Dec 17, 2015
Boris Nemets, MD, Ziva Boris Nemets, MD, Ziva Stahl,MSc,Stahl,MSc,
RH Belmaker, MD.RH Belmaker, MD.American Journal of Psychiatry, American Journal of Psychiatry,
2002, 159:477-4792002, 159:477-479
Omega-3 Fatty Acid Treatment of Depressive
Breakthrough During Unipolar Maintenance
Eicosapentaenoic acid (EPA)Eicosapentaenoic acid (EPA)
Arachidonic AcidArachidonic Acid
Docosahexaenoic Acid (DHA)Docosahexaenoic Acid (DHA)
COOH
COOH
COOH
Fish Consumption and Prevalence of Major Fish Consumption and Prevalence of Major DepressionDepression
Annual apparent fish consumption (lbs per person)Annual apparent fish consumption (lbs per person)
Annu
al pr e
vale
nc e
of
majo
r depre
s si o
nA
nnu
al pre
val e
nc e
of
majo
r depre
s sio
n (
rate
/100 p
eople
)(r
ate
/100 p
eopl e
)
Hibbeln JR. Fish consumption and major depression. Lancet, 351: 1213, 1998
R=-0.84
P<0.005
New Zealand (5.8%)
Canada (5.2%)
France (4.5%)
Korea (2.3%)
Japan (0.12%)
West Germany (5.0%)
USA (3.0%)Puerto Rico (3.0%)
Taiwan (0.8%)
2
3
1
4
5
5
20 40 160
0
60 14012010080
Depletion of Omega-3 Fatty Depletion of Omega-3 Fatty Acid Levels in Red Blood Cell Acid Levels in Red Blood Cell
Membranes of Depressive Membranes of Depressive PatientsPatients
Malcolm Peet, Brendan Murphy, Malcolm Peet, Brendan Murphy, Janet Shay, and David HorrobinJanet Shay, and David Horrobin
Biological Psychiatry, 1998;43: Biological Psychiatry, 1998;43: 315-319315-319..
Time, days
20 806040 100 120
60
100
0
40
Cum
ulat
ive
Sur
viva
l%
Cum
ulat
ive
Sur
viva
l%
Stoll A, et al. Omega 3 fatty acids in bipolar disorder .Arch Gen Psychiatry, 56:407- 412 ,1999.
-Fatty Acids(n=14)
Placebo (n=16)
Survival Analysis Survival Analysis -- Remission timeRemission time
p=0.04, Mantel-Cox
20
Omega 3 in BPOmega 3 in BP
Are 3 Fatty Acids Are 3 Fatty Acids Beneficial in Depression Beneficial in Depression
but Not Maniabut Not Mania??Kuan-Pin Su, et alKuan-Pin Su, et al
Arch Gen Psychiatry. Arch Gen Psychiatry.
2000;57:716-72000;57:716-7
Study DesignStudy DesignFour-week parallel group double-blind add-onFour-week parallel group double-blind add-on
Criteria:Criteria:
Current Major Depression without psychotic features
(HDRS at least 18)
No limits on ongoing drug therapy, except no changes in past month
In fact only patients on maintenance drug In fact only patients on maintenance drug treatment with breakthrough depression were treatment with breakthrough depression were
referredreferred
Age: 18-75
No unstable medical disease / No alcohol or drug abuse
Ethyl EPA (Laxdale) or matching placebo (liquid paraffin) was given: two 500 mg capsules twice daily (2 gm/day)
HDRS at baseline and weekly for 4 weeks
55 , ,88 , ,1111 , ,1414 , ,1717--Eicosapentaenoic acidEicosapentaenoic acid / 5, 8, 11, 14, 17- / 5, 8, 11, 14, 17-icosapentaenoic acidicosapentaenoic acid
COMMON NAMECOMMON NAME: Eicosapentanoic acid: Eicosapentanoic acid
SYMBOLSYMBOL: EPA / C20:5n-3 / C20:5: EPA / C20:5n-3 / C20:533
FORMULAFORMULA: C: C2020HH3030OO22 MOL.WT : 302.451 MOL.WT : 302.451
Ethyl EPA: source, Laxdale, UKEthyl EPA: source, Laxdale, UK
COOH
DemographicsDemographics
Omega-3 Placebo
Sex
Male 1 2 Female 9 8Age
Mean (range) 54.2 (28-73) 52.5 (38-65)Previous episodes 2.1+ 2.6 1.8 + 1.3
Current episode
Length (days) 44.6 41.8Years of illness 7.6 + 7.6 8.0 + 6.5
Comorbidity
Dysthymia 1 1 Panic Disorder 1 1 OCD 1 0Ongoing Treatment
Paroxetine 1 5 Fluoxetine 4 3 Fluvoxamine 3 0 Citalopram 1 1 Mirtazapine 1 1 Moclobemide 0 1
0
5
10
15
20
25
30H
DR
S
Baseline 1 2 3 4
time (weeks)
Placebo (n = 9)
E-EPA (n = 10)
Excluding the drop-out, two-way MANCOVA of treatment by time (Greenhouse-Geisser
corrected) with covariance for baseline was performed. There was a significant effect of
treatment (F = 5.05, df1,16, p < 0.04) and of time (F = 22.6, df3,51, p < 0.001).
Treatment and time showed a statistically Treatment and time showed a statistically significant interaction (F = 12.09, dfsignificant interaction (F = 12.09, df1.6,27.81.6,27.8, p < , p <
0.001).0.001).
Ethyl-EPA was significantly different from placebo at week three (Sheffe post-hoc test, p = 0.01) and week four (Sheffe post-hoc test, p < 0.001). If the drop-out is included with last-value carried forward, all of the differences
became even more highly significant.
Patient# Age/Sex Treatment
1 38/f placebo 20 20 18 18 182 71/f E-EPA 25 24 18 11 73 50/f placebo 23 23 21 21 234 56/m placebo 19 22 22 22 205 61/f E-EPA 21 21 12 10 96 47/f placebo 27 27 23 23 257 73/f E-EPA 24 24 17 17 178 42/f E-EPA 18 18 18 13 139 65/m placebo 21 21 21 14 1410 56/f placebo 29 29 3411 51 /f E-EPA 26 26 18 18 2012 56/f E-EPA 24 24 24 21 2113 43/f placebo 26 26 29 29 2914 52/f E-EPA 26 26 18 15 1215 64/f E-EPA 26 26 14 9 616 43/f placebo 20 11 1 0 017 63/f placebo 21 21 21 25 2518 44/f E-EPA 22 21 8 8 219 28/m E-EPA 28 28 19 15 920 64/f placebo 24 24 25 25 26
Placebo 22.3 21.7 20.1 19.7 20 2.8 4.6 7.8 8.5 8.8
Ethyl-EPA 24 23.8 16.6 13.7 11.6 2.9 3.0 4.4 4.2 6.2
54.2 (x) 13.9 (SD)
10.2 (SD)
dropped out
52.1(x)
Hamilton Depression Rating Scale Week Week Week Week Week 0 1 2 3 4
EPA (n=10) Placebo (n=9) EPA (n=10) Placebo (n=9)
1 Depressed mood 2.0 2.0 1.20 0.33 0.02 Yes*2 Feelings of guilt 0.9 0.7 0.80 0.11 0.05 Yes*3 Suicide 0.1 0.1 0.10 -0.11 0.46 Yes4 Insomnia early 0.9 0.6 0.60 -0.33 0.01 Yes*5 Insomnia middle 0.9 0.3 0.70 0.00 0.02 Yes*6 Insomnia late 0.9 0.9 0.30 0.22 0.57 Yes7 Work and activities 2.0 2.0 1.20 0.33 0.02 Yes*8 Retardation 1.5 1.9 0.80 0.22 0.14 Yes9 Agitation 0.2 0.1 0.20 0.00 0.46 Yes
10 Anxiety (psychic) 1.5 1.3 0.60 0.11 0.07 Yes11 Anxiety (somatic) 1.2 1.0 0.40 0.11 0.29 Yes12 Somatic symptoms (GI) 1.1 0.9 0.30 0.00 0.27 Yes13 Somatic symptoms (Gen.) 1.1 1.2 0.20 -0.11 0.29 Yes14 Genital symptoms 1.7 1.9 0.10 0.11 0.78 No15 Hypochondriasis 0.1 0.2 0.00 -0.11 0.68 Yes16 Actual weight change 0.4 0.6 0.30 0.22 0.78 Yes17 Insight 0.0 0.0 0.00 0.00 1.00 No18 Diurnal variation (B) 1.4 1.6 0.70 0.22 0.24 Yes
19Depersonalization and derealization
0.0 0.0 0.00 0.00 1.00 No
20 Paranoid symptoms 0.0 0.0 0.00 0.00 1.00 No
21Obsessional and compulsive symptoms
0.2 0.0 0.10 0.00 0.71 Yes
22 Helplessness 2.0 1.8 1.30 0.22 0.01 Yes*23 Hopelessness 2.0 1.7 1.30 0.22 0.01 Yes*24 Worthlessness 2.0 1.8 1.30 0.22 0.01 Yes*
24.1 22.4 12.50 2.00
Baseline Improvement Score
Total
Omega Oil Favored?
Hamilton Depression Rating Scale Items
P
* P<.05, Mann-Whitney
E P A P l a c e b oY E S 6 1N O 4 9
50% Reduction in HDRS50% Reduction in HDRS
Fisher’s exact, p = .057Fisher’s exact, p = .057
PUFAs in Bipolar Disorder StudyDiagnosisNEPA g/dDHA
g/dResultsDesign
Stoll et al (1999)
Bipolar306.23.4Longer survival till affective episode in omega group
Double-blindPlacebo controlledAdd-onProphylaxis
Keck et al (2003)
Bipolar depressed5960No benefitDouble blind Placebo controlledAdd-on to mood stabilizer; Treatment
Keck et al (2003)
Bipolar (rapid cycling) hypomanic or depressed
6260No benefitDouble blind Placebo controlledAdd-on to mood stabilizer; Treatment
Frangou et al(2002)
Bipolar depressed751 or 20Greater improvement in omega group
Double-blindPlacebo controlledAdd-onTreatment
Osher et al(2005)
Bipolar depressed12202/3 of patients > 50% reduction on HAM-D within first month
OpenAdd-on to mood stabilizer; Treatment
Osher Y, Belmaker RH, Nemets B. Clinical Trials of PUFAs in Depression: State of the Art. World Journal of Biological Psychiatry (in press).
PUFAs in Unipolar DisorderStudyDiagnosisNEPA g/dDHA g/dResultsDesign
Peet et al (2002)
Unipolar persistent
17181718
124
0 (placebo group)
0000
Greater improvement in omega No benefit No significant benefitNo benefit
Double-blindPlacebo controlledAdd-onTreatment
Su et al(2003)
Unipolar persistent
284.42.2Lower depression ratings in omega group
Double-blindPlacebo controlledAdd-onTreatment
Marangell et al(2003)
Unipolar depressed
3602No benefitDouble-blindPlacebo controlledMonotherapyTreatment
Horrobin et alPersonal communication
Unipolar depressed – low SES
11510No benefit (although omega was superior to placebo in that subgroup of patients with higher folate levels)
Double-blindPlacebo controlledAdd-on in resistant to SSRI’s; Treatment
Silvers et al(2005)
Unipolardepressed
770.62.4No benefit over placebo; both groups improved significantly after two weeks
Double-blindPlacebo controlledAdd-on; Treatment
Osher Y, Belmaker RH, Nemets B. Clinical Trials of PUFAs in Depression: State of the Art. World Journal of Biological Psychiatry (in press).
Omega-3 Treatment of Childhood Depression: Omega-3 Treatment of Childhood Depression: A Controlled Double-Blind TrialA Controlled Double-Blind Trial
Nemets H, Nemets B, Apter A, Bracha Z, Nemets H, Nemets B, Apter A, Bracha Z, Belmaker RHBelmaker RH
American Journal of Psychiatry, 163(6):1098-American Journal of Psychiatry, 163(6):1098-100100 , 2006
Omega-3 for Childhood Depression
Symptoms of Major Depressive DisorderSymptoms of Major Depressive Disorder Common to Adults, Children, and Common to Adults, Children, and
AdolescentsAdolescents •Persistent sad or irritable mood
•Loss of interest in activities once enjoyed
•Significant change in appetite or body weight
•Difficulty sleeping or oversleeping
•Psychomotor agitation or retardation
•Loss of energy
•Feelings of worthlessness or inappropriate guilt
•Difficulty concentrating
•Recurrent thoughts of death or suicide
• Five or more of these symptoms must persist for 2 or more weeks before a diagnosis of major depression is indicated.
The Prevalence of MDDThe Prevalence of MDD
• 0.3% to 1% among preschool-age children • 1% to 9% among school-age children• 4% to 8% among adolescents.• among adolescents is similar to that
among adults - 15% to 20%. • Prevalence among boys and girls is
approximately equal • In adolescence the incidence among girls is
nearly double that among boys, a disparity that persists throughout adulthood
Summary of Double Blind, Placebo-Controlled Studies of Tricyclic Summary of Double Blind, Placebo-Controlled Studies of Tricyclic Antidepressants in the Treatment of Major Depressive Disorder Among Antidepressants in the Treatment of Major Depressive Disorder Among
Children and AdolescentsChildren and Adolescents
First author
and year
Drug Doserange
Duration
weeks
Sample size
Age Male Female Inpatient or
outpatient
RESPONSE RATE(%)PLACEBO
RESPONSE RATE(%)
TCA’s
Puig-Antich 1987
Imipramine
5 mg per kg
5 38 Prepubescent 23 15 Mixed 68.2(15/22) 56.3(9/16)
Geller 1989
Nortriptyline
Plasmalevel
Fixed 8 50 Prepubescent 35 15 Outpatient 16.6(4/24) 30.8(8/26)
Geller, 1989
Nortriptyline
Plasmalevel
Fixed 8 31 Adolescent 17 14 Outpatient 21.1(4/19) 8.3(1/12)
Kutcher 1994
Desipramine
200 mg 6 42 Adolescent 15 27 Outpatient 36(9/25) 47.1(8/17)
Kye,1996 Amitriptyline
5 mg per kg
8 31 Adolescent 22 9 Outpatient 56-72 15-85
Birmaher, 1998
Amitriptyline
5 mg per kg
10 27 Adolescent 8 19 Inpatient 77-78 57-86
•Summary of Double Blind, Placebo-Controlled Studies of Selective Summary of Double Blind, Placebo-Controlled Studies of Selective Serotonin Reuptake Inhibitors and New Antidepressants in the Serotonin Reuptake Inhibitors and New Antidepressants in the Treatment of Major Depressive Disorder Among Children and Treatment of Major Depressive Disorder Among Children and
AdolescentsAdolescents
•First author
and year
•Drug •Dose range
•Duration (weeks)
•Sample size
•Scale •Age •Male •Female •Inpatient or
outpatient
•Response rate(%)
•Placebo
•Response rate(%)
•Drug
•Simeon 1990
Prozac 50mg 7 40 •HDRS•CGI-I
13-18
18 22 •Mixed 6363
7176
•Emslie, 1997
Prozac 20 mg 8 96 •CGI-I at exit
•CDI-I at
completion
7-17 52 44 •Outpatient 33
58
58
74
•Mandoki, 1997
Efexor 37.5-75mg
6 33 •HDRS•CDRS
8-18 25 9 •Outpatient nsns
nsns
•UK Committee on Safety of Medicines warning•FDA’s “black box” warning ( October 15, 2004 )
Study DesignStudy Design
Four-month parallel group double-blind placebo-Four-month parallel group double-blind placebo-controlledcontrolled
Methods:Methods:1.Current Childhood Major Depression without
psychotic features (All children are diagnosed using the Hebrew translation of the Childhood version of the Schedule for Affective Disorders and Schizophrenia) (Apter et al., 1989).
2.Age: 7 – 12
3.Mixture of Ethyl EPA and DHA (ratio 2:1) or matching placebo was given: two 500 mg capsule twice daily (1 g of active substance/day)
4.CDRS, CDI and CGI-S at baseline and CDRS, CDI, CGI-S and CGI-I at week 2, 4, 8, 12 and 16.
Children’s Depression Rating Children’s Depression Rating Scale, Revised (CDRS-RScale, Revised (CDRS-R)
by Elva O. Poznanski, M.D. and Hartmut B. Mokros, Ph.D.
• Impaired Schoolwork
• Difficulty Having Fun
• Social Withdrawal
• Appetite Disturbance
• Sleep Disturbance
• Excessive Fatigue
• Physical Complaints
• Irritability
• Excessive Guilt
• Listless Speech
• Low Self-Esteem
• Depressed Feelings
• Morbid Ideation
• Suicidal Ideation
• Excessive Weeping
• Depressed Facial Affect
• Hypoactivity
Children’s Depression Inventory (CDI)Children’s Depression Inventory (CDI) by Maria Kovacs, Ph.D
The inventory includes 27 items, each composed of three choices.
The child simply marks the choice that best describes his or her feelings
or behavior over the past 2 weeks.
The test provides five Factor Scores:
Negative Self-EsteemAnhedoniaNegative Mood Ineffectiveness Interpersonal Problems This usually requires less than 15 minutes.
DemographicsDemographics
Omega - 3 Placebo Sex
Male 7 8 Female 3 2
Age Mean (range) 10.0) 8 - 12( 10. 3 ) 8 -12 .5 (
Current episode Length (months) 3. 5 ±1. 3 3.3±1.6
Comorbidity Stable ADHD 2 3
OCD 1 Separation Anxiety /Panic Disorder 1 1/1
Dysthymia 1 2 Stable Myasthenia Gravis 1
Chronic Tic 1 Concurrent medications
Methylphenidate 2 3
ResultsResults• 28 (20 M + 8 F) patients were recruited• Of the eight who dropped out before one
month, five were on placebo and three were on omega. Only reason for dropout before one month in omega group was noncompliance. Reasons for dropout before one month in placebo group were: 1) appearance of precocious puberty leading to an endocrine workup in one patient, 2) noncompliance in two patients, 3) non response in one patient, 4) manic episode in one patient.
0
10
20
30
40
50
60
70
80
0 2 4 6 8 10 12 14 16
weeks
Ch
ild
ren
's D
epre
ssio
n R
atin
g S
cale
placebo )n=10(omega )n=10(
Two-way repeated measures ANOVA of treatment over time showed a statistically significant interaction (F = 10.2, df 5,90, p < 0.001). There was a significant main effect of treatment (F = 12.2, df 1,18, p < 0.003) and time (F = 40.8, df 5,90, p < 0.001). Omega-3 vs. placebo was significantly different at week 8 (LSD post-hoc test, p = 0.04), week 12 (LSD post-hoc test, p = 0.03) and week 16 (LSD post-hoc test, p = 0.03).
StatisticsStatistics
OmegaPlacebo
YES70
NO310
Fisher exact, p=.003
50% Reduction in CDRS
(
(
0
5
10
15
20
25
0 2 4 6 8 10 12 14 16
weeks
CD
I
(placebo )n= 8
(omega )n=10
StatisticsStatistics
The self rating CDI results were similar. The “N” in placebo group was only 8 because two patients were unable to complete the self rating scale or did it with errors. Two-way repeated measures ANOVA of treatment over time showed a statistically significant interaction (F = 3.4, df 5,80, p < 0.005). There was a significant main effect of treatment (F = 5.5, df 1,16, p < 0.04) and time (F = 7.6, df 5,80, p < 0.001).
0
1
2
3
4
5
6
0 2 4 6 8 10 12 14 16
weeks
CG
I-S
(placebo )n=10
(omega )n=10
StatisticsStatisticsCGI results were also highly significant. Two-way repeated measures ANOVA of treatment over time showed a statistically significant interaction (F = 10.0, df 5,90, p < 0.0001). There was a significant main effect of treatment (F = 27.0, df 1,18, p < 0.001) and time (F = 28.3, df 5,90, p < 0.0001). Omega group vs. placebo were significantly different at week 8 (LSD post-hoc test, p = 0.014), week 12 (LSD post-hoc test, p = 0.003) and at week 16 (LSD post-hoc test, p = 0.002).
Dietary Sources of Omega-3Dietary Sources of Omega-3
Type of Fish
(raw unless specified)
Skate 0.4 0 0.1Oyster 1.3 0.2 0.5Squid 1.7 0.1 0.5
Lobster 1.6 0.2 0.3Crab 5.5 0.5 1.2
Saithe/Coley 1 0 0.2Mussel 1.8 0.3 0.5
Shrimp(boiled) 2.4 0.4 0.8Herring 13.2 0.8 2
Mackerel 16.1 0.7 2Sprat 9.9 0.9 2.4
Pilchard/Sardine 9.2 0.9 2.2Tuna 4.6 0.3 1.6
Salmon 11 0.5 2.3Trout(Rainbow) 5.2 0.2 1.2Cod Liver Oil 100 9 20
Walnuts 65.2 0 1.02Egg 10 0 0.17
Raw spinach 0.35 0 0.5
Total w-3Lipid Content
20:5 w-3
gm/100 g edible portion
Acknowledgements
Boris Nemets, MD
Ziva Stahl, PhD
Hanah Nemets, MD
Alan Apter, MD
Ziva Bracha, MD