double-blind
of 0.5
manner,
Treatments
and effects
were
were randomly measured
for
allocated six
in a
weeks. The
Law doseneuroleptanxio~~sin~etystates
diagnosis was established Personality Inventory.
again
by
the
Minnesota Multiphasic
4.2 Results The three groups differed in none of the variables measured at the beginning of the study. After six weeks of treatment we found a clearcut dosage effect. Although target symptoms were reduced under each of the three conditions, the reduction of anxiety was most pronounced under a dosage of 1.5 mg and least so under 0.5 mg. This could be proved by the evaluation of the Hamilton Anxiety Scale (Table 3). The clear-cut dosage effect relationship was also observed for the subjective well-being in the expression of the Adjectives Check List (Janke and Debus, 1977) and its scales sensitiveness, self-confidence, mood, depressiveness, agitation, and introvertedness. Interestingly, the variables in the sector of desactivation produced another dose-effect relationship. Tiredness, desactivation, and confusion receded most noticeably with 1.0 mg. Under a dosage of 0.5 mg the higher desactivation might indicate a weaker therapeutical efficacy, while at a dosage of 1.5 mg desactivation occurred as a side effect (Lehmann, 1989). Table 3 Effects on Total score Anxiety (NAMA)
Day
0
14 28 42
Fluspirilene 0.5 mg 1.0 mg 29.3
23.6 20.2 16.1
29.3 22.4 18.1 14.2
1.5 mg
-
29.3 20.2 3.4.8 11.0
Effects: Dosage = p < 0.001; days = p < 0.001 5. Study No 4 The problem of extrapyramidal side effects in the course of longterm neuroleptic therapy is very important and gives reason to criticism of low dose neuroleptanxiolysis. 5.2
Methods A study with 276 patients suffering from anxiety, psychosomatic complaints or psychoreactive disorders was undertaken. 155 patients (fluspirilene group) had within the last three years 70.26 injections
139
140
K.Heinrlch andE.L-ehmann
with
a
other
maximum of
1.5 mg
neuroleptics.
treated last
121
continuously
fluspirilene. patients
or in
intervals with
three years. They had never had
whether
fluspirilene
5.3
neuroleptics
movements,
been
before. To find out
symptoms
or,
more qene-
Involuntary
Movements
(AIMS),
Scale (AKA).
Results sex.
The
symptoms may all
had
during the
three scales were applied:
Both groups did not differ significantly and
received no
group)
Symptoms Scale (EPS),
- the Scale for Abnormal - and the Acathisia
patients
benzodiazepines
causes extrapyramidal
rally, abnormal involuntary - The Extrapyramidal
These
(benzodiazepine
sum
scores for
the
three
in the distribution scales for
be seen in Table 4. The mean values
scales
very
are
low
in
both groups,
of age
extrapyramidal
of the sum scores of
showing
no
significant
difference. Table 4 Movement Disorders
in Lonq-Term
Fluspirilene (N = 155) X
S
Fluspirilene
Therapy
Benzodiazepines p (N = 121) X S U-Test
Number of Fluspiri70.26
53.42
0.00
0.00
AIMS
lene Injections
1.84
3.71
1.71
2.68
EE'S
0.15
0.43
0.58
2.00
0.14
AKA
4.09
4.63
3.94
4.02
0.75
-General Discussion
6. The
low-dose neuroleptics
fact that
leasing
and
already
in
Reports
on
published
relaxing effect clinical
the
even
below
earlier
neuroleptanxiolysis
the
tranquilizers
experienced
specific
and
neuroleptics to the
that
condition
experiments
was proved
(Janke 1965).
neuroleptics
antipsychotically
quality
develop
effective dose the therapeutic
of
efficacy,
such a high acceptance.
an were
use of
of preparation
side effects
(Riither and Hippius
occurring, 1982).
benzodiazepine
Secondly, the use of
was subjected
as anxiolytics
potential danger
neuroleptical
tardive dyskinesia
experience the
soothing, anxiety-re-
limited by two features. Firstly, due to their
range
reference
have a
the psychical
(Proctor 1960). However,
was
therapeutic low-dose
on
earlier pharmaco-psychological effect
anxiolytic
0.62
such
to criticism with and dose-dependent as in particular
141
Low doseneuroleptanxiolyslsin anxiety states
as an alternative
The importance of neuroleptanxiolysis concept
the
in
risk of addiction Faced with
the background (v.
conditions
Zerssen et
(Rickels 1983),
was
intention
to
ingenious
and
treatment
of anxiety
the
provide safe
of numerous
psycho- and behavioral
of
basis
in
developing
for
(Quadbeck
and Lehmann
1988) and
application
of benzodiazepines
we do
a
It was
our
therapeutically
dosed neuroleptics
in
the
neuroleptanxiolysis
the therapy
uncritical
out systematic
fluspirilene.
disorders. We considered alternatives
long-term
of
group carried
low
under
and that
to the risk
with
rational
application
is inadequate
1988)
al.
our working
neuroleptanxiolysis
on
was
because of the potential
alone
is subject
with benzodiazepines
examinations
anxiety,
symptoms
of benzodiazepines
the wide use
in particular
problem that the
abnormal anxiety
for
dependence
one
psycho-vegetative
therapeutic
from
(Haase and Linde 1981).
'lonq-term Conditions
be
or
to be problematic,
suffering
patients
realized only after
increasingly recongnized
treatment
of
disorders
psychoreactive
therapy
treatment
of
not propagate
to
replace the
by the uncritical
use of low
dosed neuroleptics. 7.
The conclusions 1. Fluspirilene
Conclusions
of the four studies are briefly as follows:
has an anxiolytic effect in patients with anxiety,
psychoreactive
disorders,
and psychosomatic
in patients with somatically
expressed
complaints.
Especially
anxiety fluspirilene
is
superior to bromazepam. 2. The tolerance
is good. If side effects occur, they have an adverse
effect on therapeutic
results.
3. There exists a clear dose-effect
relationship.
Anxiety is reduced
best by a dosage of 1.5 mg fluspirilene/week. 4. We have no proof that a long-term fluspirilene
application
dosage bears a relevant risk of abnormal movements.
to
anxiety states
in low
142
K.HelnrlchandE.Lehmann
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Low dose neuroleptanxlolysls in anxiety states RUTHER,
E. and HIPPIUS, H. (1982) Neuroleptika in niedriger Dosierung als Tranquilizer. Morbid. Mortal. Wkly Rep. 124: 683-684 -
ZERSSEN, D. von, KRIEG, C., WITTCHEN, H.U. (1988) Der langfristige Verlauf behandelter und unbehandelter Angstsyndrome. In: K. Heinrich (Hg.) Angstsyndrome - Ursachen, Erschei nungsformen, Therapie. Janssen-Symp., Dusseldorf Inquiries and reprint requests should be addressed to: Prof. Dr. Kurt Heinrich Dept. of Psychiatry Heinrich Heine University Bergische Landstrasse 2 _ D-4000 Dusseldorf 12 Germany
143