Diet and Mental HealthErik Messamore, MD, PhD

Consider• The brain operates at a very high metabolic rate• 2% of body weight, but consumes 20% of its

oxygen (and calories).• High oxygen consumption creates high oxidative

stress – and demand for antioxidants.• High metabolic activity requires amino acids, fats,

vitamins and minerals and trace elements.• Brain is 20% protein and 80% fat (dry weight)• 25 % of the body’s cholesterol is in the brain• DHA (an omega-6 fatty acid) comprises 35% of

the fatty acid content of nerve terminals

Outline of Topics

1. Current Diagnosed Illnesses (depression, schizophrenia, bipolar, etc) probably have multiple causes.

2. Understand the various types of fats, fatty acids

3. Review relationship of fatty acids to mental illness

4. Correlations between diet and mental illness

5. Obesity as a cause of inflammation/depression

6. Gluten and schizophrenia

Heterogeneity

• Mental Illnesses are HETEROGENEOUS• Hetero = ‘not the same’• Opposite of ‘homogenous’• What gets called [Insert psychiatric diagnosis

here] may actually consist of many different disease states the produce similar symptoms.

• Examples: headache, fever

Proof of Heterogeneity: drug responses

• Schizophrenia is at least 4 different diseases, based on medication response to first-line antipsychotic medication

1. Rapid response

2. Delayed response

3. Non-response (but does respond to clozapine)

4. Non-response (and non-responding to clozapine)

Proof of Heterogeneity: drug responses

• Possibly at least 7 types of depression based on medication response

1. SSRI fully responsive

2. SSRI partially responsive

3. SSRI non-responsive

4. SSRI adverse responsive

5. “atypical depression” responds to MAO inhibtor

6. “atypical depression” MAO-I non-responsive

7. Lithium responsive

Proof of heterogenity: brain waves

John ER et al. (2007) Electrophysiological subtypes of psychotic states. Acta Psychiatrica Scandinavica. 116:17-35

Quantitative electroencephalography reveals 6 distinct abnormal patterns in patients with schizophrenia

Proof of Heterogeniety: genetics

• Eight types of schizophrenia are suggested – based on a combination of symptom expression pattern and genetic variations.

• http://www.medicalnewstoday.com/articles/288051.php

Fats

Sundby P & Nyhus P (1963) Major and minor psychiatric disorders in males in Oslo. An epidemiological study. Acta Psychiatrica Scandinavica. 39:519-47.

46% of total calories in the sailors diets came from saturated fats

Christensen O & Christensen O (1988) Fat consumption and schizophrenia. Acta Psychiatrica Scandinavica. 78: 587-91.

Fats explained

• Fats and oils generally contain fatty acids• Fatty acids are long chains of carbon atoms• Carbon atoms form 4 chemical bonds

Carbon can form double-bonds and keep its ‘4-bond rule’

MethaneButane

Carbon Dioxide Butene

Fatty acids are long chains of carbon

Stearic acid, an 18-carbon-long fatty acid

“Saturated” means that all carbon atoms contain the maximum amount of hydrogen – or that all carbon atoms (in the ‘tail’) are

fully saturated with hydrogen

Stearic acid,18 carbons,fully saturated

Oleic acid,18 carbons,Mono-unsaturated

Trans fatHydrogen atoms on the same side of the double-bond

- Hydrogen atoms on opposite sides of the double-bond

- Associated with increased risk of heart disease

- May increase behavioral effects of stimulants, possibly leading to addiction

- High levels in rodents are transgenerational

Essential fatty acids

• Many highly unsaturated fatty acids cannot be made by the body.

• These are “essential” fatty acids – because they must be obtained from the diet.

Fatty acids form triglycerides and phospholipids

A triglyceride

A phospholipid

Triglycerides and Phospholipids form the cell membrane

Outer layer

Inner layer

Fatty acid composition affects membrane fluidity

Saturated fats stack tightly togetherMembrane approaches solid (like lard, butter, etc)

Polyunsaturated fats stack much more looselyIncreases fluidity (like olive oil)

Proteins exist within the cell membrane

All neurotransmitter receptors are transmembrane proteins

- Neurotransmitters or drugs bind to receptor proteins in the cell membrane.

- Receptor proteins do not function properly if the surrounding membrane is too rigid.

- Fatty acids themselves can act as signaling molecules.

- The wrong types of fatty acids lead to wrong messages in the cell.

Implications of Fatty Acid Derangements

• Changes in cell membrane fatty acid composition can profoundly impact the sensitivity of membrane proteins

• These include the receptors for serotonin, norepinephrine, dopamine, GABA, acetylcholine, and glutamate

• If the optimal fatty acids are not available (from the diet, or from metabolism), the body will substitute with suboptimal fatty acids.

Evidence for fatty acids importance to mental health

• Depression is less prevalent and less severe in countries where fish is a dietary staple (Japan, Iceland).

• Schizophrenia is less debilitating in countries with lower intake of saturated fats.

• Many (but not all) patients with mood disorders, anxiety disorders, and psychotic disorders have deficits in omega-3 fatty acids

Omega-3 fatty acid deficits in Borderline Personality Disorder

Is Omega-3 Supplementation Helpful?

• Clinical study results are mixed• Probably does benefit some subgroups of

patients (probably the ones who have essential fatty acid deficiencies)

• Dose and ratio of EPA:DHA is still uncertain• Studies finding mental health benefit use EPA at

doses between 1000 to 2000 mg per day

• 81 adolescents & young adults with subthreshold psychosis

• Half got 1200 mg/d of omega-3 fatty acids; the other half got placebo for 12 weeks.

• 40 weeks later:

Amminger, G.P., et al. (2010). Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch. Gen. Psychiatry 67, 146–154.

Percent with schizophrenia at 40 weeksomega-3 treatment group:

5%placebo group:

27%

Diet studies

Jacka et al., 2010

• Derived from large-scale osteoporosis study in southeast Australia

• Mental health and dietary data from 1,046 women

• Controlled for smoking, alcohol, socioeconomic status, education, and activity level

Odds of Depression or Dysthymia

Jacka et al., 2010

Western Diet Traditional Diet Modern DietMeat pies Vegetables

Fruits

Processed meats Fruit Salads

Pizza Beef Fish

Chips Lamb Tofu

Hamburgers Fish Beans

White bread Whole grain foods Nuts

Sugar Yogurt

Flavored milk drinks Red wine

Beer

General Health Questionnaire – 12 item

Able to concentrate Loss of sleep over worry

Playing a useful part Capable of making decisions

Feel constantly under strain Can’t overcome difficulties

Enjoy day-to-day activities Able to face problems

Feeling unhappy/depressed Losing confidence

Think of self as worthless Feeling reasonably happy

Jacka et al., 2010

Caution: Correlation ≠ Causation

Prospective Studies

• Among 8,964 college graduates who were free from depression at screening, those reporting frequent consumption of fast foods or commercial baked goods were 40% more likely to develop major depression over a 6 year followup period.

Sánchez-Villegas, A., et al. (2012). Fast-food and commercial baked goods consumption and the risk of depression. Public Health Nutrition, 15(3), 424–432.

Prospective Studies• 3,468 participants in the Whitehall II prospective cohort 2 groups

• ‘Whole food’ (vegetables, fruits, fish)

• ‘Processed food’ (sweetened desserts, fried food, processed meats, refined grains, high-fat dairy products)

• 5 year followup• High adherence to whole food diet 25% reduced

risk of depression• High consumption of processed foods 60%

increased risk of depression Akbaraly, T. N. et al. Dietary pattern and depressive symptoms in middle age. Br J Psychiatry 195, 408–413 (2009).

Interventional Study

• 95 forensic inpatients; mixed diagnoses (none with psychosis);

• 23 week food intervention.• Two groups:

• Salmon three times/week• Meat three times/week

• Hansen, A. L. et al. Reduced anxiety in forensic inpatients after a long-term intervention with Atlantic salmon. Nutrients 6, 5405–5418 (2014).

Hansen et al., 2014

Mediterranean Diet

• Emphasizes whole foods (fruits, vegetables, legumes, minimally-processed whole grains)

• Meat is primarily fish or poultry• Added oil is olive• Refined sugars are absent• Moderate intake of wine with meals• Dairy and red meats absent to minimally present

Mediterranean Diet

• Meta-analysis of research publications• 1.5 million research subjects• Adherence to Med Diet reduced:• Overall mortality (-9%)• Cardiovascular disease mortality (-9%)• Caner mortality (-6%)• Incidence of Alzheimer’s or Parkinson’s (-13%)Sofi, F., Cesari, F., Abbate, R., Gensini, G. F. & Casini, A. Adherence to Mediterranean diet and health status: meta-analysis. BMJ 337, a1344 (2008).

Mediterranean Diet

• Increase telomere length (associated with longevity)

• Improves insulin sensitivity• Reduces inflammation

Inflammation

Inflammation

• Inflammation is strongly associated with depression and psychosis.

• The body releases cytokines to stimulate immune response.

• Cytokines cause ‘sickness behavior’• Depression could be categorized into

‘inflammatory’ and ‘non-inflamed’ subtypes.• Schizophrenia can definitely be classified

according to presence/absence of inflammation.

Obesity

• Moods can influence food choice.• Some types of depression are associated with

increased food intake.• However… obesity reduces likelihood of benefit

from antidepressant medications.• Fat cells, especially those within the abdomen,

secrete inflammatory cytokines.

• Hryhorczuk, C. et al. Metabolic disturbances connecting obesity and depression. Front Neurosci 7, 177 (2013).

Causes of Obesity

• Sugar: The Bitter Truth – Robert H. Lustig

• Junk food* rewired rat dopamine receptor levels, setting the stage for addiction-like behaviors 1.Johnson, P. M. & Kenny, P. J. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat. Neurosci. 13, 635–641 (2010).

• Dopamine mediates pleasure, novelty, motivation

* Supplemental bacon, sausage, cheesecake, pound cake, frosting, and chocolate

Gluten• Celiac disease involves antibodies formed

against wheat protein.• Two case reports of schizophrenia-like

psychosis in otherwise normal individuals who – years later – developed clinical signs of celiac disease

Dohan, F.C., et al. (1969). Relapsed schizophrenics: more rapid improvement on a milk- and cereal-free diet. Br J Psychiatry 115, 595–596.

Gluten antibodies over-represented in schizophrenia

Cascella, N. G. et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull 37, 94–100 (2011).

Schizophrenian = 1,401

Control groupn = 900

Tissue transglutaminase antibodies

5.4% 0.8%

Anti-gliadin antibodies 23.1% 3.1%