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Hostility of drug-free patients with schizophrenia and n− 3 polyunsaturated fatty acid levels in red blood cells
Psychiatry Research 177 (2010) 22–26
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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 n−3 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) influence 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 significant negative correlations with the hostility score of PANSS scores after adjustment for age and sex. AA, on the other hand, showed significant 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, identification 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: [email protected] (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 deficiency 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 significantly 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 influenced 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 (Mazière 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 n−3 PUFAs with neuroleptics in a few randomized controlled studies reportedly improved
M. Watari et al. / Psychiatry Research 177 (2010) 22–26
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 fish 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 fluid 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 n−3 fatty acids in RBC. To nullify the influence 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 officer or nurse was interviewed. All patients met the International Statistical Classification 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 18–59 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). β (the standardized regression coefficient) was calculated to represent the individual correlation coefficient and compare the contribution of each fatty acid to the hostility score. P b 0.05 was considered as significant 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 flow, 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 (β = 0.24, P = 0.047) and DHA (β = 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 confirm that there were no outliers that might have biased the coefficients towards higher significance. None of the other scores in PANSS, for instance, anxiety, guilt feelings and depression were significantly associated with PUFAs. In order to compare RBC EPA + DHA levels between the United States and Japan where people eat more fish, 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 significant 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). Briefly, 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 Scientific, Folsom, California]). The entire system was controlled with the gas chromatographic software, CLASS-GC10 ver 1.3 (Shimadzu Corporation). The intra-assay coefficients 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
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Fig. 1. Flow chart of subject recruitment.
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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 fish. 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 significance (P b 0.005) only. In the present study, after adjustment for sex and age, it was found that patients with schizophrenia had significantly 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 significantly 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 significant 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 significantly 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 significant 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 n−3 and n−6 PUFA administration could respectively ameliorate and deteriorate hostility in patients with schizophrenia. Interestingly, Légaré 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 significantly decreased from 33 to 23. These findings 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-deficient 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 significantly lower density of D2 receptors and significantly lower concentration of endogenous dopamine in the frontal cortex than in control rats (Delion et al., 1994). Taken together, these findings suggest that n− 3 PUFAdeficiency 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 influencing dopamine concentrations (Hamazaki et al., 2005). Therefore, in subjects with normal levels of n− 3 PUFAs, further supplementation with n− 3 PUFAs might not influence peripheral dopamine levels, although it might change the dopaminergic system somewhere in the central nervous system. We have been investigating the effects of fish oil on aggression and hostility (Hamazaki and Hamazaki, 2008). In a placebo-controlled double-blind test with elementary school children (9–12 year olds), DHA-rich foods did not increase physical aggression, but in the control group physical aggression was increased with a significant inter-group difference (Itomura et al., 2005). Although this effect was found in girls only, there was a significant correlation between the differences in EPA/AA ratios (the end values minus start values; ΔEPA/AA) and differences in aggression scores (the end values minus start values; Δphysical aggression) in female subjects for whom blood samples were available (Itomura et al., 2005). Consequently, the significant correlation between hostility and RBC EPA/AA in the present study may not be a feature specific 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
β
P value
β
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
β; standardized regression coefficient. 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.
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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 fish, more hostile than Japanese patients? In a clinical trial, Citrome et al (2004) reported that a baseline hostility score was 2.7–2.8 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 fish 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.
References
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. β = − 0.32, P = 0.007 for EPA; β = − 0.25, P = 0.04 for DHA.
study; however, it has been suggested that the serotonergic system might be involved (Hamazaki and Hamazaki 2008). Gesch et al. (2002) reported that violent offences were reduced by 37% among prisoners supplemented with PUFAs, multivitamins and minerals in a placebo-controlled trial. Furthermore, in a double-blind test with 30 female subjects showing borderline personality disorder, EPA ethyl ester administration for 8 weeks was shown to diminish aggression (Zanarini and Frankenburg, 2003). Buydens-Branchey and Branchey (2008) reported that n−3 fatty acids were superior to a placebo in diminishing anger scores in a double-blind trial involving substance abusers with a lifelong history of aggressive behaviors. Hibbeln (2001), moreover, reported a negative correlation between seafood consumption and mortality by homicide (the ultimate aggressive behavior) using cross-national ecological analysis. Consequently, it is likely that the relationship between n−3 fatty acids and hostility or aggression may be applicable to a wide range of populations, although so far there have been few negative results (Hamazaki and Hamazaki, 2008). Several studies have reported the fatty acid composition of RBC in mostly first episode patients with schizophrenia. However, the results have not been consistent, with the reduced RBC levels of DHA in patients with schizophrenia being the only robust finding (Assies et al., 2001; Khan et al., 2002; Arvindakshan et al., 2003; Peet et al., 2004; Kale et al., 2008). In the present study DHA concentrations were
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Contents lists available at ScienceDirect
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 n−3 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) influence 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 significant negative correlations with the hostility score of PANSS scores after adjustment for age and sex. AA, on the other hand, showed significant 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, identification 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: [email protected] (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 deficiency 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 significantly 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 influenced 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 (Mazière 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 n−3 PUFAs with neuroleptics in a few randomized controlled studies reportedly improved
M. Watari et al. / Psychiatry Research 177 (2010) 22–26
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 fish 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 fluid 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 n−3 fatty acids in RBC. To nullify the influence 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 officer or nurse was interviewed. All patients met the International Statistical Classification 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 18–59 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). β (the standardized regression coefficient) was calculated to represent the individual correlation coefficient and compare the contribution of each fatty acid to the hostility score. P b 0.05 was considered as significant 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 flow, 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 (β = 0.24, P = 0.047) and DHA (β = 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 confirm that there were no outliers that might have biased the coefficients towards higher significance. None of the other scores in PANSS, for instance, anxiety, guilt feelings and depression were significantly associated with PUFAs. In order to compare RBC EPA + DHA levels between the United States and Japan where people eat more fish, 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 significant 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). Briefly, 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 Scientific, Folsom, California]). The entire system was controlled with the gas chromatographic software, CLASS-GC10 ver 1.3 (Shimadzu Corporation). The intra-assay coefficients 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
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Fig. 1. Flow chart of subject recruitment.
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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 fish. 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 significance (P b 0.005) only. In the present study, after adjustment for sex and age, it was found that patients with schizophrenia had significantly 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 significantly 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 significant 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 significantly 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 significant 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 n−3 and n−6 PUFA administration could respectively ameliorate and deteriorate hostility in patients with schizophrenia. Interestingly, Légaré 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 significantly decreased from 33 to 23. These findings 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-deficient 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 significantly lower density of D2 receptors and significantly lower concentration of endogenous dopamine in the frontal cortex than in control rats (Delion et al., 1994). Taken together, these findings suggest that n− 3 PUFAdeficiency 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 influencing dopamine concentrations (Hamazaki et al., 2005). Therefore, in subjects with normal levels of n− 3 PUFAs, further supplementation with n− 3 PUFAs might not influence peripheral dopamine levels, although it might change the dopaminergic system somewhere in the central nervous system. We have been investigating the effects of fish oil on aggression and hostility (Hamazaki and Hamazaki, 2008). In a placebo-controlled double-blind test with elementary school children (9–12 year olds), DHA-rich foods did not increase physical aggression, but in the control group physical aggression was increased with a significant inter-group difference (Itomura et al., 2005). Although this effect was found in girls only, there was a significant correlation between the differences in EPA/AA ratios (the end values minus start values; ΔEPA/AA) and differences in aggression scores (the end values minus start values; Δphysical aggression) in female subjects for whom blood samples were available (Itomura et al., 2005). Consequently, the significant correlation between hostility and RBC EPA/AA in the present study may not be a feature specific 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
β
P value
β
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
β; standardized regression coefficient. 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) 22–26
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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 fish, more hostile than Japanese patients? In a clinical trial, Citrome et al (2004) reported that a baseline hostility score was 2.7–2.8 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 fish 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.
References
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. β = − 0.32, P = 0.007 for EPA; β = − 0.25, P = 0.04 for DHA.
study; however, it has been suggested that the serotonergic system might be involved (Hamazaki and Hamazaki 2008). Gesch et al. (2002) reported that violent offences were reduced by 37% among prisoners supplemented with PUFAs, multivitamins and minerals in a placebo-controlled trial. Furthermore, in a double-blind test with 30 female subjects showing borderline personality disorder, EPA ethyl ester administration for 8 weeks was shown to diminish aggression (Zanarini and Frankenburg, 2003). Buydens-Branchey and Branchey (2008) reported that n−3 fatty acids were superior to a placebo in diminishing anger scores in a double-blind trial involving substance abusers with a lifelong history of aggressive behaviors. Hibbeln (2001), moreover, reported a negative correlation between seafood consumption and mortality by homicide (the ultimate aggressive behavior) using cross-national ecological analysis. Consequently, it is likely that the relationship between n−3 fatty acids and hostility or aggression may be applicable to a wide range of populations, although so far there have been few negative results (Hamazaki and Hamazaki, 2008). Several studies have reported the fatty acid composition of RBC in mostly first episode patients with schizophrenia. However, the results have not been consistent, with the reduced RBC levels of DHA in patients with schizophrenia being the only robust finding (Assies et al., 2001; Khan et al., 2002; Arvindakshan et al., 2003; Peet et al., 2004; Kale et al., 2008). In the present study DHA concentrations were
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