1. Fatty Acids in
Mood Disorders
Beyond ω-3 and ω-6
Johanna Assies, MD, PhD
Main co-workers:
Roel J.T. Mocking
Anja Lok
Claudi L.H. Bockting
Henricus G. Ruhé
Aart H. Schene
François Pouwer
Department of Psychiatry, University of Amsterdam
Fatty Acids in Depression, Diabetes and Schizophrenia Study Group (FADDS)

2. Depressive
MetS => Type 2 DM & CVD
disorders
FA-
metabolism
Oxidative stress Oxidative stress
1-C-Cycle
How to explain fatty acid alterations?

3. Metabolic syndrome (MetS)
• Cluster of risk factors for the development of type 2 DM and CVD
• Earliest and main hallmarks: insulin resistance and increased visceral fat
• Hypertension, dyslipidemia, non-alcoholic steatohepatitis
• Subclinical inflammation and thrombosis
• Increased activity Hypothalamo-Pituitary-Adrenal (H-P-A) axis
• Increased oxidative stress (↑ homocysteine, ↓ folate)

4. Fatty acids and the cell membrane
• Throughout the biological world, a 30 Å hydrophobic
film delimits the environments that serve as the
margin between life and death for individual cells
• “Membrane lipids: where they are and how they behave”
G. van Meer et al. Nature 2008;9:112-124

7. Fatty acids
• Essential constituents brain
– Key components
• Nerve cell membranes
• Synapses
• Regulation of cognition and emotion
McNamara RK, Carlson SE 2006

8. Fatty acids
• Fatty acids and oxidation products (eicosanoids and
docosanoids) play an important physiological role.
– Growth-development, metabolism, gene expression, signaling
– Immune system, inflammation, haemostasis
– ω-6 fatty acids (arachidonic acid) inflammation , haemostasis
– ω-3 fatty acids (EPA) inflammation , haemostasis
–
– (DHA) neuroprotective

9. Methylation
Methionine
S-adenosyl methionine
Vit B12
Folate cyclus Homocysteine Methylgroups
Vit B6 Cysteine PC/PE ratio
Transsulfuration Gluthation Antioxidant Desaturase activity
PUFA oxidation PUFA synthesis
LPOs ω-3/-6 celmembrane

10. Studies so far
• MDD Low intake of ω-3 PUFAs
- ↓ ω-3 PUFA’s, ↑ ω-6/ω-3 PUFA’s
in plasma, ery’s, AT, pm brain tissue
- ↑ Lipid peroxidation products
- ↑ Homocysteine, ↓ folate
However, these data and supplementation studies:
inconsistent results
Hibbeln JR 1998, Appleton KM 2010, Suominen-Taipale AL 2010

11. FA status plasma, tissues
• Diet
• Endogenous metabolism
Relation intake & incorporation non-linear
– Genetic factors
– Age, gender
– (Oxidative) stress
Smoking, alcohol, physical inactivity, psychological
stress, dietary glucose and saturated FA.
Hodson L 2008

12. Oxidative stress
• To live with O2 (breathe) is most basic lifelong stress.
Breathing means burning. In mitochondria food is
converted to basic energy units (ATPs) with the help of
molecular O2 and the formation of reactive oxygen
species (ROS).
• Ψυχη (soul) comes from Ψυχω (to breathe)
• Oxidative metabolism tightly controlled
• Oxidative stress = disbalance ROS production/ anti-oxidant
defense

13. • Study population
– 137 MDD-R patients
– 65 age & sex matched healthy controls

14. Results
Controls (n = 65) MDD-R (n = 137) p-value
Weight (kg ± SD) 73 ± 13 79 ± 16 < .05
BMI ± SD 24.5 ± 3.5 26.8 ± 5.2 < .001
WC (cm ± SD) 83.7 ± 12.2 89.3 ± 13.8 < .01
Current depression (%) 0% (0/65) 19% (26/136) < .001
Lok A 2011

15. Results
• Summarizing
– In erythrocytes
• SFAs and PUFAs ≥ 20 C chain length
• SFAs and PUFAs < 20 C chain length
• MUFAs equivocal results
– In plasma ~ results, but also MUFAs < 20 C
– Alterations in Desaturase and Elongase activity

16. General conclusions
• Partly explained by diet
but:
• Effects (oxidative) stress
• Genetic factors (mitochondrial dysfunction)
• Presence MetS
• Lifestyle: too much sugar and SFA, inadequate ω-3/ω-6
• Psychological stress, hyperactivity HPA-axis
• Physical inactivity

17. Methylation
Methionine -
-
S-adenosyl methionine
Vit B12
- + -
+
Folate cyclus Homocysteine Methylgroups
+ -
Vit B6 Cysteine PC/PE ratio
+ -
Transsulfuration Gluthation Antioxidant Desaturase activity
- -
PUFA oxidation PUFA synthesis
+ -
LPOs ω-3/-6 celmembrane
+ Increase during oxidative stress
- Decrease during oxidative stress

18. Discussion
• FA alterations evolve in response to ↑
oxidative stress
– (neuro)psychiatric diseases
• m. Alzheimer, m. Parkinson, schizophrenia, cystic fibrosis
• Family members
• Normal aging
– Reversible by ↓ oxidative stress

19. Hypothesis
• “adaptive”/”protective” value
– Lower unsaturation index (less double bonds) =>
more resistance against ROS)
– VLCFA incorporation: ceramide, sphingomyelins,
wax esters

20. Future research
– Lipidomics
– LPO’s
– MetS
– Risk factors
– Anti-oxidant strategies (mitochondrial)
– ↑ physical activity most effective

21. Epilogue
The Brain – is wider than the Sky –
For put them side by side –
The one the other will contain
With ease – and You – beside –
Emily Dickinson

22. Scheme