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Prostaglandins and schizophrenia: A review
Prog. Neuro-Psychopharrnacol & Biol. Psychiat. 1982, Vol. ft. pp. 87-93 Printed in Great Britain. All rights reserved.
0278-5846/82/020087-07503.50/0
Copyright © 1982 Pergamon Press Ltd.
PROSTAGLANDINS AND SCHIZOPHRENIA: A REVIEW
MOHAMED RAGHEBand THOMASA. BAN IMiddle Tenessee Mental Health Center and 2Tennessee Neurosychiatic Institute--Clinical Research Service Nashvile, TN, USA
(Final form, February 1982) Contents I. 2. 2.1 2.2 3.4.
Abstract Biochemical and physiological data Clinical hypotheses Prostaglandin E deficiency Prostaglandin E ex£ess Discussion General conclusions References
87 87 89 89 90 91 91 91 Abstract
I. 2. 3. 4. 5.
Clinical observations and experimental findings are rendered which have raised the poss i b i l i t y that schizophrenia may be related to PGE deficiency and/or excess. In favor of PGEl deficiency are the findings that ADP-induced increase in synthesis and PGEI stimulated cAMP accumulation are significantly lower in platelets of schizophrenic patients than in normal controls. In favor of PGE excess are the findings that the concentration of immunoreactive PGE in cerebrospinal f l u i d of schizophrenics is higher than that of healthy controls, neurotic patients and patients undergoing neurological examination. An argument against the PG excess hypothesis is that paracetamol, a substance which reduces PG levels has no therapeutic effect in schizophrenia. The two hypotheses--PGE deficiency and PGE excess--are not compatible because of the bell shape dose response curve with PG's in certain biological systems.
Ke~words: prostaglandins, schizophrenia, prostaglandin deficiency, prostaglandin excess, platelets, cyclic AMP. Abbreviations: arachidonic acid (AA); cerebro-spinal f l u i d (CSF); dihomo-y-linolenic acid CDGLA); prostaglandin (PG). I.
Biochemical and Physiological Data
The prostaglandins are 20-carbon chain, unsaturated, cyclic f a t t y acids with a cyclopentane ring.
The PG's can be considered as analogs of prostanoic acid (Fig l , top).
They are
synthesized through a two step reaction involving f i r s t the cleavage of a polyunsaturated f a t t y acid from a membrane l i p i d by the activation of a phospholipase A and then conversion of the free acid into the appropriate prostaglandin (PG) (Olley and Coceani, 1980). They are six PG groups identified on the basis of substituents on the cyclopentane ring
88
H. Ragheb and T.A. Ban
(Fig l , bottom).
They are referred to as PGA, PGB, PGC, PGD, PGE and PGF. PGA, PGB and
PGC are derived from the corresponding PGE by dehydration and isomerization and are probably artifacts resulting from chemical extraction (Flower, 1977). 9
7
5
,/T~l ,,\XN~ 1
0 II
~ 13
3
I
COON
2 15
Prostonoic ocid
0 17
19
0 0
A
~
C
~
R,
I
~R2
OH
, ~
D
0
\RI
R2
Fig. I.
#
R2
Those i n d i c a t e d ~
T R2
Groups indicatedi~Jui~slie behind the plane l i e in front of the cyclopentane ring.
PG's are derived from essential f a t t y acids in the diet. series.
..~ OH
F
OH
Ring structures of prostaglandin A-F.
of the cyclopentane ring.
OH ~
E
'
0
R2
They belong to one of three
Members of series one contain one double-bond on the side chain and are derived
from dihomo-y-liolenic acid (DGLA); series two contain two double-bonds and are derived from arachidonic acid (AA); and series three contain three double-bonds and are derived from 5, 8, I I , 14, 17-eicosapentenoic acid.
The F series of PG's can potentially occur in two
stereochemical forms and are further designed as a and B (Flower, 1977; Olley and Coceani,
1980). Although PG's were first described in the human semen, they seem to be present in virtually all tissues and body fluids. PGE and PGF (as well as thromboxane B2) are synthesized in the brain (Wolfe et al., lg76a&b). Once formed PG's are not accumulated in stores. Their action is terminated by enzymatic degradation in the cytosol and through choroidal and extrachoroidal transport mechanisms. The latter might be particularly important since the brain, unlike most other tissues, has very low capacity to take up or metabolize PGE2 and PGF2 a to the 15keto-13-14 dihydro metabolites (Wolfe and Coceani, Ig7g). Since the discovery in the early Ig60's that some of the PG's are endogenous to brain, a large body of evidence has accumulated which suggests that PG's play a role in the
Prostaglandins and schizophrenia
modulation or mediation of humoral and other stimuli in neurons.
89
In keeping with this are
the findings that serotonin, dopamine and norepinephrine may enhance the conversion of AA to PG's (Price and Rowe, 1972; Wolfe et a l . , 1976a). PGE2 might also modulate the release of dopamine and norepinephrine in the brain.
Results in this context have been rather con-
f l i c t i n g with both increase and diminished catecholamine release reported following PGE2 administration (Bergstr~m et a l . , 1973; Roberts and H i l l i e r , 1976; Shenoy and Ziance, 1978). There is evidence that PGE2 formed in response to norepinephrine or cyclic AMP might modulate synaptic transmission through i n h i b i t i o n of cyclic AMP synthesis in some parts of the brain.
Prostaglandins have also been attributed a stimulatory action on cyclic AMP at dopa-
minergic synapsr~ (Wolfe and Coceani, 1979). PG's are implicated in a variety of physiological and pathological conditions including shock, pain, and inflammatory responses, as well as diseases such as rheumatoid a r t h r i t i s , and numerous other conditions (Horrobin, 1977, 1978; Olley and Coceani, 1980). 2.
Clinical Hypotheses
Clinical observations and experimental findings have raised the p o s s i b i l i t y that schizophrenia may be related to PGE deficiency and/or PGE excess. 2.1.
PGE Deficiency
The hypothesis that schizophrenia is a PGE deficiency disease (Horrobin, 1977) has evolved from the observations that schizophrenic patients are resistant to pain, inflammation and shock; show reduced wheel and f l a r e responses to histamine; manifest diminished systemic effects to typhoid vaccination and suffer only rarely from rheumatoid a r t h r i t i s (Osterberg, 1978). Moreover, PGE2 and i t s l l - t h i o l - l l
desoxy analogue have a spectrum of pharmacological
a c t i v i t y similar to that of clozapine, haloperidol, thioridazine and fluphenazine (Bloss and Singer, 1978); the action of clozapine is remarkably similar to PG's in behavioral tests used in the screening for neuroleptics (Bloss and Singer, 1978). These findings suggest that clozapine exerts i t s antipsychotic properties through a PGE-like action. There are some experimental-biochemical findings in support of a PGE1 deficiency hypothesis Abdulla and Hamada (1975) studied the in v i t r o synthesis of 14C-PGEI from
of schizophrenia.
14C-DGLA in platelets of schizophrenic, manic and depressive patients and found that the basic synthesis rate of 14C-PGEI showed no difference in these groups.
On the other hand,
high concentrations of adenosine diphosphate (ADP) increased 14C-PGEI synthesis by 400% to 500% in platelets of normal controls and patients suffering from affective disorders but not in platelets of schizophrenics.
At maximum ADP-concentrations the difference in 14C-PGE1
synthesis between schizophrenic and non-schizophrenic subjects was striking and significant at the p < 10-7 level.
The possible defect in PGE1 synthesis in the platelets of schizo-
phrenic patients was further substantiated by Rosotren et al. (1980) who found that the PGE1 stimulated 3H-cAMP accumulation in platelets from schizophrenic patients is s i g n i f i c a n t l y lower than in normal controls.
In variance with expectations however, PGEl-stimulated
3H-cAMP accumulation has shown no change under the influence of neuroleptic drugs.
Further-
more in the study of Kafka et al. (1979), PGEl-stimulated cAMP production was lower only in male but not in female schizophrenics.
One possible reason for this d i f f e r e n t i a l effect i s ,
90
M. Ragheb and T.A. Ban
that eight out of the eleven male patients in the study were diagnosed as schizophrenic and only three as schizoaffective, while six out of nine female patients were diagnosed as schizoaffective and only three as schizophrenic.
I t should also be noted that in the study
of Kafka et al. (1979), washed platelets were used and rather than tracing the conversion of an isotopically labelled tracer to 3H-cAMP, absolute levels of cAMP were measured by a competitive binding method. There are also some clinical pharmacological findings in favor of the PGEl deficiency hypothesis.
Therapeutically effective neuroleptics stimulate the production of prolactin, a
selective mobilizer of DGLAand consequently PGEl synthesis, while drugs which precipitate or aggravate schizophrenia, such as levodopa and cortisol, suppress prolactin secretion or block prolactin effects (Horrobin, 1977, 1978). Similarly drugs which increase PGEl synthesis, such as p e n i c i l l i n and evening primrose oil have shown therapeutic effects in schizophrenia, while PG antagonists, such as chloroquine, quinine and quinacrine in high doses may induce schizophrenia-like states (Chouinard, et ai.,1978; Horrobin, 1977; Vaddadi, 1979). There is some evidence that niacin-induced flushing is the results of an increase in PGEl synthesis since the niacin flush is similar to the flush produced by PGEl administration~ is accompanied by increased PGE levels in the blood and can be blocked by aspirin-like drugs which i n h i b i t PG synthesis (Eklund et a l . , 1979; Horrobin,1980b).
The findings that niacin
flush--after the oral administration of 250 mg of niacin--is absent in about 80% of schizophrenic patients is in accord with the PGEl deficiency hypothesis of schizophrenia.
In
favor also are the preliminary observations that with the increase of PGEl synthesis, there is normalization of the flush threshold with a corresponding normalization of behavior (Horrobin, 1980b). 2.2.
PGE Excess
While i t is proposed that schizophrenia is a PGEl deficiency disease, i t has also been sug. gested that schizophrenia is a disease of PGE excess (Feldberg, 1976). Catatonia-like states can be induced by injecting PGE's into the CSF of animals; and catatonic states have been encountered in response to endotoxins with increased brain and CSF-PG levels (Feldberg, 1976). Furthermore, Gjessing (1953, 1954) reported febrile episodes in two-thirds of his special group of catatonic patients. In favor of the contention that schizophrenia is a disease of PG excess are the findings that the concentration of immunoreactive PGE in the CSF of schizophrenics is higher than that of healthy controls, neurotic patients and patients undergoing neurological examination (Math~et a l . , 1980).
On the other hand, an argument against the PG excess hypothesis of
schizophrenia is that paracetamol, a substance which reduces PGE levels, has no therapeutic effect in schizophrenia (Falloon et a l . , 1978; Watt, 1979). An increase of PG's in the CSF can result from CNS derangement in a variety of neurological disorders e.g., subarchnoid hemorrhage, transient ischaemic attacks, meningoencephalitis and multiple sclerosis (Egg, et a l . , 1980; Wolfe and Coceani, 1979).
Prostaglandins and schizophrenia
3.
91
Discussion
Whether schizophrenia is the result of, or associated with PG changes--deficiency or excess--is far from being resolved.
Despite studies suggesting diminished PGE synthesis in
schizophrenic platelets, Rosotren et al. (1980) have brought to attention that there is a considerable overlap in response between schizophrenic patients and controls and that at least in their study psychotropic drugs did not alter PGEl-stimulated 3HcAMP accumulation. Even more, Pandey et al. (1977) showed an enhanced instead of a diminished response in pulse labelled washed platelets from five patients with acute schizophrenia. The most convincing findings in favor of PG excess in schizophrenia that of Math~ et al. (1980). However, they did not measure separately the amounts of PGEl and PGE2 in the CSF. This has created d i f f i c u l t i e s in the interpretation of their result.
Considering that PGEl
inhibits the metabolism of AA, i t is conceivable that the findings of increased total PGE levels are the result of an increase in PGE2 concentration due to reduction in PGEl formation (Horrobin, 1980a). Independent of this Horrobin (1977, 1978) suggests that PGEl deficiency and excess might not be incompatible because of the "bell-shaded" dose response curves seen with PGEl in certain systems including axonal conduction. 4.
General Conclusions
The available evidence linking schizophrenia to PGEl deficiency and/or excess is far from being conclusive. evaluation.
The results have mainly provided indirect evidence and await further
There has been considerable overlap in the response of schizophrenic platelets
compared to controls in their a b i l i t y to increase PGE synthesis (Rosotren, 1980). The absence of niacin flushing has been only observed in about 80% of the schizophrenic population (Horrobin, 1980b). The proportion of schizophrenic patients who shows normalization of the niacin flush following adequate response to neuroleptic therapy needs further investigation.
At best, the link between schizophrenia and PGE deficiency and/or excess may be
applicable to only a fraction of the schizophrenic population, emphasizing the heterogenity of the schizophrenic process. References ABDULLA, Y.H., and HAMADA, K. (1975): Effect of ADP on PGEl formation in blood platelets from patients with depression, mania and schizophrenia.
Br. J. Psychiat. 12___7_7:591-595.
BERGSTR~I, S., FARNEBO, L.A. and FUXE, K. (1973): Effect of prostaglandin E2 on central and peripheral catecholeamine neurons. Eur. J. Pharmacol. 21: 362-368. BLOSS, J.L. and SINGER, G.H. (1978): Neuropharmacological and behavioral evaluation of PGE2 and l l - t h i o l - l l - d e s o x y PGE2 in the mouse and rat.
Psychopharmacology 57: 295-302.
CHOUINARD, G., ANNABLE, L., and HORROBIN, D.F. (1978): l i n in schizophrenia.
An antipsychotic action of penicil-
IRCSJ. Med. Sci. 6: 187-188.
EGG, D., HEROLD, M., RUMPL, E. and G~'NTHER, R. (1980): Prostaglandin F2 ~ levels in human cerebrospinal f l u i d in normal and pathological conditions.
J. Neurol. 222: 239-248.
92
M. Ragheb and T.A. Ban
EKLUND, B., ~YSER, L., NOWACK,J. and WENNMALM,A. (1979): Prostaglandins contribute to the vasodilation induced by nicotinic acid. Prostaglandins 17: 821-830. FALLOON, I., WATT, D.C., LUBBE, K., MacDONALD, A. and SHEPHERD,M. (1978): N-acetyl-Pamino-phenol (Paracetamol, acetaminophen) in the treatment of acute schizophrenia. Psychol. Med. 8: 495-499. FELDBERG, W. (1976): Possible association of schizophrenia with a disturbance in prostaglandin metabolism: a physiological hypothesis. Psychol. Med. 6: 359-369. FLOWER, R.J. (1977): Prostaglandins and related compounds. Agents Actions Suppl. 3: 99-105. GJESSING, T. (1954-1954): Beitrage zur Somatologie der periodischen Katatonie. Mitteilung V-VIII: Archiv fur Psychiatric and Nervenkrankheiten, 191: 191-219, 220-246, 247-296, 297, 326. HORROBIN, D.F. (1977): Schizophrenia as a prostaglandin deficiency disease. Lancet I: 936-937. HORROBIN, D.F. (1978): Prostaglandins, physiology, pharmacology and clinical significance. Eden Press, Chapter 19-28. HORROBIN, D. (1980a): Prostaglandins and schizophrenia.
Lancet l: 706-707.
HORROBIN, D.F. (1980b): Schizophrenia: A biochemical disorder? Biomedicine 32: 54~55. ICAFIC~, M.S., VAN KAMMEN,D.P., and BUNNEY, W.E. (1979): Reducedcyclic AMP production in the blood platelets from schizophrenic patients. Am. J. Psychiat. 136: 685-687. MATH~, A.A., SEDVALL, C., WIESEL, F.A., and NYBACK, H. (1980): Increased content of immunoreactive prostaglandin E in cerebrospinal fluid of patients with schizophrenia. Lancet l: 16-17. OLLEY, P.M. and COCEANI, F. (1980): The prostaglandins. Am. J. Dis. Child. 134: 688-696. STERBERG, E. (1978): Schizophrenia and rheumatic disease. A study on the concurrence of inflammatory joint disease and a review of 58 case records. Acta Psychiat. Scand. 58: 339-359.
b,
PANDEY, G.N., GARVER, D.L., TAMMINGA, C., ERICKSEN, S., ALl, S.I., and DAVIS, J.M. (1977): Postsynaptic supersensitivity in schizophrenia. Am. J. Psychiat. 134: 518-522. PRICE, E.J. and ROWE, C.E. (1972): Stimulation of the production of unesterified fatty acids in nerve endings of guinea pig brain in vitro by noradrenaline and 5-hydroxytryptamine. Biochem. J. 126: 575. ROBERTS, P.j. and HILLIER, K. (1976): Facilitation of noradrenaline release from rat brain synaptosomes by prostaglandin. Brain Res. If2: 425-428. ROSOTREN, J., Miller, A.D., MANDIO, D., TP~AFICANTE, L.J. and GERSHON, S. (1980): glandins, platelets and schizophrenia. Arch. Gen. Psych. 37: I047-1054.
Prosta-
SHENOY, A. and ZIANCE, R. (1978): Modulation of 3H-norepinephrine release in rat cerebral cortex by prostaglandin E2 and autonomic drugs. Fed. Proc. 37: 688. VADDADI, K.J. (1979): Penicillin and essential fatty acid supplementation in schizophrenia. Prostaglandins and Medicine 2: 77-80. WATT, D.C. (1979): Prostaglandins and schizophrenia.
Lancet i: 668-669.
WOLFE, L.S. and COCEANI, F. (1979): The role of prostaglandins in the central nervous system. Ann. Rev. Physiol. 41: 669-684.
Prostaglandins and schizophrenia
93
WOLFE, L.S., PAPPIUS, H.M., and MARION, J. (1976a): The biosynthesis of prostaglandins by brain tissue in v i t r o .
Adv. Prostaglandin Thromboxane Res. l : 345-363.
WOLFE, L.S., ROSTOWOROWSKI, K. and MARION, J. (1976b): Endogenous formation of the prostaglandin endoperoxide metabolite thromboxane B2 by brain tissue. Comm. 70: 907-I013.
Inquiries and reprint requests should be addressed to: Dr. Thomas A. Ban Tennessee Neuropsychiatric Institute 1501Murfreesboro Road, Nashville, TN 37217
Bioch. Biophys. Res.
0278-5846/82/020087-07503.50/0
Copyright © 1982 Pergamon Press Ltd.
PROSTAGLANDINS AND SCHIZOPHRENIA: A REVIEW
MOHAMED RAGHEBand THOMASA. BAN IMiddle Tenessee Mental Health Center and 2Tennessee Neurosychiatic Institute--Clinical Research Service Nashvile, TN, USA
(Final form, February 1982) Contents I. 2. 2.1 2.2 3.4.
Abstract Biochemical and physiological data Clinical hypotheses Prostaglandin E deficiency Prostaglandin E ex£ess Discussion General conclusions References
87 87 89 89 90 91 91 91 Abstract
I. 2. 3. 4. 5.
Clinical observations and experimental findings are rendered which have raised the poss i b i l i t y that schizophrenia may be related to PGE deficiency and/or excess. In favor of PGEl deficiency are the findings that ADP-induced increase in synthesis and PGEI stimulated cAMP accumulation are significantly lower in platelets of schizophrenic patients than in normal controls. In favor of PGE excess are the findings that the concentration of immunoreactive PGE in cerebrospinal f l u i d of schizophrenics is higher than that of healthy controls, neurotic patients and patients undergoing neurological examination. An argument against the PG excess hypothesis is that paracetamol, a substance which reduces PG levels has no therapeutic effect in schizophrenia. The two hypotheses--PGE deficiency and PGE excess--are not compatible because of the bell shape dose response curve with PG's in certain biological systems.
Ke~words: prostaglandins, schizophrenia, prostaglandin deficiency, prostaglandin excess, platelets, cyclic AMP. Abbreviations: arachidonic acid (AA); cerebro-spinal f l u i d (CSF); dihomo-y-linolenic acid CDGLA); prostaglandin (PG). I.
Biochemical and Physiological Data
The prostaglandins are 20-carbon chain, unsaturated, cyclic f a t t y acids with a cyclopentane ring.
The PG's can be considered as analogs of prostanoic acid (Fig l , top).
They are
synthesized through a two step reaction involving f i r s t the cleavage of a polyunsaturated f a t t y acid from a membrane l i p i d by the activation of a phospholipase A and then conversion of the free acid into the appropriate prostaglandin (PG) (Olley and Coceani, 1980). They are six PG groups identified on the basis of substituents on the cyclopentane ring
88
H. Ragheb and T.A. Ban
(Fig l , bottom).
They are referred to as PGA, PGB, PGC, PGD, PGE and PGF. PGA, PGB and
PGC are derived from the corresponding PGE by dehydration and isomerization and are probably artifacts resulting from chemical extraction (Flower, 1977). 9
7
5
,/T~l ,,\XN~ 1
0 II
~ 13
3
I
COON
2 15
Prostonoic ocid
0 17
19
0 0
A
~
C
~
R,
I
~R2
OH
, ~
D
0
\RI
R2
Fig. I.
#
R2
Those i n d i c a t e d ~
T R2
Groups indicatedi~Jui~slie behind the plane l i e in front of the cyclopentane ring.
PG's are derived from essential f a t t y acids in the diet. series.
..~ OH
F
OH
Ring structures of prostaglandin A-F.
of the cyclopentane ring.
OH ~
E
'
0
R2
They belong to one of three
Members of series one contain one double-bond on the side chain and are derived
from dihomo-y-liolenic acid (DGLA); series two contain two double-bonds and are derived from arachidonic acid (AA); and series three contain three double-bonds and are derived from 5, 8, I I , 14, 17-eicosapentenoic acid.
The F series of PG's can potentially occur in two
stereochemical forms and are further designed as a and B (Flower, 1977; Olley and Coceani,
1980). Although PG's were first described in the human semen, they seem to be present in virtually all tissues and body fluids. PGE and PGF (as well as thromboxane B2) are synthesized in the brain (Wolfe et al., lg76a&b). Once formed PG's are not accumulated in stores. Their action is terminated by enzymatic degradation in the cytosol and through choroidal and extrachoroidal transport mechanisms. The latter might be particularly important since the brain, unlike most other tissues, has very low capacity to take up or metabolize PGE2 and PGF2 a to the 15keto-13-14 dihydro metabolites (Wolfe and Coceani, Ig7g). Since the discovery in the early Ig60's that some of the PG's are endogenous to brain, a large body of evidence has accumulated which suggests that PG's play a role in the
Prostaglandins and schizophrenia
modulation or mediation of humoral and other stimuli in neurons.
89
In keeping with this are
the findings that serotonin, dopamine and norepinephrine may enhance the conversion of AA to PG's (Price and Rowe, 1972; Wolfe et a l . , 1976a). PGE2 might also modulate the release of dopamine and norepinephrine in the brain.
Results in this context have been rather con-
f l i c t i n g with both increase and diminished catecholamine release reported following PGE2 administration (Bergstr~m et a l . , 1973; Roberts and H i l l i e r , 1976; Shenoy and Ziance, 1978). There is evidence that PGE2 formed in response to norepinephrine or cyclic AMP might modulate synaptic transmission through i n h i b i t i o n of cyclic AMP synthesis in some parts of the brain.
Prostaglandins have also been attributed a stimulatory action on cyclic AMP at dopa-
minergic synapsr~ (Wolfe and Coceani, 1979). PG's are implicated in a variety of physiological and pathological conditions including shock, pain, and inflammatory responses, as well as diseases such as rheumatoid a r t h r i t i s , and numerous other conditions (Horrobin, 1977, 1978; Olley and Coceani, 1980). 2.
Clinical Hypotheses
Clinical observations and experimental findings have raised the p o s s i b i l i t y that schizophrenia may be related to PGE deficiency and/or PGE excess. 2.1.
PGE Deficiency
The hypothesis that schizophrenia is a PGE deficiency disease (Horrobin, 1977) has evolved from the observations that schizophrenic patients are resistant to pain, inflammation and shock; show reduced wheel and f l a r e responses to histamine; manifest diminished systemic effects to typhoid vaccination and suffer only rarely from rheumatoid a r t h r i t i s (Osterberg, 1978). Moreover, PGE2 and i t s l l - t h i o l - l l
desoxy analogue have a spectrum of pharmacological
a c t i v i t y similar to that of clozapine, haloperidol, thioridazine and fluphenazine (Bloss and Singer, 1978); the action of clozapine is remarkably similar to PG's in behavioral tests used in the screening for neuroleptics (Bloss and Singer, 1978). These findings suggest that clozapine exerts i t s antipsychotic properties through a PGE-like action. There are some experimental-biochemical findings in support of a PGE1 deficiency hypothesis Abdulla and Hamada (1975) studied the in v i t r o synthesis of 14C-PGEI from
of schizophrenia.
14C-DGLA in platelets of schizophrenic, manic and depressive patients and found that the basic synthesis rate of 14C-PGEI showed no difference in these groups.
On the other hand,
high concentrations of adenosine diphosphate (ADP) increased 14C-PGEI synthesis by 400% to 500% in platelets of normal controls and patients suffering from affective disorders but not in platelets of schizophrenics.
At maximum ADP-concentrations the difference in 14C-PGE1
synthesis between schizophrenic and non-schizophrenic subjects was striking and significant at the p < 10-7 level.
The possible defect in PGE1 synthesis in the platelets of schizo-
phrenic patients was further substantiated by Rosotren et al. (1980) who found that the PGE1 stimulated 3H-cAMP accumulation in platelets from schizophrenic patients is s i g n i f i c a n t l y lower than in normal controls.
In variance with expectations however, PGEl-stimulated
3H-cAMP accumulation has shown no change under the influence of neuroleptic drugs.
Further-
more in the study of Kafka et al. (1979), PGEl-stimulated cAMP production was lower only in male but not in female schizophrenics.
One possible reason for this d i f f e r e n t i a l effect i s ,
90
M. Ragheb and T.A. Ban
that eight out of the eleven male patients in the study were diagnosed as schizophrenic and only three as schizoaffective, while six out of nine female patients were diagnosed as schizoaffective and only three as schizophrenic.
I t should also be noted that in the study
of Kafka et al. (1979), washed platelets were used and rather than tracing the conversion of an isotopically labelled tracer to 3H-cAMP, absolute levels of cAMP were measured by a competitive binding method. There are also some clinical pharmacological findings in favor of the PGEl deficiency hypothesis.
Therapeutically effective neuroleptics stimulate the production of prolactin, a
selective mobilizer of DGLAand consequently PGEl synthesis, while drugs which precipitate or aggravate schizophrenia, such as levodopa and cortisol, suppress prolactin secretion or block prolactin effects (Horrobin, 1977, 1978). Similarly drugs which increase PGEl synthesis, such as p e n i c i l l i n and evening primrose oil have shown therapeutic effects in schizophrenia, while PG antagonists, such as chloroquine, quinine and quinacrine in high doses may induce schizophrenia-like states (Chouinard, et ai.,1978; Horrobin, 1977; Vaddadi, 1979). There is some evidence that niacin-induced flushing is the results of an increase in PGEl synthesis since the niacin flush is similar to the flush produced by PGEl administration~ is accompanied by increased PGE levels in the blood and can be blocked by aspirin-like drugs which i n h i b i t PG synthesis (Eklund et a l . , 1979; Horrobin,1980b).
The findings that niacin
flush--after the oral administration of 250 mg of niacin--is absent in about 80% of schizophrenic patients is in accord with the PGEl deficiency hypothesis of schizophrenia.
In
favor also are the preliminary observations that with the increase of PGEl synthesis, there is normalization of the flush threshold with a corresponding normalization of behavior (Horrobin, 1980b). 2.2.
PGE Excess
While i t is proposed that schizophrenia is a PGEl deficiency disease, i t has also been sug. gested that schizophrenia is a disease of PGE excess (Feldberg, 1976). Catatonia-like states can be induced by injecting PGE's into the CSF of animals; and catatonic states have been encountered in response to endotoxins with increased brain and CSF-PG levels (Feldberg, 1976). Furthermore, Gjessing (1953, 1954) reported febrile episodes in two-thirds of his special group of catatonic patients. In favor of the contention that schizophrenia is a disease of PG excess are the findings that the concentration of immunoreactive PGE in the CSF of schizophrenics is higher than that of healthy controls, neurotic patients and patients undergoing neurological examination (Math~et a l . , 1980).
On the other hand, an argument against the PG excess hypothesis of
schizophrenia is that paracetamol, a substance which reduces PGE levels, has no therapeutic effect in schizophrenia (Falloon et a l . , 1978; Watt, 1979). An increase of PG's in the CSF can result from CNS derangement in a variety of neurological disorders e.g., subarchnoid hemorrhage, transient ischaemic attacks, meningoencephalitis and multiple sclerosis (Egg, et a l . , 1980; Wolfe and Coceani, 1979).
Prostaglandins and schizophrenia
3.
91
Discussion
Whether schizophrenia is the result of, or associated with PG changes--deficiency or excess--is far from being resolved.
Despite studies suggesting diminished PGE synthesis in
schizophrenic platelets, Rosotren et al. (1980) have brought to attention that there is a considerable overlap in response between schizophrenic patients and controls and that at least in their study psychotropic drugs did not alter PGEl-stimulated 3HcAMP accumulation. Even more, Pandey et al. (1977) showed an enhanced instead of a diminished response in pulse labelled washed platelets from five patients with acute schizophrenia. The most convincing findings in favor of PG excess in schizophrenia that of Math~ et al. (1980). However, they did not measure separately the amounts of PGEl and PGE2 in the CSF. This has created d i f f i c u l t i e s in the interpretation of their result.
Considering that PGEl
inhibits the metabolism of AA, i t is conceivable that the findings of increased total PGE levels are the result of an increase in PGE2 concentration due to reduction in PGEl formation (Horrobin, 1980a). Independent of this Horrobin (1977, 1978) suggests that PGEl deficiency and excess might not be incompatible because of the "bell-shaded" dose response curves seen with PGEl in certain systems including axonal conduction. 4.
General Conclusions
The available evidence linking schizophrenia to PGEl deficiency and/or excess is far from being conclusive. evaluation.
The results have mainly provided indirect evidence and await further
There has been considerable overlap in the response of schizophrenic platelets
compared to controls in their a b i l i t y to increase PGE synthesis (Rosotren, 1980). The absence of niacin flushing has been only observed in about 80% of the schizophrenic population (Horrobin, 1980b). The proportion of schizophrenic patients who shows normalization of the niacin flush following adequate response to neuroleptic therapy needs further investigation.
At best, the link between schizophrenia and PGE deficiency and/or excess may be
applicable to only a fraction of the schizophrenic population, emphasizing the heterogenity of the schizophrenic process. References ABDULLA, Y.H., and HAMADA, K. (1975): Effect of ADP on PGEl formation in blood platelets from patients with depression, mania and schizophrenia.
Br. J. Psychiat. 12___7_7:591-595.
BERGSTR~I, S., FARNEBO, L.A. and FUXE, K. (1973): Effect of prostaglandin E2 on central and peripheral catecholeamine neurons. Eur. J. Pharmacol. 21: 362-368. BLOSS, J.L. and SINGER, G.H. (1978): Neuropharmacological and behavioral evaluation of PGE2 and l l - t h i o l - l l - d e s o x y PGE2 in the mouse and rat.
Psychopharmacology 57: 295-302.
CHOUINARD, G., ANNABLE, L., and HORROBIN, D.F. (1978): l i n in schizophrenia.
An antipsychotic action of penicil-
IRCSJ. Med. Sci. 6: 187-188.
EGG, D., HEROLD, M., RUMPL, E. and G~'NTHER, R. (1980): Prostaglandin F2 ~ levels in human cerebrospinal f l u i d in normal and pathological conditions.
J. Neurol. 222: 239-248.
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M. Ragheb and T.A. Ban
EKLUND, B., ~YSER, L., NOWACK,J. and WENNMALM,A. (1979): Prostaglandins contribute to the vasodilation induced by nicotinic acid. Prostaglandins 17: 821-830. FALLOON, I., WATT, D.C., LUBBE, K., MacDONALD, A. and SHEPHERD,M. (1978): N-acetyl-Pamino-phenol (Paracetamol, acetaminophen) in the treatment of acute schizophrenia. Psychol. Med. 8: 495-499. FELDBERG, W. (1976): Possible association of schizophrenia with a disturbance in prostaglandin metabolism: a physiological hypothesis. Psychol. Med. 6: 359-369. FLOWER, R.J. (1977): Prostaglandins and related compounds. Agents Actions Suppl. 3: 99-105. GJESSING, T. (1954-1954): Beitrage zur Somatologie der periodischen Katatonie. Mitteilung V-VIII: Archiv fur Psychiatric and Nervenkrankheiten, 191: 191-219, 220-246, 247-296, 297, 326. HORROBIN, D.F. (1977): Schizophrenia as a prostaglandin deficiency disease. Lancet I: 936-937. HORROBIN, D.F. (1978): Prostaglandins, physiology, pharmacology and clinical significance. Eden Press, Chapter 19-28. HORROBIN, D. (1980a): Prostaglandins and schizophrenia.
Lancet l: 706-707.
HORROBIN, D.F. (1980b): Schizophrenia: A biochemical disorder? Biomedicine 32: 54~55. ICAFIC~, M.S., VAN KAMMEN,D.P., and BUNNEY, W.E. (1979): Reducedcyclic AMP production in the blood platelets from schizophrenic patients. Am. J. Psychiat. 136: 685-687. MATH~, A.A., SEDVALL, C., WIESEL, F.A., and NYBACK, H. (1980): Increased content of immunoreactive prostaglandin E in cerebrospinal fluid of patients with schizophrenia. Lancet l: 16-17. OLLEY, P.M. and COCEANI, F. (1980): The prostaglandins. Am. J. Dis. Child. 134: 688-696. STERBERG, E. (1978): Schizophrenia and rheumatic disease. A study on the concurrence of inflammatory joint disease and a review of 58 case records. Acta Psychiat. Scand. 58: 339-359.
b,
PANDEY, G.N., GARVER, D.L., TAMMINGA, C., ERICKSEN, S., ALl, S.I., and DAVIS, J.M. (1977): Postsynaptic supersensitivity in schizophrenia. Am. J. Psychiat. 134: 518-522. PRICE, E.J. and ROWE, C.E. (1972): Stimulation of the production of unesterified fatty acids in nerve endings of guinea pig brain in vitro by noradrenaline and 5-hydroxytryptamine. Biochem. J. 126: 575. ROBERTS, P.j. and HILLIER, K. (1976): Facilitation of noradrenaline release from rat brain synaptosomes by prostaglandin. Brain Res. If2: 425-428. ROSOTREN, J., Miller, A.D., MANDIO, D., TP~AFICANTE, L.J. and GERSHON, S. (1980): glandins, platelets and schizophrenia. Arch. Gen. Psych. 37: I047-1054.
Prosta-
SHENOY, A. and ZIANCE, R. (1978): Modulation of 3H-norepinephrine release in rat cerebral cortex by prostaglandin E2 and autonomic drugs. Fed. Proc. 37: 688. VADDADI, K.J. (1979): Penicillin and essential fatty acid supplementation in schizophrenia. Prostaglandins and Medicine 2: 77-80. WATT, D.C. (1979): Prostaglandins and schizophrenia.
Lancet i: 668-669.
WOLFE, L.S. and COCEANI, F. (1979): The role of prostaglandins in the central nervous system. Ann. Rev. Physiol. 41: 669-684.
Prostaglandins and schizophrenia
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WOLFE, L.S., PAPPIUS, H.M., and MARION, J. (1976a): The biosynthesis of prostaglandins by brain tissue in v i t r o .
Adv. Prostaglandin Thromboxane Res. l : 345-363.
WOLFE, L.S., ROSTOWOROWSKI, K. and MARION, J. (1976b): Endogenous formation of the prostaglandin endoperoxide metabolite thromboxane B2 by brain tissue. Comm. 70: 907-I013.
Inquiries and reprint requests should be addressed to: Dr. Thomas A. Ban Tennessee Neuropsychiatric Institute 1501Murfreesboro Road, Nashville, TN 37217
Bioch. Biophys. Res.