Micronutrients for mental illness:

rethinking the scientific paradigm

Julia Rucklidge, PhD

Dept of Psychology, University of Canterbury

Disclosure

• No commercial interest in any company or sale of any

product

A. What do we already know?

B. What theoretical background supports research?

C. What is the new emerging evidence?

D. How can we evaluate the evidence?

Deficiencies cause psychiatric sx B12 (psychosis of pernicious anemia) iodine (‘myxedema madness’) Niacin (pellagra)

Supplementation can ameliorate mood sx

Single ingredient research 1920s-present

iron, copper, zinc, vitamins B1, B6, B12, D, E and folate

▪ Cf Kaplan et al. (2007), Vitamins, Minerals and Mood, Psych Bull.

co-enzyme in production of neurotransmitters:

norepinephrine, serotonin, GABA

coenzymes for catechol-O-methyl transferase, needed in breakdown of catecholamines

Pyridoxal phosphate (B6)

Folic acid & Vit. B12

Ascorbic acid (Vit C)necessary in synthesis of

dopamine and norepinephrine

Tryptophan

5-Hydroxy-L-tryptophan Serotonin B6

Fe

5-Hydroxy-indolepyruvate B6

5-Hydroxy-N-formylkyunrenine B6

6-Hydroxy-kynurenate

3-Indole-glycolaldehyde Fe

Indole 3-Formyl-aminobenzaldehyde

B6

Cu

5-Hydroxyindole-acetylaldehyde

Fe

Molybd

Tryptophan

Serotonin

Diverted if short of B6

Xanthurenic acid

Diverted if body needs extra B3

Vitamin B3

Xanthurenic acid

Dopamine (DA) agonists, such as methylphenidate (MPH), effective in treating ADHD symptoms Possible mechanism: inhibiting DA transporter function

B vitamins may share structural similarities with methylphenidate Similar to MPH, biochemical activity of B vitamins may be via:

competitive binding to DAT dopamine binding site (DA transporter)

Results in a concomitant increase in synaptic DA concentration

activates postsynaptic dopamine receptor

Improves psychiatric symptoms

“As many as one-third of mutations in a gene result in the corresponding enzyme having…[a] decreased binding affinity for a coenzyme, resulting in a lower rate of reaction.”Ames et al., Am J Clin Nutr. 2002 Apr;75(4):616-58.

“About 50 human genetic diseases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity.”

Ames et al., Am J Clin Nutr. 2002 Apr;75(4):616-58.

Perhaps mental disorders reflect inborn errors of metabolism in some peoplepeople inherit a polymorphism that

results in decreased binding affinity of an enzyme(s)

that results in slowed metabolic reactions

which in some cases of genetic diseases, can be corrected at the endpoint with therapeutic nutrient combination regimens (Ames et al., 2002; Kaplan et al., 2007)

“The triage theory posits that when the availability of a micronutrient is inadequate, nature ensures that micro-nutrient-dependent functions required for short-term survival are protected at the expense of functions whose lack has only longer-term consequences, such as the diseases associated with aging”

For some maybe, but not for those who are already compromised...

Genetic mutationsStarvationGut problemsAllergiesMitochondrial DisordersSeverely stressedEating nutrient deficient food

Mayer, A B. Historical Changes in the Mineral Content of Fruit and Vegetables. British Food Journal 99(6). 1997. 207- 211.

Decrease in Mineral Content In VegetablesOver a 50 Year Period in the U.K.

They may simply need more than what they can get out of food...Changes in the quality of the food supply hasn’t helped

In infectious diseasesIn sexual disorders In cardiovascular diseasesIn Alzheimer’sIn stroke recoveryIn diabetic peripheral neuropathyIn pregnancy outcomesIn cognitive function, generallyIn reducing offences in prisoners

e.g. Farvid et al., 2011; Remington et al., 2008; Schoenhaler et al., 2000; Barringer et al., 2003; Sato et al., 2005; Liu et al., 2007; Shah et al., 2009: Gesch et al., 2002; Zaalberg et al., 2010; Smith et al., 2010

What’s the evidence for multiple ingredients?

80 children who had been disciplined at least once; randomly assigned to active or placebo 4 months tx

Active (18 ingredients): 100% RDA for 8 minerals, 3 fat-soluble vitamins, folate; 300% RDA remaining 7 water-soluble vitamins

Active supplement 47% fewer rule infractions.

Multivitamin tx (Berocca) with calcium, magnesium, and zinc 28 days

Double blind RCT – 80 healthy male volunteers Berocca was associated with significant reductions in anxiety and

perceived stress, less tired, and better able to concentrate as compared to placebo Carroll et al., 2000

Replicated in 215 males in terms of vigour, stress and mental health and improved cognitive performance Kennedy et al., 2010

Another RCT looked at the administration of selenium, vit C and folate in improving mood in nursing home patients: depression was associated with low levels of selenium and a subgroup with low selenium levels improved with suppl (Gosney et al., 2008)

RCT in 231 young offenders Supplement with a broad array of minerals,

vitamins, and some EFAs (26 ingredients)

Active supplement

26.3% fewer rule infractions 35.1% fewer violent acts

↓35%

↓6.7%

↓34%

14%

Tony Stephan married into family with genetic predisposition

~1995 his wife suicided; 8 children, two with Bipolar Disorder

David Hardy Worked for 20 yrs for animal feed company

Did research on feed for pigs, cattle

Eventually, they created EMPowerplus Ingredients & story on truehope.com

Not the only multi-ingredient formula --- but the only one for which there are many peer-reviewed scientific publications

36 ingredients: not exotic 14 vitamins 16 minerals 3 amino acids 3 antioxidants Relative importance?

Disclaimer: no funds go to investigators

open label in 11 adults with BD (Kaplan et al., 2001) and 14 children with a variety of psychiatric problems (Kaplan et al., 2004)

Significant reductions in all psychiatric symptoms to 6 months

Significant reduction in medications

Replicated in two other samples of adults with BD (Simmons, 2002; Popper, 2001)

Response rates approx 80%

Three case studies:

OCD: ABAB – off-on-off-on control of symptoms (Rucklidge, 2009)

ADHD and BD II – ABAB – again off-on-off-on control of symptoms (Rucklidge & Harrison, 2010)

12 year old male with schizophrenia and significant mood symptoms (Frazier et al., 2009)

Two database analyses of over 400 adults and children with Bipolar Disorder followed up to 6 months (Gately & Kaplan, 2009; Rucklidge, Gately, & Kaplan, 2010):

53% >50% improvement at 6 m Case control study of autistic children comparing EMP with

medications (Mehl-Madrona et al., 2009)

No grp differences on the Childhood Autism Rating Scale and the Childhood Psychiatric Rating Scale

0

5

10

15

20

25

30

35

Baseline Final Baseline Final

Micronutrient Group Medication Group

Num

ber o

f Chi

ldre

n

CGI Ratings also sign better in micronutrient group

120 children (7-18 years) reporting a diagnosis of BD 79% were taking psychiatric medications

24% also reported ADHD Using Last Observation Carried Forward (LOCF), data analyzed from 3 to 6

months of micronutrient use mean symptom severity of bipolar symptoms 46% lower than baseline (ES = 0.78) (p <

0.001) Responder status: 46% experienced >50% improvement at LOCF

38% still taking psychiatric medication (52% drop from baseline) but at much lower levels (74% reduction)

Results similar for those with both ADHD and BD: 43% decline in BP symptoms (ES = 0.72) and 40% in ADHD symptoms (ES = 0.62)

Duration of reductions in symptom severity suggests benefits not attributable to placebo/expectancy effects

An alternative sample of children with just ADHD symptoms (n = 41) showed: 47% reduction from baseline to LOCF (ES = 1.04)

0 20 40 60 80 100 120

clients from 1 to 120, ordered by bipolar symptom severity at Baseline

0

5

10

15

20

25

30

35

40

45

bipolarsymptom severityat Baseline and at Last ObservationCarried Forward

Ο

•

symptom severityof client #60 wentfrom 17.5 at Baselineto 20 at LOCF

symptom severityof client #40 wentfrom 20.7 at Baselineto 5 at LOCF

10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

% of 120 clients(ordered by greatest % reduction from Baseline)

-100%

-75%

-50%

-25%

0%

25%

% change inbipolar symptom severity

from Baselineto Last Observation

Carried Forward

20% of clients

21% of clients

21% of clients

14% ofclients

19% of clients

5% ofclients

14 participants (5 female), mean age age: 37.53 (9.56) Diagnosis: SCID-I and CAADID (structured interview assessing DSM-IV

based ADHD symptoms) and >70 on one of the DSM based scales of CAARS (self/observer)

6 (43%) ADHD Pred Inatt; 8 (57%) ADHD combined Co-occurring current diagnoses: 12 Mood Disorder (9 MDD/ 3 BDII 85.7%), 6 Social Phobia (42.9%), 3

GAD (21.4%), 3 drug/alcohol abuse/dependency (21.4%)▪ Mean GAF at baseline = 53.71 (6.26)▪ CGI-ADHD: 4.86 (.35) – moderately ill range▪ CGI Dep: 4.14 (1.29) – moderately ill range

Mean visits: 6.29 (.99)

T sc

ores

ES range from .98-1.88; for observer’s .6-1.45

14 control participants 8 males, 6 females

Age: 31.4 (SD = 14.27) Matched on IQ: control group: 116.7 ADHD group: 117.8

No difference on SES, gender, IQ

Stan

dard

Sco

res ES = .65

ES = .05

Stan

dard

Sco

res ES = -.28

ES = .38

40 completed, 53 recruited, aiming for 70 8 week EMP versus placebo 8 week open label Safety and toxicity being measured 6 month follow up post-trial

T sc

ores

All ES > 1 and sig differences between groups at 6 mnths(these groups were identical at 16 weeks)

September 4th 2010 4:35am

And the aftershocks...

Pooled three studies: Found 16 taking & 17 not taking micronutrients at time

of earthquake

All had ADHD diagnosis

Measured depression, anxiety, stress one week (Time 1) and two weeks (Time 2) post earthquake

RESULTS No differences in baseline functioning, co-occurring

diagnoses, ADHD subtype, SES, gender, ethnicity, IQ

No group differences at Time 1

Results (cont.) At Time 2, those taking micronutrients reported significantly less

anxiety and stress (effect size 0.69) no change from baseline to Time 2 for the control group (effect

sizes ranged from 0.11-0.45) significant changes in all areas assessed for the micronutrient

group at Time 2 (effect sizes ranged from 0.73-1.01) Investigated whether the control group had more EMP

nonresponders than the micronutrient group – no differences

*

Feingold Diet (1975)

1990s – diet viewed by many experts as causing only a small percent of cases of ADHD

Led to a loss of interest and rejection as an important contributing factor

Last year: supplementation studies (e.g. Katz

et al., 2011)

Relationship between

Western diet and ADHD

(Howard et al., 2010)

GxE studies (e.g.,

Stevenson et al., 2010)

Impact of food additives on

ADHD behaviours

(e.g. Pelsser et al., 2011)

Side effects? minor and transitory

Compliance? No difficulties with the regimen†

Impact on bloodresults?

None to date…*

*lack of difference in fasting glucose, lipids, white blood cell count, and neutrophils, but lack of very long term data on safety

†some find taking the pills tedious and stop for that reasonSimpson, JSA, Crawford, SG, Goldstein, ET, Field, C, Burgess, E, Kaplan, BJ (2011). Safety and tolerability of a complex

micronutrient formula used in mental health: A compilation of eight datasets. BMC Psychiatry. 11:62. http://www.biomedcentral.com/1471-244X/11/62.

Therapist effect Spontaneous remission of symptoms Expectancy/placebo effect Practice effects Experimenter bias

“The tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health

effects for almost all individuals in the specified life stage group.”

- Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes. National Academy Press, Washington, D.C., 2001.

Micronutrient safety

RDA: meets the nutrient requirements of nearly all (97-98%) of individuals in a life stage

BUT not expected to replete previously undernourished individuals

Also not relevant to individuals in disease states whereby there is an increase requirement for micronutrients Average gap between RDA and UL is 2271.7% - can

consume 22 times more before reach the upper limit For minerals: 874.3%

Bradford Hill, 1952: Created the basis for modern RCTs

1965: Recognized limitations – defined Bradford Hill criteria for establishing causation – 5 are relevant hereBiologic rationale

Strength of association (clinical significance)

Consistency of the evidence (across sites, studies)

Temporal sequence (A must precede B)

Experimental evidence (RCTs and others – such as studies where the effect is manipulated like ABAB)

We are getting there…

Availability Tolerability Cost to patient Cost to health service Patient preference

All issues to contend with for general acceptability

The only cause of mental disorders is nuritional insufficiency-- NO

Everything can be cured with nutrients--NO

Psychiatric medication is bad--NO

Micronutrient deficiencies cause some psychiatric sx

Tx with micronutrients can ameliorate sx

In many genetic mutations resulting in slowed metabolic activity, supplementing with cofactors eliminates the sx

Some people may be more vulnerable to deficiencies in food due to genetic metabolic differences and biochemical individuality

Micronutrients --intriguing option for controlling symptoms of mental illness

Evidence gathering for use with depression, bipolar, anxiety, ADHD and autism

While not yet proven to be an efficacious treatment, there is enough evidence to consider it a viable research option RCTs urgently needed

Is it time to reconsider the scientific paradigm?

1. RCT with adults (>16) with ADHD End in sight – aiming for March 2012

2. Case series (ABAB) of children and adolescents (8-12 and 16-21) with ADHD/severe mood dysregulation

3. RCT comparing EMP (2 doses) with Berocca for stress/anxiety induced by the earthquakes

4. Also investigating mechanisms of action5. Preliminary animal research6. Open to suggestions…collaborations

1601: Captain James Lancaster proved that lemon juice prevented scurvy: 4 ships Crew on one ship given a teaspoon of lemon juice daily Half way, 40% of the sailors on the other three ships had died None had on the lemon juice ship

1747: James Lind repeated the experiment Took another 48 years before the British Navy ordered that citrus

fruit become part of the diet on navy ships Took the British Board of Trade another 70 years to adopt the

innovation ordering proper diets on merchant marine vessels in 1865 264 years from Lancaster’s definitive study to universal British preventive

policy on scurvy However, James Cook, in 1783, did not wait that long and insisted

(sometimes by flogging) that all his sailors eat sauerkraut, which also contains vitamin C

Graduate students Mairin Taylor Jeni Johnstone Rachel Harrison Sarah Dymond Sarah-Eve Harrow Petra Hoggarth Jason Brown Phoebe Naismith Thomass Heather Gordon

Clinical Psychologists Sarah Anticich Kathryn Whitehead Dr Nicola Ward Dr Brigette Gorman

Academics/collaborators Prof Dermot Gately Prof Rob Hughes Prof Bonnie Kaplan Prof Ian Shaw

Psychiatrists/medical practitioners Dr. Anna Boggis Dr. Stephanie Moor Dr. Lisa O’Connell Dr. Katharine Shaw Dr. David Ritchie

Funding University of Canterbury for

ongoing financial assistance Vic Davis Memorial Trust Private Donation from Marie

Lockie Summer studentships Truehope for providing the

formula for trialsThanks to: participants and families for

carefully monitoring symptoms over time