Psvchiarry Research: Neuroimaging. 55~223-235 Elsevier 223 Correlations of Phosphomonoesters Measured by Phosphorus-31 Magnetic Resonance Spectroscopy in the Frontal Lobes and Negative Symptoms in Schizophrenia Toshiki Shioiri, Tadafu~i Kato, Toshiro Inubushi, Jun Mutashita, and Saburo Takahashi Received March 8‘1993: revised version received July 15, 1993; accepted September 19, 1993. Abstract. Frontal lobe dysfunction has been linked to negative symptoms of schizophrenia. We used phosphorus-31 magnetic resonance spectroscopy (31P- MRS) to examine phosphorous metabolism in frontal brain regions in 26 schizophrenic patients compared with 26 sex- and age-matched control subjects. The relative signal intensities of phosphorous metabolites in frontal regions did not differ significantly between schizophrenic patients and control subjects. However, phosphomonoester levels were significantly decreased in frontai regions of 12 schizophrenic patients who had high scores on negative symptom subscales from the Brief Psychiatric Rating Scale (i.e., emotional withdrawal, motor retardation, and blunted affect) compared with I4 patients with low negative symptom scores on the same subscales and control subjects. The correlations between negative symptoms and phosphorous metabolism in the frontal lobes support the “hypofrontality hypothesis” in schizophrenia. Key Words. Hypofrontality, Brief Psychiatric Rating Scale, phosphodiesters, beta-adenosine triphosphate. In 1974, Ingvar and Franz&n reported a regional decrease of cerebral blood flow activity in the frontal lobes of schizophrenic patients. In 1982, Buchsbaum et al. extended this finding in a positron emission tomography (PET) study that found relatively decreased glucose metabolism in the frontal lobes of schizophrenic patients. The “hypofrontal” pattern has been confirmed in many other studies (e.g., Farkas et al., 1984; Cohen et al., 1987; Kishimoto et al., 1987; Wolkin et al., 1985, 1988, 1992), although there have been negative reports as well (e.g., Sheppard et al., 1983; Gur et al., 1987; Wiesel et al., 1987). It was initially speculated that the hypofrontal pattern might be an artifact of neuroleptic medication (Sheppard et al., 1983), but reduced metabolism in the frontal lobes has also been observed in Toshiki Shioiri, M.D., Ph.D., Tad~umi Kato, M.D., and Jun Murashita, M.D., are Assistants, and Saburo Takahashi, M.D., Ph.D., is Professor, Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan. Toshiro Inubushi, Ph.D., is Professor, Molecular Neurobiology Research Center, Shiga University. (Reprint requests to Dr. T. Shioiri, Department of Psychiatry, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520~ZI, Japan.) 016%1781/94/$07.00 @ 1994 Elsevier Science Ireland Ltd.
Correlations of Phosphomonoesters Measured by Phosphorus-31 Magnetic Resonance Spectroscopy in the Frontal Lobes and Negative Symptoms in Schizophrenia
Toshiki Shioiri, Tadafu~i Kato, Toshiro Inubushi, Jun Mutashita, and Saburo Takahashi
Received March 8‘1993: revised version received July 15, 1993; accepted September 19, 1993.
Abstract. Frontal lobe dysfunction has been linked to negative symptoms of schizophrenia. We used phosphorus-31 magnetic resonance spectroscopy (31P- MRS) to examine phosphorous metabolism in frontal brain regions in 26 schizophrenic patients compared with 26 sex- and age-matched control subjects. The relative signal intensities of phosphorous metabolites in frontal regions did not differ significantly between schizophrenic patients and control subjects. However, phosphomonoester levels were significantly decreased in frontai regions of 12 schizophrenic patients who had high scores on negative symptom subscales from the Brief Psychiatric Rating Scale (i.e., emotional withdrawal, motor retardation, and blunted affect) compared with I4 patients with low negative symptom scores on the same subscales and control subjects. The correlations between negative symptoms and phosphorous metabolism in the frontal lobes support the “hypofrontality hypothesis” in schizophrenia.
In 1974, Ingvar and Franz&n reported a regional decrease of cerebral blood flow activity in the frontal lobes of schizophrenic patients. In 1982, Buchsbaum et al.
extended this finding in a positron emission tomography (PET) study that found relatively decreased glucose metabolism in the frontal lobes of schizophrenic patients. The “hypofrontal” pattern has been confirmed in many other studies (e.g., Farkas et al., 1984; Cohen et al., 1987; Kishimoto et al., 1987; Wolkin et al., 1985, 1988, 1992), although there have been negative reports as well (e.g., Sheppard et al., 1983; Gur et al., 1987; Wiesel et al., 1987). It was initially speculated that the hypofrontal pattern might be an artifact of neuroleptic medication (Sheppard et al., 1983), but reduced metabolism in the frontal lobes has also been observed in
Toshiki Shioiri, M.D., Ph.D., Tad~umi Kato, M.D., and Jun Murashita, M.D., are Assistants, and Saburo Takahashi, M.D., Ph.D., is Professor, Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan. Toshiro Inubushi, Ph.D., is Professor, Molecular Neurobiology Research Center, Shiga University. (Reprint requests to Dr. T. Shioiri, Department of Psychiatry, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520~ZI, Japan.)
never-medicated schizophrenic patients (Buchsbaum et al., 1992). Because frontal lobe damage is associated with behavioral deficits that are analogous to the negative symptoms of schizophrenia (Stuss and Benson, 1983, it has been postulated that hypofrontality may be related to the presence of negative symptoms. Positive
correlations between negative symptoms and hypofrontality have been reported (Kurachi et al., 1988; Suzuki et al., 1992; Wolkin et al., 1992).
Phosophorus-.?I magnetic resonance spectroscopy (“P-MRS) can be used to
detect tissue concentrations of phosphorous metabolites involved in energy and membrane phospholipid metabolism (Waddington et al.. 1990). This noninvasivc technique has been freyuentlq applied to neuropsychiatric disorders (Klunk et al.. 1993). Pettegrew et al. (, 1991) used j’P-MRS to study the dorso~atera1 prefrontal cortex of 1 I drug-naive, first-episode schizophrenic patients. They found
slgnificantiy decreased levels of phosphomonoesters (PME) and increased levels ctl phosphodiesters (PDE) and /3-adenosine triphosphate (/?-ATP) in the schizophrenic patients compared with control subjects. There have now been a number of’ ‘IV- MRS studies of schizophrenic patients (Keshavan et al., 1991: O’Callaghan et al., 199 I : Williamson et al., 1991: C’alabrese et al., 1992; Fujimoto et al., 1992). In these studies, a reduction of PME levels in the frontal lobe has been the major replicated
fmdlng (Pzttegrcw et ai.. 1991. Williamson et al., 1991). Although the biochemical hasis of the reduction of P’ILIE is stiil unknown. it may be hypothesiTcd that thu
reduced ieveis oi PME in the frontal iobc are correlated with negative hymptoms.
Subjects. rwenty-six schizophrenic patients (I6 men and IO women), who ranged in age from I5 to 63 (mean age = 3 I .8 years, SD = 12.4). volunteered to participate in this study (see Table 1). All were hospitalized in Shiga University of Medical Science Hospital. ‘The patients were evaluated in two interview sessions, for I hour each by two senior psychiatrists, who made DSM-III-R diagnoses (American Psychiatric Association, 1987). Subtype diagnoses are presented in Table I. The mean duration of illness was 8.7 years (SD = 9.5). All patients were right-handed. None had a history of head injury, neurologic disorders, drug or alcohol abuse. or serious medical illnesses.
Before ‘IP-MRS was performed, all patients underwent computed tomography (CT). Patients who had structural brain abnormalities, as determined by experienced neuro- radiologists (unaware of the study’s design), were excluded. Precise volumetric measurements were not performed.
Six of the schizophrenic patients had been free of neuroleptic medications for at least 2 weeks before the study. The remaining 20 patients were treated with neuroleptics in chlor- promazine-equivalent dosages (Gelenberg, 1983) that ranged from 200 to 2150 mg per day (mean dosage = 747 mg; day. SD -= 622). Neuroleptics were the only medications being taken. except for benzodiazepines, which were prescribed for 10 of the patients as sleep aids.
Global psychopathology was assessed with the Brief Psychiatric Rating Scale (BPRS; 0,erall and Gorham, 1962) on the day of the MRS study. The BPRS “schizophrenia”factors (emotional withdrawal, motor retardation, and blunted affect) were used to divide the patients into two subgroups: one with high scores on negative symptoms and the other with low scores on negative symptoms. The former subgroup was defined by the sum of the above-mentioned three BPRS negative symptom subscales being above IO, while the latter subgroup scored below IO.
Twenty-six normal subjects, who were matched with the patients for age and sex (mean age = 3 I .9 years. SD = 12.4; I h men and IO women). volunteered to participate in the study. They
225
were hospital workers and their family members or friends. All control subjects were also right-handed. None had a history of head injury, neurological disorders, drug or alcohol abuse, or serious medical illnesses. The control subjects were not taking medication of any kind. Informed consent was obtained from all patients and control subjects.
MRS Procedure. The method of MRS data acquisition was basically the same as described in our previous report (Kato et al., 1992). Subjects were examined on a IS-Tesla General Electric Signa MR system equipped with a spectroscopy package. Subjects were lying down with their heads positioned so that the orbitomeatal line was vertical to the axis of the magnet. Surface coils for rH and 3rP supplied as options by the manufacturer were used. Both of the coils were 20 cm for the transmitter and 7.5 cm for the receiver in diameter. Sensitive volume of the coil is dependent on the diameter of the receiver coil, 7.5 cm. The surface coil for proton measurement was placed over the subject’s head on a custom-built stand, with an edge of the coil being set above the tip of nose. T,-weighted spin-echo *H MR images were obtained, and a volume of interest (VOI) was determined as the center 30-mm slice between the front pole and the front edge of the corpus callosum (Fig. 1). The VOI contained both gray and white matter.
The magnetic field over the VOI was optimized by water signals sufficient to establish the line width < IO Hz. Without any change of position, the JH coil was replaced with the 3iP coil, and )rP NMR spectra were obtained using depth-resolved surface coil spectroscopy (DRESS) pulse sequence (Bottomley et al., 1984). Repetition time (TR), delay time, and number of digitized points were set at 3 seconds, 1.5 ms, and 1024, respectiveIy. The approximate tip angle in excited region examined by phantom experiments was 50”. One hundred twenty-eight scans were averaged. Total time for examination was about 25 minutes. Free induction decays were processed using a General Electric 1280 DATA station with GEN software. Broad peaks and baseline distortion were canceled using the convolution difference method (Campbell et al., 1973). Baseline correction with linear tilt was applied to the phase-corrected spectra after manual definition of five points known to have no signal. Peak areas were calculated by manual curve fitting according to Pettegrew et al. (1991). Details of the method have been described elsewhere (Kate et al., 1992). Seven peaks assigned to phosphomonoester (PME), inorganic phosphate (Pi), phosphodiester (PDE), creatine phosphate (Per), and three phosphorous signals from nucleotide triphosphate, mainly adenosine triphosphate (ATP), were examined.
Fig. 2 shows a representative JrP-MR spectrum in a schizophrenic patient. The signal-to- noise ratio of phosphorus was 7.9 (SD = 2.7). Data were shown as peak area ratios to the total peak area. Interassay/intraindividual coefficients of variation (CVs) were caluculated in I I subjects examined more than than twice. CVs were below 10% except for 20.9Yc for Pi. Intracellular pH was calculated from the difference in chemical shifts between Pi and PCr (Petroff et al. (1985).
Analysis. The level of statistical significance was determined by Pearson’s correlation coefficient, regression analysis, Student’s f test (one-tailed for PME and two-tailed for other measures), and analysis of variance (ANOVA).
Results
There were no significant age or sex differences between the patient and control groups. There was a significant group difference in years of education between the patients (mean = 12.3 years, SD = 2.6) and the control subjects (mean = 15.5 years, SD = 2.6; t = 4.34, p < 0.01; Table 1). There were no significant correlations between phosphorous metabohte measures, including PME, and the following characteristics of the patients: age, sex, diagnostic subtype, duration of illness, and number of hospital admissions. The correlation coefficient between chlorpromazine- equivalent neuroleptic dosage and PME levels was ako not significant (r = 0.14).
Tab
le 1
. P
atie
nt
char
acte
rist
ics
Pat
ien
t n
o.
Ag
e E
du
cati
on
D
ura
tio
n o
f N
S
Do
se
Dia
gn
ost
ic
(yr)
S
ex
(yr)
ill
ness
(yr
) B
PR
S
sco
re
(w)
sub
typ
e -
- -
_ .--
._.
.CI~
I^-_
^.
- __
_-.-
._-.
. -.
- Lo
w n
egat
ive
sym
ptom
s gr
oup
(n =
14)
1 2 3 4 5 6 7 8 9 10
11
12
13
18
M
12
19
M
12
20
M
12
22
M
16
26
M
11
29
M
12
30
M
16
31
M
12
32
F
14
36
M
16
37
F
f2
39
M
9
47
F
15
0 1 4 9 6 4 8 2 13
17
t9
29
34
6
42
5
50
10
21
4
41
7
30
10
36
5
30
9
28
9
26
5
56
4
42
7
48
7
1200
2150
800
975
1125
200 0
Und
iffer
entia
ted
Cat
aton
ic
Cat
aton
ic
Cat
aton
ic
Par
anoi
d U
ndi~
eren
tiate
d P
aran
oid
Und
iffer
entia
ted
Und
~ere
ntia
t~
Res
idua
l P
aran
oid
Dis
orga
nize
d U
ndiff
eren
tiate
d
Hig
h ne
gativ
e sy
mpt
oms
grou
p (n
= 1
2)
14
15
16
17
16
19
20
21
22
23
24
25
26
15
F
9 1
39
13
750
U~
~~
ti~
18
F
12
0 46
11
0
Un~
~~a~
19
M
12
4
47
14
750
Un~
~~a~
20
M
12
2
44
13
1500
D
isor
gani
zed
23
M
9 2
42
17
1500
C
atat
onic
26
M
16
7
46
11
317
Par
anoi
d 27
M
9
0 46
12
0
Par
anoi
d 37
M
9
12
44
15
1500
D
~~g~
~~
37
F
9 7
60
14
500
Dis
orga
nize
d 4.
5 F
16
4
52
14
675
Dis
orga
nize
d 45
M
16
24
35
14
50
0 D
isor
gani
zed
52
F
9 12
48
14
15
00
Par
anoi
d 63
M
11
38
31
13
0
Und
iffer
entia
ted
Tot
al (
mea
n f
SD
) 31
.811
2.4
12.3
f2.6
’ 8.
7f9.
5 40
.3f9
.6
1 O.O
f3.7
74
7f62
2
Not
e. B
PR
S =
Brie
f Psy
chia
tric
Rat
ing
Sca
le. N
S =
the
tota
l sco
re o
f thr
ee n
egat
ive s
ympt
oms (
emot
iona
l w~d
ra~i
, m
otor
reta
rdat
ion,
and
Mun
ted
affe
ct).
Neu
rale
ptic
dos
ages
ar
e in
chl
orpr
omaz
ine
equi
vale
nts.
Dia
gnos
tic s
ubty
pes
are
base
d on
~S
~-/
//-~
cr
iteria
.
I. T
here
was
a s
igni
fican
t diff
eren
ce in
yea
rs o
f ed
ucat
ion
betw
een
both
sch
izop
hren
ic g
roup
s vs
. the
con
trol
gro
up (
t =
4.3
4, p
< 0
.01;
con
trol
sub
ject
s 15
.5 f
2.6
year
s).
Fig. 1. A ‘H-magnetic resonance image in a control subject
The region examined by 31P-magnetic resonance spectroscopy IS surrounded rn a square. whzh IS a dish-like volun!t~
Darailel to fhe surface ml
Fig. 2. A 31P-magnetic resonance spectrum of the frontal region in a schizophrenic patient
Observation frequency was 25.65 MHz. PPM means parts per million. Repetition time was 3 seconds, and 128 averages. Peak assignment is as follows: 1 = phosphomonoester; 2 = inorganic phosphate; 3 = phosphodiester; 4 = creatine phosphate 5 = y-nucleottde triphosphates (mainly adenosine triphosphate); 6 = a-adenosine triphosphate; 7 = p-adenosine Ciphosphate
229
Five metabolic measures were not observed to be altered in the frontal region of the schizophrenic patients in comparison with the control subjects (Table 2). There were also no group differences in the levels of PCr/ Pi, PCr/P-ATP, PME/ PDE, and intracellular pH (Table 2).
Table 2. Metabolite levels, metabolic ratios, and intracellular pH from the frontal region of schizophrenic patients and control subjects
Schizophrenic Normal control patients subjects
PME 11.9 It 2.0% 12.3 f 1.3%
Pi 6.3 dz 1.7% 5.8 + 1.3%
PDE 19.5 * 3.4% 20.8 + 2.7%
PCr 12.6 + 2.4% 13.4 k 2.1%
y-ATP 10.0 * 1.3% 10.4 + 1.5%
a-ATP 25.2 zt 2.6% 24.1 i 2.3%
P-ATP 12.9 + 2.5% 13.0 + 1.6%
PCriPi 2.14 I 0.65 2.34 + 0.58
PCrlP-ATP 1.02 f 0.31 1.06 + 0.27
P-ATPIPi 2.25 -t 0.96 2.29 + 0.71
PMEIPDE 0.63 + 0.17 0.60 i 0.10
Intracellular pH 7.05 + 0.09 7.06 i 0.04
Note. Values are mean f SD. PME = phosphomonoester. Pi = inorganic phosphate. PDE = phosphodiester. PCr = creatine phosphate. ATP = adenosine triphosphate.
Fig. 3 shows differences in peak areas of phosphorous metabolites between the subgroups of schizophrenic patients with high vs. low levels of negative symptoms. There were no significant differences in age, sex, years of education, or neuroleptic dosage between these two subgroups. The schizophrenic patients with high negative symptom scores had significantly reduced levels of PME (mean = 10.7, SD = 1.5) compared with levels of PME in patients with low negative symptom scores (mean = 12.9, SD = 1.7, p < 0.01) and in the control subjects (mean = 12.4, SD = 1.7, p < 0.01). The low negative symptom group differed significantly from the control subjects in PDE levels (low negative symptom group: mean = 18.7, SD = 2.5; control subjects: mean = 20.8, SD = 2.6, p < 0.05). There was also a significant difference in P-ATP levels between the low negative symptom patients (mean = 12.0, SD = 1.7) and the high negative symptom patients (mean = 14.0, SD = 2.8,~ < 0.05).
PME level in the frontal region, which may relate to hypofrontality, was signi- ficantly correlated with the total scores of three negative symptoms (r = -0.68, p < 0.001; Fig. 4). There were no significant correlations between negative symptom scores and the other two phosphorous metabolites, PDE (r = 0.28) and /I-ATP ( r = 0.36; p < 0.10).
Discussion
The most intriguing finding in this study was the reduced level of PME in the subgroup of schizophrenic patients with high negative symptom scores compared with the low negative symptom subgroup and the control group. The negative
Fig. 3. Phosphorous metabolite levels in the frontal region of schizophrenic patients with low negative symptoms (NS), schizophrenic patients with high NS, and control subjects _
The high NS subgroup (n = 12) was defmed by a combing score above 10, and the low NS subgroup (n = 14) was defined by a combined score below 10 on the folIowIng three negative symptom subscales of the Bnef Psychiatric Rating Scale: emotional withdrawal, motor retardation and blunted affect.
‘p < 0.05; “p < 0.01
Fig. 4. Relationship between the levels of PME in the frontal region and the sums of three BPRS subscales of negative symptoms in 26 schizophrenic
: l l
l
.
l
.
.
* : l .
. .
l .
.
l .
.
.
.
Sum of three BPRS subscales of negative symptom
PME = phosphomon~ster. BPRS = Brief Psychiatnc Rating Scale. Abscissa and ordinate indicate PME peak area 46 and the sum of three BPRS subscales of negative sym~om, respectively. Each dot represents an individual. The regression line was catcuiated as Y = -0.363X + 14.5.
231
correlation of PME levels with the scores on three negative symptom subscales of the BPRS was also striking. These findings appear to support our hypothesis that PME reductions may be related to negative symptoms.
It has been reported that hypofrontality measured with PET (Wolkin et al., 1992) and frontal hypoperfusion measured with single photon emission computed tomography (SPECT) (Sagawa et al., 1990; Wood and Flowers, 1990; Andreasen et al., 1992) were also correlated to negative symptoms. Keshavan et al. (1991) reported that PME was decreased in a “control” subject who had onset of schizophrenia after MRS examination, and speculated that alteration in membrane phospholipid metabolism may be a trait-dependent phenomenon. However, because negative symptoms have been thought to be quite stable over time in schizophrenic patients (Andreasen and Flaum, 1991), reduction of PME as well as hypofrontality might reflect trait-dependent abnormalities in these patients. The PME peak originates from signals of phosphoethanolamine and phosphocholine, which are precursors of membrane phospholipids (Pettegrew et al., 1991). PME measured with in vitro 3iP-MRS was reported to be increased during membrane synthesis such as develop- ment or regenaration of living tissues (Morikawa et al., 1992). However, the biochemical basis of reduced PME in schizophrenic patients with marked negative symptoms observed in this study cannot be identified because of methodological limitations of in vivo 3iP-MRS.
It should be noted that P-ATP was increased in schizophrenic patients with high negative symptom scores. Pettegrew et al. (1991) also found increased P-ATP levels in schizophrenic patients, and they hypothesized that this finding might be related to hypofrontality. Although it is not known whether an increased peak area of /?-ATP reflects hypometabolism of high energy phosphate in neuronal tissue, the fact that P-ATP was increased in schizophrenic patients with high negative symptom scores compared with those with low negative symptom scores seems to coincide with findings by other investigators of metabolic hypofrontality in schizophrenic patients with marked negative symptoms.
The finding of a significant difference in PDE levels between the schizophrenic patients with low negative symptom scores and the normal control subjects is difficult to interpret. At first, the PDE peak was thought to reflect membrane degeneration products such as phosphoethanolamine and phosphocholine (Pettegrew et al., 1991). In the relatively low magnetic field around 1.5 Tesla, however, much of the PDE peak in vivo originates from membrane phospholipid itself. A reduced peak area of PDE in this study might be due to changes in relaxation times of membrane phospholipids.
In this study, no significant difference was detected in the high energy phosphate or phospholipid measures of the frontal region in the medicated schizophrenic patients compared with the control subjects (Table 2). There have been a few reports measuring phosphorous metabolism in the frontal lobes of schizophrenic patients. Pettegrew et al. (199 1) found significantly decreased levels of PME and significantly increased levels of PDE and fi-ATP in prefrontal cortex, and Williamson et al. (1991) also reported markedly reduced levels of PME and increased levels of PCr and Pi in the dorsal prefrontal cortex compared with the control subjects. More recently, Fujimoto et al. (1992) indicated that 9?0 PCr was decreased in the
232
frontoparietal region of chronic schizophrenic patients studied with 3’P-magnetic
resonance chemical shift imaging. One explanation for our failure to detect any difference in 3’P-MRS data between
the total group of schizophrenic patients and the control subjects may involve
methodological differences in our experiments and others. Because the MRS data obtained depend on the method used, we cannot simply compare our data with data of other investigators who used different methods. Moreover, a rough localizing method such as the one that we used may confound regional abnormality with contamination from muscle activity. The tissue within the VO1 examined may not bc assumed to be homogeneous. More precise localizing techniques such as chemical shift imaging or imaging selected in vivo spectroscopy (ISIS) would be desirable when they become feasible. However, we will need to consider “resonance offset phenomena” even if MRS volume selection techniques such as 1SIS are used (Calabrese et al.. 1992). Moreover. a change in total amount of phosphorous compounds was not detectable because we used peak ratios instead of absolute molar concentrations. Although MRS techniques that can calculate absolute molar concentrations have been reported, absolute values obtained are still controversial (Tofts and Wray, 1988). In addition, PME findings are likely to reflect some sort 01 change in gray matter rather than white matter. One of the reasons for our inability to find differences in phosphorous metabolism between the patient and control groups may be the fact that actual excited volume contains much more white matter than gray matter.
Another reason for the lack of difference in “P-MRS data between the schizophrenic patients and the control subjects could involve the various neuroleptic drugs taken by patients in this study. Although it was reported that lithium increased PME in the cat brain (Renshaw et al., 1986) and diazepam did not affect brain phosphorous metabolism in humans (Deicken et al., 1992), the effect of anti- psychotic drugs on brain phosphorous metabolism is unknown. In the present study.
there was no significant correlation between the chlorpromazine-equivalent heurolep- tic dosage and the PME level.
Our results may also have been affected by differences in the level of’ severity 01 psychiatric symptoms of our patients and the patients studied by other groups. We believe that this difference may have had an important effect on our results. Pettegrew et al. (I 99 1 f and Fujimoto et al. f 1992) reported that their patients were assessed using the BPRS or the Positive and Negative Syndrome Scale (PANSS), but the clinical findings were not described. Williamson et al. (1991) indicated that their subjects were all outpatients and, as such, can be assumed to be less severely ill than hospitalized patients. Moreover, Williamson et al. reported high total scores on the Scale for the Assessment of Negative Symptoms (mean = 24.8, SD 1-2 12. I) and low scores on the Scale for the Assessment of Positive Symptoms (mean = 6.5. SD = 10.4). which indicates that the patients they examined had mainly negative symptoms. On the other hand. the patients in our study were inpatients with variable types of symptomatology; some patients had marked positive symptoms, while others had high negative symptoms. ‘Thus, differences in the characteristics of the patient samples may have been reflected in differences in the findings 01 pht~sphor~~us metab(~lism.
233
There remains a possibility that our findings may reflect subtle brain atrophy. Many CT studies have described ventricular enlargement and atrophy in schizophrenic patients (Shelton and Weinberger, 1986; Raz and Raz, 1990; Breier et al., 1992). In our study, however, neuroradiologists who evaluated the CT images without knowledge of the patients’ psychiatric symptomatology ruled out any distinct structural abnormalities.
To our knowledge, the present study was the first to find a relationship between an alteration of membrane phospholipid metabolism in the frontal region and the negative symptoms of schizophrenia. We think it will be important for future studies of schizophrenia to examine precise relationships between symptomatology and in vivo brain activity measured using MRS, SPECT, and PET simultaneously. Schizophrenia must be a disorder in which hypofunction or dysfunction in certain areas or nuclei may exist, and its peculiar clinical manifestations may be based on these underlying functional abnormalities.
Acknowledgments. This study was supported in part by a Grant-in-Aid from the Japanese Ministry of Education, #05770722.
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