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