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Ethyl-eicosapentaenoate and dexamethasone
resistance in therapy-refractory depression
R E V IE W AR T I C LE
International Journal of Neuropsychopharmacology (2004), 7, 341–349. Copyright f 2004 CINP
DOI : 10.1017/S1461145704004249
Harald Murck1, Cai Song2, David F. Horrobin1# and Manfred Uhr 3
1
Laxdale Ltd, Stirling, Scotland, UK, FK7 9JQ
Department of Psychiatry, University of British Columbia, Vancouver, Canada
3
Max-Planck-Institute of Psychiatry, Munich, Germany
2
Abstract
Preliminary evidence shows that ethyl-eicosapentaenoate (E-EPA) has a marked clinical effect when used
as an adjunct in therapy-refractory depression. EPA belongs to the class of polyunsaturated omega-3 fatty
acids. The mechanism of its action in depression is not fully understood. There are two related fields
where the pathophysiology of refractory depression meets the effect of EPA. First, a general immunosuppressive effect of EPA meets a general immunoactivation in severe depression, especially an increase
in CD4/CD8 ratio, neutrophilia, and an increase in interleukins (IL)-6 and IL-12 and of prostaglandin E2
(PGE2). Secondly, a resistance to dexamethasone (Dex) suppression of the HPA axis meets the effects of
EPA on multidrug resistance reversing and HPA axis suppression. The effects of EPA on the immune
system, the HPA axis, and multidrug resistance are connected through the action of a transport protein
called p-glycoprotein (p-gp). Physiological and synthetic steroids such as cortisol and Dex are substrates
of p-gp, and so Dex resistance in depression may be related to dysfunction of this protein. In addition,
expression of p-gp is induced by PGE2, and EPA inhibits the synthesis of PGE2. The reversal of drug
resistance by EPA may be mediated via this immunological mechanism and lead to its antidepressive
efficacy. In addition, antidepressants such as amitriptyline, which have special efficacy in severe depression, decrease p-gp function. EPA may, furthermore, enhance the action of antidepressants, like many
SSRIs that are p-gp substrates, which are actively transported out of the intracerebral space at the level of
the blood–brain barrier.
Received 9 July 2003; Reviewed 12 November 2003; Revised 3 December 2003; Accepted 10 December 2003
Key words : Eicosapentaenoic acid, HPA axis, melancholic, p-glycoprotein, peroxisome proliferatoractivated receptor, therapy-refractory depression.
Introduction
Preliminary evidence suggests ethyl-eicosapentaenoate (E-EPA) has a marked clinical effect when used as
an adjunct in therapy-refractory depression (Nemets
et al., 2002; Peet et al., 2002). E-EPA is the ethylated
form of EPA, a naturally occurring omega-3 fatty acid.
The mechanism of action for E-EPA is not yet known
but has a conceptual background very different from
that of currently used antidepressants. We wish to
outline a possible mechanism of action for E-EPA in
relation to well-described systems, especially the regulation of the hypothalamic–pituitary–adrenocortical
(HPA) axis, and the immune system, and include a
discussion of symptoms related to disturbances of
Address for correspondence : Dr H. Murck, Laxdale Ltd,
Laurelhill Business Park, Stirling, FK7 9JQ, Scotland, UK.
Tel.: ++44 1786 476022 Fax : ++44 1786 473137
E-mail : [email protected]
# Deceased 1 April 2003.
these systems. In this context we consider the characterization of a possible biological differentiation of
depression and especially discuss the biology of melancholic depression.
Subtypes of depression
Major depression is an inhomogeneous disorder. According to DSM-IV (APA, 1994) core symptoms have
to exist, i.e. depressed mood and loss of interest and
pleasure. Additional symptoms are psychomotor
changes, fatigue or loss of energy, feelings of worthlessness and guilt, cognitive impairment, recurrent
thoughts of death and vegetative features such as insomnia or hypersomnia and decreased or increased
appetite. A specification can be done to characterize
extreme and possibly better-defined syndromes, i.e.
depression with melancholic features contrasts to a
form with atypical features like hypersomnia and
hyperphagia. Early morning awakening and anorexia
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H. Murck et al.
or weight loss occur in melancholic patients. With regard to disturbances in mood, in melancholic patients
a distinct quality of mood and a lack of mood reactivity exist, whereas patients with atypical features
show a sensitivity to rejection and interpersonal problems. In the following we concentrate on the biology
of depression with melancholic features, as this type
seems to be related to distinct biological characteristics.
The biology and pharmacotherapy of atypical depression has been described elsewhere (Murck, 2003).
Laboratory correlates of clinical differentiation
One symptom of melancholic depression is pronounced sleep disturbance, especially intermittent
and early morning awakening. Highly disturbed sleep
is strongly associated with high nocturnal ACTH
(adrenocorticotropic hormone) and cortisol concentrations, as non-REM sleep duration is negatively correlated with the total secretion for both hormones
(Antonijevic et al., 2000). As intravenous administration of CRH (corticotropin-releasing hormone), the
central trigger of the HPA axis, to healthy subjects
leads to an increase of more shallow sleep (Holsboer
et al., 1988), the sleep disturbances in melancholic depression might be the consequence of an increase in
CRH release (Gold and Chrousos, 1998; Thase, 1998).
This arousal inducing and endocrine effect of CRH
seems to be mediated via the CRH1 receptor (Steckler
and Holsboer, 1999), one of two principal CRH receptors. Put together, the activity of the HPA system
could be directly linked to the sleep-EEG changes in
depression.
A further correlate of the HPA system overactivity
seems to be weight loss and decreased appetite, as
these features are correlated with increased urinary
cortisol concentration as well as with increased sleep
disturbances (Casper et al., 1987). An anorexic effect of
CRH seems to be mediated mainly by the CRH2 receptor (Hsu and Hsueh, 2001; Steckler and Holsboer,
1999), showing that the increase in HPA axis activity,
hyperarousal and weight loss are not mediated by a
dysfunction of one of the principal CRH receptor
types, but rather by increased CRH release. This assumption is further supported by a significant increase
in CRH concentration in the cerebrospinal fluid (CSF)
in depressed patients compared to normal controls
(Nemeroff et al., 1984). In a recent study in melancholically depressed patients CSF CRH was not increased in absolute values in comparison to normal
controls (Wong et al., 2000), but CSF CRH levels were
inappropriately high in relation to the elevated peripheral cortisol levels, indicating a disturbance in
the negative feedback system of the HPA system in
melancholic patients. A marked increase in CSF norepinephrine (NE) was also found in this study, pointing to a close association between an inappropriately
high CRH release and an increased NE release.
The main reason for increased CRH activity is assumed to be a disturbance of the physiological negative feedback loop of the HPA axis, i.e. the ability of
cortisol to suppress CRH and ACTH secretion. As a
marker of a disturbance of the negative feedback of the
HPA axis, the ability of the synthetic glucocorticoid
receptor (GR) agonist dexamethasone (Dex) to suppress cortisol has been widely used. Dex resistance
was primarily described in melancholic or endogenous depression (Carroll, 1982; Holsboer et al., 1986a)
and its correlation to the endogenous/melancholic
type is well established (Rush et al., 1996). Severity of
depression is furthermore related to the post-Dex cortisol concentration (Maes et al., 1986).
It is of interest that intermediate and late insomnia
(Nasr and Gibbons, 1983) and the number of awakenings (Hubain et al., 1998) are related to an increased
post-Dex cortisol concentration (Dex test), i.e. Dex
non-suppression, whereas it was negatively related to
stage-2 sleep, slow-wave sleep and REM sleep (Hubain et al., 1998). Some studies report a link between
weight loss and Dex suppression, but no relation between the core symptoms of depression (Maes et al.,
1990; Miller and Nelson, 1987), while other studies do
not support this relationship (Barocka et al., 1987).
In summary, sleep disturbances and weight loss as
features of melancholic depression are related to a
resistance of Dex to suppress HPA axis activity. This
might be mediated via the anorectic and arousing
actions of CRH.
Changes in immune function
The overactivity of the HPA axis in depression is
possibly related to changes in immune function.
Changes in the immune functions and inflammatory
response in depression have been summarized elsewhere (Licinio and Wong, 1999; Maes, 1995).
The most robust markers of major depression are an
increased CD4/CD8 T-lymphocyte ratio, neutrophilia
and lymphocytopenia, decreased cellular immune
function, increased prostaglandin E2 (PGE2) and proinflammatory cytokines such as interleukin (IL)-1 and
IL-6, and reduced natural killer cell (NKC) activity
(Zorrilla et al., 2001) and an increase in IL-12 (Kim
et al., 2002b). Further, the differentiation between melancholic and non-melancholic depression is supported
by a specific immunological pattern. The monocyte
Ethyl-EPA in therapy-refractory depression
count is decreased in melancholic depression and
increased in the non-melancholic form (Rothermundt
et al., 2001). Further, a correlation exists between the
severity of depression on the one hand and leukocytosis, monocytosis, and neutrophilia on the other
(Maes et al., 1992a). In addition, an increase in pan B,
pan T and CD8 T-cells has been described in melancholic depression (Maes et al., 1992b).
A bi-directional interaction between the immune
system and the HPA axis exists : the cytokines tumour
necrosis factor-a (TNFa), IL-1b, and IL-6 increase the
activity of the HPA axis by increasing the secretion of
CRH and the activity of the sympathetic nervous system (SNS) (Elenkov and Chrousos, 1999; Hayley et al.,
2002), whereas glucocorticoids lead to a decreased
CD4/CD8 ratio, decreased production of IL-12, TNFa,
IFNc and IL-2 (Elenkov and Chrousos, 1999), and reduced PGE2 through inhibition of cyclo-oxygenase 2
(COX2).
These observations imply that in melancholically
depressed patients corticosteroids have lost their effect
to depress the immune system activity. In fact, these
characteristics are reflected by Dex resistance, as described earlier. Moreover, Dex resistance is directly
correlated with mitogen-induced IL-1b production of
peripheral mononuclear cells in depressed patients
(Maes et al., 1993). The question arises: What does Dex
resistance mean on a cellular level ?
One observation concerning the action of Dex in
depression is important in this context : Dex-non suppression is often correlated to an increased excretion of
Dex from the bloodstream, i.e. correlated with a faster
decrease in Dex serum levels after Dex intake (Holsboer et al., 1986b; Wiedemann and Holsboer, 1987).
This links the findings of Dex-suppression to the excretion or metabolism of Dex. One protein responsible
for Dex secretion is p-glycoprotein (p-gp). P-gp is a
ubiquitous enzyme, which is also involved in the excretion of xenobiotics from the kidney into the urine
and from the liver into the bile (Haak et al., 2000). P-gp
was described initially because of its involvement in
multidrug resistance in tumour cells. P-gp is also expressed in immune cells (Frank et al., 2001) and in
endothelial cells of the blood–brain barrier (Ueda et al.,
1992; Uhr and Grauer, 2003), where it acts to hamper
the transport of corticosteroids into the cell or into the
intracerebral space respectively (Karssen et al., 2001;
Uhr et al., 2002). Reduced uptake of corticosteroids in
immune cells, mediated by p-gp, may explain the decreased sensitivity of leucocytes to Dex in melancholic
depression (Wodarz et al., 1991). Further the access of
corticosteroids to intracerebral structures, which are
involved in the negative feedback of the HPA axis, in
343
particular to the paraventricular nucleus of the hypothalamus (PVN), might be hampered. Direct evidence
for the importance of p-gp for the control of the HPA
axis activity comes from the observation, that p-gp
knock-out mice have a markedly suppressed activity
of the HPA axis and reduced CRH-mRNA expression
in the PVN (Müller et al., 2003).
How can such resistance develop ? As described
earlier, one of the most characteristic immunological
changes in severe depression is an increase in PGE2
secretion and overactivity of COX2. COX2 is responsible for the synthesis of the pro-inflamatory
PGE2. PGE2 conversely leads to an increase in p-gp
(Ratnasinghe et al., 2001; Ziemann et al., 2002). A related immunological mechanism has been described
in astroglia, were IFNc and IL-6 increase p-gp levels
(Monville et al., 2002).
Therefore immunoactivation by a variety of
reasons, including psychological stress, could lead to a
progressive increase in p-gp function and an increasing resistance to the dampening effect of glucocorticoids at the immune system and HPA axis
activity. These mechanisms could lead to a feedforward cycle, maintaining overactivity of the HPA
axis and the immune system, and as a possible consequence, the depressive state.
Relation to pharmacotherapy
Clinical evidence points to a better efficacy of tricyclic
antidepressants in patients with melancholic depression compared to other antidepressants, such as
SSRIs (Parker, 2001; Roose et al., 1994). Furthermore,
tricyclic antidepressants lead to a greater response in
Dex-resistant patients (Nelson et al., 1982). The tricyclic antidepressant amitriptyline reduces CSF CRH
concentrations in treatment-responsive depressed inpatients, but not in non-responsive patients (Heuser
et al., 1998). Additionally clinical improvement of
depression is accompanied by increased Dex suppression, i.e. decreased Dex resistance (Lisansky et al.,
1987). This points to the possibility that the presence
of melancholic features have a consequence for the
psychopharmacological treatment options.
Interestingly, amitriptyline reversed multidrug resistance in a human colon cell line (Varga et al., 1996).
Possibly both properties of this drug are related.
Accordingly, the action of several antidepressants,
which have the ability to increase GR-mediated gene
transcription in culture, is related to their ability to
affect p-gp function (Pariante et al., 2001). The tricyclic
antidepressant clomipramine showed the most pronounced effect to increase the functional activity of
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H. Murck et al.
the GR, whereas the SSRI fluoxetine seems to lack this
property. Similarly the binding of Dex to cultured
hippocampal neurons is increased by the treatment
with desipramine and amitriptyline, but less so with
paroxetine (Okugawa et al., 1999). Put together a relationship exists between melancholic depression, Dex
resistance and a response to amitripylin and other tricyclic antidepressants.
Influence of the unsaturated fatty acid EPA
A functional link between these findings comes from
measurements of unsaturated fatty acids in patients
with depression and the effect of unsaturated fatty
acids on the immune system, multidrug resistance and
therapy-refractory depression. The concentration of
omega-3 fatty acids, and especially EPA is decreased
in the serum (Maes et al., 1999) and red-cell membranes (Edwards et al., 1998) of patients with depression. Red-cell EPA levels were inversely related to
the severity of depression in one study, using a rating
scale consisting mainly of criteria for melancholic depression (Adams et al., 1996).
Administration of E-EPA showed a marked therapeutic effect in therapy-refractory depression in two
randomized double-blind, placebo-controlled trials in
patients not responding to standard pharmacotherapy, which were mainly SSRIs in these cases (Nemets
et al., 2002; Peet and Horrobin, 2002). These findings,
while promising, are preliminary and need further
replication. Nevertheless, if EPA is proven to have
antidepressant action its mechanisms of action need to
be explained.
With regard to the possible mechnism, at the cellular level EPA reduces PGE2 production in macrophages (Lo et al., 1999). Treatment with EPA leads to
a competition of EPA with arachidonic acid (AA)
and consequently to a decrease in AA-derived prostaglandin production (Calder, 2002). As AA is the
main substrate for PGE2 synthesis, this might be one
mechanism for EPA to reduce PGE2. Further, EPA
directly inhibits PKC activity in vitro (Kim et al., 2001)
and this enzyme is also involved in COX2 regulation
(Koyama et al., 1999). A correlation appears to exist
between COX2, PKC and p-gp expression (Ratnasinghe et al., 2001) and there is a direct causal link
between PKC and p-gp activity (Chambers et al.,
1992). A further mechanism of EPA action is its
effect on peroxisome proliferator-activated receptors
(PPAR). EPA is an agonist of PPAR-alpha (Sethi
et al., 2002) and of PPAR-gamma (Armstrong and
Towle, 2001), and also increases expression of these
genes (Chambrier et al., 2002; Inoue et al., 1998). PPAR
activation is known to reduce COX2 expression (Ikawa
et al., 2001; Kim et al., 2002a; Yang and Frucht, 2001).
In relation to the action of p-gp, various unsaturated
fatty acids including EPA, AA and docosahexaenoic
acid (DHA) are able to reverse vincristine resistance
in tumour cells (Das et al., 1998). Treatment with fish
oil decreased the serosal to mucosal flow of digoxin,
a substrate of p-gp, as a sign of a decreased p-gp activity ; this effect was also observed with different other
fatty acid preparations (Vine et al., 2002). Both DHA
and AA synergistically enhance Dex-induced gene
expression in HeLa cells (Vallette et al., 1995), while
both EPA and AA increase the sensitivity of human
lymphocytes to cortisol (Klein et al., 1989).
A certain interaction between AA and EPA is
necessary for normal brain function (Horrobin et al.,
2002). Low doses of E-EPA elevate membrane
phospholipid AA concentrations and in patients
with schizophrenia the improvement in symptoms is
correlated with the increase in AA concentrations.
Conversely, high doses of E-EPA reduce membrane
phospholipid AA concentrations, with a resultant loss
of clinical improvement (Horrobin et al., 2002; Peet
and Horrobin, 2002). This effect might be related to the
inverted U-shaped dose–response relationship observed in one trial in depression (Peet et al., 2002).
Experimental studies in rodent models of
depression
Olfactory bulbectomy (OB) in rats can influence
emotional aspects of behaviour based upon its disruption of the neuroanatomical connections to the
limbic system and is therefore used as a model for
depression. Many studies have demonstrated that
changes in behaviour, neurotransmission, endocrine
and immune functions in OB rats were similar to
those observed in depressed patients (Song and Leonard, 1995). Cairncross et al. (1977) reported that bulbectomy significantly elevated both basal and stressinduced plasma corticosterone concentrations. Decreased neurotrophil and lymphocyte functions and
increased acute phase proteins, reflecting an inflammatory response, also occur (Song and Leonard, 1995).
OB rats display hyperactivity in a novel ‘open field ’
environment, but in a Morris water maze they show
impairment in spatial learning and memory (Song and
Leonard, 1995). This abnormal behaviour is significantly attenuated by feeding the rats an E-EPAenriched diet for 6 wk (Song et al., unpublished observations). The elevation of corticosterone concentration
in OB rats is also blocked by E-EPA treatment (Song
et al., unpublished observations).
Ethyl-EPA in therapy-refractory depression
Modulation of HPA axis activity by E-EPA in stress
and depression was further demonstrated in another
rodent model : the IL-1b-induced stress, anxiety and
inflammation model. As mentioned above, an activation of the immune system has been found in depressed patients. IL-1b induces anxiety and stress-like
behaviour, impairs memory, and stimulates CRH release (Hayley et al., 2002; Song, 2000, 2002). We have
reported that following central IL-1b administration,
animals fed with a diet enriched with coconut oil or
palm oil showed stress-like behaviour ; they exhibited
reduced exploration and central zone entries in ‘ open
field’, and anxiety-like behaviour, shown as a reduced
number of entries into, and time spent on, open arms
of the elevated plus maze, when compared to rats
treated with saline (Song, 2000, 2002). Following IL-1b
administration to rats fed a diet of coconut or palm oil,
plasma corticosterone concentrations were markedly
increased and body weights were decreased (Song,
2002; Song et al., 2003). In contrast, in rats fed 1 % EEPA or 0.5 % EPA, but not 0.2 % EPA, IL-1b-induced
stress-like and anxiety-like behaviour, elevated corticosterone levels, and body-weight reduction were
largely reversed (Song et al., 2003).
It has also been reported that central IL-1b administration significantly impaired working and spatial
memory in the Morris water maze and 8-arm radial
maze models (Song, 2002). E-EPA attenuated this IL-1induced impairment in learning and memory, and
blocked IL-1-induced increase in corticosterone concentrations, with a GR receptor antagonist RU 486
showing a similar effect to E-EPA on learning and
memory (Song, 2002). Further, in rats exposed to cold
stress, a mixture of linoleic and alpha-linolenic acid,
the latter a precursor for EPA, reduces the increase in
corticosterone and prevents the deterioration of
learning (Yehuda et al., 2000).
Modulation of the HPA axis by EPA may be related
to the effects of EPA on the production of inflammatory cytokines and of PGE2, which can stimulate the
brain to release CRH. Recent evidence has suggested
that IL-1b induces the elevation of corticosterone via
the activation of PGE2 mRNA expression and PGE2
receptors (Engblom et al., 2002). Feeding E-EPA for
6–8 wk reverses the changes in PGE2 mRNA observed
in OB rats, and reverses the IL-1-induced changes observed in a separate model (Song et al., 2003; Song,
unpublished observations).
Therefore, these findings strongly support the hypothesis that E-EPA plays an important role in the
modulation of the HPA axis, in inflammatory stress,
mental stress, anxiety and depression. E-EPA may increase the functional activity of the GR, with a result-
345
ant higher sensitivity and an increased sensitivity to
adaptive changes. One possible mechanism could be
to normalize the feedback control of the HPA axis by
reducing p-gp activity.
Relevance to the pathophysiology and
pharmacotherapy of depression
With the p-gp inhibitory mechanism of EPA, monotherapy with EPA in melancholic depression appears
justified, although published clinical data up to now
only show the efficacy of E-EPA as an add-on therapy
in patients treated with SSRIs. A primary efficacy in
SSRI non-responders is, however, consistent with this
assumption. As stated above, SSRIs seem to be less
effective in melancholic depression. Assuming, that
responders to E-EPA are primarily those with Dex resistance, which is clinically related to melancholic depression, treatment with EPA targets a population that
is different from SSRI responders. This hypothesis is
presently being tested by a clinical trial using E-EPA
as a monotherapy. Another possibility is the effect of
EPA on the resistance to SSRIs. As the standard SSRIs
are substrates of p-gp (Uhr and Grauer, 2003 ; Uhr
et al., 2000), it might well be, that an increased p-gp
activity is linked to a low concentration in the brain.
This might be totally independent from the proposed
dysregulation of the HPA axis. The degree of drug
resistance in general is the target of the treatment with
E-EPA in these circumstances.
The first proposed mechanism of action of EPA is
to increase the efficacy of GR. However, an increase
in GR has been related to hippocampal damage
(Sapolsky, 2000). One currently examined strategy to
alleviate depression is through the blockade of GRs or
by the reduction of peripheral glucocorticoid synthesis
(Wolkowitz and Reus, 1999). The proposed strategy
with EPA may achieve the same goal through a more
physiological approach, namely by reducing the cortisol concentration at vulnerable brain loci, such as the
hippocampus and the amygdala. The increase in GR
sensitivity is suggested to reduce the cortisol concentration by increasing the strength of the feedback loop
at hypothalamic sites. Therefore the proposed strategy
is well in line with current concepts, but avoids possible side-effects, which might result from pronounced
unmodulated peripheral hypercortisolism as the result of GR blockade.
Conclusion
Put together, there is preliminary evidence that depressed individuals are deficient in EPA and that
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H. Murck et al.
EPA treatment is effective in relieving depression,
especially among treatment-resistant melancholic
patients. The mechanism remains uncertain but some
of the main possibilities include:
(1) An abnormality in post-receptor phospholipidrelated signal transduction. This could lead to
abnormal function of multiple neurotransmitter
system.
(2) An abnormality in the regulation of cytokine and
prostaglandin production by the immune system
and possibly also by endothelial cells, including
those of the blood–brain barrier.
(3) An abnormality in the regulation of the HPA axis
leading to overactivity at one or more levels.
(4) An abnormality in the p-gp system.
Of course these mechanisms are not mutually exclusive and they may well interact with each other to
produce an overall paradigm.
Acknowledgements
We gratefully thank Dr Mehar Manku and Dr Crispin
Bennett for their critical comments and improvements
of the manuscript.
Statement of Interest
Dr Murck is, and Dr Horrobin was, a full-time employee of Laxdale Ltd. Laxdale Ltd is developing
ethyl-eicosapentaenoate (E-EPA) for the treatment of
depression and other psychiatric illnesses. Laxdale
Ltd funded Dr Song’s research through a grant to her
employer, the University of British Columbia.
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