Modern Fats and Impaired Minds:

Omega-3 Fats in Aggression and Depression

CAPT Joseph R. Hibbeln, M.D.

Acting Chief, Section on Nutritional Neurosciences

Laboratory of Membrane Biochemistry and Biophysics

NIAAA, NIH, Rockville, MD

June 4, 2015

Mental Health America

This presentation does not represent any policy or position of

the US Federal Government. It is solely the scientific opinion of the presenter.

Why should psychiatry worry about nutrition?

3. Nutrition does not stop at the neck: The brain has very specific nutritional requirements Can nutrients that prevent medical illnesses also help mental illnesses?

2. The mentally ill need nutrition education focused to their needs.

Medication induced risks - Low income solutions- Simple clear advice

8 million (14.3%) deaths worldwide are attributable to mental health disorders

1. Nutrition can prevent mortality from chronic illnesses that are disproportionate among the mentally ill.

Mentally ill have higher all cause mortality 2.22 (95%CI, 2.12-2.33) (Cardiovascular disease, diabetes, pulmonary, ect)

Walker et al JAMA Psychiatry 2015

Which mammal has a greater requirement

for components to support its brain?

From: http://www.ruf.rice.edu/~pomeran/EyeBrainWorldAlumniCollege2003.htm Adaptedfrom: M Crawford

© A.J.Richardson, Food And

Behaviour Research 2010 © Professor Michael Crawford,

London

The priority of

human

development is

the brain.

60% of the brain’s

building material

is lipid.

Essential Fats: Metabolism and Dietary Sources

C- OH

O

20:4n-6, arachidonic acid

AA

Meat, Organs

FADS 1-2

Flax ~ Canola Leaf plants

C- OH

O

18:3n-3 alfa-linolenic acid,

ALA

C- OH

C- OH

O

20:5n-3, eicosapentaenoic acid,

EPA

Omega-3

Seafood

Breast milk

(DHA)

22:6n-3, docosahexaenoic acid,

DHA (brain, retina, testis)

O

C- OH

O

22:5n-6 DPA n-6

Series 2 Prostaglandins Thromboxanes

Series 4 Leukotrienes

Series 3 Prostaglandins Thromboxanes

Series 5 Leukotrienes

immune - metabolic - developmental

responses

Omega-6

O

C- OH

18:2n-6 linoleic acid,

LA Soy bean oil

Safflower oil

Corn oil

- Competition -

U.S. Diet Mediterranean Diet

COX 1-2 Aspirin

Other drugs

>$ 10 Billion

PGE2 TXA2

Thrombosis

PGE3 TXA3

COX 1-2

PLA2

G

“Marijuana like”

2-AG / AEA

Synapatmide

DHA- EA

Obesity

Addictions

Depression

New synapses

Neural

resilience

Family chaos and

social strife

Soil

Seed

Neuron

Family love and

social learning

Genetic Inheritance

Essential Brain Nutrients

Poor Soil Deficient in Nutrients

Pb Omega-3

fats

Omega-6

fats

Cao et al. J. Neurochem. 2009

Adequate DHA (22:6n-3) Deficient (22:5 n-6)

30 µm

10

Omega-3 HUFAs and

prevention of psychosis

Amminger P, 2010 Arch Gen Psych and http://www.forbes.com/sites/robertglatter/2014/11/16/can-fish-oils-prevent-development-of-psychosis/

Disorder Plausible mechanism

Epidemiological Ecological

Case control (Tissue)

RCT’s Meta-analyses

Positive clinical effect?

Size?

Major depression

Yes 54 17 42 5 Yes Large effect

ADHD Yes 6 15 10 2 Yes

Less than stimulants

Aggression

violence/conduct Yes 8 5 10 -

Replicates Large effect

40 % in felony violence

Anxiety Yes 2 5 3 - Probable

-

Alcohol/ Sub. use

Yes - 4 1 - Hopeful Large effect

Suicide Yes 6 4 1 - Hopeful

BRAVO is underway

Omega-3 HUFAs and High Risk Behaviors? Overview of human data

0

1%

2%

3%

4%

5%

6%

20 40 60 80 100 120 140 160

Apparent Fish Consumption (lbs./ person/year)

r =-0.84

p <0.005

M

ajo

r D

epressio

n,

Annual prevalence, (rate /10

0 perso

ns)

Japan (0.12%)

New Zealand (5.8%)

United States

(3.0%)

Puerto

Rico (3.0%)

Taiwan (0.8%)

Korea

(2.3%)

Canada (5.2%)

France (4.5%)

W. Germany

(5.0%)

Fish Consumption and Major Depression

Annual Prevalence by Country

Hibbeln, The Lancet 1998;351;1213

Primary Analysis n=52 g=.26 p=10-6

Hierarchical meta-analysis for omega-3 HUFA trials in depression

DHA Formula (>50% DHA) n=11 g=.02 p=.78

EPA Formula (>50% EPA) n=41 g=.34 p=10-7

Hypothesis 1

Mixed EPA (>20% DHA) n=12 g=.99 p=10-9

Enriched EPA (>80% EPA) n=9 g=.60 p=10-3

Hypothesis 3

Augmentation n=6, g=.93 p=10-6

Monotherapy n=6, g=1.06 p=10-3

Augmentation n=8, g=.61 p=10-3

Monotherapy n=1, g=.56 p=.10

Hypothesis 4

Clinically Depressed n=21 g=.81 p=10-9

Other populations n=20 g=.06 p=.09

Hypothesis 2

Hallahan, Davis, (Hibbeln group) Br J Psychiatry under revision

Key to tree diagram: When a branch’s g or n approaches 0, no further analysis occurs

Grey boxes contain branches hypothesized to decrease effect size. Orange boxes contain branches hypothesized to increase effect size.

Omega-3 HUFAs - Summary for Depression

Turner et al N Engl J Med 2008; 358:252-260, Kirsch I, et al PLoS Med. 2008 5(2):e45, Cuijpers P et al Psychol Med. 2010 ;40(2):211-23.

Therapies for Adult Major Depression - Effect sizes (Cohens d) Psychotherapy 0.22 Antidepressants 0.30-0.31 EPA enriched omega-3 HUFAs 0.81

Participants must have clinically significant depressive symptoms

EPA enriched formulations appear to be effective for clinical depressions

Publication bias in small studies and heterogeneity is evident

Effect sizes are good in comparison to other therapies

- 2015 US Dietary Guidelines for Americans. This scientific basis

identified neuropsychiatric health outcomes for nutrition. (2015

US DGA Scientific Report- Neuropsychiatric )

- 2014 American Psychiatric Association Practice Guidelines.

(2014 APA Practice Guideline for Major Depression)

- 2009 American Psychiatric Association Treatment

Recommendations of n-3’s in major depression. JRH served as

senior author (2009 APA)

Omega-3 HUFAs - Guidance for Depression

Pheneas Gage’s prefrontal cortex

Low serotonergic function in prefrontal cortex is a common mechanism underlying high risk, impulsive disorders

Frontal cortex levels of serotonin and dopamine are nearly doubled in piglet supplemented with omega-3’s

for the first 18 days of life

de la Pressa Owens and Innis 2000 Peds Research 48:1:125-130

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Serotonin 5-HIAA Dopamine HVA

Low LA/LNA formula

+ DHA (0.16%) and AA

(0.2%)

Un

its

in

mo

l/g

Std. infant formula + DHA (omega-3)

Std. infant formula (omega-6 rich)

Homicide Mortality Rates1 and Seafood

Consumption

1

2

3

4

5

6

7

8

9

10

11

0 20 40 60 80 100 120 140 160

Apparent Seafood Consumption (lbs/pers/year)

r = - 0.63

p < 0.0006

n = 26 countries

Ho

mic

ide

de

ath

s p

er

10

0,0

00 (

Ma

le +

Fe

ma

le)

Bulgaria

Chile

Finland

Hungary

Poland

Japan

Hong Kong

Norway United Kingdom

Portugal

Korea

Singapore

Spain

France

1World Health Statistics Annual 1995, WHO, Geneva Switzerland Hibbeln, JR World Rev Nutr Diet, 2001; 88; 41-46

Greece

Sweden Switzerland

Germany

Netherlands

Austria

New Zealand

Australia Canada

China

Israel

Italy

Children in Mauritius Prevention of lifetime criminal offending and schiotypy personality

Enrichment program (n=83) – Age 3 to 5, nutrition, education, and physical exercise.

– Lunch: structured nutrition program provided milk, fruit juice, a hot meal of fish

or chicken or mutton, and a salad each day.

Control group (n=355) usual community conditions, matched on temperament,

nutritional, cognitive, autonomic, and demographic variables

– Lunch: bread only, rice and bread, or rice only

Liu, Raine et al Arch Pediatr Adol Med 2003 157, 593-600 malnutrition = 22%

Criminal offending

23y

Control Enriched

Schizotypy

23 y

Conduct Disorder

17y

10

8

6

4

2

0

Sco

re

Malnourished Non-

Malnourished

25

20

10

5

0

15

Sco

re

Malnourished Non-

malnourished

%

40

35

10

5

0

15

30

20

25

36%

18%

0

0.5

1

1.5

2

0 Months 6 Months 12 Months

Delinquency

Group x Time, p = .0001

p < .001

d = .52

Mauritius Child Health Project

Age 8-16,

Randomized, stratified by age, gender

Blinded, 38.7% Creole, 61.3% Indian

n=95 omega-3, n= 89 placebo

6 mo. intervention, 6 mo. follow up

Child Behavior Checklist (parent)

Raine, Hibbeln et al 2014

1 gm omega-3

or placebo

200 ml smoothie

116 Kcal

Vitamin D (17%)

Antioxidants

4

5

6

7

8

9

0 Months 6 Months 12 Months

Internalizing Behavior

Group x Time, p = .0001

p < .0001

d = .59

Omega-3 specific

104

106

108

110

112

114

116

118

0 Months 6 Months 12 Months

Total

Group x Time, p = .0001

p < .0001

d = -.77 p < .008

d = -.39

Effect size p< Social Potency -.27

.03

Coldheartedness -.03

.01

Carefree Nonplanfulness -.31

.06

Fearlessness -.58

.07

Blame Externalization -.25

.04

Stress Immunity -.14

.03

Impulsive Nonconformity -.56

.02

Machiavellian Egocentricity -.19 .00

Parent Psychopathic Personality Inventory

Parents were less psychopathic when

their children took omega-3’s

Raine, Hibbeln et al, 2014

Child (Subjective)

↓ reactive

↓ proactive

aggression

Child (Observer)

↓ internalizing

↓ externalizing

↓ delinquency

Parent

↓ Psychopathology

Child (Observer)

- internalizing

- externalizing

- delinquency

Child (Subjective)

- reactive

- proactive

aggression

Parent

↓ Psychopathology

6 months Baseline

1 gm/d omega-3 HUFA

or placebo 12 months

No interventions

Flow of omega-3 HUFAs benefits

from child, to parent, to child

Raine, Hibbeln et al, 2014

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Before supplementation During supplementation

Rati

o o

f D

iscip

lin

ary

In

cid

en

ts S

up

ple

men

tati

on

/Baseli

ne

Active

Placebo

Error bars drawn at 2

standard errors to

indicate 95%

confidence interval

Reduced Felony Violent Offences Among Prisoners with recommended daily amounts of vitamins, minerals and

essential fatty acids

UK maximum security prison - 338 offences among 172 prisoners

over 9 months treatment in a compared to 9 months baseline.

Active -37.0%

p ‹ 0.005

Placebo -10.1%

p = ns

Gesch et al. Br J Psychiatry 2002, 181:22-28

VIOLENT CRIME

0.9

Year

Dis

ap

pearance (

kg/p

erso

n/y)

Palm/Palm Kernel

Peanut

Canola

Safflower

Sesame

Sunflower

0

2

4

6

8

10

12

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1909

1919

1929

1939

1949

1959

1969

1979

1989

1999

Coconut

Corn

Cottonseed

Olive

Soybean

Changes in Oils in the US Food Supply in the 20th Century

Blasbalg et al., Am. J. Clin. Nutr. 93: 950-962, 2011.

Ho

mic

ide

mo

rtal

ity

/10

0,0

00

Homicide mortality and availability of omega- 6 linoleic acid (en%) Combined Australia, United Kingdom, Canada

Argentina and USA data from 1961-2000

Omega-6 linoleic acid (en%)

0 2 4 6 8 10

0

2

4

6

8

10

r = 0.93 r2 = 0.86 p<1 X10 -40

1961

1985

1988 1999

1961 2000

1961

2000 1961

2000

1961

Australia

UK Canada

Argentina

USA

Hibbeln et al, Lipids 2004; 23: 1207-1213

50 mg/d 2,000 mg/d

250 mg/d 50 mg/d 2,000 mg/d

17% US MILITARY ACTIVE DUTY

2 3 6 12 9 15 18

Soy 8 en% n-6 LA

Eat less n-6 LA to help raise body n-3 HUFAs

n-3 % in HUFA

Omega-3 Index

Olive 3 en% n-6 LA

20% TAKE

URGENT ACTION

30% TAKE

REMEDIAL ACTION

40% ACTION

BENIFICIAL

50% HEALTHY OMEGA-3

LEVEL

60% ADJUST

FOR OPTIMAL

70% OPTIMAL OMEGA-3

LEVEL

+ n-3 HUFA

+ n-3 HUFA 250 mg/d 50 mg/d 2,000

mg/d

250 mg/d

Nix the omega-6

Avoid

Eat these

Better

The mentally ill need nutrition education focused to their needs.

- No US Government agency, nor Academic society provides this advice

- Every person with a mental illness deserves a dietician consult

- Medically prescribed consultations are often reimbursable

- But right now dieticians don’t know how to respond

Consider initiating a partnership - Nutritional/ Dietician Societies, - Patient Advocates, - US Govt.

ACTION ITEM: Develop a Nutrition Education Program for Mental Illness

Thank you

How to count capsules

to get 2 gm/d of EPA+DHA

Total oils

in capsule

EPA DHA EPA+DHA

/ capsule

# of

capsules

needed

1,000 mg

Unconcentrated

$ (cod liver oil)

120 mg 180 mg 300 mg =2,100 mg

7 caps

1,000 mg

molecularly distilled

$$

200 mg 300 mg 500 mg =2,000 mg

4 caps

1,100 mg

highly purified

$$$

600 mg 400 mg 1,000 mg =2,000 mg

2 caps

Vegetables

Shortening

1909

1929

1939

1949

1979

1989

19

99

Year

0

1

2

3

4

5

6

7

8

9

10

Soy Oil

>1,000 fold

Fats

Beef

Pork

Poultry

15

20

25

30

35

40

Grains

Dairy

Sugars

Perc

en

t en

erg

y

20th Century USA - Apparent consumption of commodities

Blasbalg, Hibbeln et al AJCN 2011