1385 MOLECULAR ABERRATION IN PLATELET
MONOAMINE OXIDASE IN SCHIZOPHRENIA
SIR,-In schizophrenia, monoamine oxidase (M.A.O.) activity in platelets seems to be reduced when compared with that of healthy, non-schizophrenic controls.1-3 We wondered if the M.A.o. was present in lower concentrations or if the enzyme was qualitatively different from normal. Studies in parkinsonian patients had suggested the presence of an abnormal M.A.O. in their platelets,4 so we looked for such an aberration in schizophrenia. If the active site of M.A.O. is altered, the degradation-rate of various substrates may not be affected to the same degree. This concept arose from work on an enzyme closely related to M.A.O. (viz, L-aminoacid oxidases of snake venoms) which reacted differently when we obtained it from various snake species. Since the geometry and other characteristics of the substrate molecule apparently determined the orientation of the substrate at the active site, we exposed various substrates to platelet M.A.o., using compounds with different lengths of the aliphatic moiety and with different positions of the ring-substituents. If our hypothesis were correct, the degradation-rates of the three substrates might be unequally affected by the transformation of normal M.A.O. to that of schizophrenics. We studied a group of men (average age 42) with chronic schizophrenia and a smaller group of men and women (average age 22) with acute and subacute forms of schizophrenia. For comparison we used data from a group of healthy people aged 18-50.4 The methods will be described in full elsewhere.4 In brief, platelets are isolated by differential centrifugation and broken up by sonic oscillation; degradation of pM.B.A. (p-methoxybenzylamine) is determined by spectrophotometry and tyramine and mi.B.A. (m-iodobenzylamine) oxidation is determined by spectrophotofluorometry; and results are expressed in terms of nanomoles per 109 platelets per hour. M.A.O. activity in schizophrenics was significantly reduced with all three substrates (table). There were, however, differences of response when we considered the two sexes and the three substrates individually. While M.A.O. activity is higher in control women than in men during their reproductive life period,4 this difference seemed to disappear for schizophrenics. For the discussion of the " substrate effect", we focus our remarks on the data for men; the schizophrenic women reacted in much the same way as the men. With mI.B.A. and tyramine as substrates, the activity of M.A.O. of schizophrenics is 43 and 39% of control values. Since the reaction-rates for the two
substrates are not the same, a statistical comparison can be done when they are adjusted to the same level. We did that by expressing the result obtained for each patient in terms of percent of the control values. In comparing thus the tyramine with the mI.B.A. series, no statistical significance emerged (t=0-60). The change from controls to schizophrenics with pM.B.A. as substrate, however, was quite different from that observed with the other substrates (61% of control activity). The tyramine values and pM.B.A. data were significantly different (t=2.43, P < 0-025). This pattern was different from that observed for parkinsonian patients where the mI.B.A./tyramine ratio, but not the tyramine/mi.B.A. ratio, appeared to be changed.4 We conclude that the active site of M.A.O. in schizophrenia is less capable of accommodating mI.B.A. and tyramine than pM.B.A. as compared with M.A.O. of controls, and this suggests that the platelet M.A.O. of schizophrenic patients is structurally different from that of non-schizophrenics. Whether brain M.A.o. is similarly altered and whether amine levels are affected sufficiently to contribute to the pathogenesis of schizophrenia remain to be seen. However, in paranoic schizophrenia the dopaminergic system appears to be involved,6 and a slight but significant reduction of M.A.O. activity in the globus pallidus has been recorded.7 In addition, the onset of schizophrenia (dementia prscox) approximately coincides with a reduction of M.A.o. levels due to sexual maturation.4 Further work will show whether the physicochemical analysis of platelet M.A.o. will help us in the diagnosis and classification of schizophrenics.
only
We thank M. S. Bieber and T. Holmes. This work was supported in part by research grants from the National Institute of Mental Health, Bethesda, Maryland (MH20020), and from the Sterling Morton Foundation.
Departments of Biochemistry and of Neurology, Northwestern University, Chicago, Illinois 60611, the Illinois State Psychiatric Institute, Chicago, Illinois 60608, and the Veteran’s Administration Hospital, Downey, Illinois 60064, U.S.A.
PIMOZIDE IN MONOSYMPTOMATIC PSYCHOSIS read with interest the finding of Dr Riding and SIR,-I Dr Munro (Feb. 15, p. 400) that pimozide has a specific beneficial effect in this often refractory condition. I should like to report on the use of pimozide in a patient who presented considerable diagnostic and management problems. This
1. 2.
D.
Wyatt, R. J. Nature,
Murphy, L., 1972, 238, 225. Friedman, E., Shopsin, B., Sathananthan, G., Gershon, S. Am. J. Psychiat. 1974, 131, 1392. 3. Nies, A., Robinson, D. S., Harris, L. S., Lamborn, K. R. Adv. biochem. Psychopharmac. 1974, 12, 59. 4. Zeller, E. A., Boshes, B., Arbit, J., Bieber, M., Blonsky, ’E. R., Dolkart, M., Huprikar, S. V. Unpublished. 5. Zeller, E. A., Clauss, L. M., Ohlsson, J. T. Helv. chim. Acta, 1974, 57, 2406.
54-year-old married woman has been under the care of our
department
for almost 2 years, with persistent excessive salivation, abnormal awareness of swallowing, and a " twitching " feeling in the left side of her throat. She constantly proclaimed her belief in an organic basis for these symptoms, maintaining that the 6. 7.
Snyder, S. H., Banerjee, S. P., Yamamura, H. I., Greenberg, D. Science, 1974, 184, 1243. Birkhäuser, H. Schweiz. med. Wschr. 1941, 71, 750.
(S) PATIENTS AND APPROXIMATELY nmol/109 PLATELETS/hr.
PLATELET M.A.O. ACTIVITIES RECORDED FOR SCHIZOPHRENIC IN
.
P
MONOAMINE OXIDASE IN SCHIZOPHRENIA
SIR,-In schizophrenia, monoamine oxidase (M.A.O.) activity in platelets seems to be reduced when compared with that of healthy, non-schizophrenic controls.1-3 We wondered if the M.A.o. was present in lower concentrations or if the enzyme was qualitatively different from normal. Studies in parkinsonian patients had suggested the presence of an abnormal M.A.O. in their platelets,4 so we looked for such an aberration in schizophrenia. If the active site of M.A.O. is altered, the degradation-rate of various substrates may not be affected to the same degree. This concept arose from work on an enzyme closely related to M.A.O. (viz, L-aminoacid oxidases of snake venoms) which reacted differently when we obtained it from various snake species. Since the geometry and other characteristics of the substrate molecule apparently determined the orientation of the substrate at the active site, we exposed various substrates to platelet M.A.o., using compounds with different lengths of the aliphatic moiety and with different positions of the ring-substituents. If our hypothesis were correct, the degradation-rates of the three substrates might be unequally affected by the transformation of normal M.A.O. to that of schizophrenics. We studied a group of men (average age 42) with chronic schizophrenia and a smaller group of men and women (average age 22) with acute and subacute forms of schizophrenia. For comparison we used data from a group of healthy people aged 18-50.4 The methods will be described in full elsewhere.4 In brief, platelets are isolated by differential centrifugation and broken up by sonic oscillation; degradation of pM.B.A. (p-methoxybenzylamine) is determined by spectrophotometry and tyramine and mi.B.A. (m-iodobenzylamine) oxidation is determined by spectrophotofluorometry; and results are expressed in terms of nanomoles per 109 platelets per hour. M.A.O. activity in schizophrenics was significantly reduced with all three substrates (table). There were, however, differences of response when we considered the two sexes and the three substrates individually. While M.A.O. activity is higher in control women than in men during their reproductive life period,4 this difference seemed to disappear for schizophrenics. For the discussion of the " substrate effect", we focus our remarks on the data for men; the schizophrenic women reacted in much the same way as the men. With mI.B.A. and tyramine as substrates, the activity of M.A.O. of schizophrenics is 43 and 39% of control values. Since the reaction-rates for the two
substrates are not the same, a statistical comparison can be done when they are adjusted to the same level. We did that by expressing the result obtained for each patient in terms of percent of the control values. In comparing thus the tyramine with the mI.B.A. series, no statistical significance emerged (t=0-60). The change from controls to schizophrenics with pM.B.A. as substrate, however, was quite different from that observed with the other substrates (61% of control activity). The tyramine values and pM.B.A. data were significantly different (t=2.43, P < 0-025). This pattern was different from that observed for parkinsonian patients where the mI.B.A./tyramine ratio, but not the tyramine/mi.B.A. ratio, appeared to be changed.4 We conclude that the active site of M.A.O. in schizophrenia is less capable of accommodating mI.B.A. and tyramine than pM.B.A. as compared with M.A.O. of controls, and this suggests that the platelet M.A.O. of schizophrenic patients is structurally different from that of non-schizophrenics. Whether brain M.A.o. is similarly altered and whether amine levels are affected sufficiently to contribute to the pathogenesis of schizophrenia remain to be seen. However, in paranoic schizophrenia the dopaminergic system appears to be involved,6 and a slight but significant reduction of M.A.O. activity in the globus pallidus has been recorded.7 In addition, the onset of schizophrenia (dementia prscox) approximately coincides with a reduction of M.A.o. levels due to sexual maturation.4 Further work will show whether the physicochemical analysis of platelet M.A.o. will help us in the diagnosis and classification of schizophrenics.
only
We thank M. S. Bieber and T. Holmes. This work was supported in part by research grants from the National Institute of Mental Health, Bethesda, Maryland (MH20020), and from the Sterling Morton Foundation.
Departments of Biochemistry and of Neurology, Northwestern University, Chicago, Illinois 60611, the Illinois State Psychiatric Institute, Chicago, Illinois 60608, and the Veteran’s Administration Hospital, Downey, Illinois 60064, U.S.A.
PIMOZIDE IN MONOSYMPTOMATIC PSYCHOSIS read with interest the finding of Dr Riding and SIR,-I Dr Munro (Feb. 15, p. 400) that pimozide has a specific beneficial effect in this often refractory condition. I should like to report on the use of pimozide in a patient who presented considerable diagnostic and management problems. This
1. 2.
D.
Wyatt, R. J. Nature,
Murphy, L., 1972, 238, 225. Friedman, E., Shopsin, B., Sathananthan, G., Gershon, S. Am. J. Psychiat. 1974, 131, 1392. 3. Nies, A., Robinson, D. S., Harris, L. S., Lamborn, K. R. Adv. biochem. Psychopharmac. 1974, 12, 59. 4. Zeller, E. A., Boshes, B., Arbit, J., Bieber, M., Blonsky, ’E. R., Dolkart, M., Huprikar, S. V. Unpublished. 5. Zeller, E. A., Clauss, L. M., Ohlsson, J. T. Helv. chim. Acta, 1974, 57, 2406.
54-year-old married woman has been under the care of our
department
for almost 2 years, with persistent excessive salivation, abnormal awareness of swallowing, and a " twitching " feeling in the left side of her throat. She constantly proclaimed her belief in an organic basis for these symptoms, maintaining that the 6. 7.
Snyder, S. H., Banerjee, S. P., Yamamura, H. I., Greenberg, D. Science, 1974, 184, 1243. Birkhäuser, H. Schweiz. med. Wschr. 1941, 71, 750.
(S) PATIENTS AND APPROXIMATELY nmol/109 PLATELETS/hr.
PLATELET M.A.O. ACTIVITIES RECORDED FOR SCHIZOPHRENIC IN
.
P
