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

References AMERICAN PSYCHIATRIC ASSOCIATION (APA) (1987) Diagnostic and Statistical Manual of Mental Disorders DSM-III-R, 3rd Edition revised, Wasninqton, D.C. GREENE, R.L.(1980) The MMPI, Grune et Stratton, Orlando HAASE, E.H. and LINDE, O.K. (1981) Therapeutische Aspekte zur Anwendung von Benzodiazepinen als Tranquilizer, Psycho j_~ HAMILTON, M. HAMA (1976) Hamilton Anxiety Scale. In: CIPS, Internationale Skalen fiirPsychiatric, Beltz, Weinheim HASSEL, P.: (1985) Experimental comparison of low doses of 1.5 mq fluspirilene and bromazepam in out-patients with psychovegetative disturbances. Pharmacopsychiat. 2: 297-302 HEINRICH, K., LENIN, E. (1988) Fundamentals and Results of Controlled Studies in Neuroleptanxiolysis. Eur. J. Psychiat. _2; 96-102 HOFFMEISTER, F. (1982) Zur Pharmakologie der Benzo- und Thienodiazepine. In: Gegenwartiger Wissensstand der Anwendung von Benzo- und Thienodiazepinen. Hrsg. von der Fed. Abt. der Troponwerke Ktiln. PMI-Verlang, Frankfurt/Main JANKE, W. (1965) Untersuchungen zur Frage von Wirkungsunterschieden von Fluphenazin nach erst- und mehrmaliger Applikation. Psychopharmakologia 7: 349-365 JANKE, W.; DEBUS, G. (19771 Die EigenschaftswBrterliste, Hogrefe, GSttingen LADEWIG, D. (1982) Abusus von Benzodiazepin-Tranquilizern. Med. Welt 33: 1306-1309 LAZARUS, A.A. (19831 Fragebogen zur Lebensgeschichte Deutsche Gesellschaft fiirVerhaltenstherapie, Tiibingen LEHMANN, E.; HASSEL, P.; THijRNER,G.W.; KARRAS, W. (1984) Alternatives Therapiekonzept zur Behandlung psychosomatischer Beschwerden. Fortschr. Med. 4i: 1033-1036 LEHMANN, E. (1987) Neuroleptanxiolyse: Neuroleptika in Tranquilizerindikation. In: Pichot & Mijller,Neuroleptika Riickschau 1952-1986, KiinftigeEntwicklunqen, Springer, Berlin pp 111-118 LEHMANN, E. (1989) The dose-effect relationship of 0.5 mg, 1.0 mg and 1.5 mg fluspirilene on anxious patients, Neuropsychobiology 21: 197-204 LEHMANN, E.; HEINRICH, K.; ~RT~~N, C. (1990) Niedrigdosierte Neuroleptanxiolyse. In: K. HEINRICH (Hg.f Leitlinien neuroleptischer Therapie. Springer, Berlin PACH, W., WANIER, w., PAPASPYROU, D. (1973) Zur TranquilizerWirkung des Langzeit-Neuroleptikums Fluspirilen (ImapRt. Pharmacopsychiat. $_z 198-206 PROCTOR, R.C. (1960) Results with fluphenazine in anxiety and tension. Dis Nerv Syst 21: 283-285 QUADBECK, H. and LEHMANN, E. (1988) Neue Strategien der r_..: n~r~r~lyse. In: K. iieinrich,B. Bogerts (Hg.): Angstsyndrome Schattauer, Stuttgart pp 173-187 RICKELS, K. (1983) Benzodiazepines in emotional disorders. _) Psychoactive Drugs 1_5:49-54 ".

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

Low dose neuroleptanxiolysis in anxiety states.

1. In order to prove that neuroleptanxiolysis represents a therapeutical alternative in the treatment of patients suffering from anxiety we conducted ...
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