Background 3 Fatty acids may inhibit neuronal signal transduction
pathways in a
manner similar to that of lithium carbonate and valproate, 2 effective
treatments for
bipolar disorder. The present study was performed to examine whether 3
fatty acids
also exhibit mood-stabilizing properties in bipolar disorder.
Methods A 4-month, double-blind, placebo-controlled study, comparing
3 fatty acids
(9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30
patients with bipolar
disorder.
Results A Kaplan-Meier survival analysis of the cohort found that
the 3 fatty acid
patient group had a significantly longer period of remission than the placebo
group
(P=.002; Mantel-Cox). In addition, for nearly every other outcome measure,
the 3
fatty acid group performed better than the placebo group.
Conclusion 3 Fatty acids were well tolerated and improved the short-term
course of
illness in this preliminary study of patients with bipolar disorder.
Arch Gen Psychiatry. 1999;56:407-412
BIPOLAR DISORDER (manic-depressive illness) is a common neuropsychiatric
illness
with a high morbidity and mortality.1 Despite available mood-stabilizing
drugs, such as
lithium carbonate and valproate, the illness is characterized by high rates
of
recurrence.1, 2 Recent research suggests that all of the currently available
mood-stabilizing drugs have inhibitory effects on neuronal signal transduction
systems.
These findings have led to the hypothesis that overactive cell-signaling
pathways may
be involved in the pathophysiological mechanisms underlying bipolar disorder.3-6
By
using this model of mood stabilizer action based on suppression of neuronal
signal
transduction mechanisms, novel mood-stabilizing agents can be rationally
developed.
One promising group of compounds is the 3 fatty acids, obtained from marine
or plant
sources.7 Among other effects, the ingestion of large amounts of 3 fatty
acids is
associated with a general dampening of signal transduction pathways associated
with
phosphatidylinositol, arachidonic acid, and other systems.8, 9 Thus, 3
fatty acids may
be useful in conditions such as bipolar disorder, where the pathophysiological
process
may involve overactivity of cell signal transduction.
We hypothesized that orally administered 3 fatty acids would exhibit inhibitory
effects
on signal transduction mechanisms in human neuronal membranes, and that
high-dose
3 fatty acids would be an effective mood stabilizer in bipolar disorder.
The goal of this
preliminary study was to assess the subacute mood-stabilizing effects of
3 fatty acids
in patients with unstable bipolar disorder.
PATIENTS AND METHODS
OVERVIEW
This was a 4-month, parallel-group, placebo-controlled, double-blind pilot
study in which
outpatients with bipolar disorder were randomized to receive either 3 fatty
acids or
placebo, in addition to their ongoing usual treatment.
PATIENTS
Participating subjects were men and women, 18 to 65 years old, who met
DSM-IV10
criteria for bipolar disorder (types I or II), and were free of notable
medical and
psychiatric comorbidity. The diagnosis of bipolar disorder was established
by means of
all available clinical information, including the mood disorder module
of the Structured
Clinical Interview for DSM-IV.11 Patients were required to have had at
least 1 manic or
hypomanic episode within the past year, because the expected high risk
of recurrence
in this subgroup1 enhanced the power of the study to detect a difference
between the
2 treatment groups within the study period. Forty percent of the study
cohort had
rapid-cycling symptoms, defined as 4 or more mood episodes in the 1 year
before
enrollment in the study.12 Patients were permitted to continue with their
outpatient
psychiatrist or psychotherapist, but no new psychotherapy treatment was
started.
Subjects receiving other medications at study entry continued to receive
these
medications at constant dosages, whether or not they were in the therapeutic
range.
Table 1 summarizes the demographic and clinical characteristics of the
study subjects.
This study was approved by the human studies committees of Brigham and
Women's
Hospital, Boston, Mass, and Baylor College of Medicine, Houston, Tex, and
all
participating patients gave written informed consent after receiving a
full explanation of
the study.
STUDY PROCEDURES
During the baseline visit, a detailed psychiatric and medical history was
obtained, and
the following standard rating scales were performed: Structured Clinical
Interview for
DSM-IV screening questions for current mania and depression, Young Mania
Rating
Scale13 (11-item structured interview version), Hamilton Rating Scale for
Depression14
(31-item structured interview version), investigator- and patient-rated
Clinical Global
Impression scale,15 the Global Assessment Scale,10 and a brief adverse-effect
rating
scale. The rating scales were repeated during office visits at weeks 2,
4, 6, 8, 12, and
16. Because of a presumed delay in the therapeutic effects of 3 fatty acids,
a priori
criteria mandated that subjects remain in the study for 30 days or more
to be included
in the analysis. Identical gelatin capsules containing concentrated 3 fatty
acid ethyl
esters or placebo (olive oil ethyl esters) were obtained from the Fish
Oil Test Materials
Program, a joint research program of the National Institutes of Health
and the National
Marine Fisheries Service. Each capsule of 3 fatty acid concentrate contained
440 mg
of eicosapentanoic acid (C20:5,3) and 240 mg of docosahexanoic acid (C22:6,3),
which was vacuum deodorized and supplemented with tertiary-butylhydroquinone,
0.2
mg/g, and tocopherols, 2 mg/g, as antioxidants. The source of the 3 fatty
acids was
menhaden fish body oil concentrate.
Subjects were randomized by the Brigham and Women's Hospital Research Pharmacy
to receive either 3 fatty acid treatment or placebo. The randomization
was stratified
according to sex, the presence or absence of concurrent lithium treatment,
and the
presence or absence of rapid cycling. Subjects received 7 capsules twice
daily, for a
total daily 3 fatty acid dosage of 6.2 g of eicosapentanoic acid and 3.4
g of
docosahexanoic acid. Patients randomized to placebo also received 7 identical
capsules twice daily. A relatively high dosage of eicosapentanoic acid
and
docosahexanoic acid was used, because similar doses have been safely and
effectively administered in other disease states. Furthermore, because
of the lack of
data regarding the effective dosage of 3 fatty acids in mood disorders,
a relatively
high dosage was chosen to avoid a potentially ineffective low dose. Blood
levels of 3
fatty acids were not monitored in this trial.
OUTCOME MEASURES
The main outcome measure chosen a priori was the duration of time to exit
double-blind treatment because of symptoms of bipolar disorder of sufficient
severity to
warrant a change in medication. Specifically, patients ended their participation
in the
study and treatment was considered to have change in medication. Specifically,
patients ended their participation in the study and treatment was considered
to have
failed if mood symptoms emerged, or continued beyond 30 days in patients
who were
not euthymic at baseline. Hence, duration of time in the study represented
an overall
measure of treatment efficacy. The two blinded principal investigators
(A.L.S. and
L.B.M.), in collaboration with each patient, were responsible for the decision
whether to
end a patient's participation in the study. Secondary outcome measures
were the
results of the Young Mania Rating Scale, Hamilton Rating Scale for Depression,
Clinical
Global Impression, and Global Assessment Scale ratings, before and after
treatment.
STATISTICAL ANALYSIS
A power calculation was performed before the study to determine the appropriate
sample size. Assuming a large effect size, we calculated that 60 patients
(including
dropouts) would be sufficient to demonstrate a difference between the 2
arms at 90%
power with an .05.
The study was originally intended to include 60 randomized patients, each
for 9
months of double-blind treatment. However, an unexpected cessation of production
by
the National Marine Fisheries Fish Oil Program led to a shortage of material.
Simultaneously, a preplanned, blinded, interim analysis performed when
20 subjects
had either failed treatment or completed 4 months suggested significant
differences
between the groups. The combination of these 2 factors led us to end accrual
and
then reanalyze the data after 30 patients had either failed treatment or
completed at
least 4 months of follow-up. A standard sequential design would prescribe
looking for a
P value of .02 or less to signal significance on the first interim analysis,
and a P value
of .04 or less to signal significance on the final analysis. Because of
the 2 factors cited
above, the results in this study fall between the interim and final analysis,
and the P
value designating significance could be taken conservatively as .015 or
liberally as
.042. A Kaplan-Meier "survival" analysis (Mantel-Cox log-rank statistic;
df=1) was used
to compare the duration of remission in the 2 groups. The rating scale
scores on the
last day of the study for each patient were used as the "final" data points
(last
observation carried forward). Categorical variables were analyzed by means
of the
Fisher exact test. Continuous variables were examined with the nonparametric
Mann-Whitney test. Statistical significance for the primary outcome measure
was set at
<.01 (2 tailed).
Forty-four patients were randomized, but only 30 had evaluable data, based
on the a
priori criteria for inclusion. Four subjects dropped out before the 1 month
point because
of noncompliance with the study protocol (n=2), gastrointestinal tract
side effects (n=1),
or concern over the possibility of receiving placebo (n=1). The remaining
10 subjects
had not yet reached the 4-month end point required for the main outcome
measure
when the trial was ended and therefore were not included in the analysis.
RESULTS
The results for the 30 patients with evaluable data, as defined above,
are presented
herein. There were no significant differences in the demographic and baseline
clinical
characteristics of the 3 fatty acid and placebo groups (Table 1). Figure
1 depicts a
Kaplan-Meier survival analysis of the study cohort. The duration of time
remaining in
the study was significantly greater in the 3 fatty acidtreated group
when compared
with placebo (P=.002; Mantel-Cox, log-rank statistic, 21=9.990). The time
to a 50%
rate of ending the study prematurely ("nonresponse") was 65 days for the
placebo
group, reflecting the unstable nature of the study population. A post hoc
analysis was
also performed for the subgroup of 8 subjects who entered the study while
receiving no
other mood-stabilizing drugs. As was observed in the whole study cohort,
the 4
subjects who received 3 monotherapy remained in remission for a significantly
longer
time than the 4 subjects who received placebo monotherapy (Figure 2; P=.04;
Mantel-Cox). Other post hoc analyses showed that sex, the presence or absence
of
rapid cycling, and the type of bipolar disorder (I vs II) did not predict
response to 3
fatty acids, although the number of subjects in each cell was small.
Table 1 displays the comparison of the secondary outcome measures between
the 3
and placebo groups. For nearly every outcome measure, the 3 fatty acid
group
performed better than the placebo group.
Three patients developed side effects of the study drug and were permitted
to lower
the dosage to a minimum of 5 capsules twice daily. The most common adverse
effect in
both the 3 and olive oil groups was mild gastrointestinal tract distress,
generally
characterized by loose stools. Of the patients with adverse effect data
at week 4 of the
trial, 8 (62%) of 13 3-treated subjects complained of mild gastrointestinal
tract side
effects, whereas 8 (53%) of 15 placebo-treated subjects experienced gastrointestinal
tract side effects (P=.72 by Fisher exact test; 2 subjects with missing
data). No other
adverse effects appeared with significant frequency or severity, and overall
the patients
tolerated the trial well. No research subjects were hospitalized or developed
marked
suicidal ideation or behavior. Demographic and clinical data for each subject
are listed
in Table 2.
COMMENT
3 Fatty acids used as an adjunctive treatment in bipolar disorder resulted
in significant
symptom reduction and a better outcome when compared with placebo in this
pilot
study. Improvement was significantly greater in the 3 fatty acid group
than the olive oil
control group on almost every assessment measure. The striking difference
in relapse
rates and response appeared to be highly clinically significant.
These pilot results are intriguing and suggest that the addition of 3 fatty
acids
improved the subacute course of illness in this cohort of patients with
bipolar disorder.
The baseline clinical state of the research subjects in this study did
not permit an
evaluation of the antimanic effects of 3 fatty acids. Although the study
was also not
designed to provide definitive data on antidepressant effects, most of
the patients
receiving placebo who were considered treatment failures exhibited depressive
exacerbations or recurrence. The suggestion of antidepressant effects of
3 fatty acids
in this cohort of patients is noteworthy and warrants further study.
Although this was a double-blind, placebo-controlled study, several methodological
factors must be considered. The mixture of bipolar types I and II, varied
mood states at
study entry, and varying concomitant medications was a less rigorous design
than in
the ideal clinical trial. The variability in the clinical profiles of the
study patients was
controlled to some degree by stratifying the randomization for sex, concurrent
lithium
treatment, and rapid cycling. It would be ideal, although impossible in
a small study,
also to stratify for other variables. However, the randomization did result
in a
comparable representation of key variables in the active and control groups,
including
concomitant medications and baseline mood state.
A further concern is the potential compromise of the blind. A distinct
"fishy" aftertaste
was episodically reported by subjects in both groups, but more often in
the 3 group.
When patients were asked to guess their randomization status, 86% of the
3 group
guessed correctly, compared with 63% of the placebo group. Although in
some cases
the guess was based on the presence of a fishy aftertaste, in many cases
it was based
on the patient's perceived clinical response (or lack thereof in the placebo
group).
Correctly guessing a putative active treatment in the presence of a good
clinical
response is probably unavoidable. However, the possibility that the 3 group
exhibited
a placebo effect must be considered. Future studies to replicate and extend
these
findings should consider strategies to improve the blind, such as using
a lower dose of
3 fatty acids to reduce the frequency of the fishy aftertaste, or alternatively
adding a
small amount of a fishy-tasting substance to the placebo.
If the results of this study are correct, and 3 fatty acids do possess
mood-stabilizing
action, then there are tangible implications for our understanding of the
pathophysiological mechanisms of bipolar disorder and for the development
of future
treatments. Biochemical studies of human white blood cells show that high-dose
therapy with 3 fatty acids leads to the incorporation of these polyunsaturated
compounds into the membrane phospholipids crucial for cell signaling.8,
16 Increased
concentrations of 3 fatty acids in membrane phospholipids appears to suppress
phosphatidylinositol-associated signal transduction pathways.8, 16 The
precise
mechanism of this effect remains unclear. However, the incorporation of
the
polyunsaturated 3 fatty acids into the lipid bilayer of the cell membrane
alters the
physical and chemical properties of the membrane,17 possibly producing
a local
environment in which the membrane phospholipids are more resistant to hydrolysis
by
phospholipases. This could result in reduced generation of the second messenger
molecules diacylglycerol and inositol triphosphate, thereby producing less
activation of
"downstream" intracellular signaling molecules, such as protein kinase
C and calcium
ion (Figure 3).
As in peripheral tissues, the 3 fatty acids are also highly incorporated
into neuronal
phospholipids in animal models.18 Thus, it is possible that the 3 fatty
acids also inhibit
signal transduction mechanisms in the human central nervous system. Recent
work by
several investigators3-6 strongly suggests that the mechanism of action
of typical mood
stabilizers, such as lithium and valproate, involves a similar inhibition
of postsynaptic
signal transduction processes (Figure 3).
Our results support other data suggesting that the mechanism of action
of mood
stabilizers in bipolar disorder is the suppression of aberrant signal transduction
pathways. This is consistent with a model of abnormal signal transduction
as the
pathophysiological basis of bipolar disorder. If further studies confirm
their efficacy in
bipolar disorder, 3 fatty acids may represent a new class of membrane-active
psychotropic compounds, and may herald the advent of a new class of rationally
designed mood-stabilizing drugs.
Author/Article Information
From the Psychopharmacology Unit, Division of Psychiatry, Brigham and Women's
Hospital (Drs Stoll, Severus, and Freeman, Ms Rueter, and Mr Diamond),
and
Department of Psychiatry, Harvard Medical School (Drs Stoll and Freeman),
Boston,
Mass; Free University of Berlin, Berlin, Germany (Dr Severus); and Department
of
Psychiatry, Baylor College of Medicine, Houston, Tex (Ms Zboyan and Drs
Cress and
Marangell). Dr Stoll is now with the Psychopharmacology Research Laboratory,
McLean
Hospital, Belmont, Mass, and continues with the Department of Psychiatry,
Harvard
Medical School.
Reprints: Andrew L. Stoll, MD, Psychopharmacology Research Laboratory,
McLean
Hospital, 115 Mill St, Belmont, MA 02478 (e-mail: alstoll@mclean.harvard.edu).
Accepted for publication October 2, 1998.
This study was supported in part by a grant from the National Alliance
for Research in
Schizophrenia and Depression (NARSAD), Chicago, Ill (Drs Stoll and Marangell).
Capsules of 3 fatty acids and matching olive oil placebo were provided
by the Fish Oil
Test Materials Program, a joint research program of the National Institutes
of Health,
Bethesda, Md, and the Southeastern Fisheries Science Center, National Marine
Fisheries Service of the National Oceanic and Atmospheric Administration,
Charleston,
SC.
Presented in part at the 36th Annual Meeting of the American College of
Neuropsychopharmacology, Waikoloa, Hawaii, December 10, 1997.
We thank John Orav, PhD, for his assistance with the statistical analysis.
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© 1999 American Medical Association. All rights reserved.