Safety of the omega-3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: Results from a randomized, placebo-controlled trial
Introduction
There is evidence to suggest that abnormal phospholipid and related fatty acid metabolism may play a role in the aetiology of several psychiatric illnesses, including schizophrenia, bipolar mood disorder, major depression, dementia and attention deficit hyperactivity disorder (Horrobin and Bennett, 1999, Freeman, 2000, Freeman et al., 2006, Parker et al., 2006). A growing number of studies have investigated a possible therapeutic effect for the omega-3 fatty acids in these disorders, particularly eicosapentaenoic acid (EPA), derived mainly from marine and plant sources (Stensby, 1969). Although the use of omega-3 fatty acids for psychiatric disorders remains experimental (Joy et al., 2003), these products are being used increasingly by patients worldwide, in the hope that they may have some beneficial psychotropic effect. Studies in the psychiatric literature to date have focused primarily on the efficacy of these compounds, while scant attention has been paid to their safety and tolerability. This may be in part because there is a widespread belief among the general public that naturally occurring products are safe to consume. This is not the case, however, as it is the molecular structure and dose of a substance rather than its source that determine its effect on human health, and many naturally occurring products are in fact highly toxic (Topliss et al., 2002). It is therefore essential that the safety of these products should be established, particularly in samples of psychiatric patients who may be at particular risk for certain side-effects. One such population is represented by patients with schizophrenia, who are at increased risk for various medical conditions (Goldman, 1999, Davidson, 2002) whether as a consequence of medications taken (e.g. weight gain, diabetes, cardiotoxicity), sedentary life-style, dietary factors or smoking (Ryan and Thakore, 2002).
While beneficial effects have been reported for the omega-3 fatty acids in treating certain medical disorders, including hypertension (Morris et al., 1993), Crohn's disease (Belluzi et al., 1996), rheumatoid arthritis (Kremer et al., 1995) and asthma (Broughton et al., 1997), concerns have been raised regarding possible adverse effects that these products may have. As a consequence, the Food and Drug Administration of the United States of America conducted a survey of the available data, and concluded that fish oil (specifically, menhaden oil), is generally recognized as safe when consumption is limited to 3 g/day or less (Department of Health and Human Services, 1997). However, data in the petition indicated that ingestion of EPA and docosahexaenoic acid (DHA) from fish oils can significantly prolong bleeding time. The report stated: “An increase in bleeding time is the only prominent health effect observed in humans that has been firmly established as a consequence of fish oil ingestion.” The effect was reported anecdotally in Eskimos, and consistently observed in studies of healthy human subjects with a daily intake of = 3 g omega-3 fatty acids. Increases in bleeding time did not correlate with clinically significant excessive bleeding, and no significant increases in bleeding time were observed in studies where the daily amounts of EPA or DHA were 3 g or less. Other possible relationships with diseases were investigated. The relationship of omega-3 fatty acids to heart disease was investigated for a possible beneficial effect in terms of decreased risk of coronary heart disease, but there was insufficient scientific evidence to support the claim. There were also concerns regarding possible adverse effects of fish oils on glycaemic control, and low-density lipoproteins (LDL). Some studies in type II diabetics reported increased glucose levels when large amounts of fish oils (between 4.5 and 8 g/day) were consumed. Based on the available information, the FDA concluded that consumption of up to 3 g/day of EPA or DHA by diabetics has no clinically significant effect on glycaemic control. A number of studies reported an increase in LDL and apolipoprotein B, a principal component of LDL. This was a potential concern, as increased LDL is a risk factor for coronary heart disease. The FDA report concluded after reviewing the evidence that there tends to be an increase in LDL levels with increased fish oil consumption, particularly in populations with abnormal blood lipid levels, hypertension, diabetes, and cardiovascular disease. Additional side-effects reported with fish oil supplements include belching, mild nausea, and exacerbation of asthma in aspirin-sensitive patients (Fenton et al., 2000).
Clinical trials indicate that EPA and DHA have beneficial effects against atherosclerosis and its complications. As a consequence, several cardiac societies recommend using 1 g/day of EPA and DHA for cardiovascular disease prevention, after a myocardial infarction and for prevention of sudden cardiac death (von Schacky, 2006, von Schacky, 2007). However, results of studies investigating the safety of omega-3 fatty acids have not always been consistent, and several can be criticised for their small samples and the short duration of treatment. Also, findings may not be generalisable to samples of psychiatric patients, as all but one (Caniato et al., 2006) were conducted in non-psychiatric samples. We therefore undertook a prospective study to investigate the safety of EPA in a sample of chronic psychiatric patients. This formed part of a study in patients with schizophrenia and tardive dyskinesia that investigated a possible antidyskinetic effect for EPA. The results of the efficacy analysis are reported separately (Emsley et al., 2006). The principal objectives of the present study were to examine whether EPA treatment is associated with changes in body mass, glucose metabolism, lipid profiles, prolactin secretion, bleeding time, haematology and liver functions. We also investigated trial discontinuation rates and reasons for discontinuation, adverse events and the use of concomitant medications.
Section snippets
Study design
The study comprised a 12-week double-blind, parallel-group comparison of EPA and placebo supplementation followed by an optional open-label extension phase of EPA supplementation for 40 weeks, in patients with schizophrenia or schizo-affective disorder and co-existent tardive diskinesia (TD). Full details of the study design and methodology have been described in a separate publication in which the efficacy data were reported. Essentially, we failed to demonstrate an antidyskinetic effect for
Demographic and baseline descriptive data
Out of a total of 125 patients who were pre-screened, 84 were recruited and randomized to the double-blind supplemental treatment phase with EPA or placebo. We excluded 12 patients (3 on EPA and 9 on placebo) from the analysis because they failed to complete at least one post-randomization (i.e. 6 weeks) safety assessment visit. Data from the remaining 72 patients were included in the present analysis. Demographic characteristics of the two treatment groups were similar. The EPA group comprised
Discussion
The results of this study suggest that treatment with EPA 2 g/day is generally safe when used in patients with schizophrenia for up to 1 year. The fact that there were no significant differences in adverse event reporting between the groups, and fewer patients in the EPA supplementation group than in the placebo group who discontinued the double-blinded phase of the study, suggests that EPA is well tolerated and accepted by patients. However, while there were no significant differences between
Acknowledgement
This study was supported by the Stanley Medical Research Institute, Grant ID #02T-140. Trial medication was provided by Laxdale Ltd., Stirling, Scotland (Now Amarin Neuroscience Ltd).
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