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Failure to detect by anaphylaxis antigenic abnormalities in schizophrenia
Failure to Detect by Anaphylaxis Antigenic Abnormalities in Schizophrenia B y MELVYN ROSENBLATT, M.S., Monnis GOODh~[AN,PH.D., AND E D W A R D ~EKLYS
A D D A D a n d l~abe I h a v e reported certain of the e x p e r i m e n t s d e s c r i b e d b y Malis- in his m o n o g r a p h on the h y p o t h e s i z e d virus origin of schizop h r e n i a . T hese investigators repor t tha t an a b n o r m a l i t y is p r e s e n t in t h e s e r u m of chronic s c h i z o p h r e n i c p a t i e n t s w h i c h can b e de te c te d b y the m e t h o d of a n a p h y l a x is. In their e x p e r i m e n t s g u i n e a pigs w e r e sensitized by 0.1 m], subcutaneous injections of serum from s c h i z o p h r e n i c patients. T w e n t y - o n e clays later the g u i n e a pigs w e r e g i v e n 0.5 ml. d e s e n s i t i z i n g s u b c u t a n e o u s injections of serum from "normal" non-patients. After the sensitivity to n o n - p a t i e n t ser u m a n t i g e ns ,vas e l i m i n a t e d , an i n t r a e a r d i a c c h a l l e n g i n g dose of s c h i z o p h r e n i c s e r u m still elicited ( a c c o r d i n g to these wor ke r s) a n a p h y l a c t i c shock in the g u i n e a pigs. T h u s it was c o n c l u d e d that certain of the a n t i g e n i c d e t e r m i n a n t s p r e s e n t in s c h i z o p h r e n i c serum w e r e a b s e n t from n o n - p a t i e n t serum. U s i n g a s i m i l a r protocol a n d the s a m e criteria for g r a d i n g degrees of a n a p h y l a x i s as o u t l i n e d b y H a d d a d and R abe, ~ we ha ve a t t e m p t e d to d u p l i c a t e their findings. T h e desensitization p r o c e d u r e of H a d d a d a n d R a b O consisted of a modLSeat/on of the p r o c e d u r e d e s c r i b e d b y Malls. ° T h e g u i n e a pigs w e r e c h a l l e n g e d w i t h a 0.15 ml. i n t r a c a r d i a c injection of n o n - p a t i e n t s e r u m 04 hours after th e d e s e n s i t i z i n g s u b c u t a n e o u s injection of n o n - p a t i e n t serum. Those g u i n e a pigs w h i c h s h o w e d signs of a n a p h y l a e t i c shock after the c h a l l e n g e w e r e given a n o t h e r 0.15 ml. i n t r a e a r d i a e injection of n o n - p a t i e n t serum. I f necessary, the c h a l l e nges w ere r e p e a t e d a n d only those g u i n e a pigs w h i c h f a ile d to show a n a p h y l a x i s b y or before the fourth i n t r a c a r d i a e injection of n o n - p a t i e n t s e r u m w e r e given t h e 0.15 ml. i n t r a c a r d i a e c h a l l e n g i n g dose of s e h i z o p h r e n i e serum. After carefully e v a l u a t i n g this desensitizing s c h e m e we w e r e c o n v i n c e d t h a t t h e m u l t i p l e c a r d i a c injections e m p l o y e d to elicit a state of complete desensitization could cause t r a u m a t i c d a m a g e to the he a r t a nd lungs of the a n i m a l s w h i c h in turn could l e a d to s y m p t o m a t o l o g y not r e a d i l y d i s t i n g u i s h a b l e from a n a p h y l a c t i c shock. F o r this reason we d e c i d e d to use a s o m e w h a t diff e r e n t a p p roach. I n s t e a d of c o m p l e t i n g the desensitization of the g u i n e a pigs to n o n - p a t i e n t serum by i n t r a c a r d i a c injections of this serum, we a d m i n i s t e r e d a second 0.5 ml. d e s e n s i t i z i n g s u b c u t a n e o u s injection 24 hours a f t e r the first. T h i s type of p r o c e d u r e has be e n pr ove n e x p e r i m e n t a l l y a nd clinically to be very effective for r a p i d anti c o m p l e t e desensitization in a variety of h y p e r s e n s i t i v e states. T h e n , 24 hours later, w e p r o c e e d e d to c h a l l e n g e the animals.
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From the La/agette Clinic and ~Vatine State Urffver,vitU College oJ Medicine, Detroit, ~liehigan. Supported bll Grant AIY2476 [rom the Natiotud Ir~titut¢ o/ Atental Health.
381 Cor~rnE~t~:rcstv~: PsvcltIA'rnv, VOL. 3, N o . 6 (DF_C.~:Mnma), 1902
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]ROSENBLATT~ GOOD~.[AN~ I~]~KLYS
Since it was our objective to see if the findings of H a d d a d a n d R a b e could be confirmed, the question could be raised as to w h e t h e r t h e de via tion from their desensitizing p r o c e d u r e m i g h t i n t r o d u c e n e w factors into the overall e x p e r i m e n t a l scheme. T h e r e is no reason w h y this should be the case. T h e sole p u r p o s e of their p r o c e d u r e was to c o m p l e t e l y desensitize the a n i m a l s to the a n t i g e n i e configurations of n o r m a l lauman serum. O u r p r o c e d u r e aec o m p l i s h e d t h e s a m e e n d but b y a different, less traumatic, approach. T h u s it can be c o n c l u d e d that the m e t h o d o l o g y e m p l o y e d for desensitization, so long as it is effective, is a m a t t e r of choice a n d that no single m e t h o d m u s t be r i g i d l y a d h e r e d to. I n d e e d , the desensitizing s c h e m e of H a d d a d a n d R a b e is itself different from t h a t of Malis. In our experiments, 28 m a l e g u i n e a pigs we r e each sensitized with 0.1 ml. s u b c u t a n e o u s injectiens of pooled s c h i z o p h r e n i c serum from 12 chronic s e h i z o p h r e n i e patients w ho we r e u n d e r careful die ta r y supervision in a m e t a b o l i c u n i t of the L a f a y e t t e Clinic, a n d who h a d not received drugs or convulsive t h e r a p y for several years. T h r e e weeks later the 28 a n i m a l s w e r e d i v i d e d in two equal groups. T h e a nima ls in the first group w e r e desensitized on two successive days with 0.5 ml. s u b c u t a n e o u s injections of pooled nor ma l se r u m o b t a i n e d from three donors. T h e r e m a i n i n g 14 sensitized a n i m a l s w e r e s u b d i v i d e d into two e q u a l groups a nd w e r e desensitized on two successive days with 0.5 m]. s u b c u t a n e o u s injections of a single n o r m a l serum, a different n o r m a l s e r u m b e i n g used for each group. T w e n t y four hours after the second desensitizing injection, ha lf the g u i n e a pigs in each group w e r e c h a l l e n g e d w i t h 0.15 ml. in tr a c a r dia c injections of pooled s c h i z o p h r e n i c s e r u m an d the other h a l f with nor ma l serum. O f the 14 g u i n e a pigs c h a l l e n g e d with pooled s c h i z o p h r e n i c serum, two expired d u e to p u l m o n a r y d a m a g e as e v i d e n c e d b y profuse b l e e d i n g from the nose a n d m o n t h . T w o a n i m a l s s h o w e d 2 + reactions ( s n e e z i n g a n d / o r c o u g h i n g ) , and 1 s h o w e d a 1 + reaction (ruffling of the h a i r ) . N i n e a n i m a l s s h o w e d no signs of a n a p h y l a c t i e reaction d u r i n g the 30 m i n u t e s observation period following the challenge. O f the group of g u i n e a pigs c h a l l e n g e d with n o r m a l serum, one expired d u e to p u h n o n a r y d a m a g e ( b l e e d i n g from nose a n d m o u t h ) . O n e a n i m a l s h o w e d a 3 + reaction (convulsions not e n d i n g in d e a t h ) , a nd three a n i m a l s s h o w e d 1 + reactions (ruffling of h a i r ) . The r e m a i n i n g n i n e a n i m a l s showc¢ ~ no signs of a n a p h y l a c t i c reaction. Again e a c h a n i m a l was observed for 30 m i n u t e s following challenge. In contrast to the claims of Malts e and H a d d a d and Rabe, 1 our data failed to s h o w the p r e s e n c e of an a n t i g e n i c a b n o r m a l i t y in the se r um of schizop h r e n i c patients. It has been our e xpe r ie nc e a n d p r o b a b l y that of others that m i l d degrees of a n a p h y l a x i s in g u i n e a pigs c a nnot readily be g r a d e d on an objective basis. Sneezing, coughing, ruffling of ha ir and r u b b i n g of the nose are f r e q u e n t l y seen as spontaneous e n v i r o n m e n t a l responses in untr e a te d g u i n e a pigs. F u r t h e r m o r e , in the p u r p o r t e d d e m o n s t r a t i o n ~.z of a serum a n t i g e n i e a b n o r m a l i t y in s c h i z o p h r e n i a whole s c h i z o p h r e n i a sezum was used as the sensitizing agent. T h u s the g u i n e a pigs were injected with a great variety of a n t i g e n i c specificities (all h u m a n serum proteins beings foreign to the gu in e a
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p i g s ) . Yet a h n o s t all ( i f n o t all~) of t h e s e specificities m u s t h a v e b e e n p r e s e n t i n n o r m a l l m m a n s e r u m as w e l l as in s c h i z o p h r e n i c s e r u m . A n y a n t i g e n i c abn o r m a l i t y in t h e schizophreni,c s e r u m c o u l d o n l y r e p r e s e n t a m i n u t e f r a c t i o n of t h e total a n t i g e n i c s t i m u l u s a d m i n i s t e r e d to t h e g u i n e a pigs. It s e e m s q u i t e i m p l a u s i b l e t h a t s u c h a fraction c o u l d c o n t r i b u t e s i g n i f i c a n t l y to t h e sensitization r e s u l t i n g f r o m a s i n g l e r e l a t i v e l y m i n i s c u l e injection of w h o l e s e r u m . O n - t h e o t h e r h a n d , w e c o u l d e x p e c t a s i g n i f i c a n t a n t i b o d y r e s p o n s e to "abn o r m a l " a n t i g e n i c c o n f i g u r a t i o n s if a p u r i f i e d p r o t e i n f r a c t i o n c o n t a i n i n g t h e h y p o t h e s i z e d a b n o r m a l i t y w e r e first i s o l a t e d f r o m t h e s c h i z o p h r e n i c s e r u m a n d t h e n u s e d as a n i m m u n i z i n g agent. T h u s the u n c o n v i n c i n g n a t u r e of t h e c l a i m s of M a l l s 2 a n d H a d d a d a n d l t a b e ~ does not r u l e out th~ p o s s i b i l i t y of t h e p r e s e n c e of an a n t i g e n i c a b n o r m a l i t y in s c h i z o p h r e n i c s e r u m . I n d e e d e v i d e n c e h a s b e e n p r e s e n t e d f r o m four i n d e p e n d e n t c e n t e r s 3-6 i n d i c a t i n g t h a t a n u n u s u a l p l a s m a g l o b u l i n is i n t i m a t e l y i n v o l v e d in s c h i z o p h r e n i a . W h e t h e r or n o t this p l a s m a g l o b u l i n c o n t a i n s a n t i g e n i c c o n f i g u r a t i o n s not p r e s e n t in n o r m a l p l a s m a r e m a i n s to b e d e t e r m i n e d . I~EFEItENCES 1. H a d d a d , R. K., a n d R a b e , A.: An a n a p h y lactic test f o r a b n o r m a l a n t i g e n ( s ) in s c h i z o p h r e n i c sermn, p r e s e n t e d at t h e N e w O r l e a n s S y m p o s i u m on "'Serological Fractions in S c h i z o p h r e n i a , J u n e , 1961 ( t o b e p u b l i s h e d ) . 2. Malls, G. Yu: R e s e a r c h on t h e E t i o l o g y of Schizophrenia. The International B e h a v i o r a l S c i e n c e Series, J o s e p h \ V o r tis, ed. N e w York, C o n s t d t a n t s B u r e a u , 1959, p p . 176--182. 3. F r o h m a n , C. E., G o o d m a n , M., B e c k e t t , P. G. S., L a t l m m , L. K., Senf, R., a n d C o t t l i e b , J. S.: T h e isolation of an active f a c t o r f r o m s e r u m of s c h i z o p h r e n i c p a t i e n t s . Ann. N. Y. A c a d . Sc. 9 6 : 4 3 8 - 447, 1962.
4. H e a t h , 1R. G.: Clinical s t u d i e s w i t h taraxein, in N e u r o p h a r m a c o l o g y . T r a n s . Fourth Conference, The Josiah Macy Jr. F o u n d a t i o n . H . A. A b r a m s o n , ed. N e w York, 1959, p p . 3 7 - 1 6 1 . 5. P e n n e l l , tt. B., a n d Saravis, C. A.: A l m m a n factor i n d u c i n g b e l m v i o r a l a n d e l e e t r o p h y s i o l o g i e a l c h a n g e s in a n i m a l s : I. Isolation a n d c h e m i c a l n a t u r e of t h e a g e n t . Ann. N. Y. A c a d . So. 96:46o~-468, 1962. 6. S a n d e r s , 13. E., Smith, E. V. C., F l a t a k e r , L., a n d \Vinter, C. H.: F r a c t i o n a t i o n s t u d i e s of h u m a n serima fractions affecti n g m o t o r a c t i v i t y in t r a i n e d rats. Ann. N. Y. A c a d - Se. 96:448--461. 1962.
3Iel~yn Rosenblatt, 3I.S., Research Associate, "~Vayne State U. College of Medicine; Research affiliations tvith Lafayette Clinic, Detroit and Northville State lto.~pital, Northoill¢, 51ichigan. 31orris Goodman, P[l.D., Research Associate Professor, ~Vayne State U. College oJ Medicine; Research affiliations with Lafayette Clinic, Detroit and Nolthoille State Hospital, Northville, Michigan. Edward Reklys, Laboratory Technician, Wayne Slate College of ~ledicine.
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A D D A D a n d l~abe I h a v e reported certain of the e x p e r i m e n t s d e s c r i b e d b y Malis- in his m o n o g r a p h on the h y p o t h e s i z e d virus origin of schizop h r e n i a . T hese investigators repor t tha t an a b n o r m a l i t y is p r e s e n t in t h e s e r u m of chronic s c h i z o p h r e n i c p a t i e n t s w h i c h can b e de te c te d b y the m e t h o d of a n a p h y l a x is. In their e x p e r i m e n t s g u i n e a pigs w e r e sensitized by 0.1 m], subcutaneous injections of serum from s c h i z o p h r e n i c patients. T w e n t y - o n e clays later the g u i n e a pigs w e r e g i v e n 0.5 ml. d e s e n s i t i z i n g s u b c u t a n e o u s injections of serum from "normal" non-patients. After the sensitivity to n o n - p a t i e n t ser u m a n t i g e ns ,vas e l i m i n a t e d , an i n t r a e a r d i a c c h a l l e n g i n g dose of s c h i z o p h r e n i c s e r u m still elicited ( a c c o r d i n g to these wor ke r s) a n a p h y l a c t i c shock in the g u i n e a pigs. T h u s it was c o n c l u d e d that certain of the a n t i g e n i c d e t e r m i n a n t s p r e s e n t in s c h i z o p h r e n i c serum w e r e a b s e n t from n o n - p a t i e n t serum. U s i n g a s i m i l a r protocol a n d the s a m e criteria for g r a d i n g degrees of a n a p h y l a x i s as o u t l i n e d b y H a d d a d and R abe, ~ we ha ve a t t e m p t e d to d u p l i c a t e their findings. T h e desensitization p r o c e d u r e of H a d d a d a n d R a b O consisted of a modLSeat/on of the p r o c e d u r e d e s c r i b e d b y Malls. ° T h e g u i n e a pigs w e r e c h a l l e n g e d w i t h a 0.15 ml. i n t r a c a r d i a c injection of n o n - p a t i e n t s e r u m 04 hours after th e d e s e n s i t i z i n g s u b c u t a n e o u s injection of n o n - p a t i e n t serum. Those g u i n e a pigs w h i c h s h o w e d signs of a n a p h y l a e t i c shock after the c h a l l e n g e w e r e given a n o t h e r 0.15 ml. i n t r a e a r d i a e injection of n o n - p a t i e n t serum. I f necessary, the c h a l l e nges w ere r e p e a t e d a n d only those g u i n e a pigs w h i c h f a ile d to show a n a p h y l a x i s b y or before the fourth i n t r a c a r d i a e injection of n o n - p a t i e n t s e r u m w e r e given t h e 0.15 ml. i n t r a c a r d i a e c h a l l e n g i n g dose of s e h i z o p h r e n i e serum. After carefully e v a l u a t i n g this desensitizing s c h e m e we w e r e c o n v i n c e d t h a t t h e m u l t i p l e c a r d i a c injections e m p l o y e d to elicit a state of complete desensitization could cause t r a u m a t i c d a m a g e to the he a r t a nd lungs of the a n i m a l s w h i c h in turn could l e a d to s y m p t o m a t o l o g y not r e a d i l y d i s t i n g u i s h a b l e from a n a p h y l a c t i c shock. F o r this reason we d e c i d e d to use a s o m e w h a t diff e r e n t a p p roach. I n s t e a d of c o m p l e t i n g the desensitization of the g u i n e a pigs to n o n - p a t i e n t serum by i n t r a c a r d i a c injections of this serum, we a d m i n i s t e r e d a second 0.5 ml. d e s e n s i t i z i n g s u b c u t a n e o u s injection 24 hours a f t e r the first. T h i s type of p r o c e d u r e has be e n pr ove n e x p e r i m e n t a l l y a nd clinically to be very effective for r a p i d anti c o m p l e t e desensitization in a variety of h y p e r s e n s i t i v e states. T h e n , 24 hours later, w e p r o c e e d e d to c h a l l e n g e the animals.
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From the La/agette Clinic and ~Vatine State Urffver,vitU College oJ Medicine, Detroit, ~liehigan. Supported bll Grant AIY2476 [rom the Natiotud Ir~titut¢ o/ Atental Health.
381 Cor~rnE~t~:rcstv~: PsvcltIA'rnv, VOL. 3, N o . 6 (DF_C.~:Mnma), 1902
382
]ROSENBLATT~ GOOD~.[AN~ I~]~KLYS
Since it was our objective to see if the findings of H a d d a d a n d R a b e could be confirmed, the question could be raised as to w h e t h e r t h e de via tion from their desensitizing p r o c e d u r e m i g h t i n t r o d u c e n e w factors into the overall e x p e r i m e n t a l scheme. T h e r e is no reason w h y this should be the case. T h e sole p u r p o s e of their p r o c e d u r e was to c o m p l e t e l y desensitize the a n i m a l s to the a n t i g e n i e configurations of n o r m a l lauman serum. O u r p r o c e d u r e aec o m p l i s h e d t h e s a m e e n d but b y a different, less traumatic, approach. T h u s it can be c o n c l u d e d that the m e t h o d o l o g y e m p l o y e d for desensitization, so long as it is effective, is a m a t t e r of choice a n d that no single m e t h o d m u s t be r i g i d l y a d h e r e d to. I n d e e d , the desensitizing s c h e m e of H a d d a d a n d R a b e is itself different from t h a t of Malis. In our experiments, 28 m a l e g u i n e a pigs we r e each sensitized with 0.1 ml. s u b c u t a n e o u s injectiens of pooled s c h i z o p h r e n i c serum from 12 chronic s e h i z o p h r e n i e patients w ho we r e u n d e r careful die ta r y supervision in a m e t a b o l i c u n i t of the L a f a y e t t e Clinic, a n d who h a d not received drugs or convulsive t h e r a p y for several years. T h r e e weeks later the 28 a n i m a l s w e r e d i v i d e d in two equal groups. T h e a nima ls in the first group w e r e desensitized on two successive days with 0.5 ml. s u b c u t a n e o u s injections of pooled nor ma l se r u m o b t a i n e d from three donors. T h e r e m a i n i n g 14 sensitized a n i m a l s w e r e s u b d i v i d e d into two e q u a l groups a nd w e r e desensitized on two successive days with 0.5 m]. s u b c u t a n e o u s injections of a single n o r m a l serum, a different n o r m a l s e r u m b e i n g used for each group. T w e n t y four hours after the second desensitizing injection, ha lf the g u i n e a pigs in each group w e r e c h a l l e n g e d w i t h 0.15 ml. in tr a c a r dia c injections of pooled s c h i z o p h r e n i c s e r u m an d the other h a l f with nor ma l serum. O f the 14 g u i n e a pigs c h a l l e n g e d with pooled s c h i z o p h r e n i c serum, two expired d u e to p u l m o n a r y d a m a g e as e v i d e n c e d b y profuse b l e e d i n g from the nose a n d m o n t h . T w o a n i m a l s s h o w e d 2 + reactions ( s n e e z i n g a n d / o r c o u g h i n g ) , and 1 s h o w e d a 1 + reaction (ruffling of the h a i r ) . N i n e a n i m a l s s h o w e d no signs of a n a p h y l a c t i e reaction d u r i n g the 30 m i n u t e s observation period following the challenge. O f the group of g u i n e a pigs c h a l l e n g e d with n o r m a l serum, one expired d u e to p u h n o n a r y d a m a g e ( b l e e d i n g from nose a n d m o u t h ) . O n e a n i m a l s h o w e d a 3 + reaction (convulsions not e n d i n g in d e a t h ) , a nd three a n i m a l s s h o w e d 1 + reactions (ruffling of h a i r ) . The r e m a i n i n g n i n e a n i m a l s showc¢ ~ no signs of a n a p h y l a c t i c reaction. Again e a c h a n i m a l was observed for 30 m i n u t e s following challenge. In contrast to the claims of Malts e and H a d d a d and Rabe, 1 our data failed to s h o w the p r e s e n c e of an a n t i g e n i c a b n o r m a l i t y in the se r um of schizop h r e n i c patients. It has been our e xpe r ie nc e a n d p r o b a b l y that of others that m i l d degrees of a n a p h y l a x i s in g u i n e a pigs c a nnot readily be g r a d e d on an objective basis. Sneezing, coughing, ruffling of ha ir and r u b b i n g of the nose are f r e q u e n t l y seen as spontaneous e n v i r o n m e n t a l responses in untr e a te d g u i n e a pigs. F u r t h e r m o r e , in the p u r p o r t e d d e m o n s t r a t i o n ~.z of a serum a n t i g e n i e a b n o r m a l i t y in s c h i z o p h r e n i a whole s c h i z o p h r e n i a sezum was used as the sensitizing agent. T h u s the g u i n e a pigs were injected with a great variety of a n t i g e n i c specificities (all h u m a n serum proteins beings foreign to the gu in e a
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p i g s ) . Yet a h n o s t all ( i f n o t all~) of t h e s e specificities m u s t h a v e b e e n p r e s e n t i n n o r m a l l m m a n s e r u m as w e l l as in s c h i z o p h r e n i c s e r u m . A n y a n t i g e n i c abn o r m a l i t y in t h e schizophreni,c s e r u m c o u l d o n l y r e p r e s e n t a m i n u t e f r a c t i o n of t h e total a n t i g e n i c s t i m u l u s a d m i n i s t e r e d to t h e g u i n e a pigs. It s e e m s q u i t e i m p l a u s i b l e t h a t s u c h a fraction c o u l d c o n t r i b u t e s i g n i f i c a n t l y to t h e sensitization r e s u l t i n g f r o m a s i n g l e r e l a t i v e l y m i n i s c u l e injection of w h o l e s e r u m . O n - t h e o t h e r h a n d , w e c o u l d e x p e c t a s i g n i f i c a n t a n t i b o d y r e s p o n s e to "abn o r m a l " a n t i g e n i c c o n f i g u r a t i o n s if a p u r i f i e d p r o t e i n f r a c t i o n c o n t a i n i n g t h e h y p o t h e s i z e d a b n o r m a l i t y w e r e first i s o l a t e d f r o m t h e s c h i z o p h r e n i c s e r u m a n d t h e n u s e d as a n i m m u n i z i n g agent. T h u s the u n c o n v i n c i n g n a t u r e of t h e c l a i m s of M a l l s 2 a n d H a d d a d a n d l t a b e ~ does not r u l e out th~ p o s s i b i l i t y of t h e p r e s e n c e of an a n t i g e n i c a b n o r m a l i t y in s c h i z o p h r e n i c s e r u m . I n d e e d e v i d e n c e h a s b e e n p r e s e n t e d f r o m four i n d e p e n d e n t c e n t e r s 3-6 i n d i c a t i n g t h a t a n u n u s u a l p l a s m a g l o b u l i n is i n t i m a t e l y i n v o l v e d in s c h i z o p h r e n i a . W h e t h e r or n o t this p l a s m a g l o b u l i n c o n t a i n s a n t i g e n i c c o n f i g u r a t i o n s not p r e s e n t in n o r m a l p l a s m a r e m a i n s to b e d e t e r m i n e d . I~EFEItENCES 1. H a d d a d , R. K., a n d R a b e , A.: An a n a p h y lactic test f o r a b n o r m a l a n t i g e n ( s ) in s c h i z o p h r e n i c sermn, p r e s e n t e d at t h e N e w O r l e a n s S y m p o s i u m on "'Serological Fractions in S c h i z o p h r e n i a , J u n e , 1961 ( t o b e p u b l i s h e d ) . 2. Malls, G. Yu: R e s e a r c h on t h e E t i o l o g y of Schizophrenia. The International B e h a v i o r a l S c i e n c e Series, J o s e p h \ V o r tis, ed. N e w York, C o n s t d t a n t s B u r e a u , 1959, p p . 176--182. 3. F r o h m a n , C. E., G o o d m a n , M., B e c k e t t , P. G. S., L a t l m m , L. K., Senf, R., a n d C o t t l i e b , J. S.: T h e isolation of an active f a c t o r f r o m s e r u m of s c h i z o p h r e n i c p a t i e n t s . Ann. N. Y. A c a d . Sc. 9 6 : 4 3 8 - 447, 1962.
4. H e a t h , 1R. G.: Clinical s t u d i e s w i t h taraxein, in N e u r o p h a r m a c o l o g y . T r a n s . Fourth Conference, The Josiah Macy Jr. F o u n d a t i o n . H . A. A b r a m s o n , ed. N e w York, 1959, p p . 3 7 - 1 6 1 . 5. P e n n e l l , tt. B., a n d Saravis, C. A.: A l m m a n factor i n d u c i n g b e l m v i o r a l a n d e l e e t r o p h y s i o l o g i e a l c h a n g e s in a n i m a l s : I. Isolation a n d c h e m i c a l n a t u r e of t h e a g e n t . Ann. N. Y. A c a d . So. 96:46o~-468, 1962. 6. S a n d e r s , 13. E., Smith, E. V. C., F l a t a k e r , L., a n d \Vinter, C. H.: F r a c t i o n a t i o n s t u d i e s of h u m a n serima fractions affecti n g m o t o r a c t i v i t y in t r a i n e d rats. Ann. N. Y. A c a d - Se. 96:448--461. 1962.
3Iel~yn Rosenblatt, 3I.S., Research Associate, "~Vayne State U. College of Medicine; Research affiliations tvith Lafayette Clinic, Detroit and Northville State lto.~pital, Northoill¢, 51ichigan. 31orris Goodman, P[l.D., Research Associate Professor, ~Vayne State U. College oJ Medicine; Research affiliations with Lafayette Clinic, Detroit and Nolthoille State Hospital, Northville, Michigan. Edward Reklys, Laboratory Technician, Wayne Slate College of ~ledicine.
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