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Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression
ARTICLE IN PRESS
Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 211–218 www.elsevier.com/locate/plefa
Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression$ Karen M. Silversa,, Cheryl C. Woolleyb, Frances C. Hamiltonb, Peter M. Wattsb, Rosemary A. Watsona a
New Zealand Institute for Crop & Food Research, Private Bag 4704, Christchurch, New Zealand b School of Psychology, Massey University, Private Bag 11222, Palmerston North, New Zealand Received 23 July 2004; accepted 21 November 2004
Abstract Converging evidence suggests that o-3 polyunsaturated fatty acids have aetiological importance in depression. To determine the effect of adding fish oil to existing therapy in participants who were being treated for depression in a community setting, 77 participants were randomly assigned to receive 8 g of either fish or olive oil per day in addition to their existing therapy. Fifty-nine (77%) participants completed 12 weeks of treatment. Dietary, biochemical and lifestyle factors were measured throughout the study. Mood was assessed using the Short Form Hamilton Depression Rating Scale (HDRS-SF) and the Beck Depression Inventory II. Sample size calculations were based on the HDRS-SF. Intention-to-treat and per protocol analyses were carried out using residual maximum likelihood. There was no evidence that fish oil improved mood when compared to the placebo oil, despite an increase in circulating o-3 polyunsaturated fatty acids. However, mood improved significantly in both groups within the first 2 weeks of the study (Po0:001) and this improvement was sustained throughout. In conclusion, fish oil was no more effective than the control as an add-on therapy for depression in this setting. r 2004 Elsevier Ltd. All rights reserved.
1. Introduction Depression is a common mental disorder currently causing a high level of disease burden and this is expected to increase over the next 20 years [1]. Epidemiological data suggest that the lifetime prevalence of mental and behavioural disorders is 25%, most of which is accounted for by depression [1]. Estimates in the UK suggest that 60–70% of adults will experience either depression or worry of sufficient severity to adversely affect their daily activities [2]. Despite the development of new antidepressant medications with improved side-effect profiles, it is estimated that 20–30% $
This research was funded by the Foundation for Research, Science and Technology, New Zealand. Corresponding author. New Zealand Institute for Crop & Food Research, Private Bag 4704, Christchurch, New Zealand. Tel.: +64 3 325 6400; fax: +64 3 325 2074. E-mail address: [email protected] (K.M. Silvers). 0952-3278/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2004.11.004
of those with major depressive disorder treated with antidepressant medication continue to experience residual depressive symptoms. In addition, some 50% of those who have an episode of major depressive disorder will eventually have another [3]. As the social and economic costs of depression continue to rise, alternatives to antidepressant medication with fewer side effects need to be found. The o-3 polyunsaturated fatty acids (o-3 PUFAs) found in fish oil have been hypothesised to provide an alternative. Fish and other seafood are the best dietary sources of EPA and DHA, and humans are thought to have evolved consuming diets rich in these. However, during the last century, intakes of EPA and DHA have dropped significantly, and the intake of o-6 PUFAs has increased [4]. These changes in diet are thought to have contributed to the significant increase in chronic disease and inflammatory disorders in the 20th century [5,6].
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There is evidence that people with depression have significantly lower o-3 PUFA levels in both red cell membranes [7,8] and serum cholesteryl esters [9] when compared to controls. Red cell membrane o-3 PUFA levels are also correlated with the severity of depression [10]. Consistent with this are findings showing that consuming a diet higher in seafood is associated with better mood [11] and lower rates of depression [12]. The evidence that o-3 PUFAs influence signal transduction and neurotransmission [13] and that diets low in o-3 PUFAs increase the risk of depression has led to the hypothesis that o-3 PUFAs may improve or stabilise mood in those suffering from depression. The few published reports on the use of o-3 PUFAs as a treatment for depression have involved small sample sizes and findings have been somewhat contradictory. In a 6 week trial, Marangell and coworkers [14] found that 2 g DHA per day had no effect on mood in a small number of unmedicated patients with major depression. However, both 10 g of an o-3 concentrate per day containing 4.4 g EPA and 2.2 g DHA [15], and 1–2 g pure ethyl-EPA per day [16,17] were found to improve mood in studies involving medicated patients. Two published case studies also showed that treatment with pure ethyl-EPA led to remission of patients with treatment resistant depression [18,19]. The aim of this study was to determine the effect of adding fish oil (containing both DHA and EPA) to existing therapy in community-based patients being treated for a current depressive episode. Participants met the criteria for depression based on the Short Form Hamilton Depression Rating Scale (HDRS-SF).
2. Patients and methods 2.1. Participants Participants being treated for a current depressive episode and no co-existing psychiatric disorder (except anxiety disorders) were recruited to the study if they were between 18 and 65 years old, and if female, were premenopausal with a normal menstrual cycle. Exclusion criteria included blood clotting disorders, use of anticoagulant therapy, unstable medical conditions, or conditions likely to affect gastrointestinal absorption, allergies to seafood, objections to taking fish or olive oilbased products, and those already taking fish oil. Participants were also required to have been on their current medication at a constant dose for at least 2 months, to have no objections to providing blood samples, and to be available for the length of the study. They were recruited through a Community Mental Health Service, general practices and advertisements in community newspapers in the Wellington region of New
Zealand over a 14 month period between July 2000 and September 2001. Eligible participants were sent an information sheet and consent form. Most potential participants were identified through community advertising because in New Zealand, patients diagnosed with depression are not generally seen by psychiatric clinicians unless they have co-existing psychiatric disorders. This study was approved by the Massey University Human Ethics Committee, and the Manawatu–Whanganui and Wellington Human Ethics Committees. All participants gave written informed consent and permission for researchers to request diagnosis, treatment and general health information from their general practitioner and mental health key worker. This information was used to confirm diagnosis, history and treatment information. Participants were not independently assessed. 2.2. Treatment Participants were randomly assigned to receive either 8 g of DHA enriched tuna fish oil per day or an equivalent dose of olive oil in 1 g soft gelatin capsules, according to a prearranged computer generated code. The olive oil and fish oil capsules looked identical and were supplied by Clover Corporation PLC, Australia. The fatty acid composition of the oils used is shown in Table 1. The fish oil treatment provided 3 g of o-3 PUFAs (0.6 g EPA, 2.4 g DHA, 80 mg vitamin E) per day. Fish taste and smell were minimal. Participants were advised to take four capsules in the morning and four in the evening with meals. To assist with blinding, participants were told only that both oils were natural and were associated with a range of health benefits, and that an aftertaste might be experienced. The allocation sequence was generated by a biostatistician, who was not directly involved in the study. Two research psychologists enrolled the participants, Table 1 Fatty acid composition of oils Fatty acid (% of total)
Myristic acid (14:0) Palmitic acid (16:0) Palmitoleic acid (16:1 o-7) Stearic acid (18:0) Oleic acid (18:1 o-9) Linoleic acid (18:2 o-6) a-linolenic acid (18:3 o-3) Arachidonic acid (20:4 o-6) EPA (20:5 o-3) Docosapentanoic acid (22:5 o-3) DHA (22:6 o-3)
Olive oil
Fish oil
0 12.09 1.21 2.67 63.39 13.54 0.84 0 0 0 0
2.72 16.6 3.40 4.76 13.7 1.30 0.65 1.96 6.89 1.23 27.30
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administered the interventions and collected the data. They were trained in telephone and interview techniques to minimise any experimenter effect. Participants were sequentially assigned using numbered containers 1–50 for males and 51–100 for females. The allocation sequence was concealed from both participants and the research psychologists until all data had been collected and entered into the database. 2.3. Study design The design was a 12 week, repeated measures, doubleblind addition of fish oil or a placebo to ongoing antidepressant therapy. Demographic information, information about participants’ depression and current therapies, dietary intake of o-3 and o-6 PUFAs, physical activity and health beliefs were collected at baseline. Dietary intake of o-3 and o-6 PUFAs was assessed using a food frequency questionnaire (FFQ), and information about health beliefs was collected using a Health Beliefs Questionnaire (HBQ). Mood was assessed at baseline and then at 2, 4, 8 and 12 weeks using a self-administered HDRS-SF and Beck Depression Inventory (BDI II). The HDRS-SF consists of nine items from the full scale version of the Hamilton Depression Inventory. These items show the highest sensitivity in differentiating respondents with major depression from those with other psychiatric disorders and non-psychiatric controls [20]. Changes to existing therapy, including dose or type of medication and adverse events were recorded throughout the study. Changes in diet, physical activity and health beliefs during the study were assessed using a modified FFQ and HBQ at 12 weeks. An exit interview was carried out at the end of the intervention. During the interview, participants were asked to rate their compliance with the protocol, give their reasons for noncompliance, and guess which treatment group they had been in. Interviews and questionnaires were administered at Massey University Psychology Clinics in Palmerston North and Wellington. However, some exit interviews with patients who had dropped out of the study were carried out by telephone.
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packed erythrocytes were isolated by ultracentrifugation (Sorvall OTD Combi Ultracentrifuge, AH629 rotor, 4 1C, 27,000 rpm, 90 min) following haemolysis with 10 mM Tris buffer pH 7.4 at room temperature. All blood fractions were stored at 85 1C prior to further analysis. Samples were labelled according to their identification number, analysed blind and randomly allocated to batches for further handling, with all samples from individual patients being processed in the same experimental batch. Triacylglycerols, total and HDL cholesterol, and trace elements hypothesised to be relevant to mood (iron, magnesium, selenium) were determined on an Aeroset analyser using the manufacturer’s reagents and procedures (Abbott Laboratories, Auckland, New Zealand). Plasma selenium was measured by carbon furnace atomic absorption spectroscopy on a Varian AA40 with Zeeman background correction with palladium modifier (Varian, Melbourne, Australia). Membrane lipids were extracted by modification of a standard procedure [21]. Fatty acid methyl esters (FAMEs) were derived from fatty acids of membrane lipids using boron trifluoride (BF3) by a modification of the Morrison and Smith [22] method. Cholesterol and other non-FAMEs species were removed by silicic acid column chromatography fractionation using chloroform as an eluent by a method adapted from Body and Shorland [23]. TLC verified the contents of the fractions. Purified FAMEs were separated by temperature-programmed capillary gas–liquid chromatography, and identified using a standard (GLC-463, Nu-Chek) with additions. Results were expressed as a percentage of the total area of peaks eluting in the separation range from 14:0 to 22:6 (o-3) inclusive. An in-house pig erythrocyte membrane control and reagent blanks were used to monitor inter-batch variation in both sample preparation and GC analysis. 2.5. Sample size Mood as determined by scores on the HDRS-SF was the primary outcome variable and sample size calculations were based on this. The BDI II was the secondary outcome variable. 2.6. Statistical methods
2.4. Blood analyses Blood samples were collected at 0, 2 and 12 weeks into VacutainersTM (Hemogards 15% K3 EDTA), and transported to the laboratory on ice. Initial processing was carried out within 6 h of collection. Plasma and erythrocytes were separated by centrifugation (Sorvall RC5B Plus centrifuge with SLA-1500 rotor, 4 1C, 7000 rpm, 10 min), and the erythrocytes washed three times in 0.9% w/v aqueous NaCl. Membranes from 1 ml
Two populations were used. The intention-to-treat (ITT) population included all participants who were randomised, while the per-protocol (PP) population included all participants who completed 12 weeks of treatment and met the a priori criteria for inclusion in the trial, using diagnosis and general health information provided by the participant’s general practitioner. Residual maximum likelihood (REML) was used to analyse the data [24] with the correlation between
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observations on the same participant described with an ante-dependence model [25]. To limit the number of significance tests, covariate by treatment interactions were only tested for significance if the covariate was related to the change in mood as determined by scores on the HDRS-SF. Similarly, only covariates that were related to the HDRS-SF scores were tested for a relationship with the BDI-II scores.
Assessed for eligibility (n=499) Excluded (n=422) Did not meet inclusion criteria (n=369) Refused (n=25) Other reasons (n=28) Randomised (n=77)
Allocated to olive oil (n=37) Received allocated intervention (n=35) Did not receive allocated intervention; dropped out before baseline data collected (n=2)
Allocated to fish oil (n=40) Received allocated intervention (n=38) Did not receive allocated intervention; dropped out before baseline data collected (n=2)
Discontinued intervention (n=5) GI disturbance (n=1), other (n=2), multiple (n=2)
Discontinued intervention (n=9) GI disturbance (n=2), capsule problems (n=2), other (n=2), multiple (n=3)
ITT analysis (n=37)
ITT analysis (n=40)
PP analysis (n=21) Excluded from analysis; dropped out before baseline (n=2), discontinued intervention (n=5), head trauma (n=1), personality disorder (n=3), Bipolar disorder (n=1), HDI-SF<6 at week 0 (n=4)
PP analysis (n=24) Excluded from analysis; dropped out before baseline (n=2), discontinued intervention (n=9); head trauma (n=1), physical disorder (n=1), HDI-SF<6 at week 0 (n=2)
Fig. 1. Flow diagram of the progress through the phases of the randomised double-blind placebo-controlled trial of fish oil in the treatment of depression.
3. Results 3.1. Participant flow The flow of research participants is shown in Fig. 1. Forty participants were randomly assigned to receive fish oil and 37 to receive the placebo. Four participants, two from each group, dropped out before the baseline data was collected. Fifty-nine participants completed 12 weeks of treatment. Nine (24%) of 38 in the fish oil group and five (14%) of the 35 placebo recipients dropped out for reasons stated in Fig. 1. Baseline demographic and clinical characteristics can be found in Table 2. There was no evidence of an association between baseline mood scores and dietary, biochemical or lifestyle factors. Twenty-four fish oil and 21 placebo recipients were included in the PP analysis.
3.2. Outcomes There was no evidence that fish oil improved mood in either ITT or PP analyses. Post-hoc power calculations indicate 95% power for detecting a 10–15% difference in HDRS-SF or BDI-II scores in both ITT and PP analyses. However, there was a significant improvement in the mood of both groups within the first 2 weeks of entering the study (Po0:001 for HDRS-SF and BDI-II scores). This improvement was sustained throughout (Table 3) and analysis of covariance indicated that it was proportional to baseline mood. Age, reason for taking part in the research, initial hopefulness about the supplement, alcohol intake, level of physical activity and type of medication were tested Table 2 Baseline demographic and clinical characteristics Treatment groups
Female Mean (sd) age (yr)a Mean mood scoresa HDRS-SF BDI II Background treatmenta Antidepressant medication Psychotherapy Dietary intakea Fish intake (p2 servings per wk) Mean (sd) total o-3 PUFA index Physical activity (p2.5 h in last 7 d)a Dropped out
Placebo (n ¼ 37)
Fish oil (n ¼ 40)
19 37.7 (13.6)
22 39.8 (11.9)
12.4 (5.4) 23.3 (12.3)
11.5 (5.3) 21.9 (10.6)
30 14
31 7
24 1.5 (1.3) 13 7
22 1.8 (1.3) 9 11
Data are given as number of participants, except where otherwise indicated. a Data missing for four participants that withdrew before baseline data collection.
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Table 3 Change in mood scores between consecutive measurements Group
Week
HDRS-SF (ITT)
HDRS-SF (PP)
BDI II (ITT)
BDI II (PP)
Placebo
0 2 4 8 12
12.4 3.9 0.9 0.7 0.6
(0.9) (0.9)*** (0.7) (0.5) (0.6)
13.2 5.6 0.3 1 0.3
(0.8) (0.8)*** (0.7) (0.6) (0.6)
23.3 7.4 2.1 0.8 1.5
(3.5) (1.4)*** (1.4) (1.4) (1.5)
24.8 10.57 0.1 2.6 0.8
(3.1) (2.0)*** (1.4) (1.3) (0.7)
Fish oil
0 2 4 8 12
11.5 3.6 0.4 1.1 0.3
(0.9) (0.7)*** (0.7) (0.8) (0.8)
12.3 4.3 0.4 1 0.4
(0.9) (0.8)*** (0.8) (1.0) (0.9)
21.9 7.9 0.8 2.4 0.3
(3.3) (1.4)*** (1.4) (1.5) (1.5)
22.8 9.8 1.2 1.6 0.9
(3.0) (1.9)*** (1.7) (2.1) (1.7)
Data given as change from baseline in mean (SE) mood scores ( Po0:001).
as covariates, but there was no evidence that these were related to the change in mood. There was also no evidence that the treatment affected drop-out rates (P ¼ 0:442). Mean levels of EPA and DHA measured in red cell membrane phospholipids throughout the study, are shown in Figs. 2 and 3, respectively. Levels of EPA (Po0:001) and DHA (Po0:001) were significantly increased in the fish oil group at both 2 and 12 weeks of treatment. 3.3. Blinding There was no evidence that participants were able to guess what group they were in (P ¼ 0:804). Even when a fish taste was experienced, participants did not necessarily assume they were in the group receiving fish oil. 3.4. Self-reported compliance
Fig. 2. Mean (SEM) change in % of total EPA in erythrocyte membranes in fish oil (’) and placebo (&) supplemented groups (‘***’ indicates that the difference between groups is significant at the 0.001% level).
Reasons for non-compliance with the treatment regime are summarised in Table 4. Twenty-two (63%) of 35 in the fish oil group and 20 (63%) of 32 in the placebo group who completed the exit interview, stated that they had not taken every dose as directed. There was no evidence that non-compliance was related to the treatment given (P ¼ 0:976). Most instances of noncompliance related to forgetting to take the capsules. Other reasons included gastrointestinal disturbance, inconvenience and the size of capsules. 3.5. Adverse events Adverse events for all participants who received the allocated intervention are summarised in Table 5. The events were evenly distributed across the groups. One serious adverse event was reported in the placebo group. A participant was hospitalised following a pharmaceutical drug overdose in the tenth week of the study, but the incident was not considered to be related to the
Fig. 3. Mean (SEM) change in % of total DHA in erythrocyte membranes in fish oil (’) and placebo (&) supplemented groups (‘***’ indicate that the difference between groups is significant at the 0.001% level).
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Table 4 Reasons given for non-compliance with treatment regime
improved hair and skin condition, increased energy levels and a reduction in chronic pain symptoms.
Treatment groups
Took every dose as requested Did not take every dose as requested Missing data Total number of reasons for noncompliance Not taken capsules as requested Capsules hard to swallow GI disturbance Capsules did not seem to make any difference to depression Stopped taking capsules as depression improved Other
Placebo
Fish oil
12 20 5 37
13 22 5 34
17 5 5 2
16 4 6 2
0
2
8
4
Data are given as number of patients, except where otherwise indicated. Table 5 Adverse events Treatment groups
No adverse events Participants with an event Missing dataa Total number of events Musculo-skeletal system Central nervous system Psychiatric event GI disturbance Reflux Resistance (infections) Skin General malaise/felt unwell Other
Placebo
Fish oil
21 14 2 16 0 1 2 7 1 2 1 1 1
24 14 2 20 1 4 0 8 3 0 1 1 2
Data are given as number of participants, except where otherwise indicated. a Data missing for participants that withdrew before baseline data collection.
individual’s participation in the trial. Gastrointestinal disturbance and/or reflux were the most commonly experienced events, but there was no evidence that either was related to the type of oil taken (P ¼ 0:350). Five participants were permitted to reduce the number of capsules to four per day and to then gradually increase the dosage back to eight per day. However, one participant in the placebo and three in the fish oil group dropped out as a direct result of their symptoms. Fourteen (19%) out of 73 participants who received the allocated intervention reported experiencing physical benefits that they attributed to the treatment. However, there was no evidence of an association with treatment group (P ¼ 0:672). Reported benefits included
4. Discussion and conclusions This paper describes the effect of fish oil as an adjunct to existing therapy in community-based patients being treated for a current episode of depression. The DHAenriched tuna fish oil was moderately well-tolerated as indicated by the reported adverse events and withdrawal rate. Only 14 (19%) of 73 participants who received the allocated intervention failed to complete the 12 week study. This compares favourably to withdrawal rates of around 30% in 6 week trials of antidepressant medication [26]. The only common adverse event seen in both groups was gastrointestinal disturbance, but some participants found taking the number and size of capsules required difficult to integrate into their daily routines. The ITT and PP analyses found no evidence of an effect of fish oil compared to the control. This finding cannot be attributed to poor compliance with the treatment regime because the fish oil treatment did result in a significant increase in both EPA and DHA in the red cell membranes. One possible explanation for our findings is that o-3 PUFAs are not an effective add-on treatment for depression. While our data support this possibility, this is not consistent with findings from other epidemiological studies linking o-3 PUFA intake to improved mood and reduced rates of depression [7-8,11–13]. However, the composition of fish oil is highly variable and it may not be appropriate to compare the effect of consuming fish with fish oils or purified o-3 PUFAs. Other studies have found that pure preparations of ethyl-EPA [16,17] and an omega 3 concentrate containing a 2:1 ratio of EPA to DHA [15] improved mood, whereas DHA alone did not [14]. The fish oil used in this study provided both DHA and EPA. It is also possible that the dose of 8 g of fish oil per day may not have been optimal for this population. While high doses of fish oil may rapidly correct an o-3 PUFA deficiency, optimal requirements for any nutrient are likely to fall within a range that can be met from the diet. This concept is supported by epidemiological studies showing that relatively small amounts of fish in the diet, ranging from less than once a month [11] to once or twice per week [12] were associated with better mood and lower rates of depression, respectively. Indeed, Peet and Horrobin [17] found that 2 and 4 g of a pure ethyl ester derivative of EPA per day did not have a significant effect on mood over 12 weeks, whereas a 1 g dose per day did. Other published trials included participants who were independently assessed to meet DSM-IV criteria for
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depression with symptoms in the moderate to severe range according to standardised rating scales [14–17]. In contrast, we included eligible participants with a current diagnosis of depression from their general practitioner with symptoms in the mild to severe range according to standardised rating scales. This was because our aim was to test whether a widely available low cost fish oil could assist those being treated for a current episode of depression in a community setting. While the decision to rely on a general practitioner’s assessment rather than to carry out our own independent assessment may raise questions about whether participants did indeed have a current diagnosis, our approach was relevant to the conventional management of depression. Despite not finding an effect of fish oil in this study, mood scores in all participants improved significantly within the first two weeks and this improvement was sustained throughout. One possible, although unlikely explanation for this was that both fish and olive oil were equally effective in the treatment of depressive symptoms due to an unknown mood-enhancing component of olive oil or simply to an increase in fat intake. However, an early improvement in mood in a depression trial is usually indicative of a placebo response [27]. Placebo response rates have been found to range from 30% to 70% [28] depending on the type and severity of depressive symptoms [27]. The cause of non-specific treatment effects such as this are unknown. Three reasons cited for improvements in the absence of an active treatment are: (1) the encouraging effect of being in treatment; (2) spontaneous remission; and (3) natural fluctuations in severity of symptoms, i.e. people with chronic symptoms normally seek help when their symptoms are at their worst and may have improved when next assessed [29]. These are all plausible explanations for our findings. Indeed, many of our participants described feeling unsupported in the community, and reported that they did not see their primary mental health provider on a regular basis. In addition, almost all stated the desire to help others as a primary reason for taking part in the research. Realising this goal may have helped improve mood. Expectancy is known to be an important component of any placebo effect [30]. While participants in our study were told they would be consuming a natural oil, they were not told which oil was being tested as an addon treatment. In fact, participants were told that both oils were associated with health benefits, which could have created an expectation that their health would improve on either treatment. This, coupled with the success of blinding in our study, could explain the sustained improvement in mood found. Equally, expectancy could also explain the treatment effect found in other studies where patients were told that fish oil was the treatment being investigated. If a fish taste was then experienced, participants might then have expected to
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see an improvement in their mood. While efforts are made to blind fish oil treatments, it is almost impossible to eradicate the taste of fish, which is due to the natural oxidation of long chain o-3 PUFAs over time. Humans are able to detect very low levels (parts per million) of the oxidation products as a fish taste, and so it is vital that an assessment of the success of blinding is built into future research to enable true efficacy to be assessed. In conclusion, DHA enriched fish oil was no more effective than the placebo oil as add-on therapy for depression in this setting, despite an increase in circulating levels of o-3 PUFAs. Further research is required to elucidate the role of o-3 PUFAs in the treatment of depression. Trials of add-on and sole therapy, with appropriate assessment of compliance and enough power to detect a clinically significant improvement in mood for a minimum of 12 weeks, will help to reduce bias and the possibility of chance findings due to spontaneous remission. However, care should be taken when choosing the dose and form of o-3 PUFAs to be tested as the biological effect of an oil is likely to depend on its composition. It is, therefore, important to provide detailed information about the composition of oils used in trials to assist in the assessment of efficacy.
Acknowledgements This research was funded by the Foundation for Research, Science and Technology, New Zealand. We would like to thank the participants for taking part in the research, Clover Corporation for the supply of capsules, Emmeline Taptiklis for processing many of the blood samples, and Maaike Bendall and Duncan Hedderley for their statistical advice and input. Conflict of interest statement: The authors have no financial involvement or affiliation with any organisation whose financial interests may be affected by material in this manuscript, or which might potentially bias it.
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[18] B.K. Puri, S.J. Counsell, G. Hamilton, A.J. Richardson, D.F. Horrobin, Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phosopholipid turnover, Int. J. Clin. Pract. 55 (2001) 560–563. [19] B.K. Puri, S.J. Counsell, G. Hamilton, A.J. Richardson, D.F. Horrobin, Eicosapentaenoic acid in treatment-resistant depression, Arch. Gen. Psychiatry 59 (2002) 91–92. [20] W. Reynolds, K. Kobak, Hamilton Depression Inventory: A Self Report Version of the Hamilton Depression Rating Scale. Professional Manual, Psycological Assessment Resources, Odessa, FL, 1995. [21] J. Folch, M. Lees, G.H. Sloane Stanley, A simple method for the isolation and purification of total lipides from animal tissues, J. Biol. Chem. 226 (1957) 497–509. [22] W.R. Morrison, L.M. Smith, Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoridemethanol, J. Lipid. Res. 5 (1964) 600–608. [23] D.R. Body, F.B. Shorland, The fatty acid composition of the main phospholipid fractions of the rumen and abomasum tissues of foetal and adult sheep, J. Sci. Food Agric. 25 (1994) 197–204. [24] H.D. Patterson, R. Thompson, Recovery of inter-block information when block sizes are unequal, Biometrika 58 (1971) 545–554. [25] J.K. Lindsay, Models for Repeated Measurements, Oxford University Press, New York, 1994. [26] C. Barbui, M. Hotopf, N. Freemantle, J. Boynton, R. Churchill, M.P. Eccles, J.R. Geddes, R. Hardy, G. Lewis, J.M. Mason, Selective serotonin reuptake inhibitors versus tricyclic and heterocyclic antidepressants: comparison of drug adherence, Oxford, England, Cochrane Library, Update software (2000) issue 4. CD002791. [27] C.A. Miller, C.L. Hooper, D.A. Bakish, Comparison of placebo response with major depressive disorder in patients recruited through newspaper advertising versus consultation referrals, Psychopharmacol. Bull 33 (1997) 647–651. [28] W.A. Brown, Predictors of placebo response in depression, Psychopharmacol. Bull 24 (1998) 14–17. [29] G. Andrews, Placebo response in depression: bane of research, boon to therapy, Br. J. Psychiatry 178 (2001) 192–194. [30] A. Harrington, The placebo effect, in: A. Harrington (Ed.), An Interdisciplinary Exploration, Harvard University Press, Cambridge, MA, 1997.
Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 211–218 www.elsevier.com/locate/plefa
Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression$ Karen M. Silversa,, Cheryl C. Woolleyb, Frances C. Hamiltonb, Peter M. Wattsb, Rosemary A. Watsona a
New Zealand Institute for Crop & Food Research, Private Bag 4704, Christchurch, New Zealand b School of Psychology, Massey University, Private Bag 11222, Palmerston North, New Zealand Received 23 July 2004; accepted 21 November 2004
Abstract Converging evidence suggests that o-3 polyunsaturated fatty acids have aetiological importance in depression. To determine the effect of adding fish oil to existing therapy in participants who were being treated for depression in a community setting, 77 participants were randomly assigned to receive 8 g of either fish or olive oil per day in addition to their existing therapy. Fifty-nine (77%) participants completed 12 weeks of treatment. Dietary, biochemical and lifestyle factors were measured throughout the study. Mood was assessed using the Short Form Hamilton Depression Rating Scale (HDRS-SF) and the Beck Depression Inventory II. Sample size calculations were based on the HDRS-SF. Intention-to-treat and per protocol analyses were carried out using residual maximum likelihood. There was no evidence that fish oil improved mood when compared to the placebo oil, despite an increase in circulating o-3 polyunsaturated fatty acids. However, mood improved significantly in both groups within the first 2 weeks of the study (Po0:001) and this improvement was sustained throughout. In conclusion, fish oil was no more effective than the control as an add-on therapy for depression in this setting. r 2004 Elsevier Ltd. All rights reserved.
1. Introduction Depression is a common mental disorder currently causing a high level of disease burden and this is expected to increase over the next 20 years [1]. Epidemiological data suggest that the lifetime prevalence of mental and behavioural disorders is 25%, most of which is accounted for by depression [1]. Estimates in the UK suggest that 60–70% of adults will experience either depression or worry of sufficient severity to adversely affect their daily activities [2]. Despite the development of new antidepressant medications with improved side-effect profiles, it is estimated that 20–30% $
This research was funded by the Foundation for Research, Science and Technology, New Zealand. Corresponding author. New Zealand Institute for Crop & Food Research, Private Bag 4704, Christchurch, New Zealand. Tel.: +64 3 325 6400; fax: +64 3 325 2074. E-mail address: [email protected] (K.M. Silvers). 0952-3278/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2004.11.004
of those with major depressive disorder treated with antidepressant medication continue to experience residual depressive symptoms. In addition, some 50% of those who have an episode of major depressive disorder will eventually have another [3]. As the social and economic costs of depression continue to rise, alternatives to antidepressant medication with fewer side effects need to be found. The o-3 polyunsaturated fatty acids (o-3 PUFAs) found in fish oil have been hypothesised to provide an alternative. Fish and other seafood are the best dietary sources of EPA and DHA, and humans are thought to have evolved consuming diets rich in these. However, during the last century, intakes of EPA and DHA have dropped significantly, and the intake of o-6 PUFAs has increased [4]. These changes in diet are thought to have contributed to the significant increase in chronic disease and inflammatory disorders in the 20th century [5,6].
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There is evidence that people with depression have significantly lower o-3 PUFA levels in both red cell membranes [7,8] and serum cholesteryl esters [9] when compared to controls. Red cell membrane o-3 PUFA levels are also correlated with the severity of depression [10]. Consistent with this are findings showing that consuming a diet higher in seafood is associated with better mood [11] and lower rates of depression [12]. The evidence that o-3 PUFAs influence signal transduction and neurotransmission [13] and that diets low in o-3 PUFAs increase the risk of depression has led to the hypothesis that o-3 PUFAs may improve or stabilise mood in those suffering from depression. The few published reports on the use of o-3 PUFAs as a treatment for depression have involved small sample sizes and findings have been somewhat contradictory. In a 6 week trial, Marangell and coworkers [14] found that 2 g DHA per day had no effect on mood in a small number of unmedicated patients with major depression. However, both 10 g of an o-3 concentrate per day containing 4.4 g EPA and 2.2 g DHA [15], and 1–2 g pure ethyl-EPA per day [16,17] were found to improve mood in studies involving medicated patients. Two published case studies also showed that treatment with pure ethyl-EPA led to remission of patients with treatment resistant depression [18,19]. The aim of this study was to determine the effect of adding fish oil (containing both DHA and EPA) to existing therapy in community-based patients being treated for a current depressive episode. Participants met the criteria for depression based on the Short Form Hamilton Depression Rating Scale (HDRS-SF).
2. Patients and methods 2.1. Participants Participants being treated for a current depressive episode and no co-existing psychiatric disorder (except anxiety disorders) were recruited to the study if they were between 18 and 65 years old, and if female, were premenopausal with a normal menstrual cycle. Exclusion criteria included blood clotting disorders, use of anticoagulant therapy, unstable medical conditions, or conditions likely to affect gastrointestinal absorption, allergies to seafood, objections to taking fish or olive oilbased products, and those already taking fish oil. Participants were also required to have been on their current medication at a constant dose for at least 2 months, to have no objections to providing blood samples, and to be available for the length of the study. They were recruited through a Community Mental Health Service, general practices and advertisements in community newspapers in the Wellington region of New
Zealand over a 14 month period between July 2000 and September 2001. Eligible participants were sent an information sheet and consent form. Most potential participants were identified through community advertising because in New Zealand, patients diagnosed with depression are not generally seen by psychiatric clinicians unless they have co-existing psychiatric disorders. This study was approved by the Massey University Human Ethics Committee, and the Manawatu–Whanganui and Wellington Human Ethics Committees. All participants gave written informed consent and permission for researchers to request diagnosis, treatment and general health information from their general practitioner and mental health key worker. This information was used to confirm diagnosis, history and treatment information. Participants were not independently assessed. 2.2. Treatment Participants were randomly assigned to receive either 8 g of DHA enriched tuna fish oil per day or an equivalent dose of olive oil in 1 g soft gelatin capsules, according to a prearranged computer generated code. The olive oil and fish oil capsules looked identical and were supplied by Clover Corporation PLC, Australia. The fatty acid composition of the oils used is shown in Table 1. The fish oil treatment provided 3 g of o-3 PUFAs (0.6 g EPA, 2.4 g DHA, 80 mg vitamin E) per day. Fish taste and smell were minimal. Participants were advised to take four capsules in the morning and four in the evening with meals. To assist with blinding, participants were told only that both oils were natural and were associated with a range of health benefits, and that an aftertaste might be experienced. The allocation sequence was generated by a biostatistician, who was not directly involved in the study. Two research psychologists enrolled the participants, Table 1 Fatty acid composition of oils Fatty acid (% of total)
Myristic acid (14:0) Palmitic acid (16:0) Palmitoleic acid (16:1 o-7) Stearic acid (18:0) Oleic acid (18:1 o-9) Linoleic acid (18:2 o-6) a-linolenic acid (18:3 o-3) Arachidonic acid (20:4 o-6) EPA (20:5 o-3) Docosapentanoic acid (22:5 o-3) DHA (22:6 o-3)
Olive oil
Fish oil
0 12.09 1.21 2.67 63.39 13.54 0.84 0 0 0 0
2.72 16.6 3.40 4.76 13.7 1.30 0.65 1.96 6.89 1.23 27.30
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administered the interventions and collected the data. They were trained in telephone and interview techniques to minimise any experimenter effect. Participants were sequentially assigned using numbered containers 1–50 for males and 51–100 for females. The allocation sequence was concealed from both participants and the research psychologists until all data had been collected and entered into the database. 2.3. Study design The design was a 12 week, repeated measures, doubleblind addition of fish oil or a placebo to ongoing antidepressant therapy. Demographic information, information about participants’ depression and current therapies, dietary intake of o-3 and o-6 PUFAs, physical activity and health beliefs were collected at baseline. Dietary intake of o-3 and o-6 PUFAs was assessed using a food frequency questionnaire (FFQ), and information about health beliefs was collected using a Health Beliefs Questionnaire (HBQ). Mood was assessed at baseline and then at 2, 4, 8 and 12 weeks using a self-administered HDRS-SF and Beck Depression Inventory (BDI II). The HDRS-SF consists of nine items from the full scale version of the Hamilton Depression Inventory. These items show the highest sensitivity in differentiating respondents with major depression from those with other psychiatric disorders and non-psychiatric controls [20]. Changes to existing therapy, including dose or type of medication and adverse events were recorded throughout the study. Changes in diet, physical activity and health beliefs during the study were assessed using a modified FFQ and HBQ at 12 weeks. An exit interview was carried out at the end of the intervention. During the interview, participants were asked to rate their compliance with the protocol, give their reasons for noncompliance, and guess which treatment group they had been in. Interviews and questionnaires were administered at Massey University Psychology Clinics in Palmerston North and Wellington. However, some exit interviews with patients who had dropped out of the study were carried out by telephone.
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packed erythrocytes were isolated by ultracentrifugation (Sorvall OTD Combi Ultracentrifuge, AH629 rotor, 4 1C, 27,000 rpm, 90 min) following haemolysis with 10 mM Tris buffer pH 7.4 at room temperature. All blood fractions were stored at 85 1C prior to further analysis. Samples were labelled according to their identification number, analysed blind and randomly allocated to batches for further handling, with all samples from individual patients being processed in the same experimental batch. Triacylglycerols, total and HDL cholesterol, and trace elements hypothesised to be relevant to mood (iron, magnesium, selenium) were determined on an Aeroset analyser using the manufacturer’s reagents and procedures (Abbott Laboratories, Auckland, New Zealand). Plasma selenium was measured by carbon furnace atomic absorption spectroscopy on a Varian AA40 with Zeeman background correction with palladium modifier (Varian, Melbourne, Australia). Membrane lipids were extracted by modification of a standard procedure [21]. Fatty acid methyl esters (FAMEs) were derived from fatty acids of membrane lipids using boron trifluoride (BF3) by a modification of the Morrison and Smith [22] method. Cholesterol and other non-FAMEs species were removed by silicic acid column chromatography fractionation using chloroform as an eluent by a method adapted from Body and Shorland [23]. TLC verified the contents of the fractions. Purified FAMEs were separated by temperature-programmed capillary gas–liquid chromatography, and identified using a standard (GLC-463, Nu-Chek) with additions. Results were expressed as a percentage of the total area of peaks eluting in the separation range from 14:0 to 22:6 (o-3) inclusive. An in-house pig erythrocyte membrane control and reagent blanks were used to monitor inter-batch variation in both sample preparation and GC analysis. 2.5. Sample size Mood as determined by scores on the HDRS-SF was the primary outcome variable and sample size calculations were based on this. The BDI II was the secondary outcome variable. 2.6. Statistical methods
2.4. Blood analyses Blood samples were collected at 0, 2 and 12 weeks into VacutainersTM (Hemogards 15% K3 EDTA), and transported to the laboratory on ice. Initial processing was carried out within 6 h of collection. Plasma and erythrocytes were separated by centrifugation (Sorvall RC5B Plus centrifuge with SLA-1500 rotor, 4 1C, 7000 rpm, 10 min), and the erythrocytes washed three times in 0.9% w/v aqueous NaCl. Membranes from 1 ml
Two populations were used. The intention-to-treat (ITT) population included all participants who were randomised, while the per-protocol (PP) population included all participants who completed 12 weeks of treatment and met the a priori criteria for inclusion in the trial, using diagnosis and general health information provided by the participant’s general practitioner. Residual maximum likelihood (REML) was used to analyse the data [24] with the correlation between
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observations on the same participant described with an ante-dependence model [25]. To limit the number of significance tests, covariate by treatment interactions were only tested for significance if the covariate was related to the change in mood as determined by scores on the HDRS-SF. Similarly, only covariates that were related to the HDRS-SF scores were tested for a relationship with the BDI-II scores.
Assessed for eligibility (n=499) Excluded (n=422) Did not meet inclusion criteria (n=369) Refused (n=25) Other reasons (n=28) Randomised (n=77)
Allocated to olive oil (n=37) Received allocated intervention (n=35) Did not receive allocated intervention; dropped out before baseline data collected (n=2)
Allocated to fish oil (n=40) Received allocated intervention (n=38) Did not receive allocated intervention; dropped out before baseline data collected (n=2)
Discontinued intervention (n=5) GI disturbance (n=1), other (n=2), multiple (n=2)
Discontinued intervention (n=9) GI disturbance (n=2), capsule problems (n=2), other (n=2), multiple (n=3)
ITT analysis (n=37)
ITT analysis (n=40)
PP analysis (n=21) Excluded from analysis; dropped out before baseline (n=2), discontinued intervention (n=5), head trauma (n=1), personality disorder (n=3), Bipolar disorder (n=1), HDI-SF<6 at week 0 (n=4)
PP analysis (n=24) Excluded from analysis; dropped out before baseline (n=2), discontinued intervention (n=9); head trauma (n=1), physical disorder (n=1), HDI-SF<6 at week 0 (n=2)
Fig. 1. Flow diagram of the progress through the phases of the randomised double-blind placebo-controlled trial of fish oil in the treatment of depression.
3. Results 3.1. Participant flow The flow of research participants is shown in Fig. 1. Forty participants were randomly assigned to receive fish oil and 37 to receive the placebo. Four participants, two from each group, dropped out before the baseline data was collected. Fifty-nine participants completed 12 weeks of treatment. Nine (24%) of 38 in the fish oil group and five (14%) of the 35 placebo recipients dropped out for reasons stated in Fig. 1. Baseline demographic and clinical characteristics can be found in Table 2. There was no evidence of an association between baseline mood scores and dietary, biochemical or lifestyle factors. Twenty-four fish oil and 21 placebo recipients were included in the PP analysis.
3.2. Outcomes There was no evidence that fish oil improved mood in either ITT or PP analyses. Post-hoc power calculations indicate 95% power for detecting a 10–15% difference in HDRS-SF or BDI-II scores in both ITT and PP analyses. However, there was a significant improvement in the mood of both groups within the first 2 weeks of entering the study (Po0:001 for HDRS-SF and BDI-II scores). This improvement was sustained throughout (Table 3) and analysis of covariance indicated that it was proportional to baseline mood. Age, reason for taking part in the research, initial hopefulness about the supplement, alcohol intake, level of physical activity and type of medication were tested Table 2 Baseline demographic and clinical characteristics Treatment groups
Female Mean (sd) age (yr)a Mean mood scoresa HDRS-SF BDI II Background treatmenta Antidepressant medication Psychotherapy Dietary intakea Fish intake (p2 servings per wk) Mean (sd) total o-3 PUFA index Physical activity (p2.5 h in last 7 d)a Dropped out
Placebo (n ¼ 37)
Fish oil (n ¼ 40)
19 37.7 (13.6)
22 39.8 (11.9)
12.4 (5.4) 23.3 (12.3)
11.5 (5.3) 21.9 (10.6)
30 14
31 7
24 1.5 (1.3) 13 7
22 1.8 (1.3) 9 11
Data are given as number of participants, except where otherwise indicated. a Data missing for four participants that withdrew before baseline data collection.
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Table 3 Change in mood scores between consecutive measurements Group
Week
HDRS-SF (ITT)
HDRS-SF (PP)
BDI II (ITT)
BDI II (PP)
Placebo
0 2 4 8 12
12.4 3.9 0.9 0.7 0.6
(0.9) (0.9)*** (0.7) (0.5) (0.6)
13.2 5.6 0.3 1 0.3
(0.8) (0.8)*** (0.7) (0.6) (0.6)
23.3 7.4 2.1 0.8 1.5
(3.5) (1.4)*** (1.4) (1.4) (1.5)
24.8 10.57 0.1 2.6 0.8
(3.1) (2.0)*** (1.4) (1.3) (0.7)
Fish oil
0 2 4 8 12
11.5 3.6 0.4 1.1 0.3
(0.9) (0.7)*** (0.7) (0.8) (0.8)
12.3 4.3 0.4 1 0.4
(0.9) (0.8)*** (0.8) (1.0) (0.9)
21.9 7.9 0.8 2.4 0.3
(3.3) (1.4)*** (1.4) (1.5) (1.5)
22.8 9.8 1.2 1.6 0.9
(3.0) (1.9)*** (1.7) (2.1) (1.7)
Data given as change from baseline in mean (SE) mood scores ( Po0:001).
as covariates, but there was no evidence that these were related to the change in mood. There was also no evidence that the treatment affected drop-out rates (P ¼ 0:442). Mean levels of EPA and DHA measured in red cell membrane phospholipids throughout the study, are shown in Figs. 2 and 3, respectively. Levels of EPA (Po0:001) and DHA (Po0:001) were significantly increased in the fish oil group at both 2 and 12 weeks of treatment. 3.3. Blinding There was no evidence that participants were able to guess what group they were in (P ¼ 0:804). Even when a fish taste was experienced, participants did not necessarily assume they were in the group receiving fish oil. 3.4. Self-reported compliance
Fig. 2. Mean (SEM) change in % of total EPA in erythrocyte membranes in fish oil (’) and placebo (&) supplemented groups (‘***’ indicates that the difference between groups is significant at the 0.001% level).
Reasons for non-compliance with the treatment regime are summarised in Table 4. Twenty-two (63%) of 35 in the fish oil group and 20 (63%) of 32 in the placebo group who completed the exit interview, stated that they had not taken every dose as directed. There was no evidence that non-compliance was related to the treatment given (P ¼ 0:976). Most instances of noncompliance related to forgetting to take the capsules. Other reasons included gastrointestinal disturbance, inconvenience and the size of capsules. 3.5. Adverse events Adverse events for all participants who received the allocated intervention are summarised in Table 5. The events were evenly distributed across the groups. One serious adverse event was reported in the placebo group. A participant was hospitalised following a pharmaceutical drug overdose in the tenth week of the study, but the incident was not considered to be related to the
Fig. 3. Mean (SEM) change in % of total DHA in erythrocyte membranes in fish oil (’) and placebo (&) supplemented groups (‘***’ indicate that the difference between groups is significant at the 0.001% level).
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Table 4 Reasons given for non-compliance with treatment regime
improved hair and skin condition, increased energy levels and a reduction in chronic pain symptoms.
Treatment groups
Took every dose as requested Did not take every dose as requested Missing data Total number of reasons for noncompliance Not taken capsules as requested Capsules hard to swallow GI disturbance Capsules did not seem to make any difference to depression Stopped taking capsules as depression improved Other
Placebo
Fish oil
12 20 5 37
13 22 5 34
17 5 5 2
16 4 6 2
0
2
8
4
Data are given as number of patients, except where otherwise indicated. Table 5 Adverse events Treatment groups
No adverse events Participants with an event Missing dataa Total number of events Musculo-skeletal system Central nervous system Psychiatric event GI disturbance Reflux Resistance (infections) Skin General malaise/felt unwell Other
Placebo
Fish oil
21 14 2 16 0 1 2 7 1 2 1 1 1
24 14 2 20 1 4 0 8 3 0 1 1 2
Data are given as number of participants, except where otherwise indicated. a Data missing for participants that withdrew before baseline data collection.
individual’s participation in the trial. Gastrointestinal disturbance and/or reflux were the most commonly experienced events, but there was no evidence that either was related to the type of oil taken (P ¼ 0:350). Five participants were permitted to reduce the number of capsules to four per day and to then gradually increase the dosage back to eight per day. However, one participant in the placebo and three in the fish oil group dropped out as a direct result of their symptoms. Fourteen (19%) out of 73 participants who received the allocated intervention reported experiencing physical benefits that they attributed to the treatment. However, there was no evidence of an association with treatment group (P ¼ 0:672). Reported benefits included
4. Discussion and conclusions This paper describes the effect of fish oil as an adjunct to existing therapy in community-based patients being treated for a current episode of depression. The DHAenriched tuna fish oil was moderately well-tolerated as indicated by the reported adverse events and withdrawal rate. Only 14 (19%) of 73 participants who received the allocated intervention failed to complete the 12 week study. This compares favourably to withdrawal rates of around 30% in 6 week trials of antidepressant medication [26]. The only common adverse event seen in both groups was gastrointestinal disturbance, but some participants found taking the number and size of capsules required difficult to integrate into their daily routines. The ITT and PP analyses found no evidence of an effect of fish oil compared to the control. This finding cannot be attributed to poor compliance with the treatment regime because the fish oil treatment did result in a significant increase in both EPA and DHA in the red cell membranes. One possible explanation for our findings is that o-3 PUFAs are not an effective add-on treatment for depression. While our data support this possibility, this is not consistent with findings from other epidemiological studies linking o-3 PUFA intake to improved mood and reduced rates of depression [7-8,11–13]. However, the composition of fish oil is highly variable and it may not be appropriate to compare the effect of consuming fish with fish oils or purified o-3 PUFAs. Other studies have found that pure preparations of ethyl-EPA [16,17] and an omega 3 concentrate containing a 2:1 ratio of EPA to DHA [15] improved mood, whereas DHA alone did not [14]. The fish oil used in this study provided both DHA and EPA. It is also possible that the dose of 8 g of fish oil per day may not have been optimal for this population. While high doses of fish oil may rapidly correct an o-3 PUFA deficiency, optimal requirements for any nutrient are likely to fall within a range that can be met from the diet. This concept is supported by epidemiological studies showing that relatively small amounts of fish in the diet, ranging from less than once a month [11] to once or twice per week [12] were associated with better mood and lower rates of depression, respectively. Indeed, Peet and Horrobin [17] found that 2 and 4 g of a pure ethyl ester derivative of EPA per day did not have a significant effect on mood over 12 weeks, whereas a 1 g dose per day did. Other published trials included participants who were independently assessed to meet DSM-IV criteria for
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depression with symptoms in the moderate to severe range according to standardised rating scales [14–17]. In contrast, we included eligible participants with a current diagnosis of depression from their general practitioner with symptoms in the mild to severe range according to standardised rating scales. This was because our aim was to test whether a widely available low cost fish oil could assist those being treated for a current episode of depression in a community setting. While the decision to rely on a general practitioner’s assessment rather than to carry out our own independent assessment may raise questions about whether participants did indeed have a current diagnosis, our approach was relevant to the conventional management of depression. Despite not finding an effect of fish oil in this study, mood scores in all participants improved significantly within the first two weeks and this improvement was sustained throughout. One possible, although unlikely explanation for this was that both fish and olive oil were equally effective in the treatment of depressive symptoms due to an unknown mood-enhancing component of olive oil or simply to an increase in fat intake. However, an early improvement in mood in a depression trial is usually indicative of a placebo response [27]. Placebo response rates have been found to range from 30% to 70% [28] depending on the type and severity of depressive symptoms [27]. The cause of non-specific treatment effects such as this are unknown. Three reasons cited for improvements in the absence of an active treatment are: (1) the encouraging effect of being in treatment; (2) spontaneous remission; and (3) natural fluctuations in severity of symptoms, i.e. people with chronic symptoms normally seek help when their symptoms are at their worst and may have improved when next assessed [29]. These are all plausible explanations for our findings. Indeed, many of our participants described feeling unsupported in the community, and reported that they did not see their primary mental health provider on a regular basis. In addition, almost all stated the desire to help others as a primary reason for taking part in the research. Realising this goal may have helped improve mood. Expectancy is known to be an important component of any placebo effect [30]. While participants in our study were told they would be consuming a natural oil, they were not told which oil was being tested as an addon treatment. In fact, participants were told that both oils were associated with health benefits, which could have created an expectation that their health would improve on either treatment. This, coupled with the success of blinding in our study, could explain the sustained improvement in mood found. Equally, expectancy could also explain the treatment effect found in other studies where patients were told that fish oil was the treatment being investigated. If a fish taste was then experienced, participants might then have expected to
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see an improvement in their mood. While efforts are made to blind fish oil treatments, it is almost impossible to eradicate the taste of fish, which is due to the natural oxidation of long chain o-3 PUFAs over time. Humans are able to detect very low levels (parts per million) of the oxidation products as a fish taste, and so it is vital that an assessment of the success of blinding is built into future research to enable true efficacy to be assessed. In conclusion, DHA enriched fish oil was no more effective than the placebo oil as add-on therapy for depression in this setting, despite an increase in circulating levels of o-3 PUFAs. Further research is required to elucidate the role of o-3 PUFAs in the treatment of depression. Trials of add-on and sole therapy, with appropriate assessment of compliance and enough power to detect a clinically significant improvement in mood for a minimum of 12 weeks, will help to reduce bias and the possibility of chance findings due to spontaneous remission. However, care should be taken when choosing the dose and form of o-3 PUFAs to be tested as the biological effect of an oil is likely to depend on its composition. It is, therefore, important to provide detailed information about the composition of oils used in trials to assist in the assessment of efficacy.
Acknowledgements This research was funded by the Foundation for Research, Science and Technology, New Zealand. We would like to thank the participants for taking part in the research, Clover Corporation for the supply of capsules, Emmeline Taptiklis for processing many of the blood samples, and Maaike Bendall and Duncan Hedderley for their statistical advice and input. Conflict of interest statement: The authors have no financial involvement or affiliation with any organisation whose financial interests may be affected by material in this manuscript, or which might potentially bias it.
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