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Omega-3 Fatty Acids Evaluated for Bipolar Disorder
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Omega-3 Fatty Acids Evaluated for Bipolar Disorder
December 01, 1999 | Bipolar Disorder [1], ADHD [2], Schizophrenia [3], Comorbidity In Psychiatry
[4], Mania [5], Major Depressive Disorder [6]
By Arline Kaplan [7]
Intrigued by preliminary research indicating that omega-3 polyunsaturated fatty acids found in fish,
fish oil and flaxseed may ameliorate symptoms in bipolar disorder (BD), schizophrenia and other
psychiatric disorders, investigators have launched a series of double-blind trials evaluating fatty
acids as adjunctive treatment. This article will discuss studies on bipolar disorder.
(This is the first of two articles exploring the possible adjunctive uses for omega-3 fatty acids in
treating psychiatric disorders-Ed.)
Intrigued by preliminary research indicating that omega-3 polyunsaturated fatty acids found in fish,
fish oil and flaxseed may ameliorate symptoms in bipolar disorder (BD), schizophrenia and other
psychiatric disorders, investigators have launched a series of double-blind trials evaluating fatty
acids as adjunctive treatment. This article will discuss studies on bipolar disorder.
Mid-year, a four-month, double-blind, placebo-controlled study comparing omega-3 fatty acids (9.6
g/day) versus placebo (olive oil) in 30 patients with bipolar disorder was described in Archives of
General Psychiatry (Stoll et al., 1999). The eight co-authors concluded, "Omega-3 fatty acids were
well-tolerated and improved the short-term course of illness in this preliminary study of patients with
bipolar disorder."
Andrew Stoll, M.D., director of the Pharmacology Research Laboratory at McLean Hospital in
Belmont, Mass., assistant professor of psychiatry at Harvard Medical School and lead researcher for
the pilot study, said he and colleagues are ready to conduct a longer study, under a four-year grant
from the National Institutes of Health. It involves two sites: Harvard Medical School, with Stoll as lead
researcher, and Baylor College of Medicine with Lauren B. Marangell, M.D., director of the psychiatry
department's clinical psychopharmacology and mood disorders research, as lead researcher.
"It will be a larger-scale study involving 120 patients, with a similar design, but we are going to
control for concomitant medications much more tightly, we are going to control for baseline mood
states, and we are going to mask the placebo with a fish taste," he said, adding that these were the
main criticisms of the original study.
In the published preliminary study, the subjects-all outpatients-were men and women ages 18 to 65
who met DSM-IV criteria for bipolar disorder types I and II. Forty percent of the study cohort had
rapid-cycling symptoms. To enter the study, patients had to have experienced at least one manic or
hypomanic episode within the past year. However, they also had to be free of notable medical or
psychiatric comorbidity. Patients who were on other medications at the beginning of the study were
allowed to continue on them. Subjects received seven capsules bid for a total daily omega-3 fatty
acid dosage of 6.2 g of eicosapentanoic acid (EPA) and 3.4 g of docosahexaenoic acid (DHA).
Patients randomized to placebo also received seven capsules bid.
The primary outcome measure related to the emergence or continuation of mood symptoms.
Patients ended their participation in the study and treatment was considered to have failed if the
mood symptoms emerged or continued beyond 30 days in patients who were not euthymic at
baseline. Secondary outcome measures were the results of the Young Mania Rating Scale, Hamilton
Rating Scale for Depression, Clinical Global Impression Scale and Global Assessment Scale ratings,
taken before and after treatment.
Overall, nine of the 14 patients who received omega-3 fatty acids had symptom-relief, while only
three out of 16 patients who received the placebo showed relief, according to Stoll (McLean Hospital,
1999).
"Our study results indicate fish oil does possess elements to stabilize mood," he said.
More specifically, a Kaplan-Meier survival analysis of the cohort found that the omega-3 fatty acid
patient group had "a significantly longer period of remission than the placebo group (p=0.002;
Mantel-Cox). In addition, for nearly every other outcome measure, the omega-3 fatty acid group
performed better than the placebo group."
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While most patients in the study were on mood stabilizers, eight patients received no concomitant
medications. Of those eight, the four patients who received omega-3 monotherapy remained in
remission for a significantly longer time than did the four patients who received placebo
monotherapy. However, Stoll cautioned against using omega-3 as first-line monotherapy.
"I wouldn't recommend it first for people. The patients in the study had failed other [medications].
The only way I would use omega-3s by themselves is in someone with an extremely mild form of the
illness where treatment is almost optional. Otherwise, we use omega-3s as an adjunct," he said.
The most common adverse effect in both the omega-3 and olive oil groups was mild gastrointestinal
distress, generally characterized by loose stools. In an accompanying commentary to the published
study, Stoll and co-author Marangell noted the high patient interest and acceptance of omega-3 fatty
acids as mood stabilizers (Stoll and Marangell, 1999).
"This interest was based mainly on the recognition that omega-3 fatty acids are endogenous,
'natural' compounds with few side effects and little, if any, toxic effects," they said, adding that
several patients have remained on open-label omega-3 monotherapy for longer than two years with
continued efficacy.
Stoll told Psychiatric Times he uses omega-3 fatty acids as adjunctive medication in his clinical
practice.
"You don't usually use new medicines based on one small study, but the fact that these [omega-3s]
are so nontoxic and appear to be beneficial drives the equation toward using them," he said. "In fact,
there are more data on fatty acids than on Neurontin [gabapentin], which is being widely used."
To help answer his patients' questions, Stoll has developed a user's guide. For example, he advises
patients to find dietary supplement brands with high concentrations of omega-3 fatty acids to
minimize the number of capsules to be taken daily.
Asked about the importance of the preliminary study, Stoll said there were three areas of impact:
dietary, clinical and theoretical.
The study, Stoll said, pointed out how deficient Americans and people in other developed countries
are in omega-3 fatty acids. "We evolved eating these omega-3s, and we are not getting them
anymore. They are crucial for brain function," he said.
Clinically, the study results provided early evidence of the efficacy of omega-3 fatty acids for
adjunctive treatment of BD, Stoll added. If other studies confirm the efficacy, it means that omega-3
fatty acids can be considered to be "a nice mood stabilizer that has antidepressant properties and is
nontoxic."
On the theoretical front, Stoll said he and fellow investigators were searching for an agent with a
specific mechanism-sort of a designer mood stabilizer. "This mechanism may apply to other
compounds, and we may find a whole new class of mood stabilizers that have this membrane
activity," he said, adding that this mechanism was more definitively described in the published
article (Stoll et al., 1999).
"Biochemical studies of human white blood cells show that high-dose therapy with omega-3 fatty
acids leads to the incorporation of these polyunsaturated compounds into the membrane
phospholipids crucial for cell signaling," said Stoll and colleagues (1999). "Increased concentrations
of omega-3 fatty acids in membrane phospholipids appear to suppress
phosphatidylinositol-associated signal transduction pathways [Medini et al.,1990; Sperling et al.,
1993].
"The precise mechanism of this effect remains unclear. However, the incorporation of the
polyunsaturated omega-3 fatty acids into the lipid bilayer of the cell membrane alters the physical
and chemical properties of the membrane [Barton and Gunstone, 1975], 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 ionIt is possible that the
omega-3 fatty acids also inhibit signal transduction mechanisms in the human central nervous
system. Recent work by several investigators [Berridge et al., 1982; Chen et al., 1994; Manji et al.,
1996; Stoll and Severus, 1996] strongly suggests that the mechanism of action of typical mood
stabilizers, such as lithium and valproate [Depakote], involves a similar inhibition of postsynaptic
signal transduction processes."
In addition to the Harvard/Baylor study, a double-blind, placebo-controlled trial will examine the
efficacy of omega-3 fatty acids in the form of EPA for treatment of BD. Five NIMH-Stanley Foundation
Bipolar Network sites are participating in the project. Subjects will be randomly assigned in a
double-blind manner to 6 g/day of EPA or placebo as an add-on to ongoing treatment with
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Omega-3 Fatty Acids Evaluated for Bipolar Disorder
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mood-stabilizing medications that have proven unsatisfactorily effective within therapeutic range(s)
or at maximum tolerated doses. At the end of the four-month double-blind trial, patients can enter
an eight-month, open-label trial of omega-3 fatty acid (National Institute of Mental Health, 1999).
Research is occurring on the effect of omega-3 fatty acids on several psychiatric disorders, including
major depression (Edwards et al., 1998; Hibbeln et al., 1998a, 1998b), schizophrenia and
attention-deficit/hyperactivity disorder (ADHD).
References:
References
Barton PG, Gunstone FD (1975), Hydrocarbon chain packing and molecular motion in phospholipid
bilayers formed from unsaturated lecithins. Synthesis and properties of sixteen positional isomers of
1,2-dioctadecenolyl-sn-glycero-3-phosphorylcholine. J Biol Chem 250(12):4470-4476.
Berridge MJ, Downes CP, Hanley MR (1982), Lithium amplifies agonist-dependent
phosphatidylinositol responses in brain and salivary glands. Biochem J 206(3):587-595.
Chen G, Manji HK, Hawver DB et al. (1994), Chronic sodium valproate selectively decreases protein
kinase C alpha and epsilon in vitro. J Neurochem 63(6):2361-2364.
Edwards R, Peet M, Shay J, Horrobin D (1998), Omega-3 polyunsaturated fatty acid levels in the diet
and in red blood cell membranes of depressed patients. J Affect Disord 48(2-3):149-155.
Hibbeln JR (1998a), Fish consumption and major depression. Lancet 351(9110):1213 [letter].
Hibbeln JR, Linnoila M, Umhau JC et al. (1998b), Essential fatty acids predict metabolites of serotonin
and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset
alcoholics. Biol Psychiatry 44(4):235-242.
Manji HK, Bersudsky Y, Chen G et al. (1996), Modulation of protein kinase C isozymes and substrates
by lithium: the role of myo-inositol.
Neuropsycho-pharmacology 15(4):370-381.
McLean Hospital (1999), Study finds fish oil relieves symptoms of manic depression. Available at:
www.mcleanhospital.org/PublicAffairs/199905b_FishOil.htm. Accessed July 13.
Medini L, Colli S, Mosconi C et al. (1990), Diets rich in n-9, n-6 and n-3 fatty acids differentially affect
the generation of inositol phosphates and of thromboxane by stimulated platelets, in the rabbit.
Biochem Pharmacol 39(1):129-133.
National Institute of Mental Health (1999), Omega-3 fatty acids in treatment of major depression and
bipolar disorder: a double-blind placebo-controlled study. Clinical Research Study 99-M-0181.
Available at: clinicalstudies.info.nih.nimh. gov.cgi/detail.cgi?A_99-M-0181.html. Accessed Oct. 19.
Sperling RI, Benincaso AI, Knoell CT et al. (1993), Dietary omega-3 polyunsaturated fatty acids inhibit
phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 91(2):651-660. Stoll AL,
Marangell LB (1999), In reply. Arch Gen Psychiatry 56(5):415-416.
Stoll AL, Severus WE (1996), Mood stabilizers: shared mechanisms of action at postsynaptic
signal-transduction and kindling processes. Harv Rev Psychiatry 4(2):77-89.
Stoll AL, Severus WE, Freeman MP et al. (1999), Omega 3 fatty acids in bipolar disorder. A
preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 56(5):407-412.
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Links:
[1] http://www.psychiatrictimes.com/bipolar-disorder
[2] http://www.psychiatrictimes.com/adhd
[3] http://www.psychiatrictimes.com/schizophrenia
[4] http://www.psychiatrictimes.com/comorbidity-psychiatry
[5] http://www.psychiatrictimes.com/mania
[6] http://www.psychiatrictimes.com/major-depressive-disorder
[7] http://www.psychiatrictimes.com/authors/arline-kaplan
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