new insights into depression, medications, and l-methylfolate

You’re are on an antidepressant

and it puzzles you that YOU

ARE STILL NOT WELL.

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You’re Not Alone

Significant Individual Differences in 20 Subjects Treated With An Antidepressant:

Or, in Other Words, It’s a Crapshoot.

40

20

10

00

30

Dep

ress

ion

Seve

rity

(MAD

RS)

1 2 3 4 5 6 7 9 11 12Time From Treatment Start (weeks)

8 10

MADRS = Montgomery-Asberg Depression Rating Scale.Uher R. Harv Rev Psychiatry. 2011;19(3):109-124 .

Presenter

Presentation Notes

Presentation points: -Each line represents one of twenty subjects randomly selected among those who were treated with escitalopram as part of the Genome-based Therapeutic Drugs for Depression - GENDEP study. -There are significant differences in individual response to antidepressants. -Large individual differences in the treatment response may reflect a neurobiological diversity of MDD, despite the same diagnosis. Abstract. Pharmacological and psychological treatments act on and against the background of genetic disposition, with epigenetic annotation resulting from previous experiences. Research in animal models suggests the possibility that epigenetic interventions may modify the impact of environmental stressors on mental health. Gaps in evidence are identified that need to be bridged before knowledge about causes can inform cure in personalized psychiatry.

STAR*D Study: 2/3 of Patients Remained Symptomataic Following Antidepressant

Treatment

Perc

ent o

f Pat

ient

s

~67%

Mild symptoms

~28%

Moderate symptoms

~23%

Severe symptoms

~12%

Very severe symptoms

~4%

Depressive Symptoms (QIDS-SR score) After up to 12 Weeks of Antidepressant Treatment

Remission~33%

0

1

2

3

4

5

6

7

8

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

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.

Presenter

Presentation Notes

Presentation points: -Only one in three patients reached pre-defined remission. -Two thirds of patients remained symptomatic, incurring a greater risk of relapse and functional impairment. -Although some gains have been made in safety and tolerability of newer antidepressant agents, there is still a lot of room for improvement in efficacy. -Majority of patients who were responders/remitters experienced improvement within the first two months of treatment. Method: This prospective randomized (in later phases) clinical study included outpatients with major depressive disorder who were treated in 23 psychiatric and 18 primary care “real world” settings. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks. Remission was defined as an exit score of ≤7 on the 17-item Hamilton Depression Rat- ing Scale (HAM-D) (primary outcome) or a score of ≤5 on the 16-item Quick Inventory of Depressive Symptomatology, Self-Re- port (QIDS-SR) (secondary outcome). Response was defined as a reduction of ≥50% in baseline QIDS-SR score. Results: Nearly 80% of the 2,876 outpatients in the analyzed sample had chronic or recurrent major depression; most also had a number of comorbid general medical and psychiatric conditions. The mean exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47% (QIDS-SR). A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment.

Residual Symptoms and the Risk of Relapse in Major Depressive

Disorder

Paykel ES et al. Psychol Med. 1995;25(6):1171-1180.

Patients with residual symptoms

(n=40)75%

Patients without residual symptoms

(n=17)25%

% of Patients Relapsing

Presenter

Presentation Notes

PURPOSE OF THE SLIDE This slide addresses the association of residual depressive symptoms with a greater risk of relapse. SPEAKER DIRECTION Residual depressive symptoms are associated with a poor outcome in depression. In a study of 57 patients treated to remission who were then followed up for 15 months, Paykel and colleagues found that 17 patients had residual depressive symptoms. Relapse occurred in 76% of patients with residual symptoms who were available for follow-up, compared with only 25% of patients without residual symptoms. BACKGROUND Patients with a HAM-D17 score ≥8 were considered to have residual symptoms. Inpatients and outpatients aged 18–65 years who satisfied the Research Diagnostic Criteria (RDC) for definite primary unipolar major depression were included in this study. Patients were followed systematically to the point of remission which was defined as 2 consecutive months during which patient scores were below the inclusion criteria of definite major depression; remission was retrospectively rated. Patients who did not reach remission were followed for at least 15 months. Relapse was defined as meeting the RDC criteria for major depression for at least 1 month. REFERENCE Paykel ES, Ramana R, Cooper Z, et al. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25:1171-1180.

Residual Symptoms May Hasten Relapse in Patients With MDD

Judd LL et al. J Affect Disord. 1998;50(2-3):97-108.

1.3

4.4

0 1 2 3 4 5

Recovery with 1+ mild symptoms

Recovery with no symptoms

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.

Presenter

Presentation Notes

PURPOSE OF THE SLIDE Emphasize the need to treat all symptoms of MDD in the pursuit of patient recovery. Even one or more mild residual symptoms may have significant effects on remaining well from MDD. SPEAKER DIRECTION The main finding of this study was that depressed patients who experienced recovery with no symptoms remained well for a median of 4.4 years (231 weeks) before major depression relapse, compared to 1.3 years (68 weeks) for patients who recovered with one or more mild residual symptoms. Therefore, recovery with even one or more mild residual symptoms from depression was an important clinical marker associated with early relapse in MDD. “Recovery with no symptoms” included those patients with at least 80% of well interval weeks rated as the following: “Subject is returned to ‘usual self’ without any residual symptoms of the MDD disorder, although significant symptomatology from underlying conditions may continue.” Even the mildest residual symptoms, however, can negatively impact outcomes. Patients with residual subthreshold depressive symptoms—one or more mild residual depressive symptoms—experienced on average a faster time to relapse than did asymptomatic patients. BACKGROUND Patients with MDD (as diagnosed using Research Diagnostic Criteria, or RDC) were followed naturalistically for 10 years or longer. Patients were divided on the basis of intake MDE recovery into recovery with residual subthreshold depressive symptoms (recovery with one or more mild symptoms; N=82) and asymptomatic recovery (recovery with no symptoms; N=155) groups. Trained raters interviewed patients every 6 months for the first 5 years and every year thereafter. Depressive symptomatology was rated using the Longitudinal Interval Follow-up Evaluation (LIFE) Psychiatric Status Rating (PSR) scales. Recovery with one or more mild symptoms as defined by the PSR includes those experiencing one or more depressive symptoms but of no more than a mild degree. Episode count, too, was a negative prognosticator. Patients with more than 3 MDEs tended to relapse earlier than those with histories of 3 or fewer episodes, although this did not reach statistical significance. REFERENCE Judd LL, Akiskal HS, Maser JD, et al. Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord. 1998;50:97-108.

Increase dose?Switch Medication?

Add A 2nd Medication?Change Clinicians?Go Natural?

What Should You Do?

OK. So You Are Still Depressed!

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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.

First, Think Inflammation

Miller AH, Maletic V, Raison CL.. Biol Psychiatry. 2009 May 1;65(9):732-41

http://www.ncbi.nlm.nih.gov/pubmed/19150053

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 anti-depressant, you are more likely to

be inflamed!

Other Signs You May be

Inflamed:

Inflammation

Increases the rate at which you burn through your brain chemicals: neurotransmitters

Inflammation

Decreases the rate at which you make new neurotransmitters

Inflammation

Is associated with low levels of CNS folate.

So What If You Are Inflamed?All of w

hich leads to:

Low SerotoninLow Dopamine

Low NorepinephrineLow Acetylcholine

(And that keeps you depressed!)

• 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

What Else Causes Low Folate?

Genetics? • 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 multi-vitamin.

C/T Polymorphism56%

C/C Normal

30%

T/T Polymorphism

30%• 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 L-methylfolate in your central nervous system (CNS).

• If you have low CNS L-methylfolatelevels you will have low levels of the key neurotransmitters serotonin, norepinephrine, and dopamine.

Get Tested Here!

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.

http://www.integrativepsychiatry.net/mthfr-genetic-test.html




Second, If Inflamed or Overweight:

Why L-methylfolate ? Because it is Seven Times More Bioavailable Than

Synthetic Folic Acid

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.

L-methylfolate

vs. Synthetic Folic Acid

Dihydrofolate(Dietary Folate)

Tetrahydrofolate

10-formyl-THF

DHF Reductase

MTHFR C→TPolymorphism

5, 10 Methenyl THF

5, 10 Methylene THF

L-methylfolate

MTHFD1Polymorphism

DHF Reductase

L-methylfolate

AndBecause 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.

See. I told you so.

TPHtryp

THtyr

PAHphe

NOSarg

Tyr

L-DOPA

5-HTP

NO

BH4BH2

XPH2Inflammation and

Oxidative Stress

Haroon E et al. Neuropsychopharmacology. 2012 Jan;37(1):137-62.

L-methylfolate

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

Methyl Essentials by IP Formulas

http://healthremedies.com/methyl-essentials.html






new insights into depression, medications, and l-methylfolate

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