106
SCHIZOPHRENIA BULLETIN
neuromuscular dysfunction in schizophrenia'
During the last 7 years, there have been a number of investigations of the incidence of various types of neuromuscular dysfunction in patients with schizophrenic and affective illnesses and their first-degree relatives in comparison with appropriate controls, including nonpsychotic psychiatric patients. Before reviewing these studies, it may be of value to discuss why neuromuscular dysfunction might be expected in virtually any disease of the nervous system—a category in which, thanks to recent genetic studies, we may now confidently include schizophrenia and the primary affective illnesses. The evidence for central nervous system involvement in a variety of diseases with apparently primary skeletal muscle involvement will also be presented. There are numerous instances of known disease of the brain in which pathologic changes in lower motor neurons, with consequent effects on skeletal muscle fiber morphology and function, are found. "Central atrophy" is the name given to the atrophy of skeletal muscle fibers, which frequently develops after various chronic brain diseases, particularly tumors of the parietal lobe (Fenichel, Daroff, and Glaser 1964, Koinov and Markov 1971, and Van Crevel 1969). Depth electrode studies in chronic schizophrenics have demonstrated abnormal electrical discharges in various parts of the cerebral cortex, including the parietal lobe (see Mirsky 1969). The mechanism of central atrophy is believed to be loss of the trophic (nutrient) influence of the upper •Address reprint requests to the author at Department of Psychiatry, University of Chicago Pritzker School of Medicine, 950 E. 59th St., Chicago, III. 60637.
motor neuron on the lower motor neuron (see Guth 1968 for discussion of trophism). In turn, the lower motor neuron is believed to produce and release trophic substances on which skeletal muscle fibers are dependent, such that loss of these trophic factors leads to muscle fiber atrophy (Mendell and Engel 1971). Parkinson's disease is associated with skeletal muscle atrophy (Edstrftm 1970) perhaps because of the loss of trophic influences or because of muscle rigidity. A small number of pathological muscle fibers of diverse morphology develop in rats after lesions of the substantia nigra or cuts under the globus pallidus (Kanner and Meltzer 1974). Changes in muscle fiber types also develop in monkeys following lesions of the primary or secondary sensory cortical areas (Schwartzman and Dimancescu 1974). Vitamin deficiencies such as pernicious anemia (subacute combined degeneration) can produce brain, motor neuron, and skeletal muscle fiber abnormalities (Brain 1955). Interestingly, mental disturbances may occur in pernicious anemia. These may include paranoia or severe affective illness (McAlpine 1929). There are several disorders of tryptophan metabolism, including pellagra, carcinoidosis, maple syrup disease, and Hartnup disease, in which both mental and neuromuscular symptoms and pathologic findings are present (Lehmann 1972), apparently due to an inadequate amount of tryptophan or its metabolites. Diseases such as Duchenne-type muscular dystrophy, myotonic muscular dystrophy, myasthenia gravis, and malignant hyperpyrexia are believed by some to be primarily diseases of the nervous system with secondary changes in skeletal muscle fibers (Engel 1971, Konishi et
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
Herbert Y. Meltzer
VOL. 2, NO. 1,1976
elevated in serum in a variety of diseases associated with skeletal muscle fiber breakdown. Although the increases are greatest in Duchenne-type muscular dystrophy, elevations also occur in diseases of the lower motor neuron such as amyotrophic lateral sclerosis (Achari and Anderson 1974) and various childhood degenerative diseases of lower motor neurons (Heyck and Laudahn 1967). A variety of known acute brain diseases are associated with elevated muscle-type serum CPK levels; this includes acute cerebrovascular accidents, encephalitis, meningitis, and brain trauma (Dubo et al. 1967 and Eisen and Sherwin 1968). Small increases in serum CPK activity have been found in dogs after chronic electrical stimulation of the diencephalon (Bolter and Critz 1971). Moderate increases in serum CPK activity have been found in rats 4 hours after electrolytic lesions of the anterior hypothalamus but not in 13 other brain areas (K. T. Finnegan, H. Y. Meltzer, and M. Kanner, unpublished data). There is also electrophysiological evidence of abnormalities of lower motor neurons and the skeletal muscle fibers they innervate in patients with a variety of brain diseases. McComas et al. (1973) have found a decrease in the number of viable motor units in patients, beginning 6-12 months after cerebral vascular accidents. Similarly, patients with Parkinson's disease have decreased numbers of functioning motor units (Sica et al. 1973). Current theories of the nature of the biologic factors that contribute to the pathogenesis of schizophrenia center around abnormalities of bioamines such as the catecholamines and serotonin. There is also considerable evidence that bioamines such as serotonin and adrenaline can produce pathological changes in skeletal muscle (Highman, Altland, and Garbus 1965, Meltzer and Margulies 1971, O'Steen, Barnard, and Yates 1967, and Parker and Mendell 1974). Adrenaline has been reported to have unique effects on the muscle contraction of denervated muscles (Bowman and Raper 1965 and Evans and Smith 1973), which may be relevant to schizophrenics for whom there is evidence of muscle denervation (see below). Similar effects of adrenaline were noted on the muscle of subjects with various muscular dystrophies, suggesting alteration in neurotrophic influence on skeletal muscle in these diseases (Takamori 1975). Dopamine has been shown to inhibit skeletal muscle contraction by a direct effect on muscle (Blum 1969 and Ferko and Calesnick 1971), which can be inhibited by
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
al. 1974, LaCour, Juul-Jensen, and Reske-Nielsen 1971, McComas, Campbell, and Sica 1971, McComas, Sica, and Brown 1971, and McComas, Sica, and Upton 1974), but this is not generally accepted. Nevertheless, it is important to recall the undisputed high incidence of mental retardation in Duchenne muscular dystrophy (Prosser, Murphy, and Thompson 1969 and Zellweger and Niedermeyer 1965), the dilated ventricles and cerebral atrophy associated with myotonic dystrophy (Refsum et al. 1967), and the oft-noted occurrence of psychosis in families with myotonia congenita (Johnson 1967). "Central core" and fibers with rod bodies are striking pathologic changes in skeletal muscle that appear to be nonspecific in that they do not define a disease entity. There is considerable evidence that these may be due to abnormalities of motor nerves (Dahl and Klutzow 1974, Dubowitz and Roy 1970, Engel 1966, and Karpati, Carpenter, and Andermann 1971). Munsat, Thompson, and Coleman (1969) have discussed the role of the central nervous system in the etiology of centronuclear myopathy, a rare form of myopathy in which functional but not morphological pathology has been identified. They postulated that "the CNS [central nervous system] defect in centronuclear myopathy may, therefore, be primary with muscle changes reflecting disordered central control" (p. 130). Fenichel (1967) has discussed a variety of ways in which brain damage in utero may adversely affect muscle development. Brune (1971) has called attention to older literature that details the occurrence of cases of simultaneous muscle disease and major mental illness, including a family with three siblings for whom Duchenne-type muscular dystrophy and schizophrenia were said to become clinically manifest at the same time. Although some type of psychopathology may frequently be found in chronic muscle diseases, it is rare that frank psychosis is present (Brune 1971). Beckett and Bourne (1973) summarized evidence that monkeys reared in isolation, a condition known to produce markedly disturbed behavior, had extensive myopathic changes in skeletal muscle, including the diaphragm. Although they rightly concluded that it was impossible to decide if these changes were due to physical inactivity or psychosomatic factors, it would seem that the diaphragmatic changes would argue against simple inactivity as the explanation. Several skeletal muscle enzymes—for example, creatine phosphokinase (CPK) and aldolase—have a relatively slow disappearance rate from serum so that they may be
107
SCHIZOPHRENIA BULLETIN
108
Serum Creatine Phosphokinase Activity in Acute Psychosis Demonstration of increased activity of serum enzymes associated with skeletal muscle disease—that is, CPK, aldolase, or pyruvate kinase (PK)—is the most convenient way available, other than history and physical examination, to demonstrate the possible presence of skeletal muscle abnormalities. As will be discussed, elevated serum CPK, aldolase, or PK activities may result
from causes other than significant muscle disease (Nevins et al. 1973). These factors must be considered before increases in serum enzyme activity are attributed to muscle disease. Once these factors have been taken into account, determination of serum CPK activity can be a most sensitive index of skeletal muscle disease. For example, in those vulnerable to malignant hyperpyrexia, serum CPK is moderately elevated, sometimes without any detectable muscle changes on physical examination (Denborough et al. 1970). 1 Serum CPK elevations in acutely disturbed schizophrenics have now been found in 17 studies (table 1), but the percentage of patients with elevations varies from 8 to 100 (median = 40 percent). Increased serum CPK activity has also been reported in other types of psychiatric patients, especially those with affective psychoses (table 1). Before discussing the reasons for the large variations in the incidence of increased serum CPK activity in acutely disturbed schizophrenics in various studies, it is useful to review briefly the origin of serum CPK in psychotic patients and the possible causes of increased serum CPK activity in psychotic patients that are not specific to psychosis.
Origin of Serum CPK Activity There are three major isoenzymes 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 all
'Certain general anesthetics (e.g., fluothane, halothane) and muscle relaxants (e.g., succinylcholine) can evoke massive CPK Increases In individuals who are susceptible to malignant hyperpyrexia (Britt 1972). Abundant microscopic pathology is present in the skeletal muscle of individuals susceptible to malignant hyperpyrexia, because of an inherent nerve or muscle abnormality or both (Harriman, Sumner, and Ellis 1973, Issacs, Frere, and Mitchell 1973, and LaCour, Juul-Jensen, and Reske-Nielsen 1971). Wingard (1974) has presented evidence for stress and excessive sympathetic nervous system reactivity as factors that contribute to malignant hyperpyrexia. There Is a closely related disease in pigs (soft, exudative pork) in which the trigger for muscle rigidity, hyperthermla, and massive CPK efflux appears to be stress (Jones et al. 1972). MelUer (1973a) called attention to similarities between malignant hyperthermia and the rare "lethal catatonia" syndrome reported In schizophrenia. There is no evidence as yet for the occurrence of major mental illness in the families of patients with malignant hyperpyrexia.
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
chlorpromazine and haloperidol, suggesting there is a dopamine receptor in muscle (Capetola, Ferko, and Calesnick 1974). Dopamine may also have a prejunctional facilitatory effect on neuromuscular transmission (Gallagher and Karczmar 1973). Further, either chronic administration of amphetamine (H. Meltzer, unpublished data) or phencyclidine plus restraint stress (Meltzer 1972b) can produce skeletal muscle pathology in laboratory animals. This effect has been briefly reviewed elsewhere in this issue (Meltzer and Stahl 1976, p. 00). Amphetamine and phencyclidine, both drugs capable of producing psychoses in man that are comparable in some respects to schizophrenia (Angrist et al. 1974 and Luby et al. 1962), are well known to have marked effects on bioamines, which are believed to mediate the mental changes these agents produce (Hitzemann, Loh, and Domino 1973 and Snyder et al. 1974). Monoamine oxidase (MAO) inhibitors such as pargyline can produce skeletal muscle damage in rats (Yu et al. 1974). Thus the finding of decreased MAO activity in the blood platelets of some schizophrenic and depressed patients (Wyatt and Murphy 1975) raises the possibility that decreased MAO activity could be a factor in muscle abnormalities in psychotic patients. This possibility is currently being studied in our laboratory by determining the MAO activity in the skeletal muscle of schizophrenic patients and controls. Thus, there are morphological, biochemical, and electrophysiological indications of neuromuscular dysfunction in patients with a variety of brain diseases, as well as examples of diseases of lower motor neurons that can produce skeletal muscle pathology. In addition, neurotransmitters, which may be relevant to schizophrenia and the pathogenesis of psychotomimetic drug effects, may produce skeletal muscle toxicity. We will now review some of the evidence for neuromuscular dysfunction in schizophrenia.
38/59
Acutely psychotic
Meltzer and Moline
(1970a)
21/39
2/42
14/32
10/22 18/94
2/22
2/11
10/12
Acutely psychotic
Chronic
Acutely psychotic
Chronic psychotic
'
30/60
9/24
no. studied
No. elevated/
Meltzer, Grinspoon, and Shader (1970)
Coffey, Heath, and Guschwan (1970)
Moline (1969)
Meltzer, Elkun, and
Acutely psychotic
Acutely psychotic
Warnock and Ellman
(1969)
All major types
Acutely psychotic Chronic psychotic
Meltzar (1968)
Acutely psychotic
Description
Meltzer (1969)
and Kanig (1966)
Bengzon, Hippiuj,
Kaldor (1965)
Schiavone and
Reference
?
No Yes
Yes
5 54
72
Yes No
Yes
Yes
onset
Recent
44
46 19
18
83
50
37
Percent
Schizophrenics
None
None
IMin three patients None
Excluded Excluded
Excluded
None
Intramuscular infections
Nonpsychotic Manic depressed Psychotic depression
2/21 2/6 2/4
4/19
3/4 0/94 6/6
1/1
1/1
4/4
no. studied
No. elevated/
0 33 50
0 100 21
75
100 100 100
Percent
Other psychiatric patients
Affective psychosis Nonpsychotk Acute brain syndromes Acute CMS disease
Psychotic depressive Periodic catatonia
Manic depressive
Description
Table 1. Serum creatine phosphokinase activity in psychiatric patients.
Yes
Yes Yes
Yes ? Yes Yes
Yes Yes Yes
onset
Recent
None None None
Some acute patients without increase also had recent onset of symptoms. Increase preceded psychotic symptoms in a few
Biochemical determinations performed blind
Survey of newly admitted patients, eliminating all who had received IM Injec tions. Psychotic patients without increase included six with symptoms less than 6 days
Excluded three patients with increase after IM 1 infection. Dbgnosls of schizophrenia not specified
None
None None None None
Increase at admission in 6/18. Increase liter in 10/18. Muscle type CPK identified for first time
LarQast increase in egitated patients, but increase also present in those with normal activity
Those with elevation "clinically distinguishable from those without"
Comment
None None None
Intramuscular infections
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
s
z
o
o
Psychotic (type not apedfnd)
Various typas of schlzcphrenia
Paranoid schizophrenia
Not specified
Acuta
Diagnosis not spedfied in either group
Troptano at al. (1972)
Guterman (1973)
Loebel and Robins (1973)
Foster and Kupfer (1973)
Cunningham at al. (1974)
4/6 paranoid
and effectives) Chronic (schizophrenic* and affective*)
Acute (schizophrenic*
Description
Schweid, Steinberg, and Sudah (1972)
Covm (1972)
Gosling, Kerry, and
Gosling at al. (1972)
Raftery (1971)
Meltzer, Nankin, and
Reference
7/86 2/77
8 3
100
3/3
? No
None
Excluded
40
Nona
Excluded
2/5
None None
No
Exdudtd
Intramuscular injections
Nona
76
54
67
Yas/no
Yas
40 12
Recent onset
Percent
44
8/18
19/24
19/35
4/6
16/137
83/209
No. elevated/ no. studied
Schizophrenics
0/4 5/7 1/4
0 71 25
44
Nona Nona None
duded
Ex duded Ex
7
?
None None
Serum CPK levels and motor activity correlated
Increases relatively small in both groups
CPK and motor activity. total psychopathology, thought disturbanca, and withdrawal-retardation correlated
All patient* drug free. Nonpsychotic depressed patients had increases
Excluded 16 patients with IM injection
_
Nona
CPK Increase in brhium responders during period* of remission
CPK increase associated with mania and paranoia. Increase preceded psychotic symptoms in a few cases
65% of acute patients with symptoms less than 2 weeks had an increase; 10% of acuta patient* with symptoms more than 2 weeks had Increase. Chronic* with incraas* had acuta axactrbati on
Comment
Nona Nona
Nona
None Nona
Norn
Intramuscular infections
Comment: First study was of consecutive admissions. No distinction between psychotic and nonpsychotic. IM injections given and patient* dropped from study. Questionable normal limit*. Second study was of all patient* In hospital on a given day.
Manic phase Psychotic depression Non psych otics
4/9
Nonpsychotic
0
0 0
0/2 0/3
0/2
100
6/6
4
4/93
No No
No
0
18 10 1
No
No
onset
Recent
70 14
Percent
3/17 15/140
1/7 0/12
5/7
24/319
no. studied
Manic depressive
Affective disorders Neurotic
Endogenous and neurotic depression
Nonpf yen otic
mission on lithium
No. elevated/
Manic depresshrM in re-
Mania Depression Nonpsychotic
Nonpsychotic
Description
Other psychiatric patients
Table 1. Serum creatine phosphokinase activity in psychiatric patients-Conf/ntved
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
n
zin
m
-o X 70
o
X N
Chronic
Acuta
22
11
97/123 79 (anytime increase) 62/123 50 (at admission increase) 28/40 70 (anytime increase) 17/40 42.5 (at admission increase)
0/20
Chronic
_
5/23
Acuta
1/9
—
Exdudad Exdudad
Variable Variable
Excluded
Exdudtd
—
ond group of patlants undar tha contknuoua cara of othar cHniciani but whoai btood aimptaa wart Rudiad by t h . Gosling group.
rVWtzer (1975)
Harding (1974b)
Harding (1974a)
Owen and Ktf ry (1974)
Tuason, Oltihamky. and Jaranawn (1974)
Yas Yes
Yes Yas No
100 100
75 67 5
3/3
9/12 8/12 1/19
4
1/26
SCHIZOPHRENIA BULLETIN
neuromuscular dysfunction in schizophrenia'
During the last 7 years, there have been a number of investigations of the incidence of various types of neuromuscular dysfunction in patients with schizophrenic and affective illnesses and their first-degree relatives in comparison with appropriate controls, including nonpsychotic psychiatric patients. Before reviewing these studies, it may be of value to discuss why neuromuscular dysfunction might be expected in virtually any disease of the nervous system—a category in which, thanks to recent genetic studies, we may now confidently include schizophrenia and the primary affective illnesses. The evidence for central nervous system involvement in a variety of diseases with apparently primary skeletal muscle involvement will also be presented. There are numerous instances of known disease of the brain in which pathologic changes in lower motor neurons, with consequent effects on skeletal muscle fiber morphology and function, are found. "Central atrophy" is the name given to the atrophy of skeletal muscle fibers, which frequently develops after various chronic brain diseases, particularly tumors of the parietal lobe (Fenichel, Daroff, and Glaser 1964, Koinov and Markov 1971, and Van Crevel 1969). Depth electrode studies in chronic schizophrenics have demonstrated abnormal electrical discharges in various parts of the cerebral cortex, including the parietal lobe (see Mirsky 1969). The mechanism of central atrophy is believed to be loss of the trophic (nutrient) influence of the upper •Address reprint requests to the author at Department of Psychiatry, University of Chicago Pritzker School of Medicine, 950 E. 59th St., Chicago, III. 60637.
motor neuron on the lower motor neuron (see Guth 1968 for discussion of trophism). In turn, the lower motor neuron is believed to produce and release trophic substances on which skeletal muscle fibers are dependent, such that loss of these trophic factors leads to muscle fiber atrophy (Mendell and Engel 1971). Parkinson's disease is associated with skeletal muscle atrophy (Edstrftm 1970) perhaps because of the loss of trophic influences or because of muscle rigidity. A small number of pathological muscle fibers of diverse morphology develop in rats after lesions of the substantia nigra or cuts under the globus pallidus (Kanner and Meltzer 1974). Changes in muscle fiber types also develop in monkeys following lesions of the primary or secondary sensory cortical areas (Schwartzman and Dimancescu 1974). Vitamin deficiencies such as pernicious anemia (subacute combined degeneration) can produce brain, motor neuron, and skeletal muscle fiber abnormalities (Brain 1955). Interestingly, mental disturbances may occur in pernicious anemia. These may include paranoia or severe affective illness (McAlpine 1929). There are several disorders of tryptophan metabolism, including pellagra, carcinoidosis, maple syrup disease, and Hartnup disease, in which both mental and neuromuscular symptoms and pathologic findings are present (Lehmann 1972), apparently due to an inadequate amount of tryptophan or its metabolites. Diseases such as Duchenne-type muscular dystrophy, myotonic muscular dystrophy, myasthenia gravis, and malignant hyperpyrexia are believed by some to be primarily diseases of the nervous system with secondary changes in skeletal muscle fibers (Engel 1971, Konishi et
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
Herbert Y. Meltzer
VOL. 2, NO. 1,1976
elevated in serum in a variety of diseases associated with skeletal muscle fiber breakdown. Although the increases are greatest in Duchenne-type muscular dystrophy, elevations also occur in diseases of the lower motor neuron such as amyotrophic lateral sclerosis (Achari and Anderson 1974) and various childhood degenerative diseases of lower motor neurons (Heyck and Laudahn 1967). A variety of known acute brain diseases are associated with elevated muscle-type serum CPK levels; this includes acute cerebrovascular accidents, encephalitis, meningitis, and brain trauma (Dubo et al. 1967 and Eisen and Sherwin 1968). Small increases in serum CPK activity have been found in dogs after chronic electrical stimulation of the diencephalon (Bolter and Critz 1971). Moderate increases in serum CPK activity have been found in rats 4 hours after electrolytic lesions of the anterior hypothalamus but not in 13 other brain areas (K. T. Finnegan, H. Y. Meltzer, and M. Kanner, unpublished data). There is also electrophysiological evidence of abnormalities of lower motor neurons and the skeletal muscle fibers they innervate in patients with a variety of brain diseases. McComas et al. (1973) have found a decrease in the number of viable motor units in patients, beginning 6-12 months after cerebral vascular accidents. Similarly, patients with Parkinson's disease have decreased numbers of functioning motor units (Sica et al. 1973). Current theories of the nature of the biologic factors that contribute to the pathogenesis of schizophrenia center around abnormalities of bioamines such as the catecholamines and serotonin. There is also considerable evidence that bioamines such as serotonin and adrenaline can produce pathological changes in skeletal muscle (Highman, Altland, and Garbus 1965, Meltzer and Margulies 1971, O'Steen, Barnard, and Yates 1967, and Parker and Mendell 1974). Adrenaline has been reported to have unique effects on the muscle contraction of denervated muscles (Bowman and Raper 1965 and Evans and Smith 1973), which may be relevant to schizophrenics for whom there is evidence of muscle denervation (see below). Similar effects of adrenaline were noted on the muscle of subjects with various muscular dystrophies, suggesting alteration in neurotrophic influence on skeletal muscle in these diseases (Takamori 1975). Dopamine has been shown to inhibit skeletal muscle contraction by a direct effect on muscle (Blum 1969 and Ferko and Calesnick 1971), which can be inhibited by
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
al. 1974, LaCour, Juul-Jensen, and Reske-Nielsen 1971, McComas, Campbell, and Sica 1971, McComas, Sica, and Brown 1971, and McComas, Sica, and Upton 1974), but this is not generally accepted. Nevertheless, it is important to recall the undisputed high incidence of mental retardation in Duchenne muscular dystrophy (Prosser, Murphy, and Thompson 1969 and Zellweger and Niedermeyer 1965), the dilated ventricles and cerebral atrophy associated with myotonic dystrophy (Refsum et al. 1967), and the oft-noted occurrence of psychosis in families with myotonia congenita (Johnson 1967). "Central core" and fibers with rod bodies are striking pathologic changes in skeletal muscle that appear to be nonspecific in that they do not define a disease entity. There is considerable evidence that these may be due to abnormalities of motor nerves (Dahl and Klutzow 1974, Dubowitz and Roy 1970, Engel 1966, and Karpati, Carpenter, and Andermann 1971). Munsat, Thompson, and Coleman (1969) have discussed the role of the central nervous system in the etiology of centronuclear myopathy, a rare form of myopathy in which functional but not morphological pathology has been identified. They postulated that "the CNS [central nervous system] defect in centronuclear myopathy may, therefore, be primary with muscle changes reflecting disordered central control" (p. 130). Fenichel (1967) has discussed a variety of ways in which brain damage in utero may adversely affect muscle development. Brune (1971) has called attention to older literature that details the occurrence of cases of simultaneous muscle disease and major mental illness, including a family with three siblings for whom Duchenne-type muscular dystrophy and schizophrenia were said to become clinically manifest at the same time. Although some type of psychopathology may frequently be found in chronic muscle diseases, it is rare that frank psychosis is present (Brune 1971). Beckett and Bourne (1973) summarized evidence that monkeys reared in isolation, a condition known to produce markedly disturbed behavior, had extensive myopathic changes in skeletal muscle, including the diaphragm. Although they rightly concluded that it was impossible to decide if these changes were due to physical inactivity or psychosomatic factors, it would seem that the diaphragmatic changes would argue against simple inactivity as the explanation. Several skeletal muscle enzymes—for example, creatine phosphokinase (CPK) and aldolase—have a relatively slow disappearance rate from serum so that they may be
107
SCHIZOPHRENIA BULLETIN
108
Serum Creatine Phosphokinase Activity in Acute Psychosis Demonstration of increased activity of serum enzymes associated with skeletal muscle disease—that is, CPK, aldolase, or pyruvate kinase (PK)—is the most convenient way available, other than history and physical examination, to demonstrate the possible presence of skeletal muscle abnormalities. As will be discussed, elevated serum CPK, aldolase, or PK activities may result
from causes other than significant muscle disease (Nevins et al. 1973). These factors must be considered before increases in serum enzyme activity are attributed to muscle disease. Once these factors have been taken into account, determination of serum CPK activity can be a most sensitive index of skeletal muscle disease. For example, in those vulnerable to malignant hyperpyrexia, serum CPK is moderately elevated, sometimes without any detectable muscle changes on physical examination (Denborough et al. 1970). 1 Serum CPK elevations in acutely disturbed schizophrenics have now been found in 17 studies (table 1), but the percentage of patients with elevations varies from 8 to 100 (median = 40 percent). Increased serum CPK activity has also been reported in other types of psychiatric patients, especially those with affective psychoses (table 1). Before discussing the reasons for the large variations in the incidence of increased serum CPK activity in acutely disturbed schizophrenics in various studies, it is useful to review briefly the origin of serum CPK in psychotic patients and the possible causes of increased serum CPK activity in psychotic patients that are not specific to psychosis.
Origin of Serum CPK Activity There are three major isoenzymes 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 all
'Certain general anesthetics (e.g., fluothane, halothane) and muscle relaxants (e.g., succinylcholine) can evoke massive CPK Increases In individuals who are susceptible to malignant hyperpyrexia (Britt 1972). Abundant microscopic pathology is present in the skeletal muscle of individuals susceptible to malignant hyperpyrexia, because of an inherent nerve or muscle abnormality or both (Harriman, Sumner, and Ellis 1973, Issacs, Frere, and Mitchell 1973, and LaCour, Juul-Jensen, and Reske-Nielsen 1971). Wingard (1974) has presented evidence for stress and excessive sympathetic nervous system reactivity as factors that contribute to malignant hyperpyrexia. There Is a closely related disease in pigs (soft, exudative pork) in which the trigger for muscle rigidity, hyperthermla, and massive CPK efflux appears to be stress (Jones et al. 1972). MelUer (1973a) called attention to similarities between malignant hyperthermia and the rare "lethal catatonia" syndrome reported In schizophrenia. There is no evidence as yet for the occurrence of major mental illness in the families of patients with malignant hyperpyrexia.
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
chlorpromazine and haloperidol, suggesting there is a dopamine receptor in muscle (Capetola, Ferko, and Calesnick 1974). Dopamine may also have a prejunctional facilitatory effect on neuromuscular transmission (Gallagher and Karczmar 1973). Further, either chronic administration of amphetamine (H. Meltzer, unpublished data) or phencyclidine plus restraint stress (Meltzer 1972b) can produce skeletal muscle pathology in laboratory animals. This effect has been briefly reviewed elsewhere in this issue (Meltzer and Stahl 1976, p. 00). Amphetamine and phencyclidine, both drugs capable of producing psychoses in man that are comparable in some respects to schizophrenia (Angrist et al. 1974 and Luby et al. 1962), are well known to have marked effects on bioamines, which are believed to mediate the mental changes these agents produce (Hitzemann, Loh, and Domino 1973 and Snyder et al. 1974). Monoamine oxidase (MAO) inhibitors such as pargyline can produce skeletal muscle damage in rats (Yu et al. 1974). Thus the finding of decreased MAO activity in the blood platelets of some schizophrenic and depressed patients (Wyatt and Murphy 1975) raises the possibility that decreased MAO activity could be a factor in muscle abnormalities in psychotic patients. This possibility is currently being studied in our laboratory by determining the MAO activity in the skeletal muscle of schizophrenic patients and controls. Thus, there are morphological, biochemical, and electrophysiological indications of neuromuscular dysfunction in patients with a variety of brain diseases, as well as examples of diseases of lower motor neurons that can produce skeletal muscle pathology. In addition, neurotransmitters, which may be relevant to schizophrenia and the pathogenesis of psychotomimetic drug effects, may produce skeletal muscle toxicity. We will now review some of the evidence for neuromuscular dysfunction in schizophrenia.
38/59
Acutely psychotic
Meltzer and Moline
(1970a)
21/39
2/42
14/32
10/22 18/94
2/22
2/11
10/12
Acutely psychotic
Chronic
Acutely psychotic
Chronic psychotic
'
30/60
9/24
no. studied
No. elevated/
Meltzer, Grinspoon, and Shader (1970)
Coffey, Heath, and Guschwan (1970)
Moline (1969)
Meltzer, Elkun, and
Acutely psychotic
Acutely psychotic
Warnock and Ellman
(1969)
All major types
Acutely psychotic Chronic psychotic
Meltzar (1968)
Acutely psychotic
Description
Meltzer (1969)
and Kanig (1966)
Bengzon, Hippiuj,
Kaldor (1965)
Schiavone and
Reference
?
No Yes
Yes
5 54
72
Yes No
Yes
Yes
onset
Recent
44
46 19
18
83
50
37
Percent
Schizophrenics
None
None
IMin three patients None
Excluded Excluded
Excluded
None
Intramuscular infections
Nonpsychotic Manic depressed Psychotic depression
2/21 2/6 2/4
4/19
3/4 0/94 6/6
1/1
1/1
4/4
no. studied
No. elevated/
0 33 50
0 100 21
75
100 100 100
Percent
Other psychiatric patients
Affective psychosis Nonpsychotk Acute brain syndromes Acute CMS disease
Psychotic depressive Periodic catatonia
Manic depressive
Description
Table 1. Serum creatine phosphokinase activity in psychiatric patients.
Yes
Yes Yes
Yes ? Yes Yes
Yes Yes Yes
onset
Recent
None None None
Some acute patients without increase also had recent onset of symptoms. Increase preceded psychotic symptoms in a few
Biochemical determinations performed blind
Survey of newly admitted patients, eliminating all who had received IM Injec tions. Psychotic patients without increase included six with symptoms less than 6 days
Excluded three patients with increase after IM 1 infection. Dbgnosls of schizophrenia not specified
None
None None None None
Increase at admission in 6/18. Increase liter in 10/18. Muscle type CPK identified for first time
LarQast increase in egitated patients, but increase also present in those with normal activity
Those with elevation "clinically distinguishable from those without"
Comment
None None None
Intramuscular infections
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s
z
o
o
Psychotic (type not apedfnd)
Various typas of schlzcphrenia
Paranoid schizophrenia
Not specified
Acuta
Diagnosis not spedfied in either group
Troptano at al. (1972)
Guterman (1973)
Loebel and Robins (1973)
Foster and Kupfer (1973)
Cunningham at al. (1974)
4/6 paranoid
and effectives) Chronic (schizophrenic* and affective*)
Acute (schizophrenic*
Description
Schweid, Steinberg, and Sudah (1972)
Covm (1972)
Gosling, Kerry, and
Gosling at al. (1972)
Raftery (1971)
Meltzer, Nankin, and
Reference
7/86 2/77
8 3
100
3/3
? No
None
Excluded
40
Nona
Excluded
2/5
None None
No
Exdudtd
Intramuscular injections
Nona
76
54
67
Yas/no
Yas
40 12
Recent onset
Percent
44
8/18
19/24
19/35
4/6
16/137
83/209
No. elevated/ no. studied
Schizophrenics
0/4 5/7 1/4
0 71 25
44
Nona Nona None
duded
Ex duded Ex
7
?
None None
Serum CPK levels and motor activity correlated
Increases relatively small in both groups
CPK and motor activity. total psychopathology, thought disturbanca, and withdrawal-retardation correlated
All patient* drug free. Nonpsychotic depressed patients had increases
Excluded 16 patients with IM injection
_
Nona
CPK Increase in brhium responders during period* of remission
CPK increase associated with mania and paranoia. Increase preceded psychotic symptoms in a few cases
65% of acute patients with symptoms less than 2 weeks had an increase; 10% of acuta patient* with symptoms more than 2 weeks had Increase. Chronic* with incraas* had acuta axactrbati on
Comment
Nona Nona
Nona
None Nona
Norn
Intramuscular infections
Comment: First study was of consecutive admissions. No distinction between psychotic and nonpsychotic. IM injections given and patient* dropped from study. Questionable normal limit*. Second study was of all patient* In hospital on a given day.
Manic phase Psychotic depression Non psych otics
4/9
Nonpsychotic
0
0 0
0/2 0/3
0/2
100
6/6
4
4/93
No No
No
0
18 10 1
No
No
onset
Recent
70 14
Percent
3/17 15/140
1/7 0/12
5/7
24/319
no. studied
Manic depressive
Affective disorders Neurotic
Endogenous and neurotic depression
Nonpf yen otic
mission on lithium
No. elevated/
Manic depresshrM in re-
Mania Depression Nonpsychotic
Nonpsychotic
Description
Other psychiatric patients
Table 1. Serum creatine phosphokinase activity in psychiatric patients-Conf/ntved
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at NERL on August 4, 2015
n
zin
m
-o X 70
o
X N
Chronic
Acuta
22
11
97/123 79 (anytime increase) 62/123 50 (at admission increase) 28/40 70 (anytime increase) 17/40 42.5 (at admission increase)
0/20
Chronic
_
5/23
Acuta
1/9
—
Exdudad Exdudad
Variable Variable
Excluded
Exdudtd
—
ond group of patlants undar tha contknuoua cara of othar cHniciani but whoai btood aimptaa wart Rudiad by t h . Gosling group.
rVWtzer (1975)
Harding (1974b)
Harding (1974a)
Owen and Ktf ry (1974)
Tuason, Oltihamky. and Jaranawn (1974)
Yas Yes
Yes Yas No
100 100
75 67 5
3/3
9/12 8/12 1/19
4
1/26
