The Need for Long-term Treatment Options in Depression

• • • • • Fourth most disabling condition worldwide 1 ; most disabling condition for females (US) Increased morbidity of comorbid general medical conditions 2 and increased rate of suicide as percent of total mortality 3 Loss of productivity in workplace 2 Patients with depression use substantially more healthcare services than do patients without depression 4-6 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?

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

UK Pop.

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

Chang CK, et al.

PLoS One.

2011;6:e19590.

Chapter 1:

Lack of Appropriate Treatment Response:

Impact, and Neurobiology

STAR-D Remission Rates Are Generally Low Across All 4 Levels

40 30 20

Level 1 1 11.9 weeks

Mono

Level 2 2,3 8-10 weeks

Augm Mono

Level 3 4,5 ≤14 weeks

Augm Mono

Remission Definition:

HAMD-17 ≤7

Level 4 6 ≤14 weeks

10 Augm Mono 0

Low Treatment Resistance High Mono, single medication regimen; Augm, combination medication treatment.

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

STAR-D Reveals Its Secrets – The Dangers of

Residual Symptoms & Lack of Remission

1.00

0.75

0.50

0.25

0 domains 1 domain 2 domains 3 domains 4 domains 5 domains Overall 40% relapse rate • • • • • • • • • Sleep disturbance Sad mood Appetite/weight Concentration Outlook Suicidal ideation Involvement Energy/fatigue Psychomotor 0.00

0 10 20 30 40 QIDS-IVR Relapse Time (Weeks) 50 Increasing number of symptom domains leads to increased risk of relapse (x 2 [5]=17.7155,

P

=0.0033) 60 Nierenberg AA et al. Psychol Med. 2010;40(1):41–50

• • • • •

Potential Causes of Poor Response to Antidepressant Treatment

Misdiagnosis Inadequate treatment, under-treatment, or starting treatment too late 1 Failure to achieve initial remission 2 Non-adherence Failure to address concurrent disorders 1 – 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.

Delay of Treatment May Influence the Future Course of MDD

2.5

2.0

1.5

1.0

0.5

0 1.24

2.17* Recurrences 0.31

0.65

Hospitalizations DUI >12 Months (n=23) DUI ≤12 Months (n=45) *p=0.027

0.20

0.39

Suicide Attempts

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

Altamura et al.

Int J Clin Pract

2007;61(10):1697-700.

Is antidepressant resistance a precursor to Bipolar Disorder?

30 – 25 – 20 – 15 – 10 – 5– DTT ITT ETT-1 ETT-2 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)). Li et al, 2011, Br J Psychiatry, in press

Patients With MDD Who Did Not Respond to Antidepressants Had Higher Inflammatory Cytokine Levels TNF  IL-6 p=0.004

p=0.01

Controls Depressed Euthymic Controls Depressed Euthymic 24 healthy controls and 28 patients with depression (HAMD 17 >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.

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

Psychosocial stress, social isolation, personality factors

A

IL-1



, TNF-

IL-6 

, IL-6 IL-10, TGF-

 Euthymia Stress resilience G Immunoregulation Major depression sickness behavior

NE ACh



/



-AR

 7 nAChr

GR NF-



B IL-10, TGF-



IL-1



, TNF-



, IL-6 TLR GCs Macrophage Infection, tissue trauma, neoplasm

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

Inflammatory Markers Predict the Future Development of Depression

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.

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

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

Comparison of 9 MDD patients with 9 matched healthy controls *Correlations of IL-6 level with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction IL-6=Interleukin-6; MDD=Major depressive disorder; VAS=Visual analogue scale.

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

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/m 2

2,5 2,0 1,5 1,0 0,5 0,0

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

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

Control Subjects Depressed Subjects Interleukin-6 C-Reactive Protein 1.00

0,75 0,50 0,25 0.75

0.50

0.25

0,00 Low (BMI < 30) High (BMI > 30) ADIPOSITY Low (BMI < 30) High (BMI > 30) ADIPOSITY 50 MDD patients compared with 50 healthy matched controls 0.00

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

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

HAM-D score 29 27 25 23 21 19 17 15 13 admission BMI ≤25 BMI >25 week 1 week 2 week 3 week 4 week 5 31 29 27 25 23 21 19 17 15 13 admission BMI ≤25 25< BMI ≤30 BMI >30 week 1 week 2 week 3 week 4 week 5

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

Chapter 4:

Fascinating Folate:

1. Genetic Regulation of Folate Metabolism 2. Two Sides of the Coin : L-methylfolate and Homocysteine 3. 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

Synthetic Folic Acid Dihydrofolate BBB Tetrahydrofolate 10-formyl-THF 5,10 Methyenyl THF 5,10 Methylene THF 5-MTHF 5-MTHF

Folate Metabolism

DHF Reductase MTHFD1 MTHFR

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.

The Folate Cycle From 10,000 Feet

De novo

Purine Synthesis

Thymidylate Synthesis & DNA Repair

dTMP DHF Tryptophan Tyrosine BH4 dUMP MTHFD1 10-formyl-THF MTHFD1 THF?

MTHFR

A1298C

Folic Acid Dihydrofolate DHFR Tetrahydrofolate DHFR 5,10-methyenyl-THF MTHFD1 5,10-methylene-THF MTHFR L-methylfolate

C677T

serine cSHMT serine MTR MTRR DHPR Serotonin BH2 Dopamine MAO A HIAA MAO B HVA COMT HVA COMT Promotor Norepinephrine MAO B VMA COMT VMA DNA MAT Homocysteine CBS?

SAH DNMT

Cycle

RNA, protein, lipids Cystathionine Cysteine Ammonia Glutathione

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.

Homocysteine and NMDA Toxicity

SAH HOMOCYSTEINE HCS0 4 HMS0 3 Reduced kyn acid Glutamatergic NMDA agonism Reduced NMDA antagonism Excitotoxic Cell death Reduced trophic support cardiovascular, metabolic and psychiatric disturbance

Haroon et al. Neuropsychopharmacol 2011; Epub; Oxenkrug. J Neural Trans 2011; Epub; B ottiglieri. 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 Synthesis

1 BLOOD CNS

Tryptophan Tryptophan hydroxylase

Serotonin Melatonin

MTHFR

L-methylfolate BH 4

Tyrosine Tyrosine hydoxylase

Dopamine Norepinephrine

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

2 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, Circa Circa dian regulation of pineal gland rhythmicity. Mol Cell Endocrinol, 2011, in press

Up to 70% of MDD Patients Have a Genetic Mutation Reducing Ability to Convert Folic Acid to L-methylfolate T/T Polymorphism 14%

C/C

C/C Polymorphism 30%

C/T

C/T Polymorphism 56%

T/T

•

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

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.

Risk Factors for Low CNS L-methylfolate

Drugs

•

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

•

Diabetes, atrophic gastritis, failure and hypothyroidism Crohn’s, colitis, bypass surgery, renal Lifestyle

•

Excess alcohol, smoking and poor nutrition Aging

•

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

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.

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).

Efficacy Analysis SPCD Trial Design

Randomize Phase 1 30 days Phase 2 30 days 1 SSRI + L-methylfolate 15mg X SSRI + L-methylfolate 15mg 3 SSRI + Placebo Non Responders 2 SSRI + L-methylfolate 15mg 5 4 SSRI + Placebo Non Responders SSRI + Placebo 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.

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

L-Methylfolate Placebo 40% 35% 30% 25% 20% 15% 10% 5% 0% *p=0.04 (pooled)

*

Phase 1 Response Rate (%) Phase 2 Response Rate (%) Pooled Response Rate (%)

Safety Results and Overall Discontinuation

No Difference in Discontinuation Due to Adverse Events 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% 2.4% N/S 3.7% L-methylfolate + Antidepressant Antidepressant + Placebo n = 1/42 n = 2/54 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.

HDRS-28 Treatment Effect by MTHFR C677T Genotype

CC CT TT Placebo Treated Placebo Treated Placebo Treated 0 -1 -6 -7 -8 -9 -2 -3 -4 -5 -4,28 -5,51 CC CT TT Phase I N = 39 18 6 Phase II N = 20 8 4 -4,88 -8,13 -1,38 -6,50

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

Obese (BMI > 30)

Placebo L-methylfolate

0 -1 -2 -3 -4 -5 -6 -7 -8

-2,79 p = 0.0189 -7,30 Test of treatment effect: chi-square = 6.74

Non-Obese (BMI < 30)

Placebo L-methylfolate -3,88 p = NS -3,25 Phase I N = 65 Phase II N = 33

-0,8 -1 -1,2 -1,4 -0,2 0

Efficacy Results and Obesity CGI Mean Change – 30 Days

Obese (BMI > 30)

Placebo L-methylfolate

Non-Obese (BMI < 30)

Placebo L-methylfolate -0,29 -0,4 -0,43 -0,46 -0,6 p = 0.0013

-1,22 Test of treatment effect: chi-square = 10.03

p = NS Phase I N = 65 Phase II N = 33

•

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 significance in: outcome measures achieving statistical • • 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.