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Advances in NutraceuticalResearch in Psychiatry

IMER, Melbourne; Feb, 2013

Dr Jerome Sarris

NHMRC Clinical Research Fellow

The University of Melbourne

Department of Psychiatry &

Adjunct Research Fellow

Centre for Human Psychopharmacology (SUT)

jsarris@unimelb.edu.au

S-Adenosyl Methionine (SAMe)

• SAMe serves as a necessary

methyl donor of methyl groups

involved with the metabolism and

synthesis of neurotransmitters

• Folate deficiency is implicated in

causing increased homocysteine

levels, linked to poor response to

antidepressants

• Metabolism of homocysteine to

SAMe or back to methionine

requires folate , B6 & B12

• SAMe and folate are involved

with the methylation pathways

in the „one-carbon‟ cycle,

responsible for the metabolism

and synthesis or various

monoamines

(Williams et al. 2005)

S-Adenosyl Methionine/ Folate Cycle(Mischoulon & Fava cited in Papakostas 2009)

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A 6-week RCT using adjunctive oral

SAMe (target dose: 800 mg twice daily:

n=73) in MDD patients unresponsive to

stable SSRIs

S-Adenosyl Methionine (SAMe) versus Escitalopram

and Placebo in Major Depression

Sarris J, Papakostas GI,Vitolo O, Fava M, Mischoulon D (2012 in submission)

AIMS METHODOLOGY

• We examined a subsample

(n=144) from one site of a two-

site study of adults with

diagnosed MDD

• After washout, eligible subjects

were randomized to SAMe

(1600mg-3200mg/daily),

escitalopram (10mg-20mg/day),

or placebo

• 12 weeks of double-blind

treatment (titration at week 6 in

non-response)

• SAMe versus antidepressant (escitalopram) and placebo in treating MDD

• Aims to assess outcome depression outcome &

• Analyze the relationship between histamine and carnitine levels and response &

• To determine if histamine or carnitine levels changed during the course of antidepressant treatment

SAMe vs. Escitalopram- 12wk RCT

S-Adenosyl Methionine (SAMe)

Clinical Considerations

• Most clinical studies involved parenteral or intramuscular injections of SAMe,

rather than oral preparations

• Considering pharmacokinetic variability between administration techniques, oral preparations may not provide the same alacrity of effect (still however effective)

• SAMe should be used with caution in patients with a history of (hypo)mania due

to concerns over switching from unipolar depression to mania

• SAMe is expensive and the cost may be prohibitive for some

• Not suited for “over-methylators”, or in folate or B12 deficiency

• 200mg bid titrated to 400-800mg bid (be aware of stimulation)

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• Folate deficiency has been reported in approximately one third of people suffering from depressive disorders

• Several studies exist testing folic acid as an adjunctive, concomitantly with antidepressants

• All of these studies yielded positive results in regard to enhancing either antidepressant response rates or increasing the onset of response

• Current concerns over high synthetic folic acid supplementation with increased rates of certain types of cancer

• 5-methlytetrahydrofolate form considered to be a good form

• Dosage: 400mcg 5-MTHF, or 800mcg folic acid

Omega-3 fatty acids

Thymoleptic effect:

Mood stabilisation:

• Reuptake inhibition of serotonin & dopamine

• Modulation of secondary messengers

• Enhanced cell membrane fluidity

• Anti-inflammatory effects

• Modulation of cell-signalling pathways via effects such as T2 reduction

(increasing cell membrane fluidity)

• Select cytokine modulation and arachidonic acid inhibition, and phosphoinositide(PI)-protein kinase C antagonism

(Sarris, Mischoulon, Schweitzer 2011)

(Martins 2009)

• Studies using augmentation of omega-3 in BD have

been conducted: evidence indicates a positive effect

• Often not significant. Due to small sample sizes?

• Meta-analytic pooling of the studies may be beneficial

• PubMed, CINAHL, Web of Science and Cochrane

Library databases were searched during mid 2010:

• RCTs four weeks or longer

• Omega-3 in combination with

pharmacotherapies or treatment as usual to

treat BD depression and mania

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•Essential monoamine precursor required for the

synthesis of serotonin• Studied extensively as an antidepressant

• Eight controlled adjuvancy studies using L-tryptophan

with antidepressants provide encouraging evidence

• Tryptophan augmentation was found to be effective in

increasing the antidepressant response with phenezine

sulphate, clomipramine, tranylcypromine, and fluoxetine

• Best form 5-HTP (direct precursor for serotonin)

Zinc is one of the most prevalent trace elements in the amygdala, hippocampus, and neocortex brain regions

Involved with hippocampal neurogenesis via upregulation of BDNF

Modifies N-methyl-D-aspartate (NMDA) and glutamate activity

Zinc modulates the hypothalmic-pituitary adrenal axis, and has been shown to be neuroprotective in animal models

Zinc supplementation has been found to attenuate inflammation via inhibition of TNF-alpha, and IL-1beta

Low zinc serum level is associated with depression risk, and correlated with an increase in the activation immune system biomarkers, suggesting that this effect may result in part from a depression-related alteration in the immune-inflammatory system

(Lai et al. 2010)

Emerging evidence of zinc (20mg-30mg per day) for depression

Beneficial as an adjunct to antidepressant treatment

Or in cases of deficiency and/or comorbid low immune system

Two key 12-week RCTs have examined the effects of zinc (25mg/d) monotherapy supplementation as an adjunct with antidepressants for depressed adults non-responsive to medication

Found that zinc significantly lowered depressive symptom scores of depressed patients (pooled standard mean difference over placebo on HAM-D of -2.84 points, p<0.001)

(Lai et al. 2010)

Sarris, Schweitzer, Stough, Bousman, Berk, Mischoulon 2013

• Presence of several psychoactive compounds may have a “synergistic” effect. This may be defined as:

“A working together effect seen by a combination of substances that is greater than would have been expected from a consideration of individual contributions”(Heinrich et al., 2004)

1 + 1 = 5 as opposed to an additive effect

whereas 1 + 1 = 2

A Potential Synergistic Effect?

NHMRC Project Grant: $768,000

8 week double-blind RCT

SAMe vs. Combination Nutraceutical vs. Placebo for adults with current

MDD who are taking an SSRI/SNRI and are non-responsive (MADRS >18)

MADRS primary outcome + biomarkers (including pharmacogenomics)

Sarris, Schweitzer, Stough, Bousman, Berk, Mischoulon 2013

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Aims and Design:

3-year study, 3-arm double-blind RCT using two nutraceutical interventions as adjunctive treatment of 300 depressed SSRI non-responders (100 per arm)

Group A: SAMe (1600mg/day)

Group B: Enhanced SAMe combination nutraceutical (CN) formulation consisting of SAMe (800mg/day), Ethyl-EPA (1000mg/day), 5-HTP (200mg/day), 5-MTHF: 800mcg/day), zinc picolinate (30 mg/day) + cofactors

Group C: Matching placebo

Primary outcomes will be the Montgomery-Asberg Depression Rating Scale

Blood sample will be collected at baseline to analyse: COMT, MTHFR, TPH1, SLC6A4, SLC39A8, SLC39A12, FADS1, FADS2, CBS, BHMT, MTR, TCN2 SNPs

We will measure levels of BDNF, homocysteine, zinc, folate, EFA levels

This study will be conducted at The Melbourne Clinic (Melbourne University) & Royal Brisbane Women’s Hospital, Herston (University of Queensland)

• Growing body of evidence points to a critical role for mitochondrial

dysfunction in BD

• Far higher prevalence of both BD and depression in people with

mitochondrial abnormalities than in the general population

• Changes in brain energy levels and markers of energy metabolism

are altered in depression and BD, also implicating the role of

mitochondrial changes in these illnesses

• Mounting evidence showing genetic links between BD and

mitochondrial dysfunction

• Impaired energy metabolism triggers pro-apoptotic signalling,

oxidative damage, excitotoxicity, impeding mitochondrial replication

and function

Mitochondrial Dysfunction and Bipolar Disorder

• A number of pharmacological treatments and nutritional supplements

have previously been used in individuals with conventional

mitochondrial disorders

• Antioxidants (co-enzyme Q10, idebenone, vitamin C, vitamin E

and menadione), agents that specifically improve lactic acidosis

(dichloroacetate and dimethylglycine)

• Agents that correct secondary biochemical deficiencies

(carnitine, creatine), respiratory chain co-factors (nicotinamide,

thiamine, riboflavin, pantothenic acid, pyridoxine and Co Q10)

• The addition of the antioxidant, glutathione modulating nutrient

NAC may also provide a very potent intervention in the novel

formulation of a BD combination nutraceutical

Nutraceutical Compounds

•The N-acetyl derivative of cysteine• Less reactive, less toxic and less susceptible to oxidation

than cysteine, as well as being more soluble in water

• When taken orally NAC is readily absorbed via digestive

system, then converted in liver almost entirely to cysteine

and used for glutathione (GSH) synthesis • Cysteine that is not converted to GSH is capable of

crossing the blood-brain barrier by means of sodium-

dependent transport systems

• Neuroprotective antioxidant properties, and from the

sulfur protein supporting glutathione production

N-Acetyl Cysteine (NAC)

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• Berk and colleagues 2008 published the results • A 24-week RCT using 1g bid of NAC versus placebo in a

sample of 75 participants stable on medication or therapy

with DSM-IV-TR diagnosed BD type I or BD type II

• Results revealed that NAC significantly reduced bipolar

depression levels with a strong effect size

• No significant effect was found on mania outcomes

• Dosage: 400mg bid titrated to 800-1200mg bid

NAC Bipolar Disorder Pilot Study

ARM 2:

[NAC + Combination]

N-acetyl cysteine

+

Coenzyme Q10

Alpha Lipoic acid

Acetyl L carnitine

B Vitamins

Vit E, Vit A, Vit D, Biotin

1 capsule of each BID

Supplier:

ARM 1:

[N-Acetyl cysteine]

Two 500mg capsules BID

(2gm/day)

ARM 3:

[Matching Placebo]

Berk, Mahli, Dean, Sarris, et al. 2012 CRC ($675,000) + NHMRC ($908,000)

N-Acetyl Cysteine vs. Mitochondrial Nutraceutical Combination

vs. Placebo for BD I/II: 16-week double-blind RCT

• Obsessive-compulsive disorder (OCD) is a disabling mental disorder that

affects 1% to 2% of the population, and treatments are inadequate

• Dysfunction of glutamatergic neurotransmission is implicated in OCD

• Glutamate modulating agents are potentially efficacious

• N-acetylcysteine (NAC) is an amino acid based nutraceutical, and is

another readily available agent that has been found to attenuate the synaptic

release of glutamate in subcortical brain regions

• NAC restores the extracellular glutamate concentration in the

nucleus accumbens offering a critical pharmacological action in reducing

compulsive behaviour

NAC for the Treatment of OCD (Dean et al. 2012)

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Sarris, Camfield, Berk, Schweitzer 2013

3-week RCT (n=60)

Cross-over study

Kava vs. Placebo (tablets)

(250mg of kavalactones)

Adults with generalised

anxiety and different levels

of depression

Anxiety Outcome Depression Outcome

The KALM Study

• 8 week RCT (n=75)

• Participants with GAD and no depression

• Kava (120mg kavalactones) versus

placebo (titrated to 240mg in non-response)

• Outcomes: anxiety scales, quality of life,

sexual function, liver function

• Genetic polymorphisms:

GABA & noradrenalin transporters

Kava in the Treatment of GAD: ResultsA Double-Blind, Randomized, Placebo-Controlled Study

Sarris J, Stough C, Bousman CA… Schweitzer I (2012)

A significant reduction in HAMA scores in both groups for Time

(p<0.0001), with a significant Group X Time interaction (p=0.046)

in favor of kava over placebo

From baseline to the study endpoint, kava significantly reduced

participant‟s anxiety from 21.63 (+4.2) to 14.03 (+7.01)

(-7.6 points) vs. 19.50 (+4.2) to 15.26 (+6.2) (-4.2 points) for

placebo with a moderate clinical effect (d=0.63) in favor of kava

37% of the kava group were classified as “responders” Vs. 23% of

the placebo group; 26% of the kava group were classified as

“remitted” Vs. 6% placebo group (p=0.04)

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Kava in the Treatment of GAD: ResultsA Double-Blind, Randomized, Placebo-Controlled Study

Sarris J, Stough C, Bousman CA… Schweitzer I (2012 in submission)

For participants with moderate to severe level DSM-IV anxiety

(as assessed on MINI Plus), the anxiolytic effect of kava was

greater (p=0.020), with a larger effect size (d=0.80)

ANCOVA model: effects were still significant when controlling for

baseline MADRS depression (p=0.01), baseline BAI anxiety

(p=0.05), thyroid function (p=0.02), and weekly caffeine use

(p=0.03)

For pure GAD and no other DSM-IV diagnosed comorbid

anxiety disorder- a significant Group X Time interaction

(p=0.020; d=1.28), with a reduction of -8.5 points for kava on

the HAMA compared to -2.3 points for placebo

Anxiety Reduction on HAMA

Addiction

Sexual Effects

• No significant difference in the

number of participants in the

kava group [6/25 (24%)]

compared to the placebo group

[6/25 (24%)] wanting to increase

the dose of medication

• A total of 1/25 (4%) in the kava

group took more tablets than

instructed, compared to 2/25

(8%) for placebo

• Results on the Arizona Sexual Experience Scale (ASEX) showed that kava caused no diminishment of sexual performance or enjoyment

• Amongst females there was an indication of improvement of sexual function for the kava group (but not for men)

• Kava was found to significantly increase women‟s sex drive (ASEX sub-domain)

• The relationship between anxiety reduction and ASEX score for combined genders revealed a significant positive correlation between anxiety reduction and improved sexual effects from kava

Reduction of Anxiety on HAMA in the Kava Group: GABA Transporter Genotype

Of the five GABA transporter SNPs two (rs2697153 and rs2930152) were in perfect linkage disequilibrium (selected rs2697153)

Remaining four GABA transporter SNPs showed that each SNP was significantly associated with reductions in HAMA scores

rs2601126 T-alleles (p=0.02) or rs2697153 A-alleles (p=0.046) were associated with significant reductions in HAMA scores within the kava group

Although rs1710879 (p=0.01) and rs956053 (p=0.016) were not in Hardy-Weinberg equilibrium (p<0.05)

Noradrenalin transporter SNPs NS

SLC 6A1

rs2601126 T-alleles

rs2697153 A-alleles

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Kava for the Treatment of Generalized Anxiety Disorder:

A Double-Blind RCT NHMRC APP1063383 [$580,000)

While previous research has shown Kava to be effective in reducing

anxiety symptoms...

These studies were not conducted on “clinical anxiety”, specifically GAD

These studies used alcoholic or acetonic extracts- implicated in liver toxicity

Our pilot data supports the use of a standardised traditional water-soluble

extract of Kava produced via Pharmaceutical Good Manufacturing Practice

We aim to confirm the efficacy and safety of Kava in adults with GAD

To achieve this we plan to conduct a longer-term multi-centre RCT, with a

larger sample, using a standardised pharmaceutical-grade extract of Kava.

We will also attempt to replicate the association between GABA transporter

polymorphisms and Kava treatment response.

16-week, 2-arm, double-blind RCT using a standardised pharmaceutical-

grade water-soluble extract of Kava (120mg of kavalactones twice per day),

versus placebo in 180 adults with diagnosed GAD

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www.inimh.org

Full References Available Upon Request