?-ENDORPHIN ADMINISTRATION TO ACUTE SCHIZOPHRENIC PATIENTS: A DOUBLE BLIND STUDY

8-ENDORPHIN ADMINISTRATION TO ACUTE SCHIZOPHRENIC PATIENTS: A DOUBLE BLIND STUDY

Bertalan Petho,* LBszld Gr&f,t Is tvh Karczag,* J h o s Borvendkg,t Istvhn Bitter,* Istvh Barna,t Ilona Hermann,t Judit Toha,*

and Krisztina Baraczka * * Semmelweis Medical University

Budopest, Hungary t Institute for Drug Research

Budapest, Hungary

Apparently incompatible experimental findings and considerations support the hypothesis that the endogenous opioids participate, in some way, in maintaining the psychic equilibrium. Terenius et al.18 first drew attention to the possible connection between disorders in the metabolism of endogenous opioids and the different psychoses. According to their investigations, the measurable concentration of partially purified Fraction I, an opioid peptide different from enkephalins and @-endorphin, is considerably higher in the CSF of schizo- phrenics than in that of control patients. This tendency was more marked in acute cases and parallel with the improvement of the clinical condition. Neuroleptic therapy reduced Fraction I levels that were initially above the control value.2 This recognition raised the possibility of treating schizophrenic patients with opiate antagonists (e.g., naloxone) ,s but most authors have reported on the failure of therapy.' Interpretation of the findings is greatly hampered by the fact that the opiate antagonists block the effect not only of Fraction I, but of all the other endogenous opioids, including those which other authors consider to play a psychopathological role antagonistic to that of Fraction I. This latter view is essentially based on two experimental obser- vations. Jacquet and Marks suggested a similarity between certain pharma- cological properties of &endorphin and the neuroleptics, while de Wied et al.B demonstrated neuroleptic activity for y-endorphin, one of the fragments of 8-endorphin also released under physiological condition^.^

After studying the complex psychiatric literature on alkaloid narcotics and endogenous opioids, Verebey et al.8 have proposed that the endogenous opioids contribute to maintaining psychic equilibrium through their anxiolytic, tran- quilizing, antidepressant, anger-, aggression-, and delusion-reducing effects, and their action in reducing insufficiency and suicidal tendencies. Consequently, reduction of the level of endogenous opioids would result in manifestations antagonistic to the above favorable effects (anxiety, hypersensitivity to average stress, reduced self-esteem, etc.) .

it became possible to conduct clinical tests of the polypeptide. mine and LehmaM lo

administered &endorphin in intravenous doses of 1.5-9.0 mg to 15 psychiatric patients on 42 occasions. On the basis of the nature and duration of the effects, the authors distinguished four phases in the action: I. autonomous (30-120 sec); 11. antidysphoric (1-6 hours); 111. inhibitory (2-3 hours); IV. therapeutic (1-10 days). Vegetative reactions appeared in phase I and

With the successful chemical synthesis of human &endorphin

460 3011-8923/82/0398-0460 $01.15/0 0 1982. W A S

Petho et al. : P-Endorphin and Schizophrenia 46 1

favorable therapeutic effects (improved mood, relief from anxieties, etc.) could be observed in phases 11-IV.10 The main technical shortcomings in these and in the investigations by Angst et al." giving rise to the possibility of error, were as follows: ( 1 ) the investigations were not carried out in blind design; (2) the authors did not use a structured evaluation; l2 and (3) the medication given at the same time as the treatment or its interruption could influence the effect of the 8-endorphin.

We report here studies on &endorphin treatment of six acute schizophrenic patients in a double-blind design. These patients did not receive any other medication during the trial period. During the preparation of our pre- liminary report l3 on these studies, double-blind clinical studies with &endorphin have also been reported by two other groups.14* l5

MATERIALS AND METHODS

Human @endorphin was produced by solid-phase peptide synthesis l8 in Prof. C. H. Li's laboratory (University of California, San Francisco). We checked the homogeneity of this /?-endorphin preparation with end-group and amino acid analyses and paper and gel electrophoreses (see ref. 16 for the methods). Following intracerebroventricular (i.c.v.) administration, the an- algesic effect determined by the rat tail-flick test was the same as that of pig 8-endorphin isolated from natural source.17

Synthetic human 8-endorphin was dissolved in physiological saline solution, strained through a Millipore HA 0.22 p filter, and filled in ampules under sterile conditions. Each ampule contained 4.0 mg of 8-endorphin in 10 ml of physiological saline solution. The ampules were stored at -20°C.

Since @-endorphin has not yet been administered to patients suffering from manifest psychosis, we selected such patients for our investigation (TABLE 1 ). Six patients each received 4 mg of 8-endorphin intravenously, while three patients were given the same volume of physiological saline solution. The injection lasted 5 minutes in all cases.

Our investigations were conducted in a double-blind design, with the psychopathological examination recorded according to the factor construct rating scale (FCRS) 18 in patients who had received no medication for a t least 10 days and who were not receiving any other medication during the course of the study. The injection was administered at 10 A.M. The psychopathological and pain sensation tests were conducted at the following times: (1) at 8:30 A.M. on the day of treatment; (2) in 15 minutes immediately following the treatment; (3) hourly on the day of treatment up to 5 P.M.; and (4) at 9 A.M. and 1 P.M. on the days following treatment for one week unless it became necessary before the end of this period to give other (neuroleptic, anxiolytic) medication.

One hour before the 8-endorphin injection and at the same time on the third day, we took 9-10 ml of CSF by lumbar puncture with the patient in a seated position. After removal the CSF was immediately frozen and was then lyophilized and dissolved again in 0.9-1.0 ml distilled water in order to determine the &endorphin content by radioimmunoassay (RIA). For the details of the @-endorphin RIA method we refer to the description given by Borvendeg et al.lg We used a pig &endorphin antibody produced in rabbits in a dilution of 1 : 30,000; the lower limit of sensitivity, 20 pg b-endorphin, gave a 100% cross reaction with reference human 8-endorphin.

TA

BL

E 1

P

Q\

h)

MAIN DATA

ON P

ATIE

NTS

Mon

ths S

ince

O

nset

of

NO. O

f H

OS-

Pa

tient

Sex

Age

Il

lnes

s Course of

Illn

ess

pita

lizat

ions

Pr

esen

t Syn

drom

e D

iagn

osis

1. M.N.

fem

ale

31

22

Full

rem

issi

on a

fter

firs

t 2

Acu

te a

nxie

ty

Cyc

loid

psy-

c

psyc

hosi

s; n

ow r

ecov

ered

ps

ycho

sis w

ith d

elu-

ch

osis

v1 z

sixd

ay p

rodr

omal

per

iod;

re

ligio

us a

nd m

egal

o-

chos

is

4

4 m

onth

s si

ons of

ref

eren

ce

2. B.F.

mal

e 19

%

H

yper

acut

e ons

et a

fter

1

Con

fusi

on, w

ith

Cyc

loid

PSY

- 9 % b H g

reco

vere

d in

3 m

onth

s

3. R.L.

fem

ale

42

2 Fi

rst p

sych

osis

dis

ap

2 A

udito

ry, v

isua

l and

A

ffec

t-lad

en

pear

ed a

fter

3 w

eeks

; ol

fact

ory

hallu

cina

- pa

raph

reni

a ac

ute

onse

t of

subs

eque

nt

9 ps

ycho

sis;

sec

ond

rem

is-

sion

follo

wed

by

anot

her

ence

, inc

oher

ence

Y

E! re

laps

e 2

mon

ths

late

r

chro

nica

lly au

tistic

and

m

ent,

audi

tory

hal

- ca

tato

nia

inca

pabl

e of

wor

k. De-

lu

cina

tions

. cat

aton

ic

R te

rior

atio

n ev

ery

2-3

year

s sy

mpt

oms

I

man

iac

exal

tatio

n

tions

, anx

iety

, de

lusi

ons o

f re

fer-

110

Chr

onic

schi

zoph

reni

a,

5 A

nxie

ty, b

ewild

er-

Para

kine

tic

4. C.B.

mal

e 25

5. K.B.

mal

e 25

96

C

hron

ic sc

hizo

phre

nia;

10

So

mae

sthe

sic h

allu

ci-

Cat

apha

sia

has

been

eng

aged

in h

os-

natio

ns; au

dito

ry

pita

1 w

ork

ther

apy

for 5

ha

lluci

natio

ns;

year

s; d

eter

iora

tion

anxi

ety,

dep

er-

appr

ox. e

very

six

mon

ths

sona

lizat

ion;

mild

sc

hizo

phas

ia

6. C.M.

fem

ale

24

82

Chr

onic

schi

zoph

reni

a;

has b

een

inca

pabl

e of

w

ork

for y

ears

; vag

rant

. D

eter

iora

tion

ever

y 6-

12

mon

ths

Con

trol

pat

ient

s w

ho re

ceiv

ed o

nly

intra

veno

us s

alin

e inj

ectio

n:

7. J

.I.

mal

e 27

34

H

as b

een

unab

le to

w

ork

sinc

e th

e fir

st

psyc

hosi

s; li

ves

with

fa

mily

. Chr

onic

schi

m-

phre

nia

8. T

.M.

fem

ale

36

170

Chr

onic

schi

zoph

reni

a;

lives

with

par

ents

, re

duce

d ca

paci

ty f

or

wor

k an

d ad

just

men

t. E

mot

iona

l blu

ntin

g

12

Emot

iona

l blu

ntin

g;

Shal

low

m

anne

rism

s; u

nrea

- he

beph

reni

a so

nabl

e eu

phor

ia a

nd

irrita

bilit

y; in

fant

ile

joki

ng; h

eter

onom

ous

sens

atio

ns; i

ncoh

eren

ce

cd

abno

rmal

phy

sica

l (D

g b s .. 4

Man

neris

ms,

inac

tive,

M

anne

ristic

bl

untin

g, in

diff

eren

t, ca

tato

nia

hesi

tant

, mild

anx

iety

11

Aud

itory

hal

luci

na-

Aut

istic

tio

ns, d

elus

ions

of

hebe

phre

nia

g. re

fere

nce,

mild

an

xiet

y an

d in

co-

here

nce

WJ 9.

E.L.

mal

e 22

2

Suba

cute

ons

et o

f ill

ness

1

Inhi

bite

d, s

light

ly

Cyc

loid

0

wild

ered

, mild

del

u-

m T

2.

tens

e, in

activ

e, b

e-

psyc

hosi

s

sion

s of

refe

renc

e 0

(D

Note:

The

mor

e pr

ecis

e di

agno

sis

was

bas

ed on

Leon

hard

."

We

clas

sifie

d th

e cy

cloi

d ps

ycho

sis

orde

r. in

to t

he s

chiz

ophr

enia

spe

ctru

m d

is-

rs

464 Annals New York Academy of Sciences

n + v

+ +

+ +

n n + +

+ h

v I I +

m - w - f - b - rn

+ ++ + h + + v

I + I +

I T + I I ,+

I + 1 + 1

IN I

Petho et al.: p-Endorphin and Schizophrenia

I T Y I I

I ' i l Y I

h + W

+ ? + Y

h

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h + + I I v T I Y

465


RESULTS

Marked and lasting somnolence developed in two patients (3 and 6) on the day of the &endorphin injection. A milder degree of somnolence could also be observed in the other four patients. We did not observe a reduction in the pain sensation in any of the patients when the skin was pricked with a needle. There was a change in the psychiatric symptoms in patients 1, 2, and 3 even within 30 minutes and one hour, particularly on the first day. The characteristic daily values for the FCRS scores are given in TABLE 2. Cogni- tive disorders showed a minimal improvement only in patient 6 and here too, only after days 6 and 7 following the treatment. With the exception of patient 4, psychomotor activity showed normalization in the first days. Where inhibition had been more marked before treatment with 8-endorphin it declined, and where agitation and excitement were more prominent, these were reduced. There was a similar reciprocal change in mood in patient 3 compared to the initial value before administration of &endorphin. Transient euphoria also occurred in two other patients (1 and 5 ) . Patients 2 and 6 were in such a state of prolonged euphoria prior to treatment that any further increase in euphoria would have been difficult to detect. Anxiety was defi- nitely reduced in four patients (1, 3, 4, and 5 ) but later-also in the case of patient 2-just because of the very marked increase in anxiety-neuroleptic- anxiolytic treatment had to be started. There was no substantial change in the other items of the FCRS. In four cases the intensity of the psychosis as reflected in the FCRS overall score first declined and then rose, in one case ( 5 ) it rose immediately and rapidly and in another one (6) it did not change.

Among the three control patients (whose FCRS scores are not shown), patient 7 improved suddenly and substantially after the psychological saline injection was given. For 3 days he was bright, active, and sociable, although his manneristic behavior remained unchanged. It was only in this case that the “blind” observer felt certain that the patient had received @endorphin. His symptoms returned after 3 days and he had to be given anxiolyticums for his acute anxiety. The psychosis of control patient 8 grew gradually and steadily worse until we administered a neuroleptic drug on day 4. The behavior of control patient 9 was slightly improved, but he also had to be given neuroleptics on day 3.

In agreement with the data in the literature,z0 the 8-endorphin immuno- reactivity in the CSF of the patients before the treatment gave a value in the range of 12-50 pg 8-endorphinlml. The CSF @-endorphin levels determined three days after treatment with @-endorphin in patients 4, 5, and 6 and in the two control patients examined (7 and 8), coincided with the initial values while in three patients (1, 2, and 3) we found a significant rise in the level (TABLE 3 ) .

DISCUSSION

All of our six patients given 8-endorphin treatment showed a certain improvement for a shorter or longer period. This improvement was restricted to the area of mood and activity. The nature of the improvement depended on the initial symptoms; in all cases they indicated a tendency to restore the homeostasis. Contrary to the earlier data in the literature,los l1 the formal

Petho et al. : ,&Endorphin and Schizophrenia 467

symptoms (e.g. mannerism) and cognitive disorders did not improve. For this reason, at least in the case of acute psychoses, &endorphin treatment probably represents only “temperament therapy.” There was no easing of the delusions and hallucinations and at most, the influence of the latter on experience and behavior declined as a result of the shift in mood.

It would appear that the more intensive the psychosis, the less the homeo- static influence of 8-endorphin. In the six cases we studied it is questionable whether &endorphin had any influence whatsoever in relieving the psychosis. We consider it probable that we are evaluating the so-called “own effect” of &endorphin, that is, the effect by which it invariably induces transitory improvement in healthy people too. On the other hand, &endorphin does not seem to have any real antipsychotic effect. The psychic disorders (retarda- tion, confusion, bewilderment (see refs. 10, 21) produced by &endorphin administered to persons free of psychopathological symptoms could indicate

TABLE 3

p ENDORPHIN TREATMENT AND ON THE THIRD DAY AFTER TREATMENT ENDORPHIN IMMUNOREACTIWTY (pg per ml) IN THE CSF OF THE PATIENTS BEFORE

Patient p-Endorphin Immunoactivity

Before Treatment After Treatment 1. 2. 3. 4. 5. 6. 7. 8. 9.

12 f 1.4 * 17 -C 1.5 24 & 8.4 13 -C 0.1 21 f 0.2 15 2 3.9 50 2 0.8 27 f 4.5 17 -C 0.5

24 rt 5.3 64 k 12.2 85 k 2.8 17 f 1.6 23 k 0.5 22 f 1.8 48 2 1.8 32 k 5.3

- t

* Mean -C standard deviation of 4 parallel measurements. t Measurement was not performed.

that the “own effect” of 8-endorphin also acts to upset the psychic equilibrium. The result of the “own effect,” which is bipolar from the viewpoint of homeostasis, almost certainly depends to a great extent on the initial condition of the organism which, in our cases, was seriously altered. We suggest that the widely differing duration of the “therapeutic phase” from patient to patient can be interpreted on the basis of these considerations: the “therapeutic phase” lasts only until the psychosis cancels out the “own effect”; the length of time this takes depends on the initial condition (in patient 2, for example, this was slightly less than one day).

This interpretation may help to resolve the apparent discrepancy between the two recent clinical studies showing either slight improvement l4 or significant worsening in the schizophrenic symptoms l6 after B-endorphin administration. Our results are more consistent with those of Berger et d . 1 4

who gave @-endorphin intravenously, whereas Gerner et al.15 gave @endorphin by infusion. The manner of administration may also affect the clinical results.


As regards the change in the B-endorphin level measured in the CSF (TABLE 3) it is striking that we observed a marked rise in level only in the three ( 1-3) schizophrenic syndromes accompanied by strong affective symptoms (“schizo-affective” psychosis). Since according to Foley et a1.,22 the half-life of human &endorphin administered to humans intravenously and intracerebroventricularly is 37 and 93 minutes, respectively, it is improbable that the 8-endorphin immunoactivity measured on the third day would be caused by the exogenous polypeptide. However, the possibility arises that p-endorphin introduced could stimulate the biosynthesis or release of cerebral (or hypophyseal?) pendorphin through some, as yet unknown, mechanism. If confirmed, this observation could give a new angle to the investigation of the pathogenesis of the schizo-affective psychoses. The selective susceptibility of the schizophrenic subgroups is also an open question.23

In drawing our conclusions, not only the small number of patients but also the experience with the control patients point to the need for increased cau- tion. As the example of patient 7 shows, the intravenous placebo injection can result in a transitory remission of the patient that misleadingly resembles the “temperament therapy” that can be expected from /%endorphin.

ACKNOWLELXMENT

We are grateful to Professor C. H. Li (University of California, San Francisco) for supplying us with synthetic human p-endorphin.

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1977. J. Neural. Transm. 40: GUNNE, L. M., I. LINDSTROM & L. TERENIUS. 13-19.

DAVIS, G. C., W. E. BU”EY, E. G. DE FWmS, J. E. K L E I ” , D. P. VAN KAMMEN, R. M. POST & R. J. WYAIT. 1977. Science 197: 74-77.

JACQUET, Y. F. & N. MARKS. 1976. Science 194: 632-635. DE WIED, D., G. L. KOVACS, B. Boms, J. M. VAN REE & H. M. GREVEN.

BURBACH, I. P. H., J. G. LOEBER, J. VERHOEF, V. M. WIEOANT, E. R. UOET 1978.

& D. DE WED. 1980. Nature 283: 96-97.

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?-ENDORPHIN ADMINISTRATION TO ACUTE SCHIZOPHRENIC PATIENTS: A DOUBLE BLIND STUDY

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