Several variables predict whether or not you are at risk for depression: genes (SNP in your MTHFR enzyme), ELA (early life adversity), obesity, and inflammation. These same factors predict that you will not respond well to antidepressants. What to do, what to do. First, consider whether you may have low central nervous system (CNS) folate levels (you likely do). Why this matters: L-methylfolate is a critical vitamin needed by your brain to transform amino acids (from dietary protein) into key brain chemicals (neurotransmitters) such as serotonin, dopamine, norepinephrine, and acetylcholine. If your brain folate levels are low, you cannot make sufficient neurotransmitters. If so, not even the best antidepressant will work optimally. You may get better, but will you get well? Find out what the signs (fatigue, inflammation, pain, being overweight, and other sickness behaviors), causes (diet, inflammation, environmental toxins, lifestyle, genetic mutations), and risk factors (age, depression, medications, other medical conditions) for low folate. Won’t the folic acid in your current multi-vitamin or B vitamin complex take care of this? Probably not. For many people with depression, they cannot convert this synthetic form of folate (or for that matter, they cannot convert dietary folate from green leafy vegetables) into the only form of folate – L-methylfolate - that can get through the blood-brain-barrier (BBB) and into their brains. You may be one of those. For that reason, I (Dr. Dave) only use that specific form of folate: L-methylfolate. But be careful, not all L- methyfolate is the same. The two that I trust and use the most often, depending on your insurance coverage and whether I’m your personal physician or your health consultant, are Deplin and our own IP Formula’s Methyl Esssentials. Deplin, a medical food, requires a prescription from your clinician, and if not covered by your insurance may make it unaffordable. It is of high quality made by a superb company supported by topnotch sales and marketing team. You cannot buy it directly, however. I also trust our over-the-counter form of L-methyfolate: Methyl Essentials. It too is of very high quality, is competitively priced, is ideally dosed, and combines with it the most bio-active form of Vitamin B12 (methylcobalamin). This is particularly important in our elder patients and clients. Here are the specs on Methyl Essentials: IP Formulas Methyl Essentials L 5 MTHF 6.5 mg & B12 2mg contains the most bio active form of L 5-Methyl folate and methylcobalamin-vitamin B12 and is the only form that crosses the blood brain barrier. Increases production of dopamine, melatonin, serotonin, and DNA It can be ordered online here: http://www.integrativepsychiatry.net/ip-formulas-methyl-essentials-l-five-mthf-btwelve.html

1. Image repined from rednihao.deviant.com
You’re are on an
antidepressant
and it puzzles
you that YOU
ARE STILL NOT
WELL.
You’re Not Alone

2. Significant Individual Differences in 20
Subjects Treated With An Antidepressant:
Or, in Other Words, It’s a Crapshoot.
Depression Severity (MADRS)
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
Time From Treatment Start (weeks)
10
11
12
MADRS = Montgomery-Asberg Depression Rating Scale.
Uher R. Harv Rev Psychiatry. 2011;19(3):109-124 .

3. STAR*D Study: 2/3 of Patients Remained
Symptomataic Following Antidepressant
Treatment
~67%
Mild
symptoms
~28%
Remission
~33%
8
Moderate
symptoms
~23%
Severe
symptoms
~12%
Very severe
symptoms
~4%
Percent of Patients
7
6
5
4
3
2
1
0
0
1 2
3 4
5 6
7 8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Depressive Symptoms (QIDS-SR score) After
up to 12 Weeks of Antidepressant Treatment
QIDS-SR, Quick Inventory of Depressive Symptomatology Self-Report;
STAR*D, Sequenced Treatment Alternatives to Relieve Depression.
Trivedi MH et al. Am J Psychiatry. 2006;163(1):28-40.

4. Residual Symptoms and the Risk of
Relapse in Major Depressive
Disorder
% of Patients Relapsing
Patients without
residual symptoms
(n=17)
25%
Patients with
residual symptoms
(n=40)
75%
Paykel ES et al. Psychol Med. 1995;25(6):1171-1180.

5. Residual Symptoms May Hasten
Relapse in Patients With MDD
Time (Years) to Relapse Based on # of
Residual Symptoms
Median # of weeks
well of patients who
recovered with no
residual symptoms
was 3.4 times
greater than that of
patients who
recovered having
one or more mild
symptoms.
Recovery with no symptoms
4.4
Recovery with 1+ mild symptoms
1.3
0
1
2
3
4
5
Judd LL et al. J Affect Disord. 1998;50(2-3):97-108.

6. OK. So You Are Still Depressed!
Image repinned from saatchionline.com
Increase dose?
Switch Medication?
Add A 2nd Medication?
Change Clinicians?
Go Natural?
What Should You Do?

7. First, Think Inflammation
People with evidence of
increased inflammatory
activity prior to treatment
have been reported to be
less responsive to
antidepressants, lithium,
or acute sleep deprivation.
Moreover, people with a
history of nonresponse
to antidepressants have
been found to
demonstrate increased
plasma concentrations of
IL-6 and acute phase
reactants.
Miller AH, Maletic V, Raison CL.. Biol Psychiatry. 2009 May 1;65(9):732-41

8. In other words, if you are inflamed,
you are less likely to respond to
anti-depressant medications, and if
you haven’t responded to your antidepressant, you are more likely to
be inflamed!

9. Other Signs
You May be
Inflamed:

10. So What If You Are Inflamed?
Inflammation
Decreases the rate
at which you make
new
neurotransmitters
Low Serotonin
Low Dopamine
Low Norepinephrine
Low Acetylcholine
Inflammation
Is associated with
low levels of CNS
folate.
All of which leads to:
Increases the rate at
which you burn
through your brain
chemicals:
neurotransmitters
Inflammation
(And that
keeps you depressed!)

11. What Else Causes
Low Folate?
• Overweight
• Elevated hs-CRP (a
measure of systemic
inflammation
• Age (especially > 70)
• Medications such as
Lamictal, Tegretol,
Depakote,
methotrexate,
Prozac, metformin,
birth control pills,
niacin
• Excess
alcohol/smoking and
poor nutrition
• Genetics

12. Genetics?
Get Tested Here!
T/T
Polymorphism
30%
C/C
Normal
30%
C/T Polymorphism
56%
• If you suffer from depression, you
have a 70% chance of having a
genetic in-born error impairing your
ability to make L-methylfolate from
dietary folate (green leafy
vegetables) or from the synthetic
folic acid that is in your multivitamin.
• If you have this genetic error
(formally referred to as a single
nucleotide polymorphism (SNP) of
the enzyme – MTHFR – that converts
dietary folate into L-methylfolate)
then you will have low levels of Lmethylfolate in your central nervous
system (CNS).
• If you have low CNS L-methylfolate
levels you will have low levels of the
key neurotransmitters serotonin,
norepinephrine, and dopamine.
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.

13. Second, If Inflamed or Overweight:

14. Why L-methylfolate ?
Because it is Seven Times More Bioavailable Than
Synthetic Folic Acid
L-methylfolate
vs.
Synthetic Folic Acid
DHF Reductase
Dihydrofolate
(Dietary Folate)
DHF Reductase
Tetrahydrofolate
10-formyl-THF
MTHFD1
Polymorphism
5, 10 Methenyl THF
5, 10 Methylene THF
L-methylfolate
MTHFR C→T
Polymorphism
L-methylfolate
Willems FF et al. Pharmacokinetic Study on the Utilisation of 5-methyltetrahydrofolate and Folic Acid in
Patients with Coronary Artery Disease. Br J Pharmacol. 2004;141(5):825-30.

15. Because L-methylfolate is the
only form of folate that
crosses the blood brain
barrier (BBB) and is thereby
the only form of folate that
your brain can use to make
neurotransmitters.
And

16. See. I told you so.
XPH2
Inflammation
and
Oxidative
Stress
phe
tyr
BH2
L-methylfolate
BH4
tryp
arg
PAH
Tyr
TH
L-DOPA
TPH
5-HTP
NOS
NO
Haroon E et al. Neuropsychopharmacology. 2012 Jan;37(1):137-62.

17. When To Take L-Methylfolate
• When to consider starting L-methylfolate:
• Mild to moderate depressive symptoms for
those who don’t want medications;
•
•
At initiation of new antidepressant therapy
Inadequate response to antidepressant therapy
•
•
•
Before raising/maximizing does
Before switching to a different agent
As a first-line augmentation/combination
strategy

18. Methyl Essentials
by IP Formulas