0022-3956/79/0601-0127 $02.00/0
.I. psychiat. Res., Vol. 15, pp. 127-131. Pergamon
PressLtd. 1979. Printedin GreatBritain.
PLASMA CPK LEVELS IN MONOZYGOTIC AND DIZYGOTIC TWINS DISCORDANT FOR SCHIZOPHRENIA PHILIP S. HOLZMAN,*
HERBERT Y.
MELTzER,t EINAR KRINGLEN,~ and JOHN M. DAVIS~
DEBORAH L. LEVY,$ SHELBY J. HABERMAN”
*Department
of Psychology and Psychiatry, Harvard University, William James Hall, Cambridge, MA 02138, U.S.A. TDepartment of Psychiatry, University of Chicago, Chicago, IL 60637, U.S.A. SDepartment of Behavioral Science in Medicine, University of Oslo, Box 1071, Blindern, Oslo 3, Norway GThe Menninger Foundation, Topeka, KA 66601, U.S.A. and IiDepartment of Statistics, University of Chicago, Chicago, IL 60637, U.S.A. (Received
2 January
1978; in revised form 28 July 1978)
Abstract-Plasma creatine phosphokinase (CPK) activity was determined in single samples of 9 monozygotic and 14 dizygotic twin pairs chosen from an earlier study on the basis of their having been discordant for clinical schizophrenia. The correlations within the MZ pairs was 0.89, and within the DZ pairs was 0.40. The results support a conclusion of genetic control of plasma CPK activity. The mean levels of activity were not abnormal, however.
or serum creatine phosphokinase (CPK) activity is increased in a number of diseases of skeletal musc1e.l Increased serum CPK activity has also been associated with the acute excitement phase of functional psychoses and it has also been found to be significantly increased in about 30% of the first-degree relatives of these patients.2 Plasma CPK activity, furthermore, has been shown to vary as a function of sex, race, physical exertion, and muscle damage. 2- 4 Clearly, environmental and situational variables affect at least the temporary level of CPK activity. Because of the finding that serum CPK is elevated in a substantial number of first-degree relatives of acutely psychotic patients, it becomes of interest to determine the extent to which the activity of the serum enzyme is under genetic control. In a previous paper MELTZER et aL6 reported that in a set of 12 monozygotic (MZ) twins discordant for clinical schizophrenia, the Pearson product-moment correlation for serum CPK levels between the twins was 0.57. No specific effects of phenothiazine medication were noted and the enzyme levels were within normal limits. No correlations could be estimated with respect to serum CPK activity in dizygotic (DZ) twins discordant for schizophrenia since such a group was not tested. In a second study of 14 MZ and 14 DZ twins who were free of clinical schizophrenia, the Pearson product-moment correlation was 0.75 for MZ and 0.18 for DZ twins.6 This analysis was conducted on repeated assays in those PLASMA
Supported in part by the USPHS Grant MH31340 and from the Benevolent Foundation Rite, Northern Masonic Jurisdiction. 127
of the Scottish
128
PHILIP S. HOLZMAN
et al.
few subjects whose initial CPK values exceeded 140 u/ml. These values accord with the expectation that the MZ-DZ ratio should be higher than 1 in order to support a hypothesis of genetic control. The present study undertook to explore the genetic control of plasma CPK in a sample of MZ and DZ twins who are discordant for clinical schizophrenia. A complete description of the sample, the method of ascertainment, diagnostic criteria, concordance computations, and zygosity determinations can be found in Kringlen’s account.’ In brief, the sample was selected from the Norwegian psychosis registry which was checked against the population twin registry in Norway. The twins were individually interviewed and examined by one of the authors (E.K.) a decade ago. For the present study, we selected from that sample those twins who were available for testing during a 2-month period in 1975. In order to insure that serum CPK activity would be assayed blindly, without knowledge of the twinship relationship, a list of random numbers was drawn up and each subject was assigned a random number as the subject’s blood was drawn. The identities of the subjects were retained by one of the authors (E.K.) in Norway, who kept the other authors uninformed as to the twinship, diagnoses, and relationship among the subjects. Most subjects were seen in their own homes which were located throughout the southern half of Norway. A few subjects came to the University Psychiatric Clinic in Oslo and a few schizophrenic probands who were still hospitalized were seen in the hospitals. We were able to arrange for the transportation to Oslo of four persons from the far north of Norway. Only two sets of twins were seen in the same session. All subjects were reinterviewed at the time of the blood-drawing and clinical diagnoses were assigned by the interviewer (E.K.). There were no changes from 1967 in proband diagnoses, but two of the MZ co-twins (1B and 2B), earlier free of psychosis, had been hospitalized for a psychotic condition at some period between 1968 and 1975. Two additional sets of MZ and one DZ set were judged by Dr. Kringlen to have shifted their status from discordant to partially concordant, that is, the co-twin, although never hospitalized and never psychotic, manifested some behavioral peculiarities. Severity of illness was assessed by one of the authors (E.K.) according to a 7-point rating scale which was inferred from psychiatric history, social functioning after age 15, and the psychiatric interview on the day that the blood sample was drawn. A rating of l-2 suggested normal functioning; 3-4, moderate impairment but without overt manifest psychosis, 5-7, degrees of severe impairment, including psychosis. From each subject we drew 44 ems of venous blood, 10 cm3 of which was sent to the Institute of Forensic Medicine, University of Oslo for zygosity determinations if zygosity had not been previously determined. The following systems were used: ABO, MNS, rhesus, Lewis, P., Duffy, Kell, Gm, and Gc. Complete similarity on all systems determined monozygosity. The remaining 30 cm3 were then centrifuged, and heparinized plasma samples were frozen within 8 hr of collection. All samples were sent by air freight, frozen, to the United States within 2 months of collection. They were labeled with the random-number code so that identification was not possible at this stage of the study. Plasma CPK activity was determined in duplicate by the method of ROSALKI* using CPK Stat-Pak reagents obtained from Calbiochem (U.S.A.). There is a 10-20x decline in
PLASMACPK LEVELS IN MONOZYG~TICAND DIZYG~TICTWINS
129
activity in frozen samples stored for a 2-month period. A Micromedics Reaction Rate Analyzer was used. The coefficient of variation for duplicate CPK determinations is 5%. After the plasma CPK activity was determined, the data, identified by random-number code, were sent to Kringlen in Oslo who, on the same day, sent to the other authors in the United States identifying data consisting of names, ages, sex, and zygosity. Nine sets of MZ and fourteen sets of same-sexed DZ twins were tested. Of the MZ pairs, two sets were concordant for schizophrenia, two sets were partially concordant, and five sets were discordant. One pair of DZ twins was partially concordant and thirteen were discordant. RESULTS
All values were transformed into log units in order to reduce mathematically the effect of extreme scores; this procedure is clearly warranted in studies of small sample size such as the present one; the transformation normalized the distributions for the twin sets. The data are contained in Table 1. The Pearson product-moment correlation for the MZ pairs is 0.89 (p = 0.0003) and for rMZ-rDZ the DZ pairs 0.40 (p = 0.079). The index of heritability, computed as h2 = I--rDZ. is 0.82. The small number of subjects, 9 MZ and 14 DZ, limits the statistical significance that can be inferred. Thus, although the correlation of 0.89 between MZ twins is highly significant, the r of 0.40 between the DZ twins would occur by chance about 8 times in 100. Nevertheless, the values of the correlations for MZ and DZ twins are consistent with a genetic interpretation, with the correlation of MZ sets higher than that for DZ sets, and the difference between the two correlations is significant at p = 0.0573. Increased sample size would, of course, decide the issue of the reliability of this difference. It appears that the delay between sample acquisition and assay of up to 2 months has affected the CPK levels in such a way as to lower them. Thus, the values presented here are conservative and probably underestimate both the level of CPK in the subjects and the degree of concordance. It is apparent that the CPK values are not particularly high. Indeed, they are within normal limits, except for three subjects, 2A, 2B, and 9B. These findings are consistent with previous reports that plasma CPK is elevated only during the acute phase of the psychosis. None of the schizophrenic subjects was acutely psychotic, although some were still hospitalized. Those within a hospital, however, did not differ from those living outside a hospital. Some of the schizophrenic patients were still receiving neuroleptic medication, but the CPK values of these patients are not different from those receiving no medication. The Pearson product-moment correlation between severity of illness, as measured by the 7-point scale described earlier and CPK is -0.11 (p = n.s.). These ratings arepresented in Table 1. The data support the assumption that plasma CPK is to a significant degree under genetic control. This is consistent with other reports of serum enzyme dopamine beta-hydroxylase,s and platelet and plasma monoamine oxidase activitylO which are also under genetic control. The specific aspects of the enzyme activity that are genetically regulated are, however, not clear. Environmental influences definitely affect temporary levels of CPK, and to that
130
PHUP S. HOLZMAN et al.
TABLE ~.RAWAND LOO-TRANSFORMED PLASMA ACTIVITY(CPK) FOR 9 MZ AND 14DZ ANDCLINICALSEVERITyAsRATEDIN 1975AtUAL.W NOTED
Twin sets
MZ Twins CPK Activity Log CPK (mu/ml) activity
Severity rating as of 1975
Twin sets
Sex
Age
Sex
Age
1A 1B
M
62
9 12
0.9542 1.0792
7.0 7.0
1A 1B
M
47
::
M
55
178 615
2.2504 2.7888
5.0 5.0
2A 2B
M
54
TWINSETS.
DZ Twins CPK Activity Log CPK (mu/ml) activity 33 66
SEX,AGE, Severity rating as of 1975
1.5185 1.8195
6.0 4.0
1.5314 1.5798
25::
3A 3B
M
61
027 58
2.1038 1.7634
7.0 4.0
3A 3B
F
63
20 19
1.3010 1.2787
6.0 1.0
4A 4B
M
55
20 17
1.3010 1.2304
5.5 2.0
4A 4B
F
59
30 20
1.4771 1.3010
7.0 2.0
SA 5B
M
73
61 54
1.7853 1.7313
6.0 2.5
5A 5B
M
56
26 38
1.4149 1.5797
6.5 2.0
6A 6B
F
56
50 50
1.6989 1.6989
5.5 1.0
6A 6B
M
55
20 16
1.3010 1.2041
4.0 3.0
F
35
27 24
1.4313 1.3802
6.0 2.0
7A 7B
M
55
44 51
1.6434 1.7075
7.0 2.0
F
59
18 18
1.2552 1.2552
-
8A 8B
M
58
1.7403 1.7781
6.0 3.0
F
50
60 55
1.7781 1.7403
6.0 3.5
9A 9B
F
62
46 197
1.6627 2.2944
6.0 2.0
1OA IOB
M
52
10 80
1.000 1.9030
6.0 3.0
IlA LIB
M
73
10 11
1.000 1.0413
6.0 4.0
12A 12B
M
58
32 85
1.5051 1.9294
5.0 2.0
13A 13B
F
45
20 32
1.3010 1.5051
24::
14A 14B
F
1.4149 1.6127
6.0 3.0
;; 8A 8B
53
extent, CPK correlations among MZ twins would in practice never be perfect. That the MZ correlation is as high as it is, accounting for about 80% of the variance, lends strong support for assuming genetic control of the general level of CPK activity, conceived of as a trait variable. REFERENCES 1. HEYCK, I-L and LAUDAHN, G. Muscle and serum enzymes in muscular dystrophy and neurogenic muscular atrophy. A comparative study. In: Exploratory Concepts in Muscular Dystrophy and Related Disorders, pp. 232-240. MILHORAT, A. T. (Editor). Amsterdam, Netherlands, Excerpta Medica Foundation, 1967.
PLASMACPK LEVELSIN MONOZYG~TXAND DIZYG~TICTwms
131
2. MELTZER, H. Y. and HOLY, P. A. Black-white differences in serum creatine phosphokinase (CPK) activity. Clinica chim. Acta 54,215, 1975. 3. GRWITHS, P. D. Serum levels of A.T.P.: creatine phosphotransferase (creatine kinase), the normal range and effect of muscular activity. Clinica chim. Acta 13,413,1966. 4. MELTZER,H. Y. Neuromuscular dysfunctions in schizophrenia. Schizophrenia Bull. 2, 106, 1976. 5. MELTZER,H. Y., BELMAKER,R., WYATT, R. J., POLLIN, W. and COHEN, S. Serum creatine phosphokinase (CPK) activity in monozygotic twins discordant for schizophrenia: heritability of serum CPK activity. Comp. Psychiat. 17,469, 1976. 6. MELTZER,H. Y., DORUS, E., GRUNHAUS,L., DAVIS, J. M. and BELMAKER,R. Genetic control of human plasma creatine phosphokinase activity. In preparation. 7. KRINGLEN, E. Heredity and Environment in the Functional Psychoses. Universitetsforlaget, Oslo, 1967. 8. ROSALKI,S. B. An improved procedure for serum creatine phosphokinase determination. J. Lab. clin. Med. 69, 696, 1967. 9. Ross, S. B. and WETTERBERG, L. Genetic control of plasma dopamine P-hydroxylase. Life Sci. 12,529, 1972. 10. Nrrs, A. and ROBINSON,D. S. Genetic control of platelet and platelet monoamine oxydase activity. Archs gen. Psychiat. 28, 834, 1973.
.I. psychiat. Res., Vol. 15, pp. 127-131. Pergamon
PressLtd. 1979. Printedin GreatBritain.
PLASMA CPK LEVELS IN MONOZYGOTIC AND DIZYGOTIC TWINS DISCORDANT FOR SCHIZOPHRENIA PHILIP S. HOLZMAN,*
HERBERT Y.
MELTzER,t EINAR KRINGLEN,~ and JOHN M. DAVIS~
DEBORAH L. LEVY,$ SHELBY J. HABERMAN”
*Department
of Psychology and Psychiatry, Harvard University, William James Hall, Cambridge, MA 02138, U.S.A. TDepartment of Psychiatry, University of Chicago, Chicago, IL 60637, U.S.A. SDepartment of Behavioral Science in Medicine, University of Oslo, Box 1071, Blindern, Oslo 3, Norway GThe Menninger Foundation, Topeka, KA 66601, U.S.A. and IiDepartment of Statistics, University of Chicago, Chicago, IL 60637, U.S.A. (Received
2 January
1978; in revised form 28 July 1978)
Abstract-Plasma creatine phosphokinase (CPK) activity was determined in single samples of 9 monozygotic and 14 dizygotic twin pairs chosen from an earlier study on the basis of their having been discordant for clinical schizophrenia. The correlations within the MZ pairs was 0.89, and within the DZ pairs was 0.40. The results support a conclusion of genetic control of plasma CPK activity. The mean levels of activity were not abnormal, however.
or serum creatine phosphokinase (CPK) activity is increased in a number of diseases of skeletal musc1e.l Increased serum CPK activity has also been associated with the acute excitement phase of functional psychoses and it has also been found to be significantly increased in about 30% of the first-degree relatives of these patients.2 Plasma CPK activity, furthermore, has been shown to vary as a function of sex, race, physical exertion, and muscle damage. 2- 4 Clearly, environmental and situational variables affect at least the temporary level of CPK activity. Because of the finding that serum CPK is elevated in a substantial number of first-degree relatives of acutely psychotic patients, it becomes of interest to determine the extent to which the activity of the serum enzyme is under genetic control. In a previous paper MELTZER et aL6 reported that in a set of 12 monozygotic (MZ) twins discordant for clinical schizophrenia, the Pearson product-moment correlation for serum CPK levels between the twins was 0.57. No specific effects of phenothiazine medication were noted and the enzyme levels were within normal limits. No correlations could be estimated with respect to serum CPK activity in dizygotic (DZ) twins discordant for schizophrenia since such a group was not tested. In a second study of 14 MZ and 14 DZ twins who were free of clinical schizophrenia, the Pearson product-moment correlation was 0.75 for MZ and 0.18 for DZ twins.6 This analysis was conducted on repeated assays in those PLASMA
Supported in part by the USPHS Grant MH31340 and from the Benevolent Foundation Rite, Northern Masonic Jurisdiction. 127
of the Scottish
128
PHILIP S. HOLZMAN
et al.
few subjects whose initial CPK values exceeded 140 u/ml. These values accord with the expectation that the MZ-DZ ratio should be higher than 1 in order to support a hypothesis of genetic control. The present study undertook to explore the genetic control of plasma CPK in a sample of MZ and DZ twins who are discordant for clinical schizophrenia. A complete description of the sample, the method of ascertainment, diagnostic criteria, concordance computations, and zygosity determinations can be found in Kringlen’s account.’ In brief, the sample was selected from the Norwegian psychosis registry which was checked against the population twin registry in Norway. The twins were individually interviewed and examined by one of the authors (E.K.) a decade ago. For the present study, we selected from that sample those twins who were available for testing during a 2-month period in 1975. In order to insure that serum CPK activity would be assayed blindly, without knowledge of the twinship relationship, a list of random numbers was drawn up and each subject was assigned a random number as the subject’s blood was drawn. The identities of the subjects were retained by one of the authors (E.K.) in Norway, who kept the other authors uninformed as to the twinship, diagnoses, and relationship among the subjects. Most subjects were seen in their own homes which were located throughout the southern half of Norway. A few subjects came to the University Psychiatric Clinic in Oslo and a few schizophrenic probands who were still hospitalized were seen in the hospitals. We were able to arrange for the transportation to Oslo of four persons from the far north of Norway. Only two sets of twins were seen in the same session. All subjects were reinterviewed at the time of the blood-drawing and clinical diagnoses were assigned by the interviewer (E.K.). There were no changes from 1967 in proband diagnoses, but two of the MZ co-twins (1B and 2B), earlier free of psychosis, had been hospitalized for a psychotic condition at some period between 1968 and 1975. Two additional sets of MZ and one DZ set were judged by Dr. Kringlen to have shifted their status from discordant to partially concordant, that is, the co-twin, although never hospitalized and never psychotic, manifested some behavioral peculiarities. Severity of illness was assessed by one of the authors (E.K.) according to a 7-point rating scale which was inferred from psychiatric history, social functioning after age 15, and the psychiatric interview on the day that the blood sample was drawn. A rating of l-2 suggested normal functioning; 3-4, moderate impairment but without overt manifest psychosis, 5-7, degrees of severe impairment, including psychosis. From each subject we drew 44 ems of venous blood, 10 cm3 of which was sent to the Institute of Forensic Medicine, University of Oslo for zygosity determinations if zygosity had not been previously determined. The following systems were used: ABO, MNS, rhesus, Lewis, P., Duffy, Kell, Gm, and Gc. Complete similarity on all systems determined monozygosity. The remaining 30 cm3 were then centrifuged, and heparinized plasma samples were frozen within 8 hr of collection. All samples were sent by air freight, frozen, to the United States within 2 months of collection. They were labeled with the random-number code so that identification was not possible at this stage of the study. Plasma CPK activity was determined in duplicate by the method of ROSALKI* using CPK Stat-Pak reagents obtained from Calbiochem (U.S.A.). There is a 10-20x decline in
PLASMACPK LEVELS IN MONOZYG~TICAND DIZYG~TICTWINS
129
activity in frozen samples stored for a 2-month period. A Micromedics Reaction Rate Analyzer was used. The coefficient of variation for duplicate CPK determinations is 5%. After the plasma CPK activity was determined, the data, identified by random-number code, were sent to Kringlen in Oslo who, on the same day, sent to the other authors in the United States identifying data consisting of names, ages, sex, and zygosity. Nine sets of MZ and fourteen sets of same-sexed DZ twins were tested. Of the MZ pairs, two sets were concordant for schizophrenia, two sets were partially concordant, and five sets were discordant. One pair of DZ twins was partially concordant and thirteen were discordant. RESULTS
All values were transformed into log units in order to reduce mathematically the effect of extreme scores; this procedure is clearly warranted in studies of small sample size such as the present one; the transformation normalized the distributions for the twin sets. The data are contained in Table 1. The Pearson product-moment correlation for the MZ pairs is 0.89 (p = 0.0003) and for rMZ-rDZ the DZ pairs 0.40 (p = 0.079). The index of heritability, computed as h2 = I--rDZ. is 0.82. The small number of subjects, 9 MZ and 14 DZ, limits the statistical significance that can be inferred. Thus, although the correlation of 0.89 between MZ twins is highly significant, the r of 0.40 between the DZ twins would occur by chance about 8 times in 100. Nevertheless, the values of the correlations for MZ and DZ twins are consistent with a genetic interpretation, with the correlation of MZ sets higher than that for DZ sets, and the difference between the two correlations is significant at p = 0.0573. Increased sample size would, of course, decide the issue of the reliability of this difference. It appears that the delay between sample acquisition and assay of up to 2 months has affected the CPK levels in such a way as to lower them. Thus, the values presented here are conservative and probably underestimate both the level of CPK in the subjects and the degree of concordance. It is apparent that the CPK values are not particularly high. Indeed, they are within normal limits, except for three subjects, 2A, 2B, and 9B. These findings are consistent with previous reports that plasma CPK is elevated only during the acute phase of the psychosis. None of the schizophrenic subjects was acutely psychotic, although some were still hospitalized. Those within a hospital, however, did not differ from those living outside a hospital. Some of the schizophrenic patients were still receiving neuroleptic medication, but the CPK values of these patients are not different from those receiving no medication. The Pearson product-moment correlation between severity of illness, as measured by the 7-point scale described earlier and CPK is -0.11 (p = n.s.). These ratings arepresented in Table 1. The data support the assumption that plasma CPK is to a significant degree under genetic control. This is consistent with other reports of serum enzyme dopamine beta-hydroxylase,s and platelet and plasma monoamine oxidase activitylO which are also under genetic control. The specific aspects of the enzyme activity that are genetically regulated are, however, not clear. Environmental influences definitely affect temporary levels of CPK, and to that
130
PHUP S. HOLZMAN et al.
TABLE ~.RAWAND LOO-TRANSFORMED PLASMA ACTIVITY(CPK) FOR 9 MZ AND 14DZ ANDCLINICALSEVERITyAsRATEDIN 1975AtUAL.W NOTED
Twin sets
MZ Twins CPK Activity Log CPK (mu/ml) activity
Severity rating as of 1975
Twin sets
Sex
Age
Sex
Age
1A 1B
M
62
9 12
0.9542 1.0792
7.0 7.0
1A 1B
M
47
::
M
55
178 615
2.2504 2.7888
5.0 5.0
2A 2B
M
54
TWINSETS.
DZ Twins CPK Activity Log CPK (mu/ml) activity 33 66
SEX,AGE, Severity rating as of 1975
1.5185 1.8195
6.0 4.0
1.5314 1.5798
25::
3A 3B
M
61
027 58
2.1038 1.7634
7.0 4.0
3A 3B
F
63
20 19
1.3010 1.2787
6.0 1.0
4A 4B
M
55
20 17
1.3010 1.2304
5.5 2.0
4A 4B
F
59
30 20
1.4771 1.3010
7.0 2.0
SA 5B
M
73
61 54
1.7853 1.7313
6.0 2.5
5A 5B
M
56
26 38
1.4149 1.5797
6.5 2.0
6A 6B
F
56
50 50
1.6989 1.6989
5.5 1.0
6A 6B
M
55
20 16
1.3010 1.2041
4.0 3.0
F
35
27 24
1.4313 1.3802
6.0 2.0
7A 7B
M
55
44 51
1.6434 1.7075
7.0 2.0
F
59
18 18
1.2552 1.2552
-
8A 8B
M
58
1.7403 1.7781
6.0 3.0
F
50
60 55
1.7781 1.7403
6.0 3.5
9A 9B
F
62
46 197
1.6627 2.2944
6.0 2.0
1OA IOB
M
52
10 80
1.000 1.9030
6.0 3.0
IlA LIB
M
73
10 11
1.000 1.0413
6.0 4.0
12A 12B
M
58
32 85
1.5051 1.9294
5.0 2.0
13A 13B
F
45
20 32
1.3010 1.5051
24::
14A 14B
F
1.4149 1.6127
6.0 3.0
;; 8A 8B
53
extent, CPK correlations among MZ twins would in practice never be perfect. That the MZ correlation is as high as it is, accounting for about 80% of the variance, lends strong support for assuming genetic control of the general level of CPK activity, conceived of as a trait variable. REFERENCES 1. HEYCK, I-L and LAUDAHN, G. Muscle and serum enzymes in muscular dystrophy and neurogenic muscular atrophy. A comparative study. In: Exploratory Concepts in Muscular Dystrophy and Related Disorders, pp. 232-240. MILHORAT, A. T. (Editor). Amsterdam, Netherlands, Excerpta Medica Foundation, 1967.
PLASMACPK LEVELSIN MONOZYG~TXAND DIZYG~TICTwms
131
2. MELTZER, H. Y. and HOLY, P. A. Black-white differences in serum creatine phosphokinase (CPK) activity. Clinica chim. Acta 54,215, 1975. 3. GRWITHS, P. D. Serum levels of A.T.P.: creatine phosphotransferase (creatine kinase), the normal range and effect of muscular activity. Clinica chim. Acta 13,413,1966. 4. MELTZER,H. Y. Neuromuscular dysfunctions in schizophrenia. Schizophrenia Bull. 2, 106, 1976. 5. MELTZER,H. Y., BELMAKER,R., WYATT, R. J., POLLIN, W. and COHEN, S. Serum creatine phosphokinase (CPK) activity in monozygotic twins discordant for schizophrenia: heritability of serum CPK activity. Comp. Psychiat. 17,469, 1976. 6. MELTZER,H. Y., DORUS, E., GRUNHAUS,L., DAVIS, J. M. and BELMAKER,R. Genetic control of human plasma creatine phosphokinase activity. In preparation. 7. KRINGLEN, E. Heredity and Environment in the Functional Psychoses. Universitetsforlaget, Oslo, 1967. 8. ROSALKI,S. B. An improved procedure for serum creatine phosphokinase determination. J. Lab. clin. Med. 69, 696, 1967. 9. Ross, S. B. and WETTERBERG, L. Genetic control of plasma dopamine P-hydroxylase. Life Sci. 12,529, 1972. 10. Nrrs, A. and ROBINSON,D. S. Genetic control of platelet and platelet monoamine oxydase activity. Archs gen. Psychiat. 28, 834, 1973.
