The Need for Long-term Treatment Options in Depression

Fourth most disabling condition worldwide1; most disabling condition for females (US)

Increased morbidity of comorbid general medical conditions2 and increased rate of suicide as percent of total mortality3

Loss of productivity in workplace2

Patients with depression use substantially more healthcare services than do patients without depression4-6

Depression is life shortening

Increased risk of CV events, stroke, etc.

1. World Health Organization Web Site. Accessed July 7, 2005. 2. Greden JF. J Clin Psychiatry. 2001;62(suppl 22):5-9. 3. Fawcett J. Int Clin Psychopharmacol. 1993;8:217-220. 4. Rowan PJ, et al. Psychol Med. 2002;32:903-908. 5. Druss BG, et al. Am J Psychiatry. 2000;157:1274-1278. 6. Simon GE. Biol Psychiatry. 2003;54:208-215.

Why is Treatment of Depression so Important?

MDDUK Pop.

Chang CK, et al. PLoS One. 2011;6:e19590.

Annual mortality risk (%) by age groups and diagnoses of mental illness, compared to England and Wales population in 2008.

Life expectancy was reduced by 10.6 years for males and 7.2 years in females with MDD compared with UK population.

Chapter 1:

Lack of Appropriate Treatment Response: Impact, and Neurobiology

Series10

10

20

30

40

Mono

Mono

Mono

Mono

Augm

Augm

Augm

STAR-D Remission Rates Are Generally Low

Across All 4 Levels

1Trivedi MH et al. Am J Psychiatry. 2006;163(1):28-40; 2Trivedi MH et al. N Engl J Med. 2006;354(12):1243-1252; 3Rush AJ et al. N Engl J Med. 2006;354(12):1231-1242; 4Nierenberg AA et al. Am J Psychiatry. 2006;163(9):1519-1530; 5Fava M et al. Am J Psychiatry. 2006;163(7):1161-1172; 6McGrath PJ et al. Am J Psychiatry. 2006;163(9):1531-1541.

% R

emis

sion

Remission Definition:HAMD-17 ≤7

Level 1 1

11.9 weeksLevel 2 2,3

8-10 weeks Level 3 4,5

≤14 weeks Level 4 6

≤14 weeks

Low Treatment Resistance High

Mono, single medication regimen; Augm, combination medication treatment.

STAR-D Reveals Its Secrets – The Dangers of Residual Symptoms & Lack of Remission

Nierenberg AA et al. Psychol Med. 2010;40(1):41–50

• Sleep disturbance

• Sad mood• Appetite/

weight• Concentration• Outlook• Suicidal

ideation• Involvement• Energy/fatigue• Psychomotor

Increasing number of symptom domains leads to increased risk of relapse (x2[5]=17.7155, P=0.0033)

Overall 40% relapse rate

0 domains1 domain2 domains3 domains4 domains5 domains

1.00

0.75

0.50

0.25

0.000 10 20 30 40 50 60

QIDS-IVR Relapse Time (Weeks)

Cu

mul

ativ

e P

rob

abil

ity

of

Rel

apse

Potential Causes of Poor Response to Antidepressant Treatment

• Misdiagnosis• Inadequate treatment, under-treatment, or

starting treatment too late1

• Failure to achieve initial remission2

• Non-adherence• Failure to address concurrent disorders1

–Occult substance abuse–Occult general medical conditions (GMCs)–Concurrent Axis I or II disorders

1. Thase ME, Rush JA. J Clin Psychiatry. 1997;58(suppl 13):23-29. 2. Judd LL, et al. J Affect Disord.1998;50:97-108.

Nu

mb

er o

f E

ven

ts O

ccu

rrin

g D

uri

ng

th

e 4-

year

Fo

llow

-up

Per

iod

Delay of Treatment May Influence the Future Course of MDD

Altamura et al. Int J Clin Pract 2007;61(10):1697-700.

DUI=Duration of untreated illness, interval between the onset of the first episode and the first antidepressant treatment; MDD=Major depressive disorder.

*p=0.027

Recurrences Hospitalizations Suicide Attempts

0

2.5

2.0

1.5

1.0

0.5

DUI >12 Months (n=23)

DUI ≤12 Months (n=45)

2.17*

1.24

0.650.31 0.20 0.39

Is antidepressant resistance a precursor to Bipolar Disorder?

30 – DTT

25 –

20 –

15 –

ITT

10 – ETT-1

ETT-2 5–

0– 2000 2001 2002 2003 2004 2005 2006 2007

Participants with medication-resistant history (difficult-to-treat group (DTT)) without any antidepressant use (easy-to-treat group 1 (ETT-1)) or those without any change in antidepressant (easy-to-treat group 2 (ETT-2)). Participants who changed antidepressant just once, after an adequate antidepressant trial (intermediate level of difficulty to treat (ITT)).

Rate

s of

dia

gnos

is c

hang

e fr

om M

DD

to b

ipol

ar d

isor

der

Li et al, 2011, Br J Psychiatry, in press

Patients With MDD Who Did Not Respond to Antidepressants Had Higher Inflammatory

Cytokine Levels

p=0.01p=0.004

24 healthy controls and 28 patients with depression (HAMD17 >20) after 6 weeks of SSRI treatment and 16 euthymic patients (previously resistant to SSRIs) currently successfully treated with an SNRI

or an addition of lithium to SSRI treatment.

HAM-D=Hamilton depression score; MDD=Major depressive disorder; SNRI=Serotonin–norepinephrine reuptake inhibitor; SSRI=Selective serotonin reuptake inhibitor; TNF=Tumor necrosis factor.O’Brien SM, et al. J Psychiatr Res. 2007;41:326–331.

Controls ControlsDepressed DepressedEuthymic Euthymic

TNF- IL-6

TN

F-

(pg/

ml)

IL-6

(pg/

ml)

Remission May Protect the Brain From Long-Term Depression-Related Changes

In this prospective, longitudinal study, 38 participants with MDD and 30 controls were followed for 3 years. At the start and end of this period all participants had brain morphometry assessed by MRI. Patients with MDD who went into remission showed significantly less volume reduction in brain areas of direct relevance to the path-ophysiology of MDD when compared to patients with MDD who did not achieve remission.

Frodl TS et al. Arch Gen Psychiatry 2008;65(10):1156-1165.

Chapter 2:

Inflammation and Depression: Cause, Consequence or Collaborator ?

Stress and inflammation in MDD

A Psychosocial stress,social isolation, personality

factors

IL-1, TNF-, IL-6

IL-6

EuthymiaStress resilience

Major depression sickness behavior

G

Immunoregulation

k t

i H

PA

- a

xis

- c

IL-10, TGF-

NE

/-AR IL-1,

TNF-, IL-6

NF-B

ACh TLR

7nAChr

GR

Infection, tissue trauma, neoplasm Macrophage GCs

IL-10, TGF-

Raison et al, Arch Gen Psychiatry. 2010;67(12):1211-1224

Inflammatory Markers Predict the Future Development of Depression

Pasco et al. Brit J Psychiatry 2010, 197:372-377.

In a cohort of 644 initially non-depressed females, 48 developed de novo MDD over an approximate 10 year follow up. Survival plot (Kaplan-Meier) showing the probability of remaining free of de novo major depressive disorder for women stratified into tertiles of hsCRP. The concentration of hsCRP in each tertile is: low, <1.12 mg/l; mid, 1.12-2.97 mg/l; and high, >2.97 mg.l.

Tertile 1 (low) 100 – Tertile 2 (medium) Tertile 3 (high)

98 –

96 –

Per

cent

94 –

92 –

90 –

0 3 4 6 8 10 Time, years

*Correlations of IL-6 level with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correctionIL-6=Interleukin-6; MDD=Major depressive disorder; VAS=Visual analogue scale.

Inflammatory Cytokine Levels May Be Associated With Symptom Severity in MDD Patients

Alesci et al. J Clin Endocrinol Metab 2005;90(5):2522-30.

Comparison of 9 MDD patients with 9 matched healthy controls

Elevation of Inflammatory Cytokines in CSF May Alter 5-HT and DA Metabolism

Inflammatory cytokines and monoamine metabolites were compared in 63 suicide attempters and 47 healthy controls. MADRS scores correlated significantly with CSF IL-6 levels. IL-6 and TNF-alpha correlated with CSF 5-HIAA (5-hydroxyindoleacetic acid) and HVA (homovanillic acid).Higher cytokine levels were associated with increased suicidality.

Lindqvist D, et al. Biol Psychiatry. 2009;66:287-292.

Glia–Neuron Interaction May Influence Neurotrophic Factors

Miller et al. Biol Psychiatry 2009;65(9):732-41.

Relationship between Depression & Inflammatory Cytokines and Neurotrophic Factors

Positive correlation between depression and IL-6

Negative correlation between depression and brain-derived

neurotrophic factor Yoshimura R, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(4):722–726.

Chapter 3:

Obesity and Depression: A Path to Consternation?

Relationship Between Obesity, Metabolic Syndrome and Depression

Association between the metabolic syndrome (MetS) and depression in each body massindex (BMI) category.Graph displays the odds ratio (OR) for depression after adjustment for age, gender, prior cardiovascular disease,

employment status, marital status, smoking status, dietary score, and physical activity. Obesity was defined as a BMI 30 and overweight status as a BMI between 25 and 30 kg/m2

Skilton et al, 2007, Biol Psychiatry, 62(11): 1251-7.

Obese

Overweight

Normal Weight

0.00.51.01.52.02.5

NonMetS

MetS

Axi

s Ti

tle

Odd

s Ra

tio -

Dep

ress

ion

Adiposity, Inflammation and Depression

High caloric intake in the diet leads to increased accumulations of lipids in adipocytes. Increased lipid content results in an increased release of MCP-1 (CCL2), a chemoattractant that increases the infiltration of macrophages into adipose tissue. Both adipocytes and macrophages release inflammatory mediators such as IL-6 and TNFa into the peripheral circulation.

Shelton and Miller, Progress in Neurobiology 91 (2010) 275–299

MDD, Adiposity and Inflammatory Markers

Miller GE et al. Am J of Cardiol. 2002;90(12):1279-83

0.00

0.25

0.50

0.75

1.00

Low (BMI < 30) High (BMI > 30)

CR

P ±

SE

M (

mg

/L)

ADIPOSITY

C-Reactive Protein

Low (BMI < 30)

High (BMI > 30)

0.00

0.25

0.50

0.75

Interleukin-6

Control SubjectsDepressed Subjects

ADIPOSITY

IL-6

± S

EM

(p

g/m

l)

50 MDD patients compared with 50 healthy matched controls

Kloiber et al. Biol Psychiatry. 2007, 62(4): 321-6

Body Mass Index Impacts Antidepressant Response

Response to antidepressant treatment according to weight status.Mean Hamilton Depression test (HAM-D) rating scores and SEMs for 5 weeks after

hospitalization (left) in normal-body mass index (BMI) and high-BMI patients and (right) in normal-BMI, overweight, and obese patients

29

27

25

23

21

19

17

15

13

BMI ≤25BMI >25

admission week 1 week 2 week 3 week 4 week 5

HAM-D score

admission week 1 week 2 week 3 week 4 week 5

29

27

25

23

21

19

17

15

13

31BMI ≤2525< BMI ≤30BMI >30

Chapter 4:

Fascinating Folate:

1. Genetic Regulation of Folate Metabolism2. Two Sides of the Coin : L-methylfolate and

Homocysteine3. The Role of L-methylfolate in Tri-Monoamine

Synthesis

Folate Essentials:• Folate is a B-vitamin that cannot be synthesized de

novo by the body; it must be derived from diet or augmentation

• Dietary folate found in leafy green vegetables, legumes, beans, liver, citrus fruits and yeast

• Folic acid is a synthetic molecule more highly absorbed (85-95%) than is dietary folate (dihydrofolate)

• Multiple biochemical conversions required for dietary folate (or folic acid) to become metabolically active

Miller, A.L. Alt Med Rev 2008;13:216-26

Williams FF et al. Pharmacokinetic Study on the Utilization of 5-methyltetrahydrofolate and Folic Acid in Patients with Coronary Artery Disease. Br J Pharmacol. 2004;141(5):825-30.

DHF ReductaseDihydrofolate

Tetrahydrofolate

10-formyl-THF

5,10 Methyenyl THF

5,10 Methylene THF

5-MTHF

MTHFD1

Folate Metabolism

BBB

MTHFR

5-MTHF

Synthetic Folic Acid

Morris DW et al. J Altern Complement Med. 2008;14(3):277-285; Miller AL. Alt Med Rev. 2008;13(3):216-226; Stahl SM. J Clin Psychiatry. 2008;69(9):1352-1353; Farah A. CNS Spectr. 2009;14(1 Suppl 2):2-7.

The Folate Cycle From 10,000 Feet

5,10-methylene-THF

MTHFD1

MTHFD1

MTHFD1

Folic Acid

Dihydrofolate

Tetrahydrofolate

10-formyl-THF

5,10-methyenyl-THF

serine

C677T

cSHMT

MTHFR

serine

De novo Purine Synthesis

DHF

dTMPdUMP

Thymidylate Synthesis & DNA Repair

DHFR

DHFR

Methionine

SAMeSAH

HomocysteineMAT

MTR

MTRR

DNMTDNA

Methylated DNA, RNA, protein, lipids

Cystathionine

Cysteine

Glutathione

CBS?

Ammonia

L-methylfolateBH4

BH2

DHPR

Tryptophan Tyrosine

MTHFR A1298C

MAO A

HIAA

MAO B

Serotonin Dopamine

COMT

Norepinephrine

HVA HVA

MAO B COMT

VMA VMA

THF?

COMT Promotor

MethionineHomocysteine

Cycle

cardiovascular, metabolic and psychiatric disturbance

Homocysteine and NMDA Toxicity HOMOCYSTEINE HCS04 HMS03SAH

Glutamatergic NMDA agonism

Reduced trophicsupport

Reduced kyn acid

Reduced NMDAantagonism

ExcitotoxicCell death

Haroon et al. Neuropsychopharmacol 2011; Epub; Oxenkrug. J Neural Trans 2011; Epub; Bottiglieri. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1103-12

Interface of inflammation and neurotransmitter synthesis in MDD

Tetrahydrobiopterin (BH4) is a critical cofactor for the rate-limiting enzymes involved in the synthesis of the monoamine neurotransmitters, including (1) the synthesis of tyrosine (tyr) from phenylalanine (phe) by PAH; (2) the synthesis of L-3,4-dihydroxyphenylalanine (L-DOPA) from tyrosine (tyr) by tyrosine hydroxylase (TH) leading to the production of dopamine and norepinephrine; and (3) the synthesis of 5-hydoxy-L-tryptophan (5-HTP) from tryptophan (tryp). BH4 is degraded to BH2, which can be regenerated to BH4 through pathways supported by folic acid, L-methylfolate, and SAMe. BH4 is relatively unstable and in the context of inflammation and oxidative stress can undergo non-enzymatic oxidation leading to the irreversible degradation of BH4 to XPH2.

Haroon et al,2011,Neuropsychopharmacology, in press

L-Methylfolate is a Required Cofactor for Monoamine Synthesis1

1. Adapted from: Bottiglieri T. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2005;29:1103-12. 2. Stahl SM. L-Methylfolate: A Vitamin for Your Monoamines. J Clin Psychiatry. 2008. 69;9:1352-53. 3. Borjigin J. et al, CircaCircadian regulation of pineal gland rhythmicity. Mol Cell Endocrinol, 2011, in press

Robust levels of CNS L-methylfolate may be necessary to maximize monoamine synthesis.2

MTHFR

Tryptophanhydroxylase

L-methylfolate

Tyrosine hydoxylase

BLOOD CNS Tryptophan

Tyrosine

BH4

Norepinephrine

Dopamine

Melatonin

Serotonin

Up to 70% of MDD Patients Have a Genetic Mutation Reducing Ability to Convert Folic Acid to L-methylfolate

1. Kelly CB et al. J Psychopharmacol. 2004;18(4):567-71. 2. Bottiglieri T et al. J Neurol Neurosurg Psychiatry. 2000;69:228-32. 3. Surtees R, Heales S, & Bowron. Clinical Science. 1994;86:697-702.

• Patients with the C677T MTHFR polymorphism have low CNS L-methylfolate.1

• Low CNS L-methylfolate is associated with low production of serotonin, norepinephrine and dopamine.2,3

C/TPolymorphism

56%

C/C Polymorphism

30%

T/TPolymorphism

14%C/C

C/T

T/T

Risk Factors for Low CNS L-methylfolate

1. Bottiglieri T. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2005;29:1103-12.; 2. Stahl SM. J Clin Psychiatry. 2008;69(9):1352-53.; 3. Kelly B J et al. Psychopharmacol. 2004;18(4):567-71.; 4. Amilburu A et al. Inhibition of intestinal absorption of 5-methyltetrahydrofolate by fluoxetine. J Physiol Biochem. 2201;57(2):71-80; 5. Sobczyriska-Malefora A et al. Erythrocyte folate and 5-methyltetrahydrofolate levels decline during 6 months of oral anticoagulation with warfarin. Blood Coagul Fibrinolysis. 2009; Jun;20(4):297-302.; 6. Kelly CB et al. J Psychopharmacol. 2004;18(4):567-71; 7. Bottiglieri T et al. J Neurol Neurosurg Psychiatry. 2000;69:228-32.; 8. Surtees R, Heales S, & Bowron. Clinical Science. 1994;86:697-702.

• Anticonvulsants such as lamotrigine, carbamezapine, phenobarbital and valproate, methotrexate, sulphasalazine, oral contraceptives, metformin, niacin and fenofibrates, fluoxetine, warfarin

Drugs

• Diabetes, atrophic gastritis, Crohn’s, colitis, bypass surgery, renal failure and hypothyroidismDisease

• Excess alcohol, smoking and poor nutritionLifestyle

• CNS L-methylfolate levels markedly decrease in individuals over 70 years of ageAging

Chapter 5:

Folate: Clinical Studies and Their Usefulnes in Clinical Practice

Study Inclusion Criteria Study Subjects• Adults meeting DSM-IV criteria for MDD, current• QIDS-SR ≥12 at screen and baseline visit• Has not failed more than 2 antidepressant trials of

adequate dose and adequate duration in current MDE (adequate duration = at least 8 weeks)

• Treated with SSRI during current episode for ≥8 weeks with stable SSRI dose in therapeutic range X 4 weeks

• 75 depressed patients with inadequate response to SSRIs were enrolled in a 60-day trial which was divided into two, 30-day periods (Phases 1 and 2).

SSRI + L-methylfolate

15mg

SSRI + L-methylfolate

15mg

Efficacy Analysis SPCD Trial Design

Phase 130 days

Phase 230 days

Group X is included in Phase 2 for the purpose of blinding but

not in the study results.

Groups 1 and 2 were pooled for L-methylfolate analysis and groups

3-5 were pooled for the placebo analysis.

SSRI + Placebo

Randomize

NonResponders

NonResponders

SSRI + Placebo

SSRI + Placebo

1 3 4

52X

SSRI + L-methylfolate

15mg

Efficacy Results of Study II HDRS-17 Response Rates – 30 Days

0%

5%

10%

15%

20%

25%

30%

35%

40%

Phase 1 Response Rate (%)

Phase 2 Response Rate (%)

Pooled Response Rate (%)

36.8

%

27.7

% 32.3

%

19.6

%

9.5% 14

.6%

*

*p=0.04 (pooled)

% o

f P

atie

nts

wit

h 5

0% R

edu

ctio

n H

DR

S-1

7

L-MethylfolatePlacebo

Safety Results and Overall Discontinuation

0%1%2%3%4%5%6%7%8%9%

10%

L-methylfolate + Antidepressant

Antidepressant + Placebo

2.4%3.7%

n = 1/42 n = 2/54

% o

f P

atie

nt

Dis

con

tin

uat

ion N/S

L-methylfolate patient was removed from the trial due to mood elevation. Patient’s medical history included bipolar disorder which was not detected at baseline.

No Difference in Discontinuation Due to Adverse Events

Placebo Treated Placebo Treated Placebo TreatedCC CT TT

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

-4.28

-5.51-4.88

-8.13

-1.38

-6.50Mea

n C

han

ge H

DR

S-2

8HDRS-28 Treatment Effect by MTHFR C677T

Genotype

CC CT TTPhase I N = 39 18 6Phase II N = 20 8 4

Placebo L-methylfolate Placebo L-methylfolate

-8

-7

-6

-5

-4

-3

-2

-1

0

-2.79

-7.30

-3.88-3.25

Obese (BMI > 30) Non-Obese (BMI < 30)

Ch

an

ge

in H

DR

S-1

7

Phase I N = 65Phase II N = 33

p = 0.0189

Test of treatment effect: chi-square = 6.74

p = NS

Efficacy Results and Obesity HDRS-17 Mean Change – 30 Days

Placebo L-methylfolate Placebo L-methylfolate

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-0.29

-1.22

-0.46 -0.43

Obese (BMI > 30) Non-Obese (BMI < 30)

Mea

n C

ha

ng

e in

CG

I S

core

Phase I N = 65Phase II N = 33

Test of treatment effect: chi-square = 10.03

p = NS

p = 0.0013

Efficacy Results and Obesity CGI Mean Change – 30 Days

Summary:• L-methylfolate 15mg/day as adjunctive treatment to antidepressant

therapy resulted in superior treatment outcome in 30 days (efficacy) compared to continued antidepressant therapy plus placebo in:

– both co-primary outcome measures achieving statistical significance in:

• response rates (50% ↓HDRS-17, p=0.04)

• degree of improvement (Reduction in HDRS-17, p=0.05)

– as well as in most secondary measures, including change in scores

• QIDS-SR (p=0.04)

• Clinical Global Impression Severity scale (CGI-S, p=0.01)

• Obese patients (BMI > 30; HDRS-17, p = 0.02; CGI-S, p = 0.001)

• Genetic variations of folate metabolism

• Clinical management of MDD may be optimized with adjuvant L-methylfolate 15mg.