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A Dose-Ranging Study of the Effects of Ethyl-Eicosapentaenoate in Patients With Ongoing Depression Despite Apparently Adequate Treatment With Standard Drugs
Malcolm Peet, MB, ChB, FRCPsych;
David F. Horrobin, DPhil, BM, BCh
Arch Gen Psychiatry. 2002;59:913-919.
ABSTRACT
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Background In depressed patients, low blood levels of eicosapentaenoic acid are
seen. We tested the antidepressive effect of ethyl-eicosapentaenoate in these
patients.
Methods We included 70 patients with persistant depression despite ongoing treatment
with an adequate dose of a standard antidepressant. Patients were randomized
on a double-blind basis to placebo or ethyl-eicosapentaenoate at dosages of
1, 2, or 4 g/d for 12 weeks in addition to unchanged background medication.
Patients underwent assessment using the 17-item Hamilton Depression Rating
Scale, the Montgomery-Asberg Depression Rating Scale, and the Beck Depression
Inventory.
Results Forty-six (88%) of 52 patients receiving ethyl-eicosapentaenoate and
14 (78%) of 18 patients receiving placebo completed the 12-week study with
no serious adverse events. The 1-g/d group showed a significantly better outcome
than the placebo group on all 3 rating scales. In the intention-to-treat group,
5 (29%) of 17 patients receiving placebo and 9 (53%) of 17 patients receiving
1 g/d of ethyl-eicosapentaenoate achieved a 50% reduction on the Hamilton
Depression Rating Scale score. In the per-protocol group, the corresponding
figures were 3 (25%) of 12 patients for placebo and 9 (69%) of 13 patients
for the 1-g/d group. The 2-g/d group showed little evidence of efficacy, whereas
the 4-g/d group showed nonsignificant trends toward improvement. All of the
individual items on all 3 rating scales improved with the 1-g/d dosage of
ethyl-eicosapentaenoate vs placebo, with strong beneficial effects on items
rating depression, anxiety, sleep, lassitude, libido, and suicidality.
Conclusion Treatment with ethyl-eicosapentaenoate at a dosage of 1 g/d was effective
in treating depression in patients who remained depressed despite adequate
standard therapy.
INTRODUCTION
DEPRESSION REMAINS an illness in which existing treatments have limited
efficacy. The most widely prescribed drug, fluoxetine hydrochloride, produces
a 50% improvement in symptoms in only 38% of those who start treatment and
in only 56% of those who complete a full course.1
Other drugs are similar in their effects.2
Tricyclic antidepressants and selective serotonin (SSRIs) and norepinephrine
reuptake inhibitors are similar in their efficacy.2-3
The SSRIs are marginally better tolerated, but the differences are small.
On average, for every 100 patients who start treatment, 30 patients receiving
a tricyclic compound during a 6-week trial will stop treatment compared with
27 receiving an SSRI.3-4 Discontinuation
rates in ordinary clinical practice are probably higher. Therefore, novel
approaches to the management of depression are needed.
Lipids, most of which are phospholipids, constitute 60% of the solid
mass of the brain and are absolutely required for normal brain structure and
function.5-9
Each phospholipid consists of a 3-carbon glycerol backbone with a fatty acid,
usually a highly unsaturated fatty acid, attached to the middle (Sn2) carbon.5-9
The Sn2 highly unsaturated fatty acids may be of 2 common types, n-6 (also
known as  -6) derived from linoleic acid or n-3 (also know as -3)
derived from  -linolenic acid. In the brain, the main n-6 fatty acid
is arachidonic acid, with much smaller amounts of dihomogammalinolenic and
adrenic acids. The main n-3 fatty acid is docosahexaenoic acid (DHA), with
much smaller amounts of its precursors, eicosapentaenoic acid (EPA) and docosapentaenoic
acid. The metabolic pathways are shown in Figure 1.
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An outline of the metabolism of the essential fatty acids. The middle
carbon atom of brain phospholipids almost always has an essential fatty acid
attached to it. Release of this fatty acid is involved in the phospholipase
A2 cycle after activation of various dopaminergic, serotoninergic,
and glutamatergic receptors. The main fatty acids in this position in the
brain are arachidonic acid and docosahexaenoic acid. Dihomogammalinolenic
and eicosapentaenoic acids are present in very small amounts but are active
signal transduction molecules.
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The fatty acids at the Sn2 position have important roles in neuronal
signal transduction processes.5-9
Activation of most neurotransmitter receptors leads, via a G-protein mechanism,
to activation of 1 or more of a group of enzymes called phospholipase A2, which releases the fatty acid from the Sn2 position. Depending on
its specific structure, that fatty acid may exert 1 or more of many signal
transduction effects, which regulate ion channels, calcium, cyclic nucleotides,
protein kinases, and gene function. For normal neuronal functioning, the right
balance of fatty acids must be present at the Sn2 position.5-9
The Sn2 position of phospholipids is one of the major points in the body where
gene and environment interact. The relevant enzymes are genetically determined,
but they must work with fatty acids provided by the environment.5-9
Evidence has been found that the balance of n-3 and n-6 fatty acids
at the Sn2 position may be disturbed in depression. Compared with healthy
control subjects, plasma and red blood cells from depressed patients show
absolutely low levels of n-3 fatty acids or low levels relative to the concentrations
of n-6 fatty acids. Similar findings have been reported in Australia, Japan,
Europe, and North America.10-15
Also, low levels of n-3 fatty acids have been found in several of the medical
diseases associated with depression, including cardiovascular diseases.6 Epidemiological data are consistent with these findings.
A strong inverse relationship exists between the consumption of n-3 fatty
acids in a population and the prevalence of both major depression and postpartum
depression.16-17 In individuals,
we can construct hypotheses whereby depression-induced changes in diet could
lead to biochemical changes in blood. However, it is difficult to see how
depression in a proportion of the population could lead to an overall change
in the consumption of n-3 fatty acids. If causation rather than simple correlation
is involved, it is more likely that changes in fatty acid intake in the population
influence depression prevalence than vice versa.
The n-3 fatty acids have been tested in the treatment of bipolar disorder
and schizophrenia. A partially purified mix of ethyl-eicosapentaenoate and
ethyl docosahexaenoate was effective in preventing relapse and improving mood
in bipolar disorder.18 Eicosapentaenoic acid
triglyceride but not docosahexaenoic acid triglyceride was effective in schizophrenia.19-20 When a range of ethyl-eicosapentaenoate
dosages was tested in schizophrenia, lower dosages of 1 to 2 g/d were effective,
but a higher dosage of 4 g/d was not.21 The
loss of response was associated with depletion of the n-6 fatty acid, arachidonic
acid, indicating that the balance between n-3 and n-6 fatty acids matters.
Abnormally high or low levels of either fatty acid type may be associated
with malfunction. Because of the biochemical and epidemiological data, we
hypothesized that EPA might have beneficial effects in depression. Possible
effective dosages were unknown, and we therefore conducted a dose-ranging
study of the pure ethyl ester derivative of eicosapentaenoic acid in patients
who had failed to respond satisfactorily to standard antidepressant therapy.
PATIENTS AND METHODS
PATIENTS
Patients were recruited by family physicians who had a special interest
in depression and experience in conducting clinical trials. Approval for the
study was granted by the local regional ethical committees. After full verbal
and written explanation of the study, each patient gave written informed consent.
Patients were of either sex, aged 18 to 70 years, and depressed as indicated
by a score of 15 or more on the 17-item Hamilton Depression Rating Scale (HDRS)22 despite ongoing treatment with a standard antidepressant
at an adequate dose. This score was chosen as a level of depression that in
the view of the trial investigators caused important impairment of function
and therefore justified further attempts at treatment.
TEST DRUGS
The test drugs were liquid paraffin placebo or pure ethyl-eicosapentaenoate
in 500-mg soft gelatin capsules. The placebo and ethyl-eicosapentaenoate capsules
appeared identical and were packed and coded by PCI Clinical Services, Bolton,
England, an independent clinical trials packing organization. On entry, patients
were randomly allocated by PCI Clinical Services computer to receive, each
morning and evening, 4 capsules of placebo, 3 capsules of placebo and 1 of
ethyl-eicosapentaenoate, 2 capsules of placebo and 2 of ethyl-eicosapentaenoate,
or 4 capsules of ethyl-eicosapentaenoate. The capsules were encased in blister
packs and labeled as morning and evening doses. PCI Clinical Services had
no involvement with the rest of the trial. The patients therefore received
placebo or ethyl-eicosapentaenoate at dosages of 1, 2, or 4 g/d.
TRIAL DESIGN
Patients were randomized on a double-blind basis to 1 of the 4 treatment
groups. They underwent assessment by means of 3 rating scales at baseline
and at 4, 8, and 12 weeks. We used the 17-item HDRS,22
the Montgomery-Asberg Depression Rating Scale (MADRS),23
and the patient-completed Beck Depression Inventory (BDI).24
At each visit, patients were also asked about any adverse events.
DATA MANAGEMENT AND STATISTICAL ANALYSIS
When the last patient had completed the trial, the data were verified
and the databases were locked before breaking the code. The primary variable
was the HDRS, with the MADRS and the BDI as secondary variables. Two populations
were used. The intention-to-treat (ITT) population included all patients who
were randomized, while the per-protocol (PP) population included all patients
who completed 12 weeks of treatment. For each rating scale at each time point,
we used analysis of covariance to assess whether the overall differences among
the 4 treatment groups were significant. Covariates included in the model
were baseline HDRS score, center, and antidepressant class (tricyclic, SSRI,
or other drugs that were norepinephrine or mixed reuptake inhibitors). Analysis
of variance was then used to compare each ethyl-eicosapentaenoate treatment
group with the placebo group.
RESULTS
DISPOSITION OF PATIENTS
Seventy-four patients underwent screening; of these, 70 met the entry
criteria, agreed to participate in the trial, and were randomized. Eighteen
patients were assigned each to the placebo and 2-g/d groups, and 17 were assigned
each to the 1- and 4-g/d groups. Sixty patients completed 12 weeks of treatment.
Four (22%) of 18 dropped out of the placebo group (1 was lost to follow-up,
1 withdrew consent during the study, 1 violated the protocol, and 1 had an
adverse event not thought to be related to treatment). Two patients dropped
out of each of the ethyl-eicosapentaenoate groups, making a total withdrawal
from the ethyl-eicosapentaenoate groups of 6 (12%) of 52 (3 withdrew consent,
1 withdrew because of lack of efficacy, 1 violated the protocol, and 1 had
a gastrointestinal adverse event). Compliance was estimated by results of
capsule counts and was greater than 90% in all treatment groups.
DEMOGRAPHY
The ages, sexes, and background treatments of the 4 groups are listed
in Table 1. The groups were well
matched. Women predominated.
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Table 1. Demographic Information*
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ADVERSE EVENTS
All reported adverse events are listed in Table 2. Eight of 18 patients in the placebo group and 20 of 52
patients in the ethyl-eicosapentaenoate groups reported no adverse events.
The events were evenly distributed across the groups. The only events attributed
to treatment by the physicians were the gastrointestinal events that affected
4 of 18 in the placebo group and 20 of 52 in the ethyl-eicosapentaenoate groups.
These events were attributable to the intake of 4 g/d of an oily substance,
rather than being specifically caused by the study treatment. All but 1 of
the gastrointestinal events were mild and self-limited and did not require
cessation of treatment. Diarrhea developed in 1 patient in the 1-g/d group.
None of the usual adverse events associated with antidepressant therapy and
no effect on any blood parameter or liver function test result were seen.
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Table 2. Reported Adverse Events Occurring During the Trial Using the
WHO Classification*
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THERAPEUTIC OUTCOMES
The results of the analyses of covariance for change from baseline to
the end of the study across all treatment groups are shown in Table 3. Center and background medication had no significant effects
on any rating scale in the ITT or PP populations. Baseline score had no effect
on the HDRS and MADRS outcomes in the ITT or PP population: it had an effect
on outcome on the BDI score in the ITT but not the PP population. Treatment
had a significant overall effect on all 3 scores for both populations and
was marginal only for the HDRS in the ITT population (P = .056).
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Table 3. Results of Analysis of Covariance Comparing All 4 Treatment
Groups*
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The analyses of variance comparing change from baseline to the end of
the study in each active treatment group compared with the placebo group are
shown in Table 4. For the 1-g/d
group, all of the analyses on all 3 scales showed this dosage to be significantly
better than placebo. For the 2-g/d group, none of the comparisons approached
significance. For the 4-g/d group, comparisons approached significance in
the PP population but not in the ITT population.
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Table 4. Results of the Pairwise ANOVA Comparing Active Study Treatment
With Placebo*
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For the 1-g/d and placebo groups, the changes at 4, 8, and 12 weeks
in the PP population are shown in Table
5. For the HDRS and the MADRS but not for the BDI, the difference
was already significant at 4 weeks. On all 3 rating scales, the difference
was significant, or approached significance, at 8 and 12 weeks.
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Table 5. Changes From Baseline at 4, 8, and 12 Weeks in Study Parameters*
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To probe what depressive symptoms might respond to the 1-g/d dosage
of ethyl-eicosapentaenoate, the 3 main components of the HDRS (items 1-3,
depression; items 4-6, sleep; and items 9-11, anxiety) and the 10 items of
the MADRS were compared for the placebo and 1-g/d groups in the PP population.
All 3 components of the HDRS and 9 of 10 items of the MADRS showed the 1-g/d
dosage to be significantly better than placebo. On all 20 items of the BDI,
the 1-g/d dosage was better than placebo, with particularly large and significant
differences for sadness, pessimism, inability to work, sleep disturbances,
and libido. The effect of ethyl-eicosapentaenoate applies to all major components
of the depressive syndrome and is seen equally in the patient and physician
assessments.
COMMENT
At all dosages given, ethyl-eicosapentaenoate was well tolerated, as
indicated by the reported adverse events and the low withdrawal rate. Only
12% of patients receiving ethyl-eicosapentaenoate failed to complete 12 weeks
of treatment. This compares with an average withdrawal rate in 6-week trials
of about 30% of subjects receiving tricyclic antidepressants and of about
27% of subjects receiving SSRIs.4 The only
common adverse event was mild and self-limited gastrointestinal disturbance.
All of the patients in this trial were given 4 g/d of oily material. Such
disturbance is likely to be less if in the future only the optimal dosage
of 1 g/d is administered.
Results of all 3 rating scales demonstrate clear efficacy at the 1-g/d
dosage of ethyl-eicosapentaenoate. The consistently significant effects are
surprising given that the trial was a small exploratory study. The trial was
too small to draw firm conclusions about the other treatment dosages. Although
there appeared to be a trend toward significant efficacy at the 4-g/d dosage,
larger studies would be required to elucidate possible beneficial effects
of the higher dosages. Because most of the participants in the trial were
women, it is not possible to draw conclusions about men, although inspection
of individual scores indicated that men also responded. The reality of the
antidepressant effect of ethyl-eicosapentaenoate is supported by results of
2 additional completed studies. One reported surprising improvement in a single
suicidal depressed male patient who had proved exceptionally refractory to
treatment.25 The other reported a highly significant
beneficial effect in a placebo-controlled study of patients with depression
who had initially responded to standard therapy but then relapsed while continuing
such therapy.26
Analysis of the individual components of the HDRS, the MADRS, and the
BDI indicates that the effect is a broad-spectrum one involving all of the
components of the depressive syndrome. Depression, anxiety, sleep, and lassitude
all responded equally well.
Larger studies of various dosages of ethyl-eicosapentaenoate as add-on
therapy and as sole therapy in men and women are now required. It is likely
that different individual patients will require different dosages. The substantial
effect of the 1-g/d dosage in the present study is consistent with the findings
of the epidemiological studies.16-17
These studies show a sharp fall in the prevalence of both major depression
and postpartum depression at fish/seafood intakes that translate to long-chain
n-3 fatty acid intakes of 0.5 to 1.0 g/d. If these epidemiological studies
indicate a causal relationship, then they suggest that in many depressed patients,
a 1-g/d dosage of ethyl-eicosapentaenoate should be effective. Other patients
may require higher dosages.
The issue of the specificity of the action of ethyl-eicosapentaenoate
requires further exploration. Docosahexaenoic acid was not effective in schizophrenia,
whereas eicosapentaenoic acid was.20 A high
dosage of 4 g/d of docosahexaenoic acid was slightly less effective than placebo
in depression, but it is not known whether this finding was due to the dosage
or to a lack of efficacy of DHA specifically.27
At least 2 known mechanisms could lead to EPA being more effective than DHA.
In depression, production of prostaglandins from arachidonic acid by the cyclooxygenase
system has consistently been reported to be elevated.28-32
Eicosapentaenoic acid but not DHA is an effective substrate for cyclooxygenase
and can compete with arachidonic acid at this point. Also, in some phospholipase
A2 assays, EPA but not DHA has been reported to be an effective
inhibitor.33 These different effects of EPA
and DHA, which may include synergism and antagonism, mean that the biological
effects of fish oils, which contain both in highly variable proportions, will
be uncertain and difficult to predict.
The mechanism of action of ethyl-eicosapentaenoate requires much further
exploration. We think it unlikely that it can be explained by improved pharmacokinetics
or pharmacodynamics of existing drugs. Although individual patients may benefit
from increasing antidepressant dosages, no substantial studies of existing
drugs have shown such large improvements in outcome as a consequence of increasing
the dosage as the improvement that were seen in the 1-g/d group. No differences
were seen in the effect of ethyl-eicosapentaenoate between the different classes
of antidepressants. Limited numbers of patients not receiving any antidepressant
who have been treated by us in clinical practice have shown improvements similar
to those in this trial. Patients with schizophrenia not receiving any drug
therapy have responded to EPA.19, 21
Therefore, although modulation of background drug pharmacokinetics cannot
entirely be ruled out, we think it more likely that the ethyl-eicosapentaenoate
action is on cell membranes and signal transduction systems.
Ethyl-eicosapentaenoate has one side effect that is likely to be beneficial
in depression. It lowers triglyceride levels, inhibits platelet aggregation,
and inhibits cardiac arrhythmias.6, 34-35
In 2 large trials, EPA-containing products (providing EPA at a dosage of less
than 1 g/d) have been shown to reduce mortality related to heart disease.36-37 In view of the steadily increasing
evidence of associations between various types of cardiovascular disease and
depression, and that both disorders are associated with low blood EPA levels,
ethyl-eicosapentaenoate may be of particular benefit in depressed patients
who are also at risk for cardiovascular disease.6
CONCLUSIONS
Ethyl-eicosapentaenoate offers an approach to depression that is radically
different from that of existing drugs. Its position in the treatment spectrum
will be established only by further trials.
AUTHOR INFORMATION
Submitted for publication April 27, 2001; final revision received October
19, 2001; accepted November 1, 2001.
Dr Peet received research funding from Laxdale Research, Ltd, Stirling,
Scotland.
This study was presented as a poster at the Society of Biological Psychiatry
Meeting in New Orleans, La, May 2001; at the Fourth International Conference
on Bipolar Disorder, Pittsburgh, Pa, June 2001; and at the British Association
of Psychopharmacology Meeting, Harrogate, England, July 2001.
We thank Sharon Maxwell, Westlakes Scientific Consulting, for data management;
Alastair Sword, Pharmapart UK Ltd, for statistical analysis; and Anne MacKenzie
of Kendle UK, for project management. Packaging and provision of drug and
placebo capsules were performed by PCI Clinical Services. Adverse event monitoring
was performed by ClinTrials Research Ltd, Glasgow, Scotland. The patients
were seen by the following 2 groups of family practitioners in the United
Kingdom with a specialist interest in depression and in clinical trials of
antidepressant drugs: MGB Group: George Beaumont,
MB, ChB, and Max Gringras, MB, ChB, Poynton, England; and W. R. C. Aitchison,
MB, ChB, and G. I. McLaren, Bridge of Weir, Scotland. QED
Group: S. Connolly, MB, ChB, Hamilton, Scotland; J. Thompson, MB, ChB,
P. D. Flanigan, MB, ChB, and D. Kilgour, MB, ChB, Coatridge, Scotland; and
W. Scullion, MB, ChB, Airdrie, Scotland.
Corresponding author and reprints: David Horrobin, DPhil, BM, BCh,
Laxdale Research, Ltd, Kings Park House, Laurelhill Business Park, Stirling,
Scotland FK7 9JQ (e-mail: agreen{at}laxdale.co.uk).
From the Swallownest Court Hospital, Sheffield, England (Dr Peet);
and Laxdale Research, Ltd, Stirling, Scotland (Dr Horrobin).
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37. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico
(GISSI). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin
E after myocardial infarction: results of the GISSI-Prevenzione Trial. Lancet. 1999;354:447-455.
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