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.