Integrative Therapies in the Treatment of Depression and

Mood Disorders

Dr. James M. Greenblatt, M.D.September 29, 2007

Integrative Medicine

• Integrating the best of conventional medicine and evidence base complementary therapies emphasizing patient participation in health promotion, disease prevention and medical management.

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

British Journal of Medicine 2001

Why is Psychiatry Different?

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

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

Medical Testing includes

• Blood, Urine, Saliva Assays

• Microbiology

• Tissue analysis

• X-Ray, MRI, CT Scans, PET Scans

• EKGs, EEGs

• ETC…

Psychiatric Testing

Diagnosis and Treatment

Psychiatric Treatment:

Symptoms

“Anti”-Symptom treatment given

Measure symptoms

General Medical Treatment:

Symptoms

Measure Physiology

“Anti”-physiology treatment

Measure physiology and symptoms

The “Art” of Psychopharmacology

• Heterogeneity of medication response,

• One class of medication treats multiple disorders

• SSRI’s:• PMPD• SAD• MDD• Bulimia

• Panic Disorder• Generalized Anxiety• Social Phobia• “No name distress”

Response to Psychopharmacologic Treatment

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

–20-40% do not show substantial clinical improvement

–50% who show improvement have residual symptoms that impact functioning

Unresolved Symptoms of Depression

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

Partial or Non-Response

Nutrition as “Alternative”

Nutrition and Health

Understanding the role of

Nutrition and Health is not Alternative Medicine

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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

Medicine and Nutrition

Medical Profession’s reluctance to change

• Folic Acid– 25+ years

• Aspirin – 15+ years

Neurotransmitters

• At least 250 are known• Release of these chemicals causes

electrical impulses throughout the brain resulting in:–Thoughts –Feelings–Behaviors

• Neurotransmitter levels affect every facet of a biological system

All psychotropic medications

effect levels of neurotransmitters

in the brain

Neurotransmitters

• Most neurotransmitters are under precursor control

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

• Precursors are most easily obtained from meats and animal products

Neurotransmitter Synthesis

L-Tyrosine L-Dopa DA NE Epi

L-Tryptophan 5-HTP ST

• Folic Acid• Vitamin B6• Vitamin B12• Vitamin C• Vitamin D• Vitamin B3

• Magnesium• Zinc• Iron• Copper

Neurotransmitters

What causes Neurotransmitter Deficiencies?

• Genes

• Diet

• Stress

• Neurotoxins

Neurotransmitter Precursors

Increasing Tryptophan in Diet

Decreasing Tryptophan in Diet

Increases Serotonin in the brain

Decreases Serotonin in the brain

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

• 38 healthy female volunteers

• 14 day DBPCT with 1 gm Tryptophan 3 times a days placebo

• Tryptophan supplementation resulted in a positive bias in processing emotional material in women

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

Female Volunteers

Psychopharmacology July 2006

Tryptophan boosts confidence and reduces aggression

• 1 mg Tryptophan 3 X/day–12 day DBPCT

Tryptophan increased agreeable behavior

and reduced quarrelsome behavior

Tryptophan

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

• Traced to a single batch of contaminated tryptophan from Japan

Neurotransmitter Synthesis

L-Tyrosine L-Dopa DA NE Epi

L-Tryptophan 5-HTP ST

• Folic Acid• Vitamin B6• Vitamin B12• Vitamin C• Vitamin D• Vitamin B3

• Magnesium• Zinc• Iron• Copper

5-Hydroxytryptophan (5-HTP)

• Direct precursor to serotonin

• Extracted from the seeds of the Giffonia plant

• Not produced by bacterial fermenatis

5-HTP

A guided missile directly targets increased brain serotonin levels

5-HTP

• Converted from Tryptophan with a vitamin B3 dependent enzyme

• Converted to serotonin with a vitamin B6 dependent enzyme

• Easily crosses blood brain barrier

• Not incorporated into proteins

• Not utilized to make vitamin B3

• Response usually less than two weeks

Clinical Applications

5-HTP

50-300 mg/day

Empty stomach best

Divided 2-4 does

Start low and titrate dose

Tryptophan

500-3000 mg/day

Empty stomach best

Divided 2-4 doses

Recommended Dosages:

Neurotransmitter Synthesis

L-Tyrosine L-Dopa DA NE Epi

L-Tryptophan 5-HTP ST

• Folic Acid• Vitamin B6• Vitamin B12• Vitamin C• Vitamin D• Vitamin B3

• Magnesium• Zinc• Iron• Copper

Folic Acid and SAMe

• The folate cycle synthesizes methyl groups, which are then used by SAMe in numerous methylation reactions including:

Neurotransmitters synthesis

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

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

Gilbody et al. J Epidemiol Community Health 2007

Folate and Depression

Folate Deficiency and Depression

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

• Lower serum folate concentrations are correlated with greater severity of depression

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

Causes of Folate Deficiency States

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

• Malabsorption

• Genetic polymorphism

• Medications

Drugs that Can Cause Folate Deficiency States

• Anticonvulsants (phenytoin, primidone, phenobarbital, carbamazepine)

• Oral contraceptives

• Sulfsalazine

• Methotrexate

• Triamterene

• Pyrmethamine

• Trimethoprim

• Alcohol

• Antacids

• Antibiotics

• Metformin

• Folate deficiency may hinder antidepressant response to standard antidepressants

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

• Low folate correlated with melancholia and lack of response

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

Folate and Antidepressant Response

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

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

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

controlled trial

Alec Coppen, John Bailey

Journal of Affective Disorder 60 (2000) 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 Relapse

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

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

folate levels was only 3.2%

Please Read This Again

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

15

• 102 geriatric psychiatric inpatients

• Lower levels of folate and B12 predicted poorer cognitive status

• Lower levels of folate predicted a longer psychiatric hospitalization

• Severity of psychiatric illness correlated with 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 Depression

• Low folate associated with increased incidence of depression

• Low folate associated with poor response to antidepressants

• Low folate associated with higher relapse rate

• Folate supplementation enhances effect of Antidepressants

Folic Acid Supplementation in Depression

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

Abou-Saleh & Coppen, J Psychosom Res 2006

Folic Acid Supplements

• Folic Acid:

• Folinic Acid

• Folinic Acid (Leucovorin)

• L-Methylfolate (Deplin)

Folic Acid Conversion to L-methylfolate

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

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

• L-methylfolate is unaffected by the CT polymorphism.

MTHFR Polymorphisms

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

• Polymorphisms increase risk of depression • Patients who have MTFR CT genotypes have a

1.36 times greater chance of developing depression

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

MTHFR Gene

NORMAL677CC

Variation 1677CT

Variation 2677TT

Enzyme Activity

100% 71% 34%

DNA Effects “Normal” DNA Production and Repair

Reduced DNA Production and Repair

Reduced DNA Production and Repair

Folic Acid Required

400 mcg 800 mcg 1,200 mcg

MTHFR PolymorphismsMTHFR Polymorphisms

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

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

20

How Deplin Differs from Folic Acid • Folic acid requires a 4 step transformation process to be converted to the

active form of folate, L-methylfolate. Dietary folate requires 3-steps• L-methylfolate is absorbed directly in the active form that can immediately

cross the blood brain barrier for use. • L-methylfolate is unaffected by the CT polymorphism

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

No*YesDoes not bind to BBB receptors inhibiting L-

methylfolate absorption into the CNS4,8

58%67%Reduction in risk of NTD (Significant

improvement in folate status. P=0.001)9

NoYesUnlikely to mask pernicious anemia from a B-12 deficiency2

52.5 mg(52.5 1mg tablets)

7.5mg(1 tablet)

Bioequivalent Dose1

NoYesAble to Cross Blood Brain Barrier & aid in the

synthesis of neurotransmitters6,7

NoYesUnaffected by MTHFR C>T Polymorphism

(70% in the depressed population)5

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

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 doner located throughout the body.

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

• Neurotransmitter Synthesis

• Formed in the body by methinine

Fatty Acids

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

• 60% dry weight of the brain is fat.

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

The Human Brain: The Franklin Institute

Fatty Acids

Function as building blocks of every cell in the body.• 20 specific Fatty Acids required by the

human body to maintain normal functioning.

• The body can make all but two:• Omega 3; linolenic acid• Omega 6; linolenic acid

Essential Fatty Acids are Involved in Neurotransmission

•Synthesis

•Degradation

•Release

•Re-uptake

•Binding

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

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

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

Hanah Nemets, Boris Nemets, Alan Apter, Ziva Bracha, and R. H. Belmaker

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

Depression and Serum Adipose EPA

Mamalakis et al. Pharmacol Biochem Behav 2006

Predicting Suicide Risk

Sublette et al. Am J Psychiatry 2006

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

Placebo-Controlled Pilot Study

Zanari, et al

Am J of Psychiatry, 2003

Integrative Therapies

• Folate/B12• Thyroid• Vitamin D• Magnesium/Zinc• Copper• Celiac Disease

• Food Allergies• Vitamin Deficiencies• Mineral Deficiencies• Amino Precursors• Heavy Metals

ConclusionsConclusions

• A partial response is common, and associated with poorer outcome

• Augmentation and combination strategies may be effective approaches to partial and non-responders to antidepressant treatment

• Despite available strategies, many MDD patients fail to achieve remission

• Elements of one carbon cycle metabolism including Deplin

may prove to be effective, safe and tolerable when used as adjuncts for a partial response.

Vitamin D• Vitamin D in conjunction with calcium influences

the growth and regulation of all body cells• 41 – 57% of the general population in the US are

Vitamin D deficient• Dark skinned individuals are more prone to

Vitamin D deficiency because dark skin requires more sunlight to manufacture Vitamin D

Vitamin D

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

• TH is the rate limiting enzyme for the synthesis of :– Dopamin– Epinephrine– Norepinephrine

Vitamin D Case Study

• 17 y/o African American female, Honors Student, Athlete, Popular

• Increasingly depressed, cutting self with scissors, erratic sleep patterns, labile moods, energy variable, hyper, restless, tired, and suicidal thoughts. “Death would be better than this.” Up at 4 a.m. cleaning room.

• FH + Bipolar

Vitamin D Case Study

• Mother refused psychotropics• Vitamin D: 8 ng/ml (10-68 ng/ml)

Treatment x2 months• 3000 iu of Vitamin D• No medication• Vitamin D level: 33 ng/ml• Mood improved• No evidence of hypomania and depression

Inostiol

• A naturally occurring isomer of glucose

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

• Influences many aspects of cellular function and organ maturation

Controlled Trials of Inositol in Psychiatry

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

– Depression – Panic Disorder– OCD – Bullimia

• Double-blind, placebo controlled trial – 8 weeks• 113 patients (mean age 46, 69% females) with

atypical depression• 600 mg/day chromium picolinate or placebo• Chromium picolinate group showed significant

improvements in HAM_D scores compared to controls

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

carbohydrate craving.

JP Docherty, DA Sack, M Roffman, M Finch, JR KomorowskiJ of Psych Practice, 11 (5) 2005

Medical Research

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

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

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

Medical Research

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

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

Medical Research

Eat and drink what you like.

Speaking English is apparently what kills you.