Psych 06: NHP for Depression and Anxiety Syndromes

What NHPs are used for depression?

• St. John's Wort

• SAM-e

• Omega 3 Fatty Acids

• Folate

What NHPs are used for anxiety?

• Kava

• Passion Flower

• Bach Remedy

Can NHPs be used to augment?

maybe

What part of St. John's Wort is used?

the flower

What is the active constituent in SJW?

hyperforin

SJW MoA

• Inhibits reuptake of 5-HT, NE, DA, GABA and L-glutamate

• Reduce cytokine production (suggesting antiinflammatory MOA)

SJW evidence for mild-moderate MDD

• Superior to placebo in patients with mild-moderate major depression

• Similarly effective as standard anti-depressants

SJW evidence for severe MDD

insufficient to draw conclusions

SJW common AEs

- Dry mouth

- headache

- fatigue

- GI upset

- insomnia (take in AM)

SJW sexual dysfunction

Fewer ADRs than SSRIs and less sexual dysfunction.

SJW serious AEs

• Phototoxicity (avoid sun/ use sunscreen)

• Withdrawal syndrome (caution patient to taper) - Similar to SSRIs

• Mania, hypomania (AVOID in bipolar disorder)

What happens to the [drug] that are eliminated via CYP450 .. etc when adminstered w/ SJW?

- Reduces serum levels of susceptible drugs

- Decreases therapeutic effects

• > 45 drug interactions (19 MAJOR) and any other P-glycoprotein / P450 3A4 substrates

SJW effect on drug metabolism

Strong inducer of P-glycoprotein and CYP450 (mainly 3A4; but also 1A2, 2C19 and 2C9)

SJW DI

• Immuno-suppressants: cyclosporine

• Anti-retrovirals: reported to decrease plasma level of indinavir (57% decrease in AUC)

• Digoxin (up to 25% decrease in AUC)

• Opiates (methadone, oxycodone)

• Warfarin

• Oral contraceptives (many reports of pregnancies!)

• SSRIs and related anti-depressants

SJW dosing

Most clinical trials have used: 300 mg tid

(extract standardized to 0.3% hypericin and 2-5% hyperforin)

SJW time to effect

usually seen after 10 - 14 days (with significant clinical response seen at 4 - 6 wks)

What should be done when a patient wants to d/c SJW?

taper, due to risk of withdrawal syndrome

SAMe sources

- Found throughout the body: Amino acid derivative synthesized in the body from ATP and methionine

- Available from meat

- Produced synthetically

SAMe (S-adenosylmethionine) uses

MDD

osteoarthritis

SAMe MoA

an amino acid that acts as a universal methyl donor needed in the synthesis of monoamine transmitters (DA, NE and 5-HT) and membrane phospholipids

What are the effects of SAMe use on neurotransmission?

- increased NE, 5-HT & DA levels

- Alter cellular membrane fluidity helps with facilitation of signal transduction across membrane

- Anti-inflammatory effects

SAMe evidence vs TCA

Monotherapy with SAMe was comparable to TCAs, SSRI for mild-moderate MDD

SAMe evidence vs SSRI

may be a safe and effective adjunct to SSRIs for non-responders to SSRIs alone

Quality of SAMe evidence

Conclude: quality of trials was too low to make any recommendations

SAMe common SEs

Headache

dry mouth

insomnia

jitters (take in AM)

$$$

SAMe serious AEs

Possible mania & hypomania (in pts with bipolar disorder) - AVOID

Is serotonin syndrome a SE of SAMe?

Serotonin syndrome NOT reported in studies

SAMe dosing in mild-moderate MDD

800 mg po bid

O3FA MoA in MDD

Change membrane structure and function leading to:

- Improved cellular communication

- Reduced inflammatory processes (less PGE2)

- Improved neurotransmission

O3FA dosing in MDD

1 - 4 g EPA + DHA daily

Well tolerated at doses up to 3 g/d

Ratio of EPA:DHA that has been shown to be effective in the studies

supplements usually 3:2 (EPA>60%)

O3FA AEs

D, N, GI disturbance

O3FA DI

Hypotensive agents: can decrease blood pressure (additive effects)

How to reduce fishy aftertaste and belching?

Take with meals or freeze capsules before taking

Does O3FA prevent depression?

no evidence suggests this

O3FA monotherapy evidence

- Effective vs placebo (small-modest clinical effect)

- No difference in remission rates & QoL in some trials, similar adverse events to placebo

O3FA evidence as adjunct to SSRI

Mixed study results, safe to try?

Folate MoA for MDD

Body uses folate (from diet or synthetic) to make the active form, methyl folate, which then synthesizes monoamines (DA, NE, serotonin)

- Also required in the production of SAMe

Who might benefit from folate supplementation in MDD?

Some ppl may lack the gene that activates this enzymatic pathway and may benefit from supplementation

Folate evidence as adjunct

A number of small studies show improvement in depression when used as an adjunct with other treatments (200-500 mcg/d)

Does folate supplementation improve mood in ppl who are not deficient in this vitamin?

no

Folate safety

Well tolerated and safe when dose is below the UL (1000 mcg/d)

NICE guidelines 2022 regarding SJW

do not prescribe or advise its use

despite evidence of benefit, due to uncertain optimal doses, variations in preparations, potential serioius interactions

What NHPs can cause/exacerbate anxiety?

• Caffeine-containing natural medicines:

- black tea, coffee, guarana, yerba mate

• Synephrine-containing NHPs:

- Bitter orange

What is the main psychoactive constituent in Kava Kava?

Kavalactones

- Standardized to 30-70%

Kava MoA

Anxiolytic & sedative mechanisms largely unknown

Kava possible MoAs for anxiety

• Possibly increase effects of GABA by increasing number of GABA binding sites

• May inhibit uptake of NE

• Similar effects as benzo's but non-habit forming

Kava Kava safest duration of use

Appears to be safe if used for short durations (up to 8 weeks) - concern over hepatoxicity/liver failure

Kava SEs

GI upset

drowsiness

fatigue

HA

• May affect ability to drive

Kava drug-drug interactions

- CNS depressants

- alcohol

Kava drug-disease interactions

AVOID in patients with liver disease

- Long term effects of Kava and its relationship with hepatotoxicity need to be studied further

Kava evidence

Limited evidence shows better than placebo, but still many unknowns (duration, safety)

Kava dosing

120-240 mg PO OD standardized to 30-70% kavalactones

- May be more effective over 200 mg

Passion flower evidence for monotherapy in anxiety

Some +ve small trials showing comparable results to other anxiolytics (but onset of action believed to be longer)

Passion flower evidence for augment therapy in anxiety

Case studies show additive effects with barbiturates, CNS depressants, sertraline and lorazepam

Passion flower safest duration

Has been used safely for up to 8 wks

Bach remedy evidence for monotherapy

3 small studies showing no better than placebo

Bach remedy safety

Safe to try; effectiveness not proven