Serum
Creatine
BY HERBERT
Phosphokinase
Y. MELTZER,
in Schizophrenia
M.D.
The author notes that increased serum creatine phosphokinase (CPK) actii’it’ isfound in the majority ofhospitalized acutely disturbed schizophrenics and patients Ft’ith affective psychoses. It is probable that some ofthese increases do not resultfrom nonspecific f actors such as activity, trauma, or stress, which do cause increases in some cases. Those patients who show increased CPK actit’itv hate more florid psychopathology and tend to have higher CPK levels in nonacute periods than those without increases. First-degree relatives ofpsvchotic patients with elevated serum CPK hate high-normal or slightly increased serum CPK. There is also evidence of other neuromuscular dysfunction in psychotic patients The author concludes that the investigation ofCPK may have considerable heuristic t’aluefor the study of schizophrenia and other psychoses. .
SERUM OR PLASMA and the formed blood elements have proved to be convenient and safe sources of biologic material for investigators studying biochemical aspects of the schizophnenias and affective psychoses. This article will review one such approach to the biology of schizophrenia-the investigation of serum crcatinc phosphokinase (CPK) activity. I will focus on seven areas: 1) the origin ofthc serum enzyme, 2) nonspecific causes for increased CPK activity, 3) clinical characteristics of patients with and without increases, 4) serum CPK activity in nonpsychotic periods in psychotic patients with and without increases, 5) serum CPK activity in first-degree relatives of psychotic patients, 6) comparison with serum CPK increases in patients with acute brain diseases, and 7) other cvidence of neuromuscular dysfunction in psychoses. Increased serum CPK activity has been found in
Presented Association. Dr.
at the 128th Anaheim.
Meltzer
meeting
May
,
is Professor,
Department
University
of Chicago.
of Medicine, 60637, and stitute.
annual Calif.
Director
of Adult
of the 5-9.
American
of Psychiatry.
950 East
Services,
Psychiatric
1975.
Illinois
59th
Pritzker School , Chicago, III. Psychiatric In-
St.
State
This
work was supported by Alcohol, Drug Abuse, and Mental Administration grants MH-16217and MH-l8396from the National Institute of Mental Health and by State of Illinois Department
Health
of Mental Health grant 431-13-RD. Dr. Meltzer is recipient Public Health Service career scientist award MH-47808. The
author
Moretti
192
wishes
for assistance
Am
to thank
Pamela
in research
J Psychiatry
/33:2,
Holy,
design
Glenn
Lucht,
and data
February
of U.S.
and
analysis.
1976
Robert
some schizophrenic patients experiencing an acute psychotic phase (1-10). Increases arc also present in patients with acute affective psychoses (2, 5. 1 1). In a recent study of 187 acutely psychotic patients-163 with schizophrenia and 24 with affective psychoses-it was found that 47.1% of the patients (N=88) had increased serum CPK activity in samples obtained within 48 hours of admission (5). Serum CPK levels were then determined each weekday throughout hospitalization, and nearly two-thirds of the patients who showed increases at admission also had one or more increases later in hospitalization. Fifty-four patients who had not shown increased CPK activity at admission did so later during their hospitalization. This indicates that serum CPK determinations must be made throughout hospitalization if all patients with increased CPK activity arc to be identified. The increascs range fnomjust above the 95% upper limit of normal for each race-sex group up to 50 times the upper limit; the median increase is 2 to 3 times the 95% upper limit. The increase lasts I to 3 days in half of the cases but is much longer in others (4. 5).
ORIGIN
OF
SERUM
CPK
ACTIVITY
There arc now 3 known isozyrnes of CPK: a brain type (BB), a skeletal muscle type (MM), and a cardiac muscle type (MB). Each type is a dimer made up of some combination of B and M subunits. Brain and skeletal muscle have almost exclusively BB and MM type CPK, respectively; cardiac muscle has a mixture of MB, BB, and MM (12, 13). Other organs have only small amounts of CPK and generally do not contribute to any increase in serum CPK activity. The isozymes of CPK can be identified by chromatographic, dcctrophoretic, or radioimmunologic methods. The CPK in the serum of schizophnenics has been identified as the skeletal muscle type by chromatographic and dcctrophoretic methods; no brain type was found (3, 4). This suggests that the origin of the CPK is skeletal muscle, a hypothesis that is further supported by findings ofincreased serum aldolase (2, 3) and pynuvate kinase (according to the unpublished data of Gordon R. Pschedit and myself) in psychotic patients with increased serum CPK activity. Like CPK. elevated aldolase and pyruvate kimase levels in serum are associated with skeletal muscle disease. There is some controversy as to whether cenebrospinal fluid CPK activity is increased in acute schizophre-
HERBERTY.
nia. No increases were found in several studies (4, 14, 15), but there is one report of increased cerebrospinal fluid CPK levels in acute schizophnemics (16) and another ofincreases in patients with LSD psychoses (17). Further study ofthis problem with scmsitive methods for determination of CPK activity on protein and careful attention to potential artifacts is needed. Although the evidence I have reviewed may seem to indicate that the origin of the serum CPK in psychotic patients is skeletal muscle, uncertainty has been introduced by a report that brain type CPK is unstable in serum, especially in vivo, with rapid conversion to the cardiac and skeletal muscle types (18). We (Hyong Won Cho, Jomg I. Joung, David J. Goode, and myself) have partially confirmed this in work that showed human brain type CPK to be unstable in vitro; after incubation for 42 hours it migrated like the cardiac type and a species intermediate between cardiac and skeletal muscle type developed. We could not identify any skeletal muscle type even after prolonged incubation in vitro; however, it is possible that a species that migrates like skeletal muscle type CPK could be produced in vivo from brain CPK.
FACTORS
NOT
POSSIBLE
CAUSES
ACTIVITY
IN
RELATED OF
PSYCHOTIC
TO
PSYCHOSIS
ELEVATED
SERUM
AS CPK
PATIENTS
Intramuscular injections may elevate serum CPK activity. Although less than 50% of patients given intramuscular chlorpromazine (Thorazine) have increased serum CPK levels following injection (19). all patients who have received such injections should be excluded from studies of serum CPK. In order to avoid the mecessity of eliminating the majority of psychotic patients whose serum CPK would be of research interest, intramuscular injections should be avoided. Oral psychotropic medication does not influence serum CPK levels in man, and if parentenal medication is needed, subcutaneous pnolixin enanthate or intravenous haloperidol might be used. Alcoholism (20) amd muscle trauma may also increase serum CPK activity and must be excluded by history, laboratory, amd physical examination. Restraining psychotic patients for purposes of management frequently causes sufficient trauma to produce large increases in CPK activity. Dietary factors, including starvation. have not been found to increase serum CPK activity (21). Stress does not usually increase serum CPK activity in people without psychotic disorders: monpsychotic psychiatric patients experiencing severe anxiety, agitatiom, on depressive symptoms do not have increased serum CPK levels (4, 5, 1 1), and preoperative patients generally have normal serum CPK activity (22). However, we have found moderate increases in serum CPK levels in some psychotic patients before hospital discharge and in several volunteers before psycho-
MELTZER
tomirnetic drug administration that may be related to stress (4. 23). Physical activity is a well-known cause of increased serum CPK activity (24). However, very strenuous activity (e.g. crew racing or marathon running) is generally required to produce increases, except in a small percentage of so-called enzyme-labile subjects who have large increases in serum CPK activity with relatively slight motor activity (24). A variety of indirect evidence summarized elsewhere (25) suggests that increased motor activity is not a sufficient explanation of the increased serum CPK levels in most psychotic patients. We have recently found that exhausting isometric exercise does not produce increases in serum CPK levels in psychiatric patients that exceed those present during other phases of hospitalization (26). Although Foster and Kupfer (8) reported correlations between serum CPK levels during certain periods of the day and non-dominant-arm motor activity monitored by telemetry. and we have found that nurses’ ratings of motor activity and CPK activity are significantly correlated (5). this does not prove causality. In some patients, both motor activity and serum CPK activity could be the consequence ofa basic neurochemical abnormality in psychosis. e.g. increased dopaminergic activity. Sleep disturbance in psychotic patients, particulanly non-REM sleep time, is negatively correlated with serum CPK levels (27) and may be another cxample ofa central nervous system function that correlates with serum CPK levels without requiring a causal relationship. In normal volunteers, sleep deprivation for 48 hours can produce modest increases in serum CPK activity (28). ,
CLINICAL
CHARACTERISTICS
PATIENTS
WITH
SERUM
CPK
AND
OF WITHOUT
PSYCHOTIC INCREASED
ACTIVITY
My colleagues (Glenn Lucht and Pamela Holy) and I have studied the clinical characteristics of psychotic patients with and without increased serum CPK activity at admission or at any time during hospitalization to identify the factors that correlate with and perhaps contribute to the increases (5). Such analyses are critical in biologic investigations ofthis type because of the high likelihood of heterogeneity in the schizophrenic syndrome and because the biologic characteristic umden study may be a state-dependent variable rather than a stable trait. This would mean that the clinical state of the patient at the time(s) of study would exert an important influence on the presence ofthe biochemical abnormality. I will summarize only our major findings here. The time of onset of psychotic symptoms was significantly related to the presence or absence of increased serum CPK activity. Increased serum CPK activity at admission was significantly more frequent in patients who had had gross psychotic symptoms for less than I week (54 of92 patients. or 58.7%) than in patients who
AmfPsvchiatry
/33:2,
Februa
1976
193
SERUM
CREATINE
PHOSPHOKINASE
had had symptoms for more than 1 week (34 of 95 patients. or 35.8%) (x28.94S p
Creatine
BY HERBERT
Phosphokinase
Y. MELTZER,
in Schizophrenia
M.D.
The author notes that increased serum creatine phosphokinase (CPK) actii’it’ isfound in the majority ofhospitalized acutely disturbed schizophrenics and patients Ft’ith affective psychoses. It is probable that some ofthese increases do not resultfrom nonspecific f actors such as activity, trauma, or stress, which do cause increases in some cases. Those patients who show increased CPK actit’itv hate more florid psychopathology and tend to have higher CPK levels in nonacute periods than those without increases. First-degree relatives ofpsvchotic patients with elevated serum CPK hate high-normal or slightly increased serum CPK. There is also evidence of other neuromuscular dysfunction in psychotic patients The author concludes that the investigation ofCPK may have considerable heuristic t’aluefor the study of schizophrenia and other psychoses. .
SERUM OR PLASMA and the formed blood elements have proved to be convenient and safe sources of biologic material for investigators studying biochemical aspects of the schizophnenias and affective psychoses. This article will review one such approach to the biology of schizophrenia-the investigation of serum crcatinc phosphokinase (CPK) activity. I will focus on seven areas: 1) the origin ofthc serum enzyme, 2) nonspecific causes for increased CPK activity, 3) clinical characteristics of patients with and without increases, 4) serum CPK activity in nonpsychotic periods in psychotic patients with and without increases, 5) serum CPK activity in first-degree relatives of psychotic patients, 6) comparison with serum CPK increases in patients with acute brain diseases, and 7) other cvidence of neuromuscular dysfunction in psychoses. Increased serum CPK activity has been found in
Presented Association. Dr.
at the 128th Anaheim.
Meltzer
meeting
May
,
is Professor,
Department
University
of Chicago.
of Medicine, 60637, and stitute.
annual Calif.
Director
of Adult
of the 5-9.
American
of Psychiatry.
950 East
Services,
Psychiatric
1975.
Illinois
59th
Pritzker School , Chicago, III. Psychiatric In-
St.
State
This
work was supported by Alcohol, Drug Abuse, and Mental Administration grants MH-16217and MH-l8396from the National Institute of Mental Health and by State of Illinois Department
Health
of Mental Health grant 431-13-RD. Dr. Meltzer is recipient Public Health Service career scientist award MH-47808. The
author
Moretti
192
wishes
for assistance
Am
to thank
Pamela
in research
J Psychiatry
/33:2,
Holy,
design
Glenn
Lucht,
and data
February
of U.S.
and
analysis.
1976
Robert
some schizophrenic patients experiencing an acute psychotic phase (1-10). Increases arc also present in patients with acute affective psychoses (2, 5. 1 1). In a recent study of 187 acutely psychotic patients-163 with schizophrenia and 24 with affective psychoses-it was found that 47.1% of the patients (N=88) had increased serum CPK activity in samples obtained within 48 hours of admission (5). Serum CPK levels were then determined each weekday throughout hospitalization, and nearly two-thirds of the patients who showed increases at admission also had one or more increases later in hospitalization. Fifty-four patients who had not shown increased CPK activity at admission did so later during their hospitalization. This indicates that serum CPK determinations must be made throughout hospitalization if all patients with increased CPK activity arc to be identified. The increascs range fnomjust above the 95% upper limit of normal for each race-sex group up to 50 times the upper limit; the median increase is 2 to 3 times the 95% upper limit. The increase lasts I to 3 days in half of the cases but is much longer in others (4. 5).
ORIGIN
OF
SERUM
CPK
ACTIVITY
There arc now 3 known isozyrnes of CPK: a brain type (BB), a skeletal muscle type (MM), and a cardiac muscle type (MB). Each type is a dimer made up of some combination of B and M subunits. Brain and skeletal muscle have almost exclusively BB and MM type CPK, respectively; cardiac muscle has a mixture of MB, BB, and MM (12, 13). Other organs have only small amounts of CPK and generally do not contribute to any increase in serum CPK activity. The isozymes of CPK can be identified by chromatographic, dcctrophoretic, or radioimmunologic methods. The CPK in the serum of schizophnenics has been identified as the skeletal muscle type by chromatographic and dcctrophoretic methods; no brain type was found (3, 4). This suggests that the origin of the CPK is skeletal muscle, a hypothesis that is further supported by findings ofincreased serum aldolase (2, 3) and pynuvate kinase (according to the unpublished data of Gordon R. Pschedit and myself) in psychotic patients with increased serum CPK activity. Like CPK. elevated aldolase and pyruvate kimase levels in serum are associated with skeletal muscle disease. There is some controversy as to whether cenebrospinal fluid CPK activity is increased in acute schizophre-
HERBERTY.
nia. No increases were found in several studies (4, 14, 15), but there is one report of increased cerebrospinal fluid CPK levels in acute schizophnemics (16) and another ofincreases in patients with LSD psychoses (17). Further study ofthis problem with scmsitive methods for determination of CPK activity on protein and careful attention to potential artifacts is needed. Although the evidence I have reviewed may seem to indicate that the origin of the serum CPK in psychotic patients is skeletal muscle, uncertainty has been introduced by a report that brain type CPK is unstable in serum, especially in vivo, with rapid conversion to the cardiac and skeletal muscle types (18). We (Hyong Won Cho, Jomg I. Joung, David J. Goode, and myself) have partially confirmed this in work that showed human brain type CPK to be unstable in vitro; after incubation for 42 hours it migrated like the cardiac type and a species intermediate between cardiac and skeletal muscle type developed. We could not identify any skeletal muscle type even after prolonged incubation in vitro; however, it is possible that a species that migrates like skeletal muscle type CPK could be produced in vivo from brain CPK.
FACTORS
NOT
POSSIBLE
CAUSES
ACTIVITY
IN
RELATED OF
PSYCHOTIC
TO
PSYCHOSIS
ELEVATED
SERUM
AS CPK
PATIENTS
Intramuscular injections may elevate serum CPK activity. Although less than 50% of patients given intramuscular chlorpromazine (Thorazine) have increased serum CPK levels following injection (19). all patients who have received such injections should be excluded from studies of serum CPK. In order to avoid the mecessity of eliminating the majority of psychotic patients whose serum CPK would be of research interest, intramuscular injections should be avoided. Oral psychotropic medication does not influence serum CPK levels in man, and if parentenal medication is needed, subcutaneous pnolixin enanthate or intravenous haloperidol might be used. Alcoholism (20) amd muscle trauma may also increase serum CPK activity and must be excluded by history, laboratory, amd physical examination. Restraining psychotic patients for purposes of management frequently causes sufficient trauma to produce large increases in CPK activity. Dietary factors, including starvation. have not been found to increase serum CPK activity (21). Stress does not usually increase serum CPK activity in people without psychotic disorders: monpsychotic psychiatric patients experiencing severe anxiety, agitatiom, on depressive symptoms do not have increased serum CPK levels (4, 5, 1 1), and preoperative patients generally have normal serum CPK activity (22). However, we have found moderate increases in serum CPK levels in some psychotic patients before hospital discharge and in several volunteers before psycho-
MELTZER
tomirnetic drug administration that may be related to stress (4. 23). Physical activity is a well-known cause of increased serum CPK activity (24). However, very strenuous activity (e.g. crew racing or marathon running) is generally required to produce increases, except in a small percentage of so-called enzyme-labile subjects who have large increases in serum CPK activity with relatively slight motor activity (24). A variety of indirect evidence summarized elsewhere (25) suggests that increased motor activity is not a sufficient explanation of the increased serum CPK levels in most psychotic patients. We have recently found that exhausting isometric exercise does not produce increases in serum CPK levels in psychiatric patients that exceed those present during other phases of hospitalization (26). Although Foster and Kupfer (8) reported correlations between serum CPK levels during certain periods of the day and non-dominant-arm motor activity monitored by telemetry. and we have found that nurses’ ratings of motor activity and CPK activity are significantly correlated (5). this does not prove causality. In some patients, both motor activity and serum CPK activity could be the consequence ofa basic neurochemical abnormality in psychosis. e.g. increased dopaminergic activity. Sleep disturbance in psychotic patients, particulanly non-REM sleep time, is negatively correlated with serum CPK levels (27) and may be another cxample ofa central nervous system function that correlates with serum CPK levels without requiring a causal relationship. In normal volunteers, sleep deprivation for 48 hours can produce modest increases in serum CPK activity (28). ,
CLINICAL
CHARACTERISTICS
PATIENTS
WITH
SERUM
CPK
AND
OF WITHOUT
PSYCHOTIC INCREASED
ACTIVITY
My colleagues (Glenn Lucht and Pamela Holy) and I have studied the clinical characteristics of psychotic patients with and without increased serum CPK activity at admission or at any time during hospitalization to identify the factors that correlate with and perhaps contribute to the increases (5). Such analyses are critical in biologic investigations ofthis type because of the high likelihood of heterogeneity in the schizophrenic syndrome and because the biologic characteristic umden study may be a state-dependent variable rather than a stable trait. This would mean that the clinical state of the patient at the time(s) of study would exert an important influence on the presence ofthe biochemical abnormality. I will summarize only our major findings here. The time of onset of psychotic symptoms was significantly related to the presence or absence of increased serum CPK activity. Increased serum CPK activity at admission was significantly more frequent in patients who had had gross psychotic symptoms for less than I week (54 of92 patients. or 58.7%) than in patients who
AmfPsvchiatry
/33:2,
Februa
1976
193
SERUM
CREATINE
PHOSPHOKINASE
had had symptoms for more than 1 week (34 of 95 patients. or 35.8%) (x28.94S p
