Integrative Therapies in the Integrative Therapies in the Treatment of Depression and Treatment of Depression and

Mood DisordersMood Disorders

James M. Greenblatt, James M. Greenblatt, M.D.M.D.

Integrative MedicineIntegrative Medicine

Integrating the best of conventional Integrating the best of conventional medicine and evidence base medicine and evidence base complementary therapies.complementary therapies.

““It might be too pretentious to say that It might be too pretentious to say that such a growth of integrative medicine such a growth of integrative medicine might restore the soul to medicine – the might restore the soul to medicine – the soul being that part of us that is the most soul being that part of us that is the most important but the least easy to deliniate.”important but the least easy to deliniate.”

British Journal of Medicine 2001British Journal of Medicine 2001

Why is Psychiatry Why is Psychiatry Different?Different?

Medical treatment for mental Medical treatment for mental disorders differs from disorders differs from treatment of all other medical treatment of all other medical specialties.specialties.

Psychiatrists typically do not Psychiatrists typically do not use objective measurements use objective measurements to guide treatment of mental to guide treatment of mental or addictive illnessor addictive illness

Medical Testing includesMedical Testing includes Blood, Urine, Saliva AssaysBlood, Urine, Saliva Assays MicrobiologyMicrobiology Tissue analysisTissue analysis X-Ray, MRI, CT Scans, PET ScansX-Ray, MRI, CT Scans, PET Scans EKGs, EEGsEKGs, EEGs ETC…ETC…

Psychiatric TestingPsychiatric Testing

Diagnosis and TreatmentDiagnosis and Treatment

Psychiatric Treatment:

Symptoms

“Anti”-Symptom treatment given

Measure symptoms

General Medical Treatment:

Symptoms

Measure Physiology

“Anti”-physiology treatment

Measure physiology and symptoms

Response to Psychopharmacologic Response to Psychopharmacologic TreatmentTreatment

50% improvement of the primary 50% improvement of the primary symptoms of depression is the symptoms of depression is the standard measure of treatment standard measure of treatment responseresponse

20-40% do not show substantial clinical 20-40% do not show substantial clinical improvementimprovement

50% who show improvement have 50% who show improvement have residual symptoms that impact residual symptoms that impact functioningfunctioning

Unresolved Symptoms of Depression

Factors Associated with Insufficient Symptom Improvement Following an Adequate Trial of Antidepressants

Partial or Non-Response

Nutrition and Health

UnderstandinUnderstanding the role of g the role of Nutrition and Nutrition and Health is not Health is not Alternative Alternative MedicineMedicine

34.3

24.2 21.7 21.814.8

28.3

54.7

35.329.9

48.3

85.9

42.0

30.7

75.172.968.0

020

4060

8010

0

Calci

um

Folate

Iron

Mag

nesiu

m

Niaci

n

Phosphoru

s

Ribofla

vin

Selen

ium

Thiam

in

Vitam

in A

Vitam

in B

6

Vitam

in B

12

Vitam

in C

Vitam

in E

Zinc

Copper

Per

cen

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f P

op

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Percentages of U.S. Population Not Meeting the DRI For Specific Nutrients

Nutrient Deficiencies Are Common

Variability in Individual Nutrient Needs are Established

All psychotropic medications

effect levels of neurotransmitters

in the brain

Most neurotransmitters are Most neurotransmitters are under precursor control.under precursor control.

Precursors are substances obtained Precursors are substances obtained in whole or part from our dietin whole or part from our diet

Neurotransmitter SynthesisNeurotransmitter Synthesis

L-Tyrosine L-Dopa DA NE Epi

L-Tryptophan 5-HTP ST

Folic AcidFolic Acid Vitamin B6Vitamin B6 Vitamin B12Vitamin B12 Vitamin CVitamin C Vitamin DVitamin D Vitamin B3Vitamin B3

MagnesiumMagnesium ZincZinc IronIron CopperCopper

Neurotransmitter Precursors

Increasing Increasing Tryptophan in DietTryptophan in Diet

Decreasing Decreasing Tryptophan in DietTryptophan in Diet

Increases Increases Serotonin in the Serotonin in the brainbrain

Decreases Decreases Serotonin in the Serotonin in the brainbrain

In any normal diet animal based or vegetarian Tryptophan is the least plentiful of all 20 amino acids (9:1)

38 healthy female volunteers38 healthy female volunteers 14 day DBPCT with 1 gm Tryptophan 14 day DBPCT with 1 gm Tryptophan

3 times a days placebo3 times a days placebo Tryptophan supplementation Tryptophan supplementation

resulted in a positive bias in resulted in a positive bias in processing emotional material in processing emotional material in womenwomen

Tryptophan Supplementation Induces a Positive Bias in the Processing of Emotional Material in Healthy Female Volunteers

Psychopharmacology July 2006

Tryptophan

1989, The FDA removed 1989, The FDA removed tryptophan due to outbreak of tryptophan due to outbreak of Eosinaphilia Myolgia (EMS)Eosinaphilia Myolgia (EMS)

Traced to a single batch of Traced to a single batch of contaminated tryptophan from contaminated tryptophan from JapanJapan

Neurotransmitter SynthesisNeurotransmitter Synthesis

L-Tyrosine L-Dopa DA NE Epi

L-Tryptophan 5-HTP ST

Folic AcidFolic Acid Vitamin B6Vitamin B6 Vitamin B12Vitamin B12 Vitamin CVitamin C Vitamin DVitamin D Vitamin B3Vitamin B3

MagnesiumMagnesium ZincZinc IronIron CopperCopper

5-Hydroxytryptophan (5-5-Hydroxytryptophan (5-HTP)HTP)

Direct precursor to serotoninDirect precursor to serotonin Extracted from the seeds of the Giffonia Extracted from the seeds of the Giffonia

plantplant Not produced by bacterial fermentationNot produced by bacterial fermentation Converted from Tryptophan with a vitamin Converted from Tryptophan with a vitamin

B3 dependent enzyme

Converted to serotonin with a vitamin Converted to serotonin with a vitamin BB66 dependent enzymedependent enzyme

Easily crosses blood brain barrierEasily crosses blood brain barrier Not incorporated into proteinsNot incorporated into proteins

Folic Acid and SAMeFolic Acid and SAMe

The The folatefolate cycle synthesizes methyl cycle synthesizes methyl groups, which are then used by groups, which are then used by SAMeSAMe in numerous methylation in numerous methylation reactions including:reactions including:

Neurotransmitters Neurotransmitters synthesissynthesis

HomocysteineHomocysteine

Homocysteine is a functional marker Homocysteine is a functional marker of folate deficiencyof folate deficiency

Increased Homocysteine levels are Increased Homocysteine levels are found in depressed patientsfound in depressed patients

CAD and depression both associated CAD and depression both associated with increased Homocysteine and with increased Homocysteine and decreased folatedecreased folate

Homocysteine level as a marker for folate Homocysteine level as a marker for folate deficiency in severe depressiondeficiency in severe depression

Depressed patients with increased Depressed patients with increased homocysteine levels had homocysteine levels had significantly lower serum, RBC and significantly lower serum, RBC and CSF folate CSF folate and and – CSF SAMe CSF SAMe – CSF Monoamine metabolitesCSF Monoamine metabolites

Bottiglieri et al J. Neurol Neurosurg Psychiatry 2001 70(3) 419

The Homocysteine The Homocysteine Hypothesis of DepressionHypothesis of Depression

Since the 1960’s the association between low folate and depression was described

Folate and Depression

CNS Spectrum October 2007CNS Spectrum October 2007

11 relevant studies (15,315 11 relevant studies (15,315 participants, 3 case-control studies, 7 participants, 3 case-control studies, 7 population surveys, and 1 cohort population surveys, and 1 cohort study) were systematically analyzedstudy) were systematically analyzed

A significant correlation between A significant correlation between folate levels and folate levels and depressiondepression – low – low folate status is linked to depressionfolate status is linked to depression

Gilbody et al. J Epidemiol Community Health Gilbody et al. J Epidemiol Community Health 20072007

Folate and DepressionFolate and Depression

Folate Deficiency and Folate Deficiency and DepressionDepression

≥ ≥ 56% of patients with affective 56% of patients with affective disorders had folate deficiencydisorders had folate deficiency

Lower serum folate concentrations are Lower serum folate concentrations are correlated with greater severity of correlated with greater severity of depressiondepression

Red blood cell folate levels are Red blood cell folate levels are significantly lower in depressive significantly lower in depressive patients than those suffering from patients than those suffering from other psychiatric disordersother psychiatric disorders

Folate deficiency may hinder Folate deficiency may hinder antidepressant response to standard antidepressant response to standard antidepressantsantidepressants

– 213 adults (ages 18-65) with Major 213 adults (ages 18-65) with Major Depressive Disorder (MDD) treated with Depressive Disorder (MDD) treated with fluoxetine 20mg qd x 8 weeksfluoxetine 20mg qd x 8 weeks

Low folate correlated with lack of Low folate correlated with lack of responseresponse

No correlation of levels and lack of No correlation of levels and lack of appetite or weight lossappetite or weight loss

Folate and Antidepressant Folate and Antidepressant ResponseResponse

Effective augmentation study of Prozac:Effective augmentation study of Prozac:– Placebo controlled studyPlacebo controlled study– 500 mcg/day500 mcg/day– Effective in women, not menEffective in women, not men

““Folic acid is a simple method of greatly Folic acid is a simple method of greatly improving the antidepressant action of improving the antidepressant action of fluoxetine and probably other fluoxetine and probably other antidepressant agents.”antidepressant agents.”

Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo

controlled trial

Coppen, Alec, Journal of Affective Disorders, 2000; 60:121-130.

Folate Augmentation in First Episode Depression*

* Coppen, Alec, Journal of Affective Disorders, 2000; 60:121-130.

• Double blind trial of 127 patients experiencing their first episode of depression. Patients randomized to receive either 20mg fluoxetine + 500mcg folate or 20mg fluoxetine + placebo.

• Treatment with fluoxetine augmented with folate resulted in a significantly greater improvement in depression compared to fluoxetine alone. Folate treatment resulted in greater remission rates over placebo among women but not men with depression.• No additional adverse events were reported with the addition of folate.

Percentage of women who achieved HAM-D <9 Percentage of Reported Side Effects

Folate and RelapseFolate and Relapse

After 28 weeks of fluoxetine After 28 weeks of fluoxetine treatment, (71 pts) 20mg/day:treatment, (71 pts) 20mg/day:– Relapse rate for patients with low folate Relapse rate for patients with low folate

levels (< 2.5ng/mL) waslevels (< 2.5ng/mL) was 42.9%42.9%– While relapse rate for patients with While relapse rate for patients with

normal folate levels was onlynormal folate levels was only 3.2%3.2%

Papakostas et al, J Clin Psychiatry, 2004; 65: 1096-1098

1515

102 geriatric psychiatric inpatients102 geriatric psychiatric inpatients

Lower levels of folate predicted a longer Lower levels of folate predicted a longer psychiatric hospitalizationpsychiatric hospitalization

Severity of psychiatric illness correlated Severity of psychiatric illness correlated with lower folate levelswith lower folate levels

Folate and Severity of Illness

Bell IR; Edman et al, Biological Psychiatry, 1990;15, 27(2):125-37.

Folic Acid and the Treatment of Folic Acid and the Treatment of DepressionDepression

Low folate associated with Low folate associated with increased incidence of depressionincreased incidence of depression

Low folate associated with poor Low folate associated with poor response to antidepressantsresponse to antidepressants

Low folate associated with higher Low folate associated with higher relapse raterelapse rate

Folate supplementation enhances Folate supplementation enhances effect of Antidepressantseffect of Antidepressants

Folic Acid Supplementation in Folic Acid Supplementation in DepressionDepression

““We suggest the use of 2mg of folic We suggest the use of 2mg of folic acid, which would be expected to acid, which would be expected to increase plasma folate to more than increase plasma folate to more than 20ng/mL in both sexes…Adding 2mg of 20ng/mL in both sexes…Adding 2mg of folic acid to antidepressant treatment folic acid to antidepressant treatment would be easy in everyday clinical would be easy in everyday clinical practice. The daily supplement could practice. The daily supplement could be easily taken. It is inexpensive and be easily taken. It is inexpensive and safe.”safe.”

Abou-Saleh & Coppen, J Psychosom Res 2006Abou-Saleh & Coppen, J Psychosom Res 2006

Causes of Folate Deficiency Causes of Folate Deficiency StatesStates

Inadequate intake:Inadequate intake: Dietary Dietary sources heat labile, easily oxidized (≥ sources heat labile, easily oxidized (≥ 50% during food shortage and 50% during food shortage and processing)processing)

MalabsorptionMalabsorption Genetic polymorphismGenetic polymorphism MedicationsMedications

Drugs that Can Cause Folate Deficiency Drugs that Can Cause Folate Deficiency StatesStates

Anticonvulsants Anticonvulsants (phenytoin, (phenytoin, primidone, primidone, phenobarbital, phenobarbital, carbamazepine)carbamazepine)

Oral Oral contraceptivescontraceptives

SulfsalazineSulfsalazine MethotrexateMethotrexate

TriamtereneTriamterene PyrmethaminPyrmethamin

ee TrimethoprimTrimethoprim AlcoholAlcohol AntacidsAntacids AntibioticsAntibiotics MetforminMetformin

Folic Acid Conversion to L-methylfolateFolic Acid Conversion to L-methylfolate

Folic acid requires a 4 Folic acid requires a 4 step transformation step transformation process to be process to be converted to the converted to the active form of folate, active form of folate, L-methylfolate. L-methylfolate. Dietary folate requires Dietary folate requires 3-steps.3-steps.

L-methylfolate is L-methylfolate is absorbed directly in absorbed directly in the active form that the active form that can immediately cross can immediately cross the blood brain barrier the blood brain barrier for use.for use.

Folic Acid SupplementsFolic Acid Supplements

Folic Acid:Folic Acid:

Folinic Acid Folinic Acid

Folinic Acid (Leucovorin) Folinic Acid (Leucovorin)

L-Methylfolate (Deplin) L-Methylfolate (Deplin)

MTHFR PolymorphismsMTHFR Polymorphisms

Polymorphisms in the gene coding for Polymorphisms in the gene coding for methylenetetrahydrofolate reductase methylenetetrahydrofolate reductase (MTHFR) reduce efficiency of folic acid (MTHFR) reduce efficiency of folic acid metabolismmetabolism

Polymorphisms increase risk of depression Polymorphisms increase risk of depression Patients who have MTFR CPatients who have MTFR CT genotypes T genotypes

have a 1.36 times greater chance of have a 1.36 times greater chance of developing depressiondeveloping depression

The odds of having the T/T genotype is twice The odds of having the T/T genotype is twice as great in depressed patients verses the as great in depressed patients verses the normal populationnormal population

MTHFR MTHFR GeneGene

NORMALNORMAL677CC677CC

Variation Variation 11677CT677CT

Variation Variation 22677TT677TT

Enzyme Enzyme ActivityActivity

100%100% 71%71% 34%34%

DNA DNA EffectsEffects

““Normal” Normal” DNA DNA Production Production and Repairand Repair

Reduced Reduced DNA DNA Production Production and Repairand Repair

Reduced Reduced DNA DNA Production Production and Repairand Repair

Folic Acid Folic Acid RequiredRequired

400 mcg400 mcg 800 mcg800 mcg 1,200 mcg1,200 mcg

MTHFR MTHFR PolymorphismsPolymorphisms

MTHFR MTHFR PolymorphismsPolymorphisms

The odds of having the T/T genotype is twice as great in depressed patients verses the normal The odds of having the T/T genotype is twice as great in depressed patients verses the normal population.population.1,41,4

Deplin, not Folic Acid, bypasses a common genetic mutation present in the majority of patients with MDD

Prevalence of C→T Polymorphism in the Depressed Population1

1. Kelly B., Journal of Psychopharmacology 18(4) (2004) 567–571 3. Procopciuc L.M., Presented at Biological Psychiatry, Poster P862. Bjelland, I., et. al; . Arch. Gen. Psychiatry 2003, 618– 626 4. Arinami T, AM J. Medical Genetics 1997

T/T Polymorphism

14%

CC Normal 30%

C/T Polymorphism

56%

• Allelic frequency of the C/T-T/T mutation is 70% in the depressed population.1

• Patients who have the MTHFR C→T genotypes have a 1.36 times greater chance of developing depression (and reported as high as 4 times the general population).2,3

No*No*YesYesDoes not bind to BBB receptors inhibiting Does not bind to BBB receptors inhibiting L-methylfolate absorption into the CNS L-methylfolate absorption into the CNS4,84,8

58%58%67%67%Reduction in risk of NTDReduction in risk of NTD

(Significant improvement in folate status. P=0.001)(Significant improvement in folate status. P=0.001)9 9

NoNoYesYesUnlikely to mask pernicious anemia from a Unlikely to mask pernicious anemia from a B-12 deficiencyB-12 deficiency22

52.5 mg52.5 mg(52.5 1mg tablets)(52.5 1mg tablets)

7.5mg7.5mg(1 tablet)(1 tablet)Bioequivalent DoseBioequivalent Dose11

NoNoYesYesAble to Cross Blood Brain Barrier & aid in Able to Cross Blood Brain Barrier & aid in the synthesis of neurotransmittersthe synthesis of neurotransmitters6,76,7

NoNoYesYesUnaffected by MTHFR C>T PolymorphismUnaffected by MTHFR C>T Polymorphism

(70% in the depressed population) (70% in the depressed population)55

Deplin Folic Acid

1. Willems, et al, British Jrnl of Pharmacology, 2004 6. Bottiglieri T, Prog in Neuro-Psychopharm & Bio Psych, 2005 2. Scott, J.M. et al. Lancet. 1981 2:337-340 7. Wu, D and Pardridge WM, Pharmaceutical Research, 1999; 16, 415-4193. Troen AM, et al, J. Nutrition. 136: 189-194, 2006. 8. Reynolds, EH, J. Neurol. Neurosurg. Psychiatry 2002;72;567-571. 4. College of Medicine, University of South Alabama (data file) 9. Lamers Y, et al. CUVILLIER VERLAG, Gottingen 2006 pp 43-59:5. Popakostas , J. Clinical Psychiatry; 2004, 1090-1095

Deplin vs. Folic Acid

* Unmetabolized folic acid (especially doses > 1.0mg) binds to the “folate receptor” transport mechanism with a greater affinity than 5-MTHF resulting in a reduction in the transfer of MTHF across the BBB, which may lead to a lowering of the CNS MTHF level4

Crossing the Blood Brain Barrier Unmetabolized folic acid is unable to cross the blood brain barrier (BBB) and may

become bound to receptors (folate binding protein) on the membrane, thereby blocking the absorption of L-methylfolate*.

Consequently, the amount of L-methylfolate crossing the BBB into cerebral spinal fluid (CSF) is reduced.

L-methylfolate, in the absence of unmetabolized folic acid, passes more readily into the CSF which aids in neurotransmitter synthesis.

*University of South Alabama, College of Medicine; Data on file

Well tolerated in both acute and chronic therapy Folate augmentation to standard psychotropic medication was well tolerated in acute and maintenance

trials(12 months).1,2,6,7

Up to 90mg 5-MTHF (45mg L-methylfolate) has been administered for 4 weeks with good tolerability4

Deplin is not contraindicated with any medications

Does not appear to be associated with weight gain, sexual dysfunction, or sleep disturbances1-7

Suicide/Overdose No suicidal ideation or suicides were reported with folate.1-7

Up to a 1,000mg of folate (more than 4 months of Deplin) was administered for 1-3 weeks in

4 patients with no adverse events reported8

L-methylfolate Safety Profile

Pregnancy L-methylfolate does not currently have a pregnancy category Up to 1mg of folate is approved by the FDA as Pregnancy Category A.9

L-methylfolate was shown to be more effective in increasing folate concentrations and reducing NTD risk compared to folic acid.10

No titration required

10. Lamer Y., et al. CUVILLIER VERLAG, Gottingen 2006

9. Folic acid prescribing info, Watson Labs 20056. Coppen, A et al J. of Affective Disorders, 2000; 9-13

3. Guaraldi et al. Annals Clin Psych 1993; 101-105

8. Carney M.,J Nerv Mental Disorders 1970

5. Di Palma, C., et al. Therapeutic Research, 19942. Godfrey, PSA., et al. The Lancet, 1990; 392-395

7. Alpert, JE, et al Annals of Clin Psychi, 2002; 14: 33-38

4. Passeri, M., et al. Aging Clin. Exp. Res, 1993; 63-711. Coppen, A. et al, J. Affective Disorders, 1986. 121-130

A ubiquitous methyl A ubiquitous methyl doner located doner located throughout the throughout the body.body.

A key role in A key role in numerous metabolic numerous metabolic pathways that pathways that invoke transfer of invoke transfer of methyl group.methyl group.

Neurotransmitter Neurotransmitter SynthesisSynthesis

Formed in the body Formed in the body by methinineby methinine

Fatty AcidsFatty Acids

At least 25% of the brain’s At least 25% of the brain’s white matter consists of white matter consists of phospholipids derived from phospholipids derived from essential fatty acids.essential fatty acids.

60% dry weight of the brain is 60% dry weight of the brain is fat.fat.

““By modifying natural fats, we have altered By modifying natural fats, we have altered the basic building blocks of the human brain the basic building blocks of the human brain – weakening cerebral architecture. And, like – weakening cerebral architecture. And, like unstable buildings that come apart in an unstable buildings that come apart in an earthquake or storm, poorly structured earthquake or storm, poorly structured human brains are failing to cope with human brains are failing to cope with mounting stress of modern life.”mounting stress of modern life.”

The Human Brain: The Human Brain: The Franklin InstituteThe Franklin Institute

Essential Fatty Acids are Involved in Essential Fatty Acids are Involved in NeurotransmissionNeurotransmission

Synthesis Synthesis DegradatioDegradatio

nn ReleaseRelease Re-uptakeRe-uptake BindingBinding

28 children 8-1228 children 8-12 16 week DBPC trial of 400 mg EPA/200 mg DHA16 week DBPC trial of 400 mg EPA/200 mg DHA Depressed for at least 3 monthsDepressed for at least 3 months

– 7/10 on Omega-3 had 50% reduction in CDRS7/10 on Omega-3 had 50% reduction in CDRS– 0/10 on placebo0/10 on placebo– 4/10 met criteria for remission4/10 met criteria for remission

Omega-3 treatment of childhood depression: a Omega-3 treatment of childhood depression: a controlled, double-blind pilot studycontrolled, double-blind pilot study

American Journal of Psychiatry Vol. 163, No. 6, June 2006

Omega-3 Fatty Acid Treatment of Women with Borderline Personality Disorder: A Double-Blind,

Placebo-Controlled Pilot Study

Am J of Psychiatry, 2003

Vitamin DVitamin D Vitamin D in conjunction with calcium Vitamin D in conjunction with calcium

influences the growth and regulation of all influences the growth and regulation of all body cellsbody cells

41 – 57% of the general population in the 41 – 57% of the general population in the US are Vitamin D deficientUS are Vitamin D deficient

Dark skinned individuals are more prone Dark skinned individuals are more prone to Vitamin D deficiency because dark skin to Vitamin D deficiency because dark skin requires more sunlight to manufacture requires more sunlight to manufacture Vitamin DVitamin D

Vitamin DVitamin D

Activated Vitamin D in the adrenal Activated Vitamin D in the adrenal glad regulates Tyrosine Hydroxylose glad regulates Tyrosine Hydroxylose (TH)(TH)

TH is the rate limiting enzyme for the TH is the rate limiting enzyme for the synthesis of :synthesis of :– DopamineDopamine– EpinephrineEpinephrine– NorepinephrineNorepinephrine

InostiolInostiol

A naturally occurring isomer of glucose A naturally occurring isomer of glucose

A key intermediate of the phosphatidl-A key intermediate of the phosphatidl-inositol (PI) cycle, a second messenger inositol (PI) cycle, a second messenger system used by several noradrenergic, system used by several noradrenergic, serotonergic and cholinergic receptorsserotonergic and cholinergic receptors

Influences many aspects of cellular Influences many aspects of cellular function and organ maturationfunction and organ maturation

Controlled Trials of Inositol in Controlled Trials of Inositol in PsychiatryPsychiatry

Inositol may have therapeutic effects Inositol may have therapeutic effects in the spectrum of psychiatric illness in the spectrum of psychiatric illness responsive to serotonin selective responsive to serotonin selective reuptake inhibitors, including: reuptake inhibitors, including:

– Depression Depression – Panic DisorderPanic Disorder– OCD OCD – BullimiaBullimia

Double-blind, placebo controlled trial – 8 Double-blind, placebo controlled trial – 8 weeksweeks

113 patients (mean age 46, 69% females) 113 patients (mean age 46, 69% females) with atypical depressionwith atypical depression

600 mg/day chromium picolinate or 600 mg/day chromium picolinate or placeboplacebo

Chromium picolinate group showed Chromium picolinate group showed significant improvements in HAM_D scores significant improvements in HAM_D scores compared to controlscompared to controls

A double-blind, placebo-controlled, exploratory trial of chromium picolinate in atypical depression: effect

on carbohydrate craving.

J of Psych Practice, 11 (5) 2005

Integrative TherapiesIntegrative Therapies

Folate/B12Folate/B12 ThyroidThyroid Vitamin DVitamin D Magnesium/ZincMagnesium/Zinc CopperCopper Celiac DiseaseCeliac Disease

Food AllergiesFood Allergies Vitamin Vitamin

DeficienciesDeficiencies Mineral Mineral

DeficienciesDeficiencies Amino PrecursorsAmino Precursors Heavy MetalsHeavy Metals

Methylfolate Supplementation in High Risk Methylfolate Supplementation in High Risk PatientsPatients

Depression with Comorbid Alcohol Depression with Comorbid Alcohol useuse

Adolescent DepressionAdolescent Depression Patients on Medications interfering Patients on Medications interfering

with folate absorption or metabolismwith folate absorption or metabolism Geriatric DepressionGeriatric Depression Eating DisordersEating Disorders

SummarySummary

Antidepressants are weak Therapeutic Antidepressants are weak Therapeutic Agents – little improvement in efficacy Agents – little improvement in efficacy since the 1950’ssince the 1950’s

Major Depression ranked as the 4Major Depression ranked as the 4thth most most important cause of premature mortality important cause of premature mortality and disability in the worldand disability in the world

Trials of L-methylfolate are inexpensive Trials of L-methylfolate are inexpensive and safe and might save lives and the and safe and might save lives and the tremendous burden of depression for tremendous burden of depression for many patients and familiesmany patients and families

Medical ResearchMedical Research

The Japanese eat very little fat and The Japanese eat very little fat and suffer fewer heart attacks than the suffer fewer heart attacks than the British or Americans.British or Americans.

The French eat a lot of fat and also The French eat a lot of fat and also suffer fewer heart attacks than the suffer fewer heart attacks than the British or Americans.British or Americans.

The Japanese drink very little red The Japanese drink very little red wine and suffer fewer heart attacks wine and suffer fewer heart attacks than the British or Americans.than the British or Americans.

Medical ResearchMedical Research

The Italians drink excessive amounts The Italians drink excessive amounts of red wine and also suffer fewer of red wine and also suffer fewer heart attacks than the British or heart attacks than the British or Americans.Americans.

The Germans drink a lot of beer and The Germans drink a lot of beer and eat lots of sausages and fats and eat lots of sausages and fats and suffer fewer heart attacks than the suffer fewer heart attacks than the British or Americans.British or Americans.

Medical ResearchMedical Research

Eat and drink what you like. Eat and drink what you like.

Speaking English is apparently Speaking English is apparently what kills you.what kills you.