Psychiatry Research 177 (2010) 2226

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Psychiatry Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s

Hostility of drug-free patients with schizophrenia and n3 polyunsaturated fatty

acid levels in red blood cells
Michiko Watari a,1, Kei Hamazaki b,2, Toyoaki Hirata c,3, Tomohito Hamazaki b,, Yoshiro Okubo a
a
b
c

Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan

Department of Clinical Sciences, Institute of Natural Medicine, University of Toyama, Toyama, Japan
Chiba Psychiatric Medical Center, Chiba, Japan

a r t i c l e

i n f o

Article history:
Received 18 February 2009
Received in revised form 26 January 2010
Accepted 17 February 2010
Keywords:
EPA
Hostility
Positive symptom

a b s t r a c t
Many reports suggest that n 3 polyunsaturated fatty acids (PUFAs) inuence the symptoms of psychiatric
disorders. Moreover, it has also been reported that n 3 PUFAs control aggression and hostility. Acute
symptoms of schizophrenia such as aggression can be a formidable clinical problem resulting in
hospitalization. However, few investigations have determined the relationships between acute symptoms
of drug-free schizophrenia and n 3 PUFAs. We recruited 75 inpatients with acute drug-free schizophrenia
admitted to Chiba Psychiatric Medical Center, an emergency psychiatric hospital. Blood was sampled
immediately after admission. The red blood cell (RBC) fatty acid composition and hostility score of Positive
and Negative Syndrome Scale (PANSS) scores were measured. Multiple regression analysis showed that the
concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the ratio of EPA/
arachidonic acid (AA) in RBC showed signicant negative correlations with the hostility score of PANSS
scores after adjustment for age and sex. AA, on the other hand, showed signicant positive correlations. The
tissue n 3 PUFA and n 6 PUFA levels were negatively and positively associated with the hostility score of
PANSS scores, respectively, suggesting possible effects of PUFA levels on hostile behavior in patients with
schizophrenia.
2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Acute symptoms of schizophrenia such as aggression, agitation
and psychosis can be a formidable clinical problem in psychiatric
hospitals. Positive and general psychotic symptoms appear to enhance the violence risk of inpatients (Steinert, 2002, Buckley et al.,
2004), with violence currently being one of the primary reasons for
admission to psychiatric hospitals (Colasanti et al., 2008). In Japan,
there were an estimated 1.5 million inpatients in 2005, with
schizophrenia accounting for 14% (The Patient Survey Conducted by
the Ministry of Health, Labour and Welfare in 2005). Consequently,
identication of the manageable risks for severe acute symptoms in
patients with schizophrenia is therefore important. However, so far,
few studies have focused on such symptoms.

Corresponding author. Department of Clinical Sciences, Institute of Natural

Medicine, University of Toyama, 2630 Sugitani, Toyama-city, Toyama 9300194, Japan.
Tel.: +81 76 434 7615; fax: +81 76 434 5057.
E-mail address: hamazaki@inm.u-toyama.ac.jp (T. Hamazaki).
1
Present address: Psychiatric Center, Prefectural Miyazaki Hospital, 5-30 Kitatakamatsucho, Miyazaki-city, Miyazaki 880-8510, Japan.
2
Present address: Department of Public Health, Faculty of Medicine, University of
Toyama, 2630 Sugitani, Toyama 9300194, Japan.
3
Present address: Shizuoka Psychiatric Medical Center, 4-1-1 Yoichi, Aoi-ku,
Shizuoka-city, Shizuoka, Japan.
0165-1781/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.psychres.2010.02.016

Since Horrobin (1977) hypothesized that schizophrenia might be a

prostaglandin deciency disease, several studies have reported
various changes in polyunsaturated fatty acid (PUFA) levels in the
brain (Horrobin et al., 1991; McNamara et al., 2007), plasma (Bates
et al., 1991; Kaiya et al., 1991; Kale et al., 2008) and red blood cell
(RBC) membranes (Assies et al., 2001; Khan et al., 2002; Arvindakshan
et al., 2003; Peet et al., 2004; Kale et al., 2008) of patients with
schizophrenia. Recently, McNamara et al. (2007) also determined the
total fatty acid composition of the postmortem orbitofrontal cortex of
patients with schizophrenia and age-matched normal controls, and
found that, after correction for multiple comparisons, docosahexaenoic acid (DHA) was signicantly lower in the patients with
schizophrenia by 20%. It was also reported that patients with predominantly negative symptoms have lower levels of RBC eicosapentaenoic acid (EPA) and DHA than those with persistently positive
symptoms (Glen et al., 1994). PUFA levels are reportedly inuenced
by a number of factors other than diet. For example, age, gender,
physical activity (Itomura et al., 2008), alcohol (Pawlosky and Salem,
1999), antipsychotic medication (Mazire et al., 1988) and smoking
(Hibbeln et al., 2003) have all been reported to affect PUFA metabolism, especially EPA and DHA. Consequently, it is likely that prior
reports revealing differences in PUFA levels between patients with
schizophrenia and healthy controls have been more or less confounded. On the other hand, supplementation of n3 PUFAs with neuroleptics in a few randomized controlled studies reportedly improved

M. Watari et al. / Psychiatry Research 177 (2010) 2226

the clinical course (Peet et al., 2001; Emsley et al., 2002; Peet et al.,
2002), whereas other studies showed no positive results (Fenton
et al., 2001; Emsley et al., 2006).
Hamazaki et al. (1996) found that DHA-rich sh oil administration
suppressed aggression against others at times of mental stress in a
placebo-controlled double-blind study using college students as
subjects. Scores of anger were shown to reduce in healthy subjects
supplemented with n 3 fatty acids in a double-blind test (Fontani
et al, 2005). In addition, the intake of n 3 fatty acids was further
correlated with lower hostility levels in the CARDIA study (Iribarren
et al 2004). Moreover, plasma DHA levels were negatively correlated
with cerebrospinal uid 5-hydroxyindoleacetic acid in violent subjects (Hibbeln et al., 1998). Based on these reports regarding n 3
PUFAs and aggression/hostility (see a review by Hamazaki and
Hamazaki (2008)), we hypothesized that there might be a negative
correlation between the severity of acute symptoms, especially
hostility, in schizophrenia and n3 fatty acids in RBC. To nullify the
inuence of confounding factors such as antipsychotic medication, we
examined this correlation in drug-free patients with schizophrenia.
2. Methods
2.1. Study subjects and procedure
The research design was cross sectional. Subjects were recruited between July 2004
and March 2007 in the Chiba Psychiatric Medical Center (CPMC), a public emergency
psychiatric hospital in Chiba city. Only patients with severe acute symptoms are admitted
to this hospital, with the average period of hospitalization being only 37 days. Severe acute
symptoms include psychomotor excitement, hallucination, delusion, stupor, catatony,
self-harm, and depression. During the recruitment period, 144 study subjects were
sampled consecutively. In the case that the patient had a history of impulsive or violent
behavior, a family member, police body, health center ofcer or nurse was interviewed. All
patients met the International Statistical Classication of Diseases and Related Health
Problems 10th Revision (ICD-10) criteria for schizophrenia or schizoaffective disorder.
Inclusion criteria for the present study were: 1) aged 1859 years, 2) Japanese, 3) met ICD10 criteria for schizophrenia or schizoaffective disorder, 4) never medicated or drug-free
for at least 90 days prior to admission, and 5) admitted to CPMC. Exclusion criteria were: 1)
major medical illness including diabetes mellitus, dyslipidemia, endocrine disorders and
malnutrition; 2) mental retardation; 3) alcohol or substance abuse or dependence; and 4)
incompetence to consent to the study.

illness and past history of treatment in model 2. We also analyzed the relationship
between hostility and PUFAs using the above models. Data were analyzed with SPSS ver
17.0 software (SPSS Japan Inc., Tokyo, Japan). (the standardized regression
coefcient) was calculated to represent the individual correlation coefcient and
compare the contribution of each fatty acid to the hostility score. P b 0.05 was
considered as signicant unless otherwise stated.

3. Results
Seventy-eight inpatients agreed to participate in the study. However, three could not be included because of incomplete data. Fig. 1
shows the subject recruitment ow, and Tables 1 and 2 show the
background characteristics and psychopathology of these 75 subjects,
respectively. The hostility score (PANSS item P7) was 3.5 1.8. The
fatty acid composition is shown in Table 3.
The total, positive and negative PANSS scores were not correlated
with PUFAs in models 1 (adjusted for age and sex) or 2 (adjusted for age,
sex, smoking status, alcohol use, education, duration of illness and past
history of treatment), whereas the general PANSS score was positively
correlated with EPA ( = 0.24, P = 0.047) and DHA ( = 0.28, P = 0.02)
in model 2 only. We also examined the correlations between the
hostility score of the positive syndrome score and PUFAs. As shown in
Table 4, EPA, EPA/AA and DHA were negatively correlated with the
hostility score in both models, whereas AA was positively correlated
with the hostility score. Fig. 2 shows the correlation between hostility
and EPA and DHA shown in Table 4 (model 2) to conrm that there were
no outliers that might have biased the coefcients towards higher
signicance.
None of the other scores in PANSS, for instance, anxiety, guilt
feelings and depression were signicantly associated with PUFAs.
In order to compare RBC EPA + DHA levels between the United
States and Japan where people eat more sh, we measured the fatty
acid composition in RBCs. As expected, Japanese RBC EPA + DHA
levels were much higher than the levels in the United States (Itomura
et al., 2008). Considering signicant differences in DHA concentrations in RBCs between patients with schizophrenia and normal

2.2. Assessment
Patients were rated for psychopathology using the Positive and Negative Syndrome
Scale (PANSS). Assessment was carried out by well trained psychiatrists on admission. As
an emergency psychiatric hospital, blood samples were taken from all patients
immediately after admission, and therefore, no additional blood samples were taken for
the present study. After clinical examinations, the remaining RBCs with butylated
hydroxytoluene were stored at 80 C until fatty acid analysis. The fatty acid composition
of the total phospholipid (PL) fraction of RBC was determined as described previously
(Hamazaki et al., 2005). Briey, the total lipids were extracted from RBC then the total PL
fraction was separated by thin-layer chromatography. Fatty acids of this fraction were then
transmethylated and analyzed by gas chromatography (GC-14A gas chromatograph
[Shimadzu, Kyoto, Japan] with a capillary column DB-225 [30 m, J&W Scientic, Folsom,
California]). The entire system was controlled with the gas chromatographic software,
CLASS-GC10 ver 1.3 (Shimadzu Corporation). The intra-assay coefcients of variance for
EPA and DHA were 2.9% and 4.1%, respectively. The research protocols and consent forms
were approved by the internal review board of the CPMC. Written informed consent was
obtained from each participant. Because study subjects were in the middle of an acute state
of the illness, they were not always competent enough to consent to participation. In such
cases, consent was obtained from their guardians in the interim then from the patients
themselves after treatment. During treatment, blood samples were stored with their
guardians' consent. The competence of patients was evaluated using the MacArthur
Competence Assessment Tool for Clinical Research (Grisso et al., 1997), which is a
structured interview for assessing decision-making capacity for research participation. A
scoring manual provided raters with possible scores ranging from 0 to 26 on the
Understanding scale, 0 to 6 on the Appreciation scale, 0 to 8 on the Reasoning scale, and 0
to 2 on the Choice scale. If each score was lower than averages minus one S.D., the patient
was excluded.
2.3. Statistical analysis
Data are shown as means S.D. The positive, negative, general and total scores of
PANSS were analyzed for correlations with PUFAs such as EPA, DHA and arachidonic
acid (AA) in RBC using a multiple regression method. Independent variables were age
and sex in model 1, and age, sex, smoking status, alcohol use, education, duration of

23

Fig. 1. Flow chart of subject recruitment.

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M. Watari et al. / Psychiatry Research 177 (2010) 2226

Table 1
Background characteristics of subjects.
Characteristic

Age (years)
Gender (male/female)
Education (years)
Duration of illness (months)
Duration of admission (days)
Past history of treatment (yes/no)
Current smoker (yes/no)
Alcohol consumption (less than 12 g/day/or more)

Table 3
Fatty acid composition (%) of red blood cells.
Subjects

Score

n = 75

Mean S.D.
36.3 9.9

36/39
12.5 2.5
61 66
43 29
26/49
36/39
58/17

controls in several studies (see the Discussion section), it might be

interesting to investigate whether brain DHA levels are also depressed
in patients with schizophrenia in countries like Japan where people
eat a considerable amount of sh. At present, no such brain data are
available. Because our method for determination of the RBC fatty acid
composition in normal subjects (Itomura et al., 2008) was the same as
that used in the present study, here we compared major fatty acids
between Japanese normal volunteers (n = 456) and patients with
schizophrenia. Taking into account that measurement of normal
volunteers was not intended for comparison with patients with
schizophrenia, here we showed differences in major fatty acids with
highly statistical signicance (P b 0.005) only. In the present study,
after adjustment for sex and age, it was found that patients with
schizophrenia had signicantly lower concentrations of stearic acid
(13.5 1.2 vs 14.9 2.4, patients vs controls, respectively), EPA
(1.2 0.5 vs 1.6 0.7) and EPA/AA (0.12 0.06 vs 0.16 0.08), and
signicantly higher concentrations of oleic acid (13.8 1.1 vs 13.2
0.9), arachidonic acid (11.6 1.2 vs 10.7 1.4) and palmitic acid
(25.4 1.6 vs 23.8 2.1) than controls. DHA was marginally lower
in patients with schizophrenia than controls (6.1 1.2 vs 6.8 1.3,
P = 0.02, not signicant according to our criteria for this comparison).
4. Discussion
As mentioned in the Introduction section, the tissue PUFA
composition is important in research; however, the effects of certain
characteristics have not yet been signicantly taken into account; for
example, age, gender, drug therapy, smoking, and alcohol use.
Furthermore, few psychiatric studies have focused on severe acute
symptoms of schizophrenia such as hostility. In the present study, we
found signicant correlations between hostility and PUFAs in RBC in
drug-free patients with schizophrenia after adjustment for several
confounders. The present study had a horizontal style, and therefore,
it was not clear whether n3 and n6 PUFA administration could
respectively ameliorate and deteriorate hostility in patients with
schizophrenia. Interestingly, Lgar et al. (2007) performed a pilot

Table 2
Psychopathology of subjects.
Score (n = 75)
Mean S.D.
PANSS
PANSS-P (max 49)
PANSS-N (max 49)
PANSS-G (max 112)
Total PANSS (max 210)
MacCAT-CR
Understanding score (max 26)
Appreciation score (max 6)
Reasoning score (max 8)

Palmitic acid
Stearic acid
Oleic acid
Linoleic acid
Arachidonic acid
Eicosapentaenoic acid
Docosahexaenoic acid
The values are area percentage of the total phospholipid fraction of RBCs.

study in which 12 violent male inpatients with chronic schizophrenia

received a daily dose of 1.2 g EPA, 0.6 g DHA and vitamin E for
12 weeks. The average number of pro re nata administrations of
anxiolyics as an index of agitation signicantly decreased from 33 to
23. These ndings imply that n 3 PUFAs might be able to control
violent behavior in patients with schizophrenia.
In schizophrenia, hypofunction of the cortical and prefrontal
dopamine systems is considered the cause of negative symptoms and
cognitive disorders, while hyperactivity of the subcortical and limbic
dopamine systems, which occurs through suppressed negative control from the prefrontal dopamine system, causes positive symptoms
(Davis et al., 1991; Abi-Dargham 2004; Ohara 2007). Rats fed a longterm n 3 PUFA-decient diet showed a decrease in DHA concentrations in the total PL fraction in the frontal cortex to one third of that of
control values, as well as induced a signicantly lower density of D2
receptors and signicantly lower concentration of endogenous
dopamine in the frontal cortex than in control rats (Delion et al.,
1994). Taken together, these ndings suggest that n 3 PUFAdeciency might depress the frontal cortex dopaminergic system,
which in turn might enhance the limbic dopamine system. EPA + DHA
supplementation of normal subjects was shown to decrease peripheral blood adrenaline and noradrenalin concentrations while not
inuencing dopamine concentrations (Hamazaki et al., 2005).
Therefore, in subjects with normal levels of n 3 PUFAs, further supplementation with n 3 PUFAs might not inuence peripheral
dopamine levels, although it might change the dopaminergic system
somewhere in the central nervous system.
We have been investigating the effects of sh oil on aggression and
hostility (Hamazaki and Hamazaki, 2008). In a placebo-controlled
double-blind test with elementary school children (912 year olds),
DHA-rich foods did not increase physical aggression, but in the control
group physical aggression was increased with a signicant inter-group
difference (Itomura et al., 2005). Although this effect was found in girls
only, there was a signicant correlation between the differences in
EPA/AA ratios (the end values minus start values; EPA/AA) and
differences in aggression scores (the end values minus start values;
physical aggression) in female subjects for whom blood samples
were available (Itomura et al., 2005). Consequently, the signicant
correlation between hostility and RBC EPA/AA in the present study
may not be a feature specic to patients with schizophrenia. How n 3
PUFAs are correlated with hostility was not analyzed in the present
Table 4
Correlations between the hostility subscale of the positive syndrome score and PUFAs.
Fatty acids

28.2 7.7
19.0 9.1
46.3 15.0
92.7 24.2
23.1 4.3
5.2 1.2
6.7 1.9

PANSS: Positive and Negative Syndrome Scale, P: positive syndromes, N: negative

syndromes, G: general syndromes, MacCAT-CR: MacArther competence assessment
tool for clinical research.

25.4 1.6
13.5 1.2
13.8 1.1
9.2 1.3
11.6 1.2
1.2 0.5
6.1 1.2

AA
EPA
EPA/AA
DHA

Model 1

Model 2

P value

P value

0.23
0.32
0.31
0.23

0.04
0.005
0.006
0.04

0.26
0.32
0.32
0.25

0.03
0.007
0.008
0.04

; standardized regression coefcient.

Multiple regression analysis.
Model 1: adjusted with age and sex.
Model 2: adjusted with age, sex, smoking status, alcohol, education, duration of illness
and past history of treatment.

M. Watari et al. / Psychiatry Research 177 (2010) 2226

25

also lower in patients with schizophrenia than healthy controls, although the difference was marginal.
One question that arises to us is, are American patients with
schizophrenia, who are presumed to eat less sh, more hostile than
Japanese patients? In a clinical trial, Citrome et al (2004) reported that
a baseline hostility score was 2.72.8 in study subjects who had to be
hospitalized for acute exacerbation of schizophrenia. In our study, the
hostility score was 3.5 1.8, which is much higher than that in the
above report. In addition, Binder and McNiel (1998) reported that 10%
of patients with schizophrenia who were admitted to a locked
university-based psychiatry unit physically attacked other patients,
with 43% engaging in fear-inducing behavior. This suggests that the
hostility score was obviously higher than in our study. As a result, it
may not be easy to compare the scores of different populations under
different circumstances.
The present study has the following limitations: 1. it was not an
intervention study, and therefore, confounding factors including
lifestyle and sh intake may exist (Appleton et al., 2007). 2. We did
not include appropriate control groups. 3. The sample size was not
large. 4. Patient diet and nutritional status were not assessed.
In conclusion, the present study showed that tissue EPA, EPA/AA
and DHA were negatively correlated with the hostility score, whereas
AA had a positive correlation. Further studies are necessary to determine the possible clinical application of n 3 PUFAs in controlling
this acute symptom (i.e., hostility) in patients with schizophrenia.
Acknowledgements
We are grateful to Ms Hiroko Hamatani (University of Toyama) and Ms Shizuko
Takebe (University of Toyama) for their technical assistance. This study was partly
supported by the Open Research Center, Kinjogakuin University.

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Fig. 2. Scattergram of hostility and EPA (panel a) and DHA (panel b) in the total
phospholipid fraction in RBCs. Values were adjusted for age, sex, smoking status,
alcohol consumption, education, duration of illness and past history of treatment.
Values 0 indicate the means. = 0.32, P = 0.007 for EPA; = 0.25, P = 0.04 for
DHA.

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