• Antidepressant Partial Response

• Association of Depression and Low Folate

• Deplin Overview

• Clinical Trials and Mechanism of Action

• Comparison with Folic Acid

• Safety

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

Partial or Non-Response

Risks Associated with Failure to Achieve and Sustain Remission

Full Remission Decreases Risk of Relapse

Naturalistic Outcomes of Patients with TRD (24 months)*

* Dunner et. al; J. Clin Psych, May 2006

3 month 12month 24 monthResponse 5.8% 11.6% 18.4%Remission 1.7% 3.6% 7.8%

124 patients with Treatment Resistant Depression using Treatment as Usual (TAU) Therapy

Medication/Treatment

Prestudy Lifetime (N=124)

Baseline (N=124)

12 Months (N=112)

24 Months (N=103)

Heterocyclics/TCAs 70.2 8.9 8.9 13.6

SSRIs 100.0 35.5 45.5 53.4

Other antidepressants 98.4 51.6 58.0 66.0

Lithium 46.8 7.3 10.7 10.7

Anitconvulsants 51.6 32.3 36.6 35.0

Typical antipsychotics 14.5 3.2 2.7 2.9

Stimulants 32.3 11.3 17.9 15.5

Anxiolytics 68.5 42.7 42.0 45.6

Hormones --- 9.9 13.4 11.7

Hypnotics --- 8.9 8.9 10.7

ECT 25.8 0.0 1.8 1.9

Mood Medication/Treatment Distribution (%)

Unresolved Symptoms of Depression

STAR*D Trial Level 2 Trials

Switch1

N = 727

Augmentation / Combination2

N = 565

Patients were not randomized to either arm and therefore switching and augmentation cannot be directly compared.

Outpatients with MDD treated with citalopram for

12-14 weeks

~30% achieved remission

Patients with MDD who could not tolerate or did not

achieve remission on citalopram monotherapy

(12-14 weeks)

1. Rush J., et al, Buporprion-SR, Sertraline, or Venlafaxine XR after Failure of SSRIs for Depression, NEJM, March 2006; 1231-12422. Trivedi M., et al, Medication Augmentation after the Failure of SSRIs for Depression, NEJM, March 2006; 1243-1252

Remission RatesDiscontinuation

due to Intolerance

Buproprion-SR 29.7% 13%

Buspirone 30.1% 21%

Remission RatesDiscontinuation

due to Intolerance

Bupropion-SR 21.3% 27%

Sertraline 17.6% 21%

Venlafaxine-XR 24.8% 21%

Switching Augmentation

Advantages Switching or Augmenting a Non -Response

• Minimize drug interaction potential

• Minimize side effects

• Possibly Better compliance (1 pill)

• Potential Cost Savings (if generic)

• Potential synergistic effect

• Maintain any response that may exist with current treatment

• No risk of withdrawal symptoms

• Can be used to target side effects of treatment

Neurotransmitter Functional Domains

Adapted from: Healy and McMonagie. J Psycopharmacol 1997;1 (suppl 4) S25-S31

432 psychiatrist responding to a survey on how they would respond to a patient who is a partial responder, non-responder and a patient who relapses

Fredman et. al, Partial Response, Nonresponse, and Relapse with Selective Serotonin Reuptake Inhibitors in Major Depression: A Survey of Current “Next Step” Practices; J.Clin. Psych,61:6, June 2000

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Raise theDose

Augment Switch SSRIs Switch to Non-SSRI

Partial Responder

Nonresponder

Next Step Survey After 8-Weeks SSRI Treatment

• Patients with TRD have 19 times greater depression related costs compared to non-TRD depression

• TRD patients consumed 1.4 to 3 times more psychotropic medications (including antidepressants)

• TRD patients are twice as likely to be hospitalized and had at least 12% more outpatient visits.

Treatment Resistant Depression (TRD) Cost*

Crown, W. et al, The Impact of Treatment Resistant Depression on Health Care Utilization and Costs J Clinical Psychiatry, 2002; 63: 963-971

Other Common Symptoms of Depression (may be categorized in the same degree as hallmark MDD symptoms: depressed mood & diminished interest)1

• fatigue or loss of energy: 73%-97%

• sleep disturbances: 63%-77%

• impaired concentration: 51%-84%

Residual Symptoms of Depression

1. Fava, M., Thase, M. A Multicenter, Placebo Controlled Study of Modifinil Augmentation to Selective Serotonin Inhibitors; J. Clin.Psych; Jan 2005 2. Fava, M. Pharmacological approaches to the treatment of residual symptoms, Journal of Psychopharmacology; 20(3) (2006) 29–343. Alpert J, Folinic Acid (Leucovorin) as an Adjunctive Treatment for SSRI-Refractory Depression; Annals of Clin Psychiatry, 2002

Common residual symptoms associated with depressed outpatients treated with fluoxetine: sleep disturbances, fatigue, and lack of interest.”2

Common depressive symptoms associated with folate deficiency: apathy, fatigue, insomnia, irritability, and impaired concentration3

• 55 depressed outpatient non-responders to fluoxetine 20 mg over 8 weeks continued on for next step treatment (60-80 mg fluoxetine, lithium or desipramine augmentation)

• Low vs. normal folate predicted greater rate of non-response: 93% vs. 55% (p<0.05)

Low Folate and Treatment Resistance

Papakostas et al, J. Clin Psychiatry, 2004; 65: 1090-1095

• 71 outpatients with remitted MDD who proceeded to longer-term treatment with fluoxetine 20 mg qd

• Relapse rates were higher for patients with low vs. normal folate (42.9% vs. 3.2%) (P<0.003)

Low Folate and Depressive Relapse

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

• 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.

• Depressed patients with low RBC folate are 6 times more likely not to respond to antidepressant therapy and less likely to achieve remission.1,2

• Low serum or low red blood cell folate levels have been reported in 15%-56% of depressed patients.3,4

• The severity of a depressive episode, length of an episode, and later onset of clinical improvement are inversely correlated with RBC folate levels.5-8

• Depressed patients with low RBC folate are associated with impairment in the synthesis and release of monoamine neurotransmitters: serotonin, norepinephrine, and dopamine5

• Higher folate levels in patients taking SSRIs and TCAs predicted a better response, but the trend was stronger with SSRIs1

Association of low folate levels and depression

1. Alpert M: Journal Clin Pharmacology 2003 5. Bottiglieri T, Prog in Neuro-Psychopharm & Bio Psych, 20052. Popakostas G, Psychiatry Research, 2005;140(3):301-7. 6. Levitt A, Biol Psychiatry 19893. Alpert, J.E., Fava, Maurizio. Nutrition Reviews, 1997 7. Wesson VA, J. of Psychiatry Research, 19944. Coppen A, et al, Journal of Psychopharm; 2005 8. Abou_Saleh MT, J. of Affective Disorders, 1989

Patients at Risk for Low Folate Levels

Bottiglieri T, Prog in Neuro-Psychopharm & Bio Psych, 2005

Deplin Overview

• Deplin tablets contains 7.5 mg of L-methylfolate. Deplin is available by prescription and marketed as a Medical Food as defined by the FDA.

• Mechanism of Action: Increase plasma and RBC folate in the cerebrospinal fluid. L-methylfolate crosses the blood brain barrier to aid in the synthesis of monoamine neurotransmitters: serotonin, norepinephrine and dopamine

• Indication: DEPLIN® is indicated for the distinct nutritional requirements of individuals who present with low folate levels in the cerebrospinal fluid, plasma, and/or red blood cells, with particular emphasis, as an adjunctive treatment (augmentation) for individuals experiencing an episode of major depressive disorder that has not fully remitted following an adequate trial of an antidepressant. DEPLIN® treatment is indicated regardless of MTHFR C677T polymorphism genotype.

Treatment with DEPLIN® should always occur under the care of a Physician.

Implication of Folate Levels in Depression

*Adapted with permission: Bottiglieri T, Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2005; 1103-1112

L-methylfolate Mechanism of Action

• The modulation and release of neurotransmitters has been associated with L-methylfolate binding to pre-synaptic glutamate receptors1.

• Neurotransmitter synthesis with Deplin is independent of antidepressant therapies2.1. Alpert M: Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. Journal Clin Pharmacology 20032. Mischoulon D. Role of S-adenosyl-l-methionine in the treatment of depression: a review of the evidence, AM J Clin Nutr, 2002

Methylfolate Augmentation in Depressed Patients with Low Folate Levels*

• Augmentation of 15mg 5-MTHF (= 7.5mg L-methylfolate) in depressed patients on a TCA or MAOI compared to augmentation with placebo

• Methylfolate-treated patients experienced significantly greater clinical and social improvement at 3 and 6 months compared to patients treated with placebo

• Methylfolate-treated patients maintained this improvement over the 6-month period compared to placebo-treated patients who began to experience a recurrence of symptoms by the end of 6 months.

• No additional adverse events were reported with the addition of methylfolate.

* Godfrey, P.S.A., et al. The Lancet, 1990; 18:392-395.

Folinic Acid Augmentation in TRD Patients with Normal Folate Serum Levels*

• Augmentation of SSRIs with 15mg-30mg folinic acid (leucovorin – racemic mixture) in SSRI resistant patients with normal folate levels in an open label trial.

• Folinic acid treatment demonstrated a significant improvement in HAM-D scores over baseline at the end of 8 weeks and a modest response rates (~1/3).

• No additional adverse events were reported with the addition of folate

SSRI Augmentation with 5-FTHF Reduction in HAM-D 17 Score

0

5

10

15

20

25

30

Baseline 8 weeks

*

* p < 0.01n = 2215mg-30mg 5-FTHF(folinic acid) adjunct to sertraline, fluoxetine or paroxetine

* Alpert J et al. Annals of Clin Psychiatry, 2002;14(1):33-38.

5-FTHF Response Rates

31%

41%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

HAM-D > 50% reduction CGI < 2 (much or very muchimproved)

P=NS

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

Methylfolate Monotherapy vs. Amitriptyline in Depression*

• After a 2-week placebo run-in period, this double-blind trial randomized 31 depressed outpatients to 50mg methylfolate (25mg L-methylfolate) or 150mg amitriptyline each in monotherapy for 6 weeks. All but 3 patients had normal folate levels (90%).

• MADRS response rate was similar with methylfolate and amitriptyline (42%, 35% respectively).

• No side effects were reported with methylfolate, whereas 3 patients (15%) were withdrawn due to unacceptable side effects with amitriptypline.

* Crellin R, Bottiglieri T et al. Drugs 45(5):623-636, 1993.

35%

42%

0%

10%

20%

30%

40%

50%

60%

Methylfolate Amitriptyline

p = NS; n = 31

Response Rate(25% reduction in MADRS score)

15%

0%0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

Methylfolate Amitriptyline

n = 0/19 MTHF, 3/20 amitriptyline

Discontiuation due to Adverse Events

Open-label trial of Methylfolate in Geriatric Depression*

• Open label trial of 50mg methylfolate (6(R,S)-5MTHF)(25mg L-methylfolate) in 20 geriatric outpatients with MDD. Only two patients (10%) had low folate levels pre-trial. A 1-week placebo washout was administered.

• Methylfolate demonstrated an 81% overall response rate (>50% reduction in HAM-D). A significant improvement over baseline reported by week 1 and continued throughout 6 weeks

* Guaraldi GP, Fava M, et al, Annals of Clinical Psychiatry. 1993 Jun;5(2):101-5.

0

5

10

15

20

25

30

35

40

Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 6

*

***

***

***

*p<0.01 vs baseline, **p<0.001 vs baseline, ***p<0.0001 vs baseline

HAM-D-21 Scores

12 Mo Folate vs. Placebo in Depressed Patients on Lithium*

• Daily supplement of 200 mcg folate compared to placebo in 75 patients on lithium therapy over 12 months (folate group included 30 unipolar & 11 bipolar patients)

• All patients were considered stable and maintained on their current psychotropics

• When plasma folate increased to 13ng/ml or above, patients experienced a 40% reduction in affective morbidity significant reduction in AMI (Affective Morbidity Index) (p = 0.02)

•There were no difference in side effects between the folate group and placebo group

* Coppen A, et al J Affective Disorders; 1986 Jan-Feb;10(1):9-13.

Affective Morbidity Index

0.104

0.043

0.088

0.024

0

0.02

0.04

0.06

0.08

0.1

0.12

Folate < 12.9 Folate > 13.0

Pre-Trial

End of Trial

*

**

* Lower than low folate group, P < 0.01** Lower than folate group, P , 0.0025, and lower than own pre-trial AMI, P , 0.02

Beck Depression Scores

8.7

7.4

9.2

6.3

0

1

2

3

4

5

6

7

8

9

10

Unipolar placebo Unipolar folate

Pre-Trial

End of Trial

*

Methylfolate vs. Trazodone in Depressed Patients with Dementia*

• Compared methylfolate to trazodone in 96 normofolatemic elderly depressed patients with mild to moderate dementia. 2 week placebo run-in, patients were randomized to 50mg 6(R,S)-5MTHF (25mg L-methylfolate) or 100mg trazodone.

• Both treatments demonstrated a significant improvement in symptoms over baseline and a comparable response rate. Methylfolate demonstrated a significantly greater improvement of immediate recall (Rey’s Verbal Memory Test) (53% vs. 37% respectively).

• No adverse events reported with methylfolate. Vertigo & blurred vision reported by one trazodone pt.

* Passeri M, Aging, 1993 Feb;5(1):63-71.

29%

45%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

5-MTHF

Trazadone

Partial to Complete Response

p = NS

29%

45%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

5-MTHF

Trazadone

Partial to Complete Response

p = NS

16

17

18

19

20

21

22

23

24

Baseline Wk 4 Wk 8

5-MTHF

Trazodone

Mean scores in 21-Item HDRS

*

** **

**

* p<0.05 vs baseline; ** p<0.01 vs baseline

HAM-D 21 Scores

Monotherapy Methylfolate in Depression with Chronic Alcoholics*

* C. Di Palma, Current Therapeutic Research; Volume 55, 1994; 5: 559-568

10

15

20

25

30

35

40

Baseline Wk 1 Wk 2 Wk 3 Wk 4

*

*

*p<0.01 vs baseline; n = 36; 46.6% reduction in average scores from baseline

HAM-D-21 Scores

*

0

1

2

3

4

5

6

7

8

Baseline Wk 1 Wk 2 Wk 3 Wk 4

PainFatigueWell BeingSleep

*

****

**

**

******

**

*p<0.01 vs baseline, **p<0.001 vs baseline; N = 36

Visual Analogue Scale

**

• Open-label trial investigating 90mg 6(R,S)-5MTHF (45mg L-methylfolate) administered 30mg TID in 36 chronic alcoholics with depression over a 4 week period.

• Methylfolate separated from HAM-D baseline scores by week 2 (week 1- Zung Score) and the improvement continued throughout the 4 week trial.

• A significant improvement in well being as well as a reduction in fatigue and pain was reported through the Visual Analogue Scale. Sleep was not statistically significant.

• No adverse events were reported with methylfolate.

Folate Clinical Trials in DepressionReference Design Folate &/or Comparator Sample characteristics Outcome

Coppen, A.et al; J. Affective Disorders, 1986; 10:9-13.

Double-blind, controlled 12 monthsFolic acid (200 mcg) or

placebo in combination with lithium

75 patients on lithium therapy. Patients with highest plasma folate had a greater reduction in affective morbidity7

Godfrey, et al.,The Lancet, 1990; 18:392-395.

Double blind controlled 6 monthsMTHF (15mg) or placebo. Other psychotrophic medication allowed

24 depressed and 17 schizophrenic subjects with low RBC folate (<200 ng/ml). DSM-III diagnosis.

Significant decrease in mean outcome scores in MTHF group at 3 and 6 months8

Crellin R, Bottiglieri T et al. Drugs 45(5):623-636, 1993.

Double-blind randomized trial for 6 wks. Nonresponders crossed over for an additional 6 wks. Responders were followed for 6 months.

MTHF @ 50mgs or amitriptyline @ 150mgs. No other psychotropic medications allowed

31 mild to moderately depressed subjects enrolled in the study. Investigators blinded to plasma data collected. DSM-III-R and MADS >or=14.

Of 19 subjects randomized (n=16) or crossed over (n=3) to treatment (MTHF) 8 responded (MADS < by 25% or more). Of 20 subjects (n=15) or crossed over (n=5) to treatment (amitriptyline) 7 responded. Only 3 patients (10%) had low or borderline RBC folate values at randomization.9

Guaraldi, Gian Paolo, et al. 1993; 5:101-105

Open trial 6 weeks MTHF (50 mg), no other psychotropic medication

20 Elderly depressed subjects. DSM-III-R, HAM-D-21 > or = 18

16 completed at least 4 weeks, 81% response rate (decrease in HAM-D >50%)10

Passeri, M., et al. Aging Clin. Exp. Res., 1993; 5:63-71.

Double blind, controlled 8 weeks

MTHF (50mg) or Trazodone (100 mg). Psychotropic medication allowed but not AD

96 patients with dementia, MMSE 12 -23, and depression, HAM-D score >18.

Significant decrease in HAM-D scores at 4 and 8 weeks in the MTHF and TRZ groups. Response rate: 45% MTHF, 29% TRZ (NS)11

DiPalma, C., et al. Therapeutic Research, 1994; 55:5559-568.

Open trial 4 weeks. One week run-in placebo period

MTHF @ 90mgs/day (30mg TID) as monotherapy.

36 chronic alcoholics with major depression then treated with 90mg/day of MTHF for 4 weeks.

All 36 subjects completed. The HSRD, ZSRS, face scale and VAS showed a statistical significance of P<0.01 Folate deficiency may be primary or secondary to the depressive disorder but in either case it improves mental function.12

Coppen A, et al. Journal of Affective Disorders, 2000; 60:121-130.

Double blind controlled 10 weeksFolic acid (500 mcg) or placebo in combination with fluoxetine (20mg)

127 depressed subjects. DSM-III-R, HAM-D-17 score > or = 20.

Significantly greater improvement in Folic acid + fluoxetine group in females only. Effect linked to higher plasma folate and lower tHcy levels13

Alpert, JE, et al. Annals Clin Psychiatry, 2002;14:33-38.

Open trial 8 weeks Folinic acid in combination with an SSRI

22 depressed subjects. DSM-IV, HAM-D-17 score > or = 12. Partial or no response to an SSRI

16 subjects completed. 31% achieved a response (decrease in HAM-D >50%), 19% achieved remission.14

• 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

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

Bioavailability

• The peak concentration (Cmax) of L-methylfolate (6(S)5-MTHF) following the administration of L-methylfolate is more than 7 times higher compared to the peak concentration of L-methylfolate following the administration of folic acid.*

• Extrapolated, 7.5 mg L-methylfolate is bioequivalent to 52.5mg folic acid.

* Willems, et al, British Jrnl of Pharmacology, 2004

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

L-methylfolate Metabolism

• L-methylfolate is water soluble and rapidly excreted via the kidneys.

• L-methylfolate does not affect CP-450 system

• Potential Drug Interactions: High dose folate may lower the serum level of first generation anticonvulsants and pyrimethamine.

PDR® For Nutritional Supplements, 2001;ISBN: 1-56363-364-7:157-167.

High Folate Impact on

Drug Serum Levels

Drug Impact on Folate Levels

Anticonvulsants    

First Generation

Carbamazepine, valproic acid, fosphenytonin, phenytonin,

phenobarbital, primidone

Second Generation    

Lamotrigine, Divalproex sodium

Anti-Cancer    

Methotrexate

Rhumatoid Arthritis & Colitis    

Sulfasalazine

Lipid Lowering Drugs    

Cholestyramine

Colestipol

Other    

High dose NSAIDs

Pyrimethamine

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

L-methylfolate Unlikely to Mask Pernicious Anemia1,2,3

1. Scott, J.M. et al. The Methylfolate Trap. A Physiological Response in Man to Prevent Methyl Group Deficiency in Kwashiokor and an Explanation for Folic-Acid-Induced Exacerbation of Subacute Combined Degeneration in Pernicious Anemia; Lancet. 1981 2:337-340

2. Kelly P, et al. Unmetabolized Folic Acid in Serum: Acute Studies in Subjects Consuming Fortified Food and Supplements. Am J Clin Nutr 1997;65:1790 –5.3. Morris, SM, Folate and Vitamin B-12 Status in Relation to Anemia, Macrocytosis, and Cognitive Impairment in Older Americans. Am J Clin Nutr 2007;85:193–200.

• Folic Acid can be metabolized and utilized for DNA biosynthesis even in vitamin B-12 deficient cells allowing remission of the anemia from a vitamin B-12 deficiency.

• L-methylfolate (5-MTHF) is unlikely to mask the anemia because in the absence of vitamin B-12, it would remain metabolically “trapped” as L-methylfolate.

L-methylfolate

DHF(dihydrofolate)

DNA synthesis

THF(tetrahydrofolate)

Folic acid

N5,N10-methylene-THF

methyl-B12

Hcy

methionine

Low [SAM]activates MTHFR

SAM 10,formyl-THF

Schematic prepared by T.Bottiglieri PhD.

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.

Dose: one 7.5mg tablet a day or as directed by physician

No need for initial titration or tapering when discontinuing treatment

AWP: $1.46 per tablet or $43.75/30 daysWAC: $1.17 per tablet or $35.00/30 days

Dosing and Cost of Deplin

Thank you

ReferencesAbou_Saleh MT, Serum and Red Blood Cell Folate in Depression; J. of Affective Disorders, 1989

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