DEPLIN

1
Welcome

• DEPLIN
• Methyl Folate
• Antidepressant Augmentation Agent
• METANX
• Methyl Folate ,Methyl B12, P5P(B6)
• Diabetic Neuropathy and Hyperhomocysteinemia
• CERAFOLIN NAC
• Methyl Folate, Methyl B12, N acetyl L-cysteine
• Memory Loss , Neuropathy, Hyperhomocysteinuria
• The Bomb

Dorothy F. Merritt, MD
2

• Major depression is among the most treatable
  illnesses in medicine, but continues to have the
  highest morbidity and mortality.
• 70 more cost with depression codes
• 48 more cost with stress related illness codes

Zajecka, John M., Goldstein, Corey Barowski,
Jeremy (2006). CHAPTER 6 - Combining Medications
to Achieve Remission. Depression, 1 (1), 161-200.
3
Can Treatment Prevent or Reverse the Damage?
??
STRESS1
Dendritic branching2
Increased survival and growth
Atrophy/death of neurons
Glucocorticoids
BDNF
BDNF
Glucocorticoids
Normal survival and growth
5-HT and NE
Pharmacotherapy, ECT, psychotherapy1
5-HTserotonin NEnorepinephrine
ECTelectroconvulsive therapy. 1. Duman RS, et
al. Neuronal plasticity and survival in mood
disorders. Biol Psychiatry. 200048(8)732-739. 2.
Sapolsky RM. Glucocorticoids and Hippocampal
Atrophy in Neuropsychiatric Disorders Arch Gen
Psychiatry. 200057(10)925-935.
4
Phases of Treatment for Depression
Kupfer DJ. Long term treatment of depression. J
Clin Psychiatry. 199152(5)28-34.
5
Switch? Combine? Augment?

• General guidelines
• lt25 efficacy SWITCH vs. augment
• (COMBINE during SWITCH?)
• 25-50 efficacy SWITCH vs AUGMENT
• gt50 efficacy AUGMENT vs switch

Zajecka, John M., Goldstein, Corey Barowski,
Jeremy (2006). CHAPTER 6 - Combining Medications
to Achieve Remission. Depression, 1 (1), 161-200.
6
Antidepressant Augmentation

• Vagus Nerve Stimulation
• L-methylfolate
• Aripiprazole
• Atypical antipsychotics
• Lithium
• Thyroid hormone (T3)
• Stimulants
• Modafinil
• Buspirone
• Lamotrigine
• Carbamazepine

• Divalproex sodium
• Dopamine agonists
• Estrogen (as replacement)
• Buprenorphine
• SAMe
• Phototherapy (for SAD)
• Psychotherapy - CBT - CBASP - ITP
• Electroconvulsive therapy

• Indicated for augmentation of MDD

Zajecka, John M., Goldstein, Corey Barowski,
Jeremy (2006). CHAPTER 6 - Combining Medications
to Achieve Remission. Depression, 1 (1), 161-200.
7
Risk Factors Associated with Low Folate

• Genetic polymorphism MTHFR C677T
• 7 out of 10 depressed patients
• 56 - C/T polymorphism
• 4 X more likely to have depression than general
  population
• 14 - T/T polymorphism
• Lifestyle
• ETOH
• Smoking
• Poor nutrition

• Medications
• anticonvulsants
• oral contraceptives
• lithium
• fenofibrates, niacin
• sulphasalazine
• methotrexate
• metformin
• Illness
• diabetes
• atrophic gastritis
• crohns disease
• hypothyroid
• renal failure

Alpert M, et al. Jrnl Clin Psychopharmacology.
200323(3)309-13. Arinami T, et al.
Am J Genetics. 199774526-28. Fava M, et al. Am
J Psychiatry. 1997154(3)426-28.
Procopciuc L.M., Poster Pres. P86 presented at
Biol Psych. 2005. Popakostas G, et al. Psychiatry
Research, 2005140(3)301-7.
Bjelland I. et al. Arch Gen Psychiatry.
200360(6)618-26. Bottigleri T. Prog
Neuro-Psychopharmacology Biol Psychiatry. 2005
291103-12. Kelly B J, et al.
Psychopharmacol. 2004 18(4)567-71.
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Deplin as a Trimonoamine Modulator
Stahl S.M. Novel Therapeutics for Depression
L-methylfolate as a Trimonoamine Modulator and
Antidepressant Augmenting Agent. CNS Spectrums.
200712(10)739-744.
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Bioavailability
Folic Acid
L-methylfolate
Vs.
DHF Reductase Enzyme
Dihydrofolate (Dietary Folate)
Tetrahydrofolate
5, 10 Methylene THF
MTHFR CgtT Polymorphism
L-methylfolate

• Folic acid requires a 4 step transformation
  process to be converted to the active form of
  folate, L-methylfolate (5-MTHF).
• L-methylfolate is unaffected by the MTHFR C?T
  polymorphism.

10
Summary

• A partial response in clinical depression is
  common and associated with a poorer outcome.
• Augmentation strategies can build-off a partial
  antidepressant response and may accelerate onset
  of action.
• Despite available strategies, many MDD patients
  fail to achieve remission.
• L-methylfolate acts as a TMM boosting the
  synthesis of serotonin, norepinephrine and
  dopamine which, if deficient, may enhance an
  antidepressant response.
• DEPLIN? (7.5mg L-methylfolate) is well tolerated
  and has a low potential for drug interactions.1,2

1. Deplin Full Prescribing Information 2. Deplin
clinical Evaluation Patient Response Survey
11
My Waiting Room
Methylation Pathway Cycles
Urea Cycle
1
Neurotransmitter (BH4) cycle
2
Folate cycle
3
Methionine
4
Methionine (methylation) cycle
3
4
THF
Cancer
SAMe
Transulfuration cycle
5
Mutatioins anywhere in this pathway can
compromise critical functions in the body
Thymidine synthesis
DNA, RNA Protein, lipds
methylation
2
dUMP
Tryptophan
Tyrosine
MTRR
DMG
Guanido Ac
1
MTR
BHMT
Arginine
BH4
TMG
Creatine
Creatinine
SAH
MTHFR
Ornithine
DHPR
adenosine
NOS
SAHH
Homocysteine
Vascular
Urea
5 Methyl THF
CBS
5
BH2
Cystathionine
Mood
2 BH4
B6, P5P
Brain Fog
Dopamine
Serotonin
Ammonia
MAO B
MAO A
Cystine a KG
NorEp
Citrulline NO
1 BH4
HIAA
MAO B
COMT
Taurine
Glutathione
Sulfite
COMT
Peroxynitrate
Neuronal Damage
SUOX
moly
HVA
0 BH4
Sulfate
VMA
Superoxide
Microglia Activation
Neuropathy/Inflammation
METHYLATION MAP
Oxidative-Inflammatory Disease
12
The Pharmacological Management of Diabetic
Peripheral Neuropathy
A Review of Remittive vs. Palliative Therapy
13
I marvel that society would pay a surgeon a
large sum of money to remove a persons leg - but
nothing to save it.
George Bernard Shaw
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Impact of Diabetic Neuropathy

• 15 of Diabetics will develop an ulcer
• 85,000 amputations per year
• 13.7 billion industry
• 27 direct medical cost of Diabetes

Diabetes Care 261790-1795, 2003
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Diabetic Neuropathy Symptoms
39
50
11
Majority of DPN Patients are Insensate
Boulton AJM. Clin. Diab. 23, 2005 Argoff C, Cole
BE, Fishbain DE, Irving G. Mayo Clin. Proc.
200681 (S4) Boulton AJM et al. Diab. Care 27,
2004
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Etiology of Diabetic Neuropathy
Proposed Mechanisms in the Pathogenesis of
Diabetic Neuropathy
Hyperglycemia
?
Endothelial Dysfunction
Microvascular Insufficiency
?
Neuronal Dysfunction
Nerve Degeneration
Vinik Aaron. Diabetic Neuropathy Pathogenesis
and Therapy. The Amer. Journal of Med. August
1999107 (2B)17S-26S.
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L-Methylfolate IMPROVES Nitric Oxide Synthesis
Verhaar MC, et al. Arterioscler Thromb Vasc Biol.
2002226-13.
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Metanx IMPROVES Endothelial Function
Clinical Based Evidence
35 patients patients with endothelial
dysfunction were randomized to Metanx or placebo
for 8 weeks In a randomized, placebo-controlled,
double-blind trial, Metanx significantly
improved endothelial function by 136 at 8 weeks.
P0.021
See Full Prescribing Information Abstracts of
the 7th Annual Conference on Arteriosclerosis,
Thrombosis, and Vascular Biology. Oral
Presentations. Arterioscler Thromb Vasc Biol.
2006 26 e43-e52
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MethylB12 IMPROVES Symptomatic DPN
Dull pain or tightness, numbness, cramps, fatigue
and weakness
43 patients with DPN were randomized to 1500 µg
MethylB12 compared to placebo for 4 months The
MethylB12 group showed a significant improvement
in peripheral and autonomic symptoms with signs
of diabetic peripheral neuropathy
Sensations, power, deep tendon reflexes and blood
pressure changes


Recurrent diarrhea, vomiting, urinary
disturbances, diminished sexual potency and
gastric severity

Yaqub, Basim A . et al. Clinical Neurology and
Neurosurgery. 199294105-111.

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Comparison of L-methylfolate and Folic Acid on
Plasma Homocysteine A Randomized
Placebo-Controlled Study
What did the researchers find?

• L-methylfolate over a 24 hour period,
  significantly reduced homocysteine levels
  compared to folic acid and placebo.
• The reduction in tHcy (21.3) in the
  L-methylfolate group was significantly greater
  (P0.02) than the reduction seen in the folic
  acid group (7.7).

Study conducted by the College of Medicine,
University of South Alabama. Submitted for
Publication. Data on file.
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RESTORATION OF CUTANEOUS SENSORUM IN DIABETIC
PERIPHERAL NEUROPATHY UTILIZING A UNIQUE
PHARMACOLOGICAL APPROACH
RESULTS - 6 Month Outcome
Abstracts of the Diabetic Foot Global Conference.
Oral Presentations 2008.
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RESTORATION OF CUTANEOUS SENSORUM IN DIABETIC
PERIPHERAL NEUROPATHY UTILIZING A UNIQUE
PHARMACOLOGICAL APPROACH
RESULTS - 1 Year Outcome
Abstracts of the Diabetic Foot Global Conference.
Oral Presentations 2008.
23
HOMOCYSTEINE AND DIABETIC AUTONOMIC NEUROPATHY
(DAN)

• An elevated homocysteine level is an independent
  risk factor for DAN
• Each 5µmol/L increase in tHcy resulted in a 35
  increased risk of developing DAN

Cohen JA etal. Auton. Neuro 23 (87) 2001
24
RESTORATION OF CUTANEOUS SENSORUM IN DIABETIC
PERIPHERAL NEUROPATHY UTILIZING A UNIQUE
PHARMACOLOGICAL APPROACH
CONCLUSION

• Metanx demonstrated a significant improvement in
  regenerating nerve fibers resulting in the
  restoration of sensation in patients with DPN.

Abstracts of the Fiabetic Foot Global Conference.
Oral Presentations 2008.
25
Orally Administered L-methylfolate, Me-Cbl, and
P-5-P Reduces Diabetic Peripheral Neuropathic
Pain

• Objective
• Examine the efficacy of L-methylfolate, Me-Cbl,
  and P-5-P compared to acetaminophen for the
  reduction of DPNP
• Methodology
• 130 patients enrolled in RCT
• Patients received either L-methylfolate, Me-Cbl,
  and P-5-P twice daily (study group) or
  acetaminophen 500mg twice daily (active control
  group) for 20 weeks.
• A baseline visual analog scale (VAS) neuropathy
  pain scale was obtained and evaluated at 10 and
  20 weeks.

Jacobs, Allen M. Abstacts of New Cardiovascular
Horizons Meeting. Oral Presentations 2008.
26
Orally Administered L-methylfolate, Me-Cbl, and
P-5-P Reduces DPNP Allen M. Jacobs, DPM, FACFAS

• Results from a 20 week, randomized,
• controlled study of 97 patients to evaluate
• Metanx in patients with DPNP.
• The average absolute pain reduction after
• 20 weeks in the study group was 1.73
• compared to .44 in the active group
• (plt0.008)
• Compared to baseline, after 10 weeks the
• study group demonstrated a reduction in
• VAS of 32.92 compared to the active
• control group of 11.57 reduction in VAS
• (Plt0.01)
• Compared to baseline, after 20 weeks the
• study group demonstrated a reduction in
• VAS of 35.28 compared to the active
• control group of 11.73 reduction in VAS

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Medical Based Evidence in DPNP
Study 1 Orally Administered L-Methylfolate,
Me-Cbl, and P-5-P Reduces Diabetic Peripheral
Neuropathic Pain
Study 2 L-Methylfolate, Me-Cbl, and P-5-P
Supplementation to Pregabalin Partial-Responders
for Management of Painful Diabetic Neuropathy 
Jacobs, Allen M. Abstacts of New Cardiovascular
Horizons Meeting. Oral Presentations 2008.
28
L-Methylfolate, Me-Cbl, and P-5-P Supplementation
to Pregabalin Partial-Responders for Management
of Painful Diabetic Neuropathy 

• Objective
• Determine the effects of L-methylfolate, Me-Cbl,
  and P-5-P on burning paresthesias in patients
  with DPNP who had obtained partial symptoms
  resolution with pregabalin.
• Methodology
• 24 consecutive patients who received pregabalin gt
  4 months
• with partial (lt50 NPS reduction) resolution of
  paresthesias
• were enrolled.
• Study group (n16) continued the pretrial
  pregabalin dose to
• which oral L-methylfolate, Me-Cbl, and P-5-P was
  added twice daily.
• Control group (n8) maintained pregabalin
  therapy.
• A numeric pain scale (0-10) was evaluated at
  baseline and 20
• weeks.

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L-Methylfolate, Me-Cbl, and P-5-P Supplementation
to Pregabalin Partial-Responders for Management
of DPNP
Allen M. Jacobs, DPM, FACFAS

• Results from a 20 week, open
• trial of 24 patients to evaluate
• Metanx.
• The average absolute pain
• reduction after 20 weeks in the
• study group was 3.0 compared
• to .25 in the active control
• group (plt0.001)
• After 20 weeks, the study group
• experienced greater pain relief
• compared to the active control
• group, 87.5 vs. 25.0
• reduction in NPS respectively (p0.005)

30
Relationship to Length of Symptomatology
Duration of Symptoms Average Pain Reduction
Jacobs, Allen M. Abstacts of New Cardiovascular
Horizons Meeting. Oral Presentations 2008.
31
Folate and Risk of AD

• High total folate intake is associated with
  reduced risk of incident AD.1
• High total folate intake may protect against AD.2
  
  

1. Luchsinger et al, Arch Neurol 2007.
2. Corrada et al, Alz Dem 2005.
CEREFOLINNAC is an orally administered
prescription medical food for the dietary
management of certain metabolic processes
identified with early memory loss.
32
Folate Therapy, Homocysteine Reduction and
Cognitive Performance in Healthy Elderly

• 3-year folate regimen confers an individual the
  performance of someone
• 6.9 yrs younger for delayed recall
• 4.7 yrs younger for memory
• 2.1 yrs younger for information processing
• 1.5 yrs younger for global function

Durga et al, Lancet 2007.
CEREFOLINNAC is an orally administered
prescription medical food for the dietary
management of certain metabolic processes
identified with early memory loss.
33
Folate and B12 Status in Relation to Cognitive
Impairment

• High folate and normal B-12 are associated with
  a 50 decrease in risk of cognitive impairment
  compared to those with normal folate levels.
• Normal folate and normal B-12 are not enough to
  decrease the risk of cognitive impairment.

Morris MS et al, Am J Clin Nutr 2007.
CEREFOLINNAC is an orally administered
prescription medical food for the dietary
management of certain metabolic processes
identified with early memory loss.
34
N-acetylcysteine Prevents Oxidative Stress
Associated with Homocysteine and Beta Amyloid

• Hcy increases beta amyloid induced oxidative
  stress
• Oxidative stress can lead to neuronal cell death
• N-acetylcysteine provides potent antioxidant
  protection and prevents neuronal death

Ho P et al, Journal of Neurochemistry 2001.
CEREFOLINNAC is an orally administered
prescription medical food for the dietary
management of certain metabolic processes
identified with early memory loss.
35
CerefolinNAC is a prescription medical food,
specifically formulated for neurovascular
oxidative stress and hyperhomocysteinemia in
patients with memory loss from deficient
glutathione and folate levels.

• CerefolinNAC offers
• Protection of neurons from the toxic effects of
  beta-amyloid and homocysteine1
• Improved performance of memory through synthesis
  of acetylcholine within the neuron2,3
• Increase in methylation resulting in a decrease
  of phospho tau /neurofibrillary tangles4
• Reduced excitotoxic effects of neuron by
  decreasing NMDA activation5

• Ho P et al. Journal of Neurochemistry, 2001 3.
  Zeisel SH, J of Neurochemistry, 2001
• Blusztajn et al. J Neural Transm Suppl, 1987
  4. Lipton, SA et al, J of
  Neurochemistry, 2001

CEREFOLINNAC is an orally administered
prescription medical food for the dietary
management of certain metabolic processes
identified with early memory loss.
36
New Options in Early Memory Loss
CEREFOLINNAC is an orally administered
prescription medical food for the dietary
management of certain metabolic processes
identified with early memory loss.
37
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