Serum Creatine Phosphokinase (CPK) Activity in Monozygotic Twins Discordant for Schizophrenia: Heritability of Serum CPK Activity Herbert
Y. Meltzer,
Robert
Belmaker,
Richard J. Wyatt,
and Steven
William
Pollin,
Cohen
R
ECENT STUDIES with normal monozygotic and dizygotic twins have established that serum creatine phosphokinase (CPK) activity in man is under genetic control (Meltzer, Dorus, and Davis, in preparation). This is of interest because of the reports that serum CPK activity is increased in many acutely psychotic patients, provided that they are studied in the first days after the onset of gross psychotic symptoms and throughout hospitalization.‘-‘2 The increases range from slightly above the 95% upper limits of normal to 50-75 times the limits for each race-sex group. Furthermore, 25%30% of the first degree relatives of psychotic patients have slight but persistent increases in serum CPK These increases occur significantly more frequently in relatives of psychotic patients who have themselves had increases in serum CPK activity (Meltzer and Moretti, in preparation). Prior to the studies with normal twins which established that serum CPK activity is under some genetic control, we had the opportunity to study serum CPK activity in twins discordant for schizophrenia. These results will be reported here. activity.2.3.i
MATERIALS The twin pairs have been previously original
hospitalization
AND
reported
METHODS
on.13-21 Monozygosity
of the index twin by demonstrating
the identity
was established of multiple
during the
red cell anti-
gens.L:‘-‘5 There were nine female and three male sets with ages ranging from 25S51, median 36 (Table I). The index twins had all been hospitalized schizophrenia.
at least once with the diagnosis of acute or chronic
One of the index twins (3) was currently
hospitalized;
considered to be in remission. Diagnosis and degree of impairment
five (7, 14, 18, 21, and 22) were
were established on the basis of an
From the Department of Psvchiatrv, Universit), of Chicago Prit:ker School of Medicine and the Illinois State Psychiatric Institute, Chicago, Ill.; the Adult P.svchiatrv Branch, National Institute o/ Mental Health, Bethesda, Md.; and the Laborator_v of Clinical P.s.vchopharmaco1og.v. National In.stitute oJ‘Mental Health. St. Elizabeth’s Hospital, Washington. D.C. Herbert Y. Meltzer. M.D.: Professor, Department of Psychiatry. University of Chicago Prit:ker School of Medicine and the Illinois State Psvchiatric Institute: Robert Belmaker. M.D.: Clinical .4ssociate, Section on Twin and Sibling Studies, Adult Psvchiatr!, Branch, National Institute ol Mental Health: Richard J. Wyatt, M.D.: Chief: Laboratory oJ Clinical Psvchopharmacologv. National Institute of Mental Health, St. Elizabeth’s Hospital; William Pollin, M.D.: Chief. Section on Twin and Sibling Studies, Adult Psychiatry Branch, National Institute of Mental Health; Steven Clinical .4ssociate, Section on Twin and Sibling Studies, Adult P.yychiatry Branch, ,Yational Institute qf Mental Health. Supported in part by USPHS MH Grant 16. l-77 and Grant 231-12 R. D. from the State of Illinoi.~ Department of Mental Health. Dr. Meltzer is a recipient OJ C’SPHS Career Development Award K@-MH 47,808. Keprint requests should be addressed to H. Z’. Meltzer. M.D., Department oJ’ P.svchiatrv. L’niversiiv oJ’Chicago Pritzker School oJ‘Medicine. 950 E. 59th Street, Chicago. Ill. 60649. c 1976 bv Grune & Stratton. Inc. Cohen. M.D.:
Comprehensive Psychiatry. Vol. 17. No. 3 (May/June).
1976
469
MELTZER ET AL.
470
Table 1. Clinical Characteristics
and Serum CPK Activity Impairment
for Twelve Pairs of Monozygotic
Ratings Treatment
Index Twin
Diagnosis Twin
Forced
Twins
Co-twin
Impair-
with
Impair-
Age and
Index
CO-
Rank
ment
ment
Index
CO-
No.
Sex
Twin
twin
Order
Rating
Rating
Twin
twin
2
0 0 0 0
Yes Yes
No No No No
1
33 F
cus cus
None
9
4
28 F
None
12
5
5
37 M
CPS
None
8
4
7
34F
AUS
None
1
Activity
(IU/liter)
Pair
3
CPK
Phenothiazines
Yes Yes
Index
CO-
Twin
twin
23
24
9
9
32
27
16
23
33
45
in Remission 8
30 M
CPS
None
11
4
0
No
No
10
42 F
CPS
In SS
3
3
1
14
25 F
cus
None
6
3
0
No Yes
No No
119
56
32
32
in Partial Remission 17
37 F
CPS
None
7
3
0
APS
None
2
2
0
No No
17
51 F
No No
29
18
32
32
21
44 F
AUS
In ss
5
3
1
Yes
No
21
24
None
10
3
0
Yes
No
17
21
AUS
4
4
1
No
No
54
109
in Remission in Remission 22
CPS
37 F
in Remission 23
cus
31 M
CUS = chronic undifferentiated
undifferential schizophrenia;
schizophrenia;
CPS = chronic
APS = acute paranoid
paranoid
schizophrenia;
schizophrenia;
AUS = acute
SS = schizophrenic
spectrum.
at the time of the blood sampling and a review of previous records. The criteria used to assess degree of impairment are given in Table 2. Two raters (R. B. and R. W.) next rank ordered the index twins for severity of illness with the highest number assigned to the twin who was most ill. These rankings were made prior to determination of serum CPK activity. None of the 12 co-twins were on drugs. Nine of the 12 co-twins had never been hospitalized for a behavioral disorder, and were generally functioning normally within their families and at work. One of the co-twins (23) had borderline psychosocial functioning at the time of interviewing and blood sampling. Two weeks later, he was considered to be psychotic or close to psychotic by two of us (R. B. and R. W.), but was not hospitalized. Co-twin 21 had had a 3-day period characterized by delusions at a time of stress, but did not manifest serious psychopathology at other times. Co-twin 10 was characterized by very eccentric thinking and was considered to have borderline schizophrenic symptomatology within the definition of schizophrenic spectrum disease. Only two of the twin pairs were living together in the same household at the time of the study; in nine cases, the co-twins were living in different cities. Clinical characteristics and serum CPK activity for the 12 twin pairs appear in Table I. Blood samples were obtained by venipuncture and the plasma was kept frozen at -70°C. The saminterview
Table 2. Criteria 1. History
of poor functioning
transient
for Degree of impairment*
at work and in interpersonal
relationships,
or hospitalization
for a
illness, or both
2. Hospitalization
with a clearly schizophrenic
Year, but subject has functioned
illness lasting longer than 1 month but less than 1
well since (multiple
hospitalizations
within
1 year categorized
here) 3. Two or more clearly schizophrenic function 4.
inability
at work or as a housewife to function
5. Continuous ‘In
episodes separated
at work or as a housewife
hosoitalization
by at least 1 year, but subject able to
while in remission even between
hospitalizations
for the last 5 vears
the forced rank order of index twins, the highest number was assigned to the most ill.
CPK ACTIVITY
471
pies were assayed approximately CPK activity from
6 months later. The method of Rosalki”
coded samples on a blind basis. There
ples in 6 months with this assay (unpublished data). The normal in Caucasian samples statistical
males and females in our laboratory
assayed
within
48 hr. 23 The coefficient
tests were two-tailed
was used to determine
is a 50% loss in CPK activity in frozen samupper limits for serum CPK activity
are 70 IU/liter
of variation
t tests except where otherwise
and 50 IU/liter,
for duplicate
respectively
determinations
for
is 5Q’. All
noted.
RESULTS
The serum CPK values for each twin pair are presented graphically in Fig. I. The mean serum CPK activity of the schizophrenic twins was not significantly different from that of the co-twins (Table 3). One of the index twins (10) and two of the co-twins (10 and 23) had slightly elevated CPK activity. Co-twin 23, who had the highest serum CPK activity of all the co-twins, was the one who had a psychotic-like episode 2 weeks following the drawing of the blood sample. Cotwin 10 was the twin diagnosed within the schizophrenic spectrum. The product moment correlation coefficient for the serum CPK activities of the twin pairs was 0.565 (p < 0.05) (Table 4). The Spearman r between forced ranked order of illness and for serum CPK activities of the index twins was not significant (r = -0.259). The mean serum CPK activity of the five index twins who were not receiving medication just missed being significantly greater than those of the seven index twins who were receiving phenothiazines (p < 0.10). This was also true for the respective co-twins (p < 0.10). There were no significant differences between the mean serum CPK activities of the index twins who received medication and their co-twins or between the mean serum CPK activities of the index twins who received no medication and their co-twins (Table 3). The forced rank order of illness ratings of the index twins who were or were not receiving phenothiazines were not significantly different (Mann-Whitney U = 11,~ = 0.344). The product moment correlation coefficient for the serum CPK activities of the seven twins who were receiving medication and their co-twins was significant (r = 0.897; p < 0.01; Table 4). But, the product moment correlation coefficient for the serum CPK activities of the five index twins who were not receiving medication and their co-twins was not significant (r = 0.323; p > 0.5; Table 4).
Fig. 1.
Serum CPK activity of twin pairs.
MELTZER ET AL.
472
Table 3.
Summary
of Serum CPK Activity
in Twins with Tests of Difference Serum
Group
I.
All index twins
2. All co-twins
CPK
Activity
N
Mean
12
34.8 f 28.9
12
34.9
i SD
? 26.4
3.
Index twins receiving phenothiazines
7
21.4 f
8.5
4.
Co-twins
7
22.9 f
7.1
5
53.4 f 38.0
5
51.8 f 35.1
of Group
3
5. Index twins without 6.
Co-twins
of Group
phenothiazines 5 Difference Degree
Tests of
Freedom
Comparison
t Value
P -
Group
1 vs. Group 2
10
-0.022”
Group
3 vs. Group 4
5
-1 .oo*
Group
5 vs. Group 6
3
-0.084”
-
5
10
2.192t