Micronutrients for mental illness:
rethinking the scientific paradigm
Julia Rucklidge, PhD
Dept of Psychology, University of Canterbury
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
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
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)
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)
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
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)
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