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Psychiatry Research 167 (2009) 266 – 278 www.elsevier.com/locate/psychres
Plasma omega-3 and psychological distress among Nunavik Inuit (Canada) Michel Lucas a , Éric Dewailly a,b,⁎, Carole Blanchet a , Suzanne Gingras a , Bruce J. Holub c a
Public Health Research Unit, Laval University Medical Research Centre (CHUQ), Sainte-Foy, Québec, Canada b Department of Social and Preventive Medicine, Laval University, Sainte-Foy, Québec, Canada c Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada Received 20 October 2006; received in revised form 14 December 2007; accepted 12 April 2008
Abstract Marine omega-3 (n−3) fatty acid eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids have been associated with beneficial effects in mental health. Cultural and social changes have been related to a decline in mental health of the Inuit, but the role of diet has received scant attention. We examined the relationship between psychological distress (PD) and plasma n−3 among 368 Nunavik Inuit aged 18–74 years who took part in a survey in 1992. Participants were categorized as high-level PD if they scored over the 80th percentile of the PD Index Santé-Québec Survey (PDISQS-14), and non-distressed subjects were those who scored less than this cutoff. Compared with the non-distressed group, n−3 concentrations in the PD group were significantly lower in women but not in men. Compared with the lowest tertile of EPA + DHA, the odds ratios for high-level PD among women were 0.32 (95% CI: 0.13–0.82) for the second, and 0.30 (95% CI: 0.10–0.90) for the third tertile, after controlling for confounders. In males, there were no significant associations between EPA + DHA and PDISQS-14 scores. Our findings suggest that marine n−3 may play a role in PD among Inuit women. The gender difference observed in our analysis must be examined more carefully in future studies. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Omega-3 fatty acids; Psychological distress; Inuit; Eicosapentaenoic acid; Docosahexaenoic acid; Plasma phospholipids; Women
1. Introduction Before World War II, the majority of the Inuit populations mainly lived according to a traditional lifestyle, which was based on subsistence activities ⁎ Corresponding author. Delta Building #2, Office 600, 2875 Laurier Blvd., 6th Floor, Sainte-Foy, QC, Canada G1V 2M2. Tel.: +1 418 525 4444x46518; fax: +1 418 654 2726. E-mail address:
[email protected] (É. Dewailly).
such as hunting and fishing (Santé-Québec, 1994; Blanchet et al., 2002; Kirmayer et al., 2000a; McGrathHanna et al., 2003). In recent decades, however, changes in lifestyle and dietary patterns have been observed among Inuit populations (Kirmayer et al., 2000a; McGrath-Hanna et al., 2003). Traditional food system use is declining rapidly, though not uniformly across the Arctic, but for most circumpolar regions, dietary intake from market foods exceeds those from traditional foods (Blanchet et al., 2002). In several native populations, this
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M. Lucas et al. / Psychiatry Research 167 (2009) 266–278
shift away from traditional lifestyle and diet was associated with increased health problems (Kirmayer et al., 2000a; McGrath-Hanna et al., 2003). Some aboriginal groups have reported evidence of severe psychological distress (PD) (with high rates of depression, suicide, violence, alcoholism and substance abuse), the most profound impact being seen among the young (Santé-Québec, 1994; Waldram et al., 1995; Chandler and Lalonde, 1998; Boothroyd et al., 2000; Haggarty et al., 2000; Kirmayer et al., 2000a,b). The Nunavik region, located above the 55th parallel in the province of Quebec (Canada), is inhabited primarily by Inuit. The traditional Inuit diet mainly consists of marine mammals (white whale (beluga) and seal), fish and caribou, which are eaten fresh (raw or cooked) or dried, with the skin, blubber, liver, and fat added in different meals (Santé-Québec, 1994; Blanchet et al., 2000). The consumption of fish and marine mammals, rich in omega3 (n−3) fatty acids, represented a significant part of the Inuit diet in 1992 (Santé-Québec, 1994; Blanchet et al., 2000; Dewailly et al., 2001). Data from 24-h dietary recalls revealed that mean traditional food consumption of marine origin was 131.2 g/day (95% confidence interval (CI): 110.8–152.1) (Dewailly et al., 2001, 2003). Existent evidence points to a decrease in the traditional diet of the Inuit, especially among young adults and youth for whom market foods (which generally have a higher content of trans-fatty acids, lower omega-3, higher omega-6/ omega-3 ratio, etc.) appear to be more attractive. We reported earlier that young adults (18–34 years) had onehalf the eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) concentrations in plasma phospholipids compared with Inuit aged 50 years and over (6.5% vs. 11.5%, P b 0.0001) (Dewailly et al., 2003). Several studies have identified EPA and DHA concentrations in blood as indicators of past individual dietary intake of marine n−3 fatty acids (Hjartaker et al., 1997; Kobayashi et al., 2001; Kuriki et al., 2002, 2003; Kobayashi et al., 2003). It has been suggested that dietary changes occurring in our societies, mainly a decrease in marine n−3 and an increase in omega-6 (n−6), could be contributing to the increasing incidence of depression (Hibbeln and Salem, 1995). Epidemiological studies have shown that the prevalence of major depression (Hibbeln, 1998), bipolar depression (Noaghiul and Hibbeln, 2003), post-partum depression (De Vriese et al., 2003; Hibbeln, 2002), hostility (Iribarren et al., 2004) and suicidal ideation (De Vriese et al., 2004) is associated with lower dietary intake and/or blood concentrations of marine n−3. The Omega-3 Fatty Acids Subcommittee, assembled by the Committee on Research of Psychiatric Treatment of the American Psychiatric Association, has concluded that
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studies support a protective effect of marine omega-3 in mood disorders (Freeman et al., 2006). Human (Hamazaki et al., 2000; Maes et al., 2000; Delarue et al., 2003) and animal (Takeuchi et al., 2003) investigations suggest that marine n−3 may have an anti-stress function. Specific diagnostic measures concerning mental health among the Inuit of Nunavik are lacking (Santé-Québec, 1994). This population and the representatives of various sectors of activity recognize that psychological and social problems are growing. The modernization of Inuit society has been associated with cultural and social changes, increased chronic diseases (obesity, cardiovascular disorders and diabetes) as well as a decline in mental health (Kirmayer et al., 2000a; McGrath-Hanna et al., 2003). However, the role of their traditional diet has received scant attention in regard to mental health. A generalized measure of PD was used in a cross-sectional survey undertaken by the Government of Quebec among the Inuit of Nunavik in 1992 (Santé-Québec, 1994). We considered it important to examine the potential role of marine n−3 fatty acids in PD among the Nunavik Inuit. 2. Methods 2.1. Study design and population The Santé-Québec Health Survey among the Inuit of Nunavik in 1992 has been described in detail elsewhere (Santé-Québec, 1994; Dewailly et al., 2001). Briefly, Santé-Québec, an organization of the Quebec Health and Social Services Ministry, undertook a health survey among the Inuit population of Nunavik in 1992. The primary objective of the survey was to collect relevant information on the physical, social and psychosocial health of the Inuit population (Santé-Québec, 1994). These data were gathered in several stages. Face-to-face interviews were conducted in English and/or Inuktitut (the Inuit language) at each participant's home to fill out a lifestyle questionnaire along with a confidential and a self-administrated socio-demographic questionnaire. A clinical session was organized for the same participants, in the village health clinic to obtain physiological and anthropometric measurements. Information on demographic characteristics was collected from the SantéQuébec data files. Our team was responsible for analyzing the fatty acids in blood samples. The target population of the survey comprised all permanent residents of Nunavik aged 18–74 years, excluding households consisting of only non-Inuit persons, individuals not related to an Inuit, and institutionalized subjects (Santé-Québec, 1994). Of the household respondents, 560 participants submitted to clinical
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measurements and blood tests. Of these, 183 did not have information on PD, and nine were pregnant women; all of them were therefore excluded from the present analysis. In this survey, signed informed consent was obtained from the study subjects before inclusion. The study protocol was approved by the Ethics Committee of MaisonneuveRosemont Hospital (Montreal). 2.2. Psychological distress PD among the Inuit was measured via a modified version of the 14-Item PD Index used in the 1987 SantéQuébec Survey (PDISQS-14) (Préville et al., 1992, 1995). The PDISQS-14 is an adaptation of the Psychiatric Symptom Index (PSI), developed and validated by Ilfeld (1976, 1978). The self-administered PDISQS-14 contained 14 statements addressing psychological symptoms experienced in the previous week (Table 1). The structure of the PSI is based on the existence of four distinct dimensions (depression, anxiety, aggressiveness and psychomotor perturbations) connected at a second level with the more general concept of PD (Martin et al., 1989). Scores range from a minimum of 0 to a maximum of 100. The internal consistency of the scale within the Inuit sample was found to be satisfactory (Cronbach's alpha = 0.88) (Santé-Québec, 1994). As in the 1987 SantéQuébec master survey, a high level of PD was defined by any score above the 80th percentile of index distribution observed in the Inuit (Boyer et al., 1993). Participants were categorized as having high-level PD if they scored over the 80th percentile of the PDISQS-14 (score of 39.3). Non-distressed participants were those scoring less than this cutoff. Seventy participants scored over the cutoff, 18 men and 52 women. Table 1 The Psychological Distress Index Santé-Québec Survey (PDISQS-14) used in the Santé-Québec Health Survey among the Inuit of Nunavik (1992). How often, during the past week, did you… • feel hopeless about the future? • have your mind go blank? • feel down or blue? • feel tense or under pressure? • lose your temper? • feel bored or have little interest in things? • feel fearful or afraid? • have trouble remembering things? • cry easily or feel like crying? • feel nervous or shaky inside? • feel critical of others? • feel easily annoyed or irritated? • get angry over things that are not too important? • feel like being alone? Three answers were offered to the Inuit (Never, From time to time, Often).
2.3. Plasma phospholipid fatty acids Plasma samples, stored at −80 °C for ≤4 months, were measured for the fatty acid composition of phospholipids (PLs). Fatty acid analysis of these plasma biomarkers (PLs) was based on previously published methods (Stark and Holub, 2004). The results and methods have been described in detail elsewhere (Dewailly et al., 2001). Briefly, the fatty acid composition of plasma PLs was determined by capillary gas–liquid chromatography. Fatty acid concentrations in plasma PLs were expressed as percentages of the total area of all fatty acid peaks from 14:0 to 24:1. In this study, plasma PL concentrations of fatty acids corresponded to the relative percentages of total fatty acids by weight. The concentrations of only polyunsaturated fatty acids (PUFAs) are reported for the present purpose. 2.4. Covariables Self-reported problem drinking was estimated with the CAGE (Cutting down, Annoyance by criticism, Guilty feelings, and Eye-openers) alcoholism risk questionnaire (Ewing, 1984). A total score of 2 or greater, considered to be clinically significant, was the recommended standard cutoff (Ewing, 1984). Subjects were asked if they had experienced any of six stressful events during the past 12 months: moved away from the family, lost their job, were rejected or disapproved of by the community, suffered a serious illness, lost a family member (death of husband/wife/common law spouse), or lost a relative (death of father/mother/family member when they were under the age of 12 years). A favourable answer (yes) was coded as 1 for each of these events (on scores between 0 and 7). The variable “Recent stress events” was dichotomized, meaning that they either experienced stress or not (score= 0). “Occasional smokers” represented persons who answered no to smoking cigarettes on a daily basis. Subjects were also asked: “How would you describe your relationship with other people in your community?” One of four answers could be chosen: “1 — very satisfactory, 2 — somewhat satisfactory, 3 — somewhat unsatisfactory, 4 — very unsatisfactory”. Subjects were considered to have a good relationship with the community if they answered “very satisfactory”. 2.5. Statistical analysis The statistical distribution of plasma fatty acid concentrations was checked and found to be skewed for some fatty acids. Therefore, we used log transformation
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to compare fatty acid concentrations between PD groups. Arithmetic means were also calculated for the fatty acid data to facilitate comparisons with other studies. Student's t test was performed to compare fatty acids between PD groups. Analysis of variance (ANOVA) with Bonferroni correction for multiple comparisons served to compare EPA + DHA plasma PL concentrations according to quintiles of PDISQS-14 scores. All analyses were stratified by gender. Since only 18 men presented highlevel PD, logistic regression analysis was conducted only among the women. In all subjects and women, the distribution of n−3 fatty acids was taken to compute cutoff points for tertiles of n−3. Associations between the tertiles of n−3 fatty acids and the risk of high-level PD were expressed as odds ratios (ORs), with the lowest tertile as the reference group. Trends across tertiles of n−3 were discerned by assigning the log-transformed median value for each tertile to all subjects in that group. Selection of covariables was based on simulation studies (Peduzzi et al., 1996; Steyerberg et al., 2001; Babyak, 2004). These studies suggest a minimum number of events per variable (minimally 10–15 events were needed per covariate). After that, all relevant covariates that remained significant at P b 0.50 in a multivariate model without the predictor of interest were included in the final multivariate model with
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the independent variable (here n−3). The covariates tested were: age, good relationship with the community, abused sexually, depression in lifetime, no recent stressful events, coastal region, total plasma cholesterol (b 5.2 mmol/l), physical activities in leisure time, body mass index (kg/m2), maternal language (non-native vs. native), education, occupation, alcoholism, smoking and marital status. The final models satisfied collinearity criteria. Statistical analyses were performed with the SAS program for Windows v.9 (SAS Institute, Inc., Cary, NC). Differences between groups and associations were considered significant at P b 0.05 (bilateral). 3. Results Table 2 reports the prevalence of PD according to study subject characteristics. Fig. 1 shows EPA + DHA plasma PL concentrations according to PDISQS-14 quintiles for men and women. Higher PDISQS-14 quintiles indicate higher PD scores, and the fifth quintile corresponds to the high-level PD category. In all participants, a lower EPA + DHA concentration (P for trend = 0.0028) was observed according to quintiles of PDISQS-14 scores, especially among those categorized as high-level PD. Stratification analysis revealed that
Table 2 Prevalence of psychological distress (PD) according to characteristics of the study subjects. Characteristics
PD prevalence (%)
Age Gender Total plasma cholesterol Abused sexually Coastal region Marital status a Education b Good relationship with community Maternal language Depression in lifetime c Recent stress events Occupational status d Drugs in lifetime e CAGE f score Smoking status BMI g
18–24 years (n = 84) 29.8, 25–44 years (n = 188) 18.6, ≥45 years (n = 94) 9.5 Female (n = 221) 23.1, Male (n = 145) 12.4 b5.2 mmol/l (n = 211) 23.2, ≥5.2 mmol/l (n = 155) 12.9 Yes (n = 102) 30.4, No (n = 248) 14.5 Hudson (n = 204) 23.5, Ungava (n = 164) 13.4 Single (n = 93) 25.8, Others (n = 254) 16.5 No education or on job training (n = 75) 12.0, Others (n = 270) 21.5 Yes (n = 138) 10.9, No (n = 221) 24.0 Non-native (n = 29) 10.3, Native (Inuktitut) (n = 339) 19.8 Yes (n = 13) 38.5, No (n = 353) 18.1 Yes (n = 114) 25.4, No (n = 229) 15.3 Remunerated employment (n = 199) 15.1, Others (n = 140) 21.4 Abstinent (n = 130) 15.4, Users (n = 176) 21.6, No response or refused to answer (n = 62) 19.4 b2 (n = 208) 16.4, ≥2 (n = 160) 22.5 Never (n = 32) 18.8, Ex-smokers (n = 61) 11.5, Occasionally (n = 23) 21.7, Regularly (n = 242) 20.7 b25 kg/m2 (n = 134) 22.4, 25–30 kg/m2 (n = 149) 16.8, ≥30 kg/m2 (n = 70) 12.9
The category “others” combines married/cohabiting, divorced/separated and widowed. The category “others” combines persons who reach (completed or not) the elementary or secondary school grade. c Self-reported by the principal respondent of the household who answered each chronic health problem listed in the questionnaire for every member of the household. d Remunerated employment group combines professionals, executives, white and blue collar workers. The category “others” combines trappers, houseworkers, students, unemployed, retired and independent workers. e The category “users” combines users and ex-users of marijuana, hashish, cocaine, substance sniffing (solvents, glue, gasoline) and other illicit drugs. To be considered “abstinent”, the subject must never have consumed any illicit drugs. f CAGE (Cutting down, Annoyance by criticism, Guilty feelings, and Eye-openers) alcoholism risk questionnaire. g The BMI (body mass index) is weight (kg) divided by the square of height (m2). Only 3 subjects (n = 2 for the non-distressed group) had BMI b 18.5. a
b
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linolenic acid (LNA), were significantly lower in the PD group compared with the non-distressed group. Stratification established that these differences were significant only among women. Table 4 presents the ORs for high-level PD according to plasma PL concentration tertiles of n−3, with the lowest tertile group as the reference group. In all subjects, EPA + DHA concentration was inversely related to the risk of high-level PD in analyses adjusted for age and gender (P for trend = 0.0403), and was of borderline significance by multivariate model analysis (P for trend = 0.0545). Compared with EPA + DHA concentrations in the lowest tertile (median = 4.2), the ORs for high-level PD were 0.60 (95% CI: 0.29–1.24) for the second tertile (median = 7.3), and 0.44 (95% CI: 0.18– 1.03) for the third tertile (median = 12.9), after controlling for confounders in the multivariate model. However, for women, EPA + DHA concentrations were inversely related to the risk of high-level PD in all analyses. Compared with women with EPA + DHA concentrations in the lowest tertile (median = 4.6), the ORs for high-level PD were 0.32 (95% CI: 0.13–0.82) for women with concentrations in the second tertile (median = 8.0) and 0.30 (95% CI: 0.10–0.90) for women in the third tertile (median = 13.1), after controlling for confounders in the multivariate model. 4. Discussion
Fig. 1. Mean concentrations of EPA + DHA in plasma PLs according to quintiles of PDISQS-14 scores in all subjects, men and women. Higher quintiles signify higher PD scores. The bars represent mean values with the SEM shown as a positive error bar. The black bar is the highlevel PD group, and the grey bars are the non-distressed groups. Values with different superscript letters are significantly different (P b 0.05).
trends in EPA + DHA concentrations across quintiles of PDISQS-14 scores were significant in women (P for trend = 0.0003) but not in men (P for trend = 0.3932). PUFA concentrations in plasma PLs are enumerated in Table 3. Mean concentrations of n−3 fatty acids, except
There is accumulating evidence of the beneficial effects of marine n−3 on mental health. In this crosssectional study of Nunavik Inuit, we found that women in the high-level PD group had lower marine n−3 concentrations in plasma PLs than women in the nondistressed group. However, we did not observe this difference among men. Our main finding was that women in the second and third tertiles of EPA + DHA concentrations in plasma PLs had a 3 times lower risk of having a high-level PD score than women in the lowest tertile. Neither EPA nor DHA was significantly associated in the multivariate model among women, indicating that the combination of these fatty acids may be a better independent variable to assess the health effects of marine n−3 consumption (Harris and Von Schacky, 2004). 4.1. Relationship between omega-3 and depressive mood in other cross-sectional and cohort studies Our results are in line with the studies of Tanskanen et al. and Timonen et al., who reported that fish consumption was significantly associated with depression among
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Table 3 Polyunsaturated fatty acid concentrations in plasma PLs. All PD Fatty acids (% of total)
Total n−6 b Linoleic (LA, 18:2 n−6) Arachidonic (AA, 20:4 n−6) Total n−3 c Linolenic (LNA, 18:3 n−3) Eicosapentaenoic (EPA, 20:5 n−3) Docosapentaenoic (DPA, 22:5 n−3) Docosahexaenoic (DHA, 22:6 n−3) ∑ EPA + DHA ∑ EPA + DPA + DHA Total n−3/total n−6 ratio EPA/AA ratio
Men a
Women
PD
Yes
No
(n = 70)
(n = 298)
28.3 ± 5.1 19.3 ± 4.8 5.9 ± 1.6 9.0 ± 5.2 0.2 ± 0.1 2.8 ± 3.0 1.2 ± 0.5 4.6 ± 2.3 7.4 ± 4.8 8.6 ± 5.2 0.4 ± 0.4 0.5 ± 0.7
27.9 ± 4.8 18.3 ± 4.3 6.3 ± 2.0 10.5 ± 4.8 0.2 ± 0.1 3.5 ± 2.9 1.4 ± 0.4 5.3 ± 1.9 8.8 ± 4.4 10.2 ± 4.8 0.4 ± 0.3 0.6 ± 0.6
P
0.67 0.27 0.11 0.002 0.64 0.01 0.007 0.007 0.002 0.002 0.01 0.05
PD
Yes
No
(n = 18)
(n = 127)
27.3 ± 6.7 17.6 ± 5.0 6.4 ± 2.6 10.2 ± 6.8 0.1 ± 0.1 3.7 ± 4.5 1.4 ± 0.6 4.8 ± 2.3 8.5 ± 6.3 9.8 ± 6.7 0.5 ± 0.6 0.8 ± 1.3
29.0 ± 4.4 18.9 ± 4.0 6.7 ± 2.3 9.5 ± 4.6 0.2 ± 0.1 3.1 ± 2.7 1.3 ± 0.4 4.7 ± 1.8 7.8 ± 4.2 9.1 ± 4.6 0.4 ± 0.2 0.5 ± 0.5
P
0.25 0.29 0.50 0.99 0.07 0.94 0.88 0.97 0.98 0.96 0.68 0.86
Yes
No
(n = 51)
(n = 170)
28.6 ± 4.5 19.9 ± 4.6 5.7 ± 1.1 8.5 ± 4.6 0.2 ± 0.1 2.5 ± 2.3 1.2 ± 0.5 4.5 ± 2.3 7.0 ± 4.2 8.2±4.6 0.3 ± 0.3 0.4 ± 0.3
27.1 ± 5.0 17.9 ± 4.5 6.1 ± 1.6 11.3 ± 4.8 0.2 ± 0.1 3.8 ± 3.1 1.4 ± 0.5 5.7 ± 1.8 9.5 ± 4.4 10.9 ± 4.8 0.5 ± 0.3 0.7 ± 0.6
P
0.05 0.02 0.14 b0.0001 0.10 0.001 0.0006 0.0004 b0.0001 b0.0001 0.0002 0.004
Plus–minus values are means ± S.D. P values were calculated for log-transformed fatty acids. a Participants were included as high-level PD if they scored over the 80th percentile on the PD Index Santé-Québec Survey (PDISQS-14). Nondistressed participants were those scoring less than this cutoff. b Sum of n−6 polyunsaturated fatty acids (18:2 + 18:3 + 20:2 + 20:3 + 20:4 + 22:2 + 22:4 + 22:5). c Sum of n−3 polyunsaturated fatty acids (18:3 + 18:4 + 20:3 + 20:4 + 20:5 + 22:5 + 22:6).
women only (Tanskanen et al., 2001b; Timonen et al., 2004). In a random sample of the Finnish population participating in a health survey (n = 3204), Tanskanen et al. discerned a higher risk (OR: 1.31, 95% CI: 1.10–1.56) of having mild depressive symptoms (score ≥ 10 on the 21-item Beck Depression Inventory) among infrequent fish consumers (less than once a week) (Tanskanen et al., 2001b). When men and women were analyzed separately, depressive symptoms were only significantly associated with infrequent fish consumption in women (OR: 1.40, 95% CI: 1.11–1.78), not in men (Tanskanen et al., 2001b). Timonen et al. found a 2.6-fold higher risk of being depressed (Hopkins Symptom Checklist-25 depression subscale score N 2.01 and doctor-diagnosed, auto-reported lifetime depression) among women who rarely ate fish (monthly or more seldom) compared with regular eaters (Timonen et al., 2004). However, this association was not significant among males. In a sample drawn from the general Finnish population (n = 1767), Tanskanen et al. noted a decreased risk of being depressed in frequent lakefish consumers compared with infrequent consumers (Tanskanen et al., 2001a). A longitudinal study among 29,133 Finnish men failed to find an association between marine n−3 and self-reported depressed mood or hospital treatment for major depression (Hakkarainen et al., 2004). However, it had several limitations that could explain these negative findings (Sontrop and Campbell, 2006). In 771 patients with newly diagnosed lung cancer, Suzuki et al. reported no association between EPA + DHA intake
and the Depression Subscale of the Hospital Anxiety and Depression Scale (cutoff ≥ 5) (Suzuki et al., 2004). However, they observed a 2 times lower risk (P b 0.05) in the fourth quartile of LNA intake compared with the first quartile. In our analyses, we did not see a relationship between LNA and PDISQS-14 scores. 4.2. Omega-3 effects on the nervous system It has been shown that n−3 deficiency is associated with increased violent behaviour, more anxiety, and reduced attention and motivation (Haag, 2003). A decrease in n−3 fatty acids in neuronal cell membranes may affect membrane fluidity, signal transduction processes, ion channel modulation, and gene expression, possibly leading to changes in the synthesis of neurotransmitters involved in depression (Bruinsma and Taren, 2000; Locke and Stoll, 2001; Horrobin, 2002; Haag, 2003). Animal studies have indicated that n−3 deficiency alters serotonin neurotransmission (Delion et al., 1994, 1996, 1997; de la Presa Owens and Innis, 1999; Kodas et al., 2004). In humans, higher plasma n−3 has been demonstrated to predict concentrations of serotonin and dopamine metabolites in cerebrospinal fluid (Hibbeln et al., 1998a,b). Dysfunction of the serotonergic system is a considerable risk factor for suicidality (Mann, 2003). Two studies indicate that low n−3 blood levels, mainly of DHA, are associated with higher suicide attempt risk (Huan et al., 2004; Sublette et al., 2006). In a cross-
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Table 4 Odds ratios (ORs) for high-level PD according to tertiles of n−3 fatty acids in plasma PLs of Nunavik Inuit. Fatty acid tertiles
PD a
Median (range)
Yes
Odds ratio (95% confidence interval) No
Crude
Model 1 b
Model 2 c
Model 3 d
29 24 17
93 99 106
1.00 0.78 (0.42–1.43) 0.51 (0.27–1.00) 0.0488
1.00 0.81 (0.43–1.53) 0.69 (0.34–1.42) 0.3059
1.00 0.84 (0.44–1.61) 0.77 (0.37–1.61) 0.4801
1.00 0.72 (0.35–1.50) 0.60 (0.27–1.34) 0.2033
34 21 15
88 102 108
1.00 0.53 (0.29–0.99) 0.36 (0.18–0.70) 0.0020
1.00 0.54 (0.28–1.04) 0.43 (0.20–0.92) 0.0226
1.00 0.55 (0.28–1.07) 0.49 (0.23–1.07) 0.0523
1.00 0.52 (0.25–1.09) 0.45 (0.19–1.06) 0.0505
32 24 14
90 99 109
1.00 0.68 (0.37–1.24) 0.36 (0.18–0.72) 0.0035
1.00 0.70 (0.37–1.33) 0.45 (0.21–0.97) 0.0403
1.00 0.72 (0.38–1.39) 0.51 (0.23–1.12) 0.0910
1.00 0.60 (0.29–1.24) 0.44 (0.18–1.03) 0.0545
33 23 14
92 99 107
1.00 0.65 (0.35–1.18) 0.37 (0.18–0.72) 0.0035
1.00 0.64 (0.34–1.21) 0.44 (0.21–0.95) 0.0333
1.00 0.65 (0.34–1.25) 0.51 (0.23–1.12) 0.0826
1.00 0.59 (0.29–1.21) 0.47 (0.20–1.11) 0.0766
23 18 10
50 56 64
1.00 0.70 (0.34–1.44) 0.34 (0.15–0.78) 0.0118
1.00 0.90 (0.43–1.91) 0.56 (0.23–1.38) 0.2435
1.00 0.90 (0.41–1.94) 0.58 (0.23–1.45) 0.2832
1.00 0.72 (0.29–1.79) 0.41 (0.14–1.18) 0.1048
28 15 8
45 59 66
1.00 0.41 (0.20–0.85) 0.20 (0.08–0.47) 0.0001
1.00 0.53 (0.24–1.18) 0.31 (0.12–0.84) 0.0173
1.00 0.53 (0.24–1.19) 0.32 (0.12–0.88) 0.0217
1.00 0.50 (0.20–1.27) 0.38 (0.12–1.20) 0.0828
29 13 9
44 61 65
1.00 0.32 (0.15–0.69) 0.21(0.09–0.49) 0.0001
1.00 0.40(0.18–0.88) 0.34(0.13–0.86) 0.0113
1.00 0.41 (0.19–0.92) 0.35 (0.13–0.92) 0.0157
1.00 0.32(0.13–0.82) 0.30 (0.10–0.90) 0.0166
28 15 8
45 59 66
1.00 0.41 (0.20–0.85) 0.20 (0.08–0.47) 0.0001
1.00 0.51 (0.24–1.11) 0.31 (0.12–0.81) 0.0118
1.00 0.50 (0.23–1.08) 0.31 (0.12–0.84) 0.0147
1.00 0.48 (0.19–1.18) 0.32 (0.11–0.97) 0.0331
e
n All (n = 368) EPA T1: 0.9 (0.1–1.3) T2: 2.3 (1.4–3.8) T3: 5.8 (3.9–19.9) P for trend DHA T1: 3.1 (0.5–3.9) T2: 4.8 (4.0–5.9) T3: 7.4 (6.0–11.9) P for trend EPA + DHA T1: 4.2 (1.4–5.4) T2: 7.3 (5.5–9.9) T3: 12.9 (10.1–27.6) P for trend Total n−3 T1: 5.6 (2.2–6.9) T2: 9.0 (7.0–11.9) T3: 15.4 (12.0–30.4) P for trend Women only (n = 221) EPA T1: 0.87 (0.12–1.53) T2: 2.7 (1.6–4.1) T3: 6.9 (4.2–17.3) P for trend DHA T1: 3.5 (0.6–4.3) T2: 5.3 (4.3–6.2) T3: 7.3 (6.30–11.9) P for trend EPA + DHA T1: 4.6 (1.4–5.9) T2: 8.0 (6.0–10.8) T3: 13.1 (10.8–26.5) P for trend Total n−3 T1: 6.0 (2.2–7.5) T2: 9.8 (7.5–12.6) T3: 15.3 (12.7–29.3) P for trend
a Participants were included as high-level PD if they scored over the 80th percentile on the PD Index Santé-Québec Survey (PDISQS-14). Nondistressed participants were those scoring less than this cutoff. b Multivariate model 1 controlled for age and gender. For women, model 1 included only age. c Multivariate model 2 included the variables in multivariate model 1 and good relationship with the community. d Multivariate model 3 included the variables in multivariate model 2 and CAGE score ≥ 2, depression in lifetime, no recent stress events, coastal region and abused sexually.
sectional analysis of baseline data in a non-psychiatric and healthy (although hypercholesterolemic) community sample of adults (n = 105), serum EPA and DHA were
inversely associated with neuroticism, depressive symptomatology and cognitive impulsivity, after multivariate adjustment (Conklin et al., 2007). A recent meta-analysis
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of double-blind, placebo-controlled studies suggested that omega-3 significantly improved symptoms in patients with clearly defined depression (Lin and Su, 2007). However, no major clinical trial has been published (Appleton et al., 2006), and the most significant trials (Nemets et al., 2002; Peet and Horrobin, 2002) tested omega-3 supplementation as an adjunct to anti-depressant therapy. Moreover, two recent meta-analyses on omega-3 and depression noted significant heterogeneity and publication bias (Appleton et al., 2006; Lin and Su, 2007). 4.3. Strengths and limitations Our results must be interpreted in the context of limitations and strengths of any cross-sectional study, and therefore, cannot ascertain any causal relationship. Since we excluded 183 persons who did not have information on PD, our results are probably not representative of the Nunavik Inuit population. This might have introduced an external validity bias. However, several strengths of our study deserve attention. The Santé-Québec Health Survey followed a standard protocol with face-to-face interviews, clinic sessions and multiple validated instruments administered by well-trained interviewers (Santé-Québec, 1994, 1995; Santé-Québec et al., 1994). The use of fatty acid composition in tissues (adipose tissue, erythrocytes, serum and plasma) as a biological marker of fatty acid intake has some advantages. A single measurement of marine n−3 in blood reflects the ranking of usual marine n−3 intakes (Hjartaker et al., 1997; Kobayashi et al., 2001, 2003; Kuriki et al., 2002, 2003). Such biomarkers of fatty acid intake provide quantitative measurements independently of memory and/or knowledge of the subjects. They are less likely to be due to social desirability bias than dietary self-reporting (Hebert et al., 1997). The risk of failing to correctly control for all cofactors associated with frequent fish consumption is highly probable in observational studies, especially with respect to cofactors associated with socio-economic status. Fish consumption is more frequent among people with higher socio-economic status (occupation, education and income) (Galobardes et al., 2001; Barberger-Gateau et al., 2005). More than half (51.7%) of our respondents did not answer the question on income (38% answered “Don't know”, and 13.7% refused to answer) which makes it impossible to analyze the data according to income. Therefore, we cannot rule out that failure to control for income may have biased our results. However, education and occupation were tested as cofactors and did not significantly influence the relationship between EPA + DHA and PD. Because fish and mammals came mainly from fishing or hunting but could also have
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been obtained for free in the cooperative store in Nunavik (Kishigami, 2000; Duhaime et al., 2002), the risk of bias due to uncontrolled socio-economic status was unlikely in this population. We cannot rule out the possibility that higher PD (especially if it was characterized by depression) influenced marine n−3 intake. In a populations such as the Inuit of Nunavik, where marine products play a major role in their cultural identity (Blanchet et al., 2000, 2002), analysis of plasma EPA + DHA is not only a measure of traditional food consumption but also a yardstick of adherence to traditional behaviours. It is, therefore, difficult to separate the biological effect of social behaviour adherence to Inuit culture when EPA + DHA concentrations are measured. Modification of the traditional diet of Nunavik Inuit has been linked with market food integration, especially among the younger generation for whom market foods appear to be more attractive (Dewailly et al., 2001; Blanchet et al., 2002). The Santé-Québec Health Survey indicated that younger Inuit (15–24 years) suffered 3 times as much PD as older Inuit (more than 45 years) (Santé-Québec, 1994). The suicide rate among Inuit in 1987–1994 was 6.5 times higher than in the rest of Québec, and the rate in the younger age group (15– 24 years) was 20 times higher (Boothroyd et al., 2000). The nature of communities and how they deal with ongoing stressors (loss of cultural practices, loss of traditional food resources and habitats, sedentary living, economic disparity, environmental change, etc.) have been mentioned as factors that explain different rates of suicide and other stressors among aboriginal communities (Berry, 1997; Kirmayer et al., 2000a). 4.4. PD questionnaire A weakness of this study is that the PDISQS-14 cannot be used to establish specific psychiatric disorders. However, the present analysis did not aim to assess the prevalence of specific psychiatric disorders but rather to identify if marine n−3 could be associated with the global index of PD. This measure of distress probably cannot be adapted culturally to the Inuit and, moreover, its sensitivity to the range of expression of distress across gender and age is unknown for this population. The PDISQS-14 serves to define mental health over a continuum by means of quantitative variations recorded in the symptoms often experienced by individuals suffering from anxiety or depression (Santé-Québec, 1994). Analyses relating to the validity of PDISQS-14 criteria showed that this PD index was correlated with overall individual health, with the consumption of psychotropic substances and the presence of suicidal ideation and gestures (Preville et al., 1995).
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Using epidemiological data where 15 to 20% of the general population presented high-level PD, an arbitrary threshold defining high PD symptomatology has been adopted in Santé-Québec surveys to categorize high-level PD, the 80th percentile of PDISQS-14 distribution (Ilfeld, 1978; Boyer et al., 1993; Santé-Québec, 1994). This threshold may not reflect the Inuit reality since the prevalence of mental disorders has never been accurately estimated in that population. However, establishing a cutoff based on score distribution appears to be an interesting way to compare the risk of being in a category with much more symptoms. Analyses of PDISQS-14 reliability and validity indicated that it could be used among the Inuit with a view to identifying sub-groups experiencing more PD (Santé-Québec, 1994). However, the 80th percentile cutoff set for high-level PD could have led to non-differential misclassification and, therefore, biased ORs to the null hypothesis. It is possible that the outcomes noted in the PDISQS14 were due not only to omega-3 effects on depression, but also on anxiety and hostility items. However, the literature on the relationship between omega-3 and anxiety and hostility is less abundant than for depression. Indeed, some studies show the benefits of omega-3 in anxiety disorders (Buydens-Branchey and Branchey, 2006; Green et al., 2006) but others do not (Fux et al., 2004; Raeder et al., 2007). According to Hibbeln et al., it is reasonable to expect that DHA and EPA might reduce aggression and/or hostility (Hibbeln et al., 2006). However, no clinical trial has directly addressed this issue. 4.5. Gender difference in the relationship between marine n−3 and PD The gender difference in relation to marine n−3 and PD is intriguing. Since only 18 men were classified in the high-level PD group, we were unable to perform logistic regression analysis among males. However, the trend in EPA + DHA concentration according to quintiles of PDISQS-14 scores was not significant in men, only in women (Fig. 1). It is known that depression is much more common among women than men, with a female/male ratio between 1 1/2 to 3 (Kessler et al., 1993; Weissman et al., 1993). Many reasons have been given for the higher rate of major depression in women, but none seems to fully explain it (Nolen-Hoeksema et al., 1999; Cahill, 2005; Altemus, 2006; Nes et al., 2007; Pohl et al., 2007). Women seem to be more sensitive to the depressogenic effects of stressful situations involving interpersonal concerns (Taylor et al., 2000; Kendler et al., 2001). Gender differences in activation of the hypothalamic–pituitary– adrenal (HPA) axis in response to stressful stimuli may be
another mechanism underlying sex differences in depression (Kudielka and Kirschbaum, 2005; Uhart et al., 2006). Nolen-Hoeksema et al. suggested that women are more vulnerable to chronic negative circumstances (e.g. sexual and physical abuse, poverty) and, therefore, they are more likely to manifest dysregulated HPA responses to stressors (Nolen-Hoeksema et al., 1999). Moreover, ovarian hormones could affect brain systems, such as the HPA axis, that are involved in depression and anxiety (McEwen and Alves, 1999; Young et al., 2000; Becker et al., 2005; Altemus, 2006). Some authors have also suggested the existence of a subpopulation of women with particular vulnerability to mood disturbances during periods of intense hormonal fluctuations (such as premenstrual periods, puerperium or menopausal transition) (Studd, 1992; Arpels, 1996). Young et al. proposed that women are more willing than men to admit their depression (Young et al., 1990). However, Kessler suggested that men are as likely to be depressed as women, but they are more likely to manifest it with irritability than dysphoria or anhedonia (Kessler, 2003). Due to different effects of omega-3 on the nervous system, higher omega3 status might permit better mood adaptation (lower depression, anxiety and hostility symptoms) among more vulnerable women and/or during hormonal fluctuations. Gender and hormonal factors have been proposed as determinants of DHA synthesis (Burdge and Calder, 2005). Estrogen seems to play a role in upregulating the conversion pathway of LNA to DHA (Giltay et al., 2004). This is unlikely among Inuit women because their high intakes of marine n−3 (24-h dietary recall established EPA + DHA intake to be 2031 mg/day) should downregulate enzymes implicated in this pathway (Lefkowitz et al., 2005). Indeed, Pawlosky et al. observed that gender had a stronger effect when humans were on a beef-based diet, whereas it had a lesser effect when they were on a fish-based diet (Pawlosky et al., 2003). Women in the high-level PD group were those who had the lowest EPA + DHA concentrations. This observation is also intriguing since it is not explained by differences in age, smoking status and alcohol consumption. However, the lower EPA + DHA concentrations in women with highlevel PD might be explained by lower dietary EPA + DHA intake and/or by perinatal depletion. Since the fetus is unable to synthesize sufficient DHA for the development of its nervous system, it thus depends on the mother for DHA (Crawford, 2000). Therefore, women can become depleted of DHA during pregnancy and lactation if their dietary intakes are insufficient (Al et al., 1995, 1996; Van Houwelingen et al., 1999; Hornstra, 2000). This relative depletion may increase women's risk of developing depressive symptoms or of having disturbing moods.
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