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augmentation :using psychotropic
interventions that are not established
mono-therapies in conjunction with pharmaceutical
psychotropics,in order to enhance response
or limit side-effects
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Combination:
• strategies involve using two or more establishedpharmaceutical psychotropics for the same purpose
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can be initiated either at the start of
the prescription, or later if there is
insufficient response to
initial treatment
Adjuvancy:
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• 1-response time • 2-response rate • 3-remission rate
4-reduction of side effects5-remission of physiological or psychological symptoms
• 6-subjective changes in quality of life
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Polypharmacy combinations commonly include:
multiple antidepressants in MDDantidepressants with benzodiazepines in anxious depression
combinations of atypicalantipsychotics in psychotic disorders mood stabilizers with
antidepressants in bipolar depression
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Antipsychotics side effects: tardive dyskinesia weight gain somnolescence constipation cardiovascular disorder metabolic disorders
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open or controlled clinical trials:
adjuvant applications of nutritional and herbal
medicineswith antipsychotics
for:
amelioration of side-effects and increased
efficacy
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beneficial effects in attenuating either extra-pyramidal side-effects or positive schizophrenic symptoms:
• Traditional Chinese medicine formulas and Ginkgo biloba
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Mixed results with omega-3 fatty acidsand vitamin E
A review concluded that while vitamin E may not effectively treattardive dyskinesia, it may have a role in its prevention.
Controlled studies using vitamin B6 havedemonstrated beneficial effects on the reduction of extra-pyramidal
symptoms
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Despite an increased practice of synthetic poly pharmacy, co-prescription of
herbal medicines is often met with
alarm over concerns of:
potential drug–herb
interactions
While caution is indicated in any
case where multiple
prescriptions have potential for
interactions, a differential
concern over drug–herb
interactions needs further examination
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Our intention is to provide a comprehensive review of the literature focusing on the current evidence of adjuvant use of herbal and nutritional medicines with commonly used pharmacotherapies for mood and anxiety disorders A secondary aim is to provide a perspective on future research and integrative clinical applications of natural and synthetic medicines.
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1-MEDLINE (Pubmed) 2-CINAHL
3-Psyc INFO4-Chinese Science Citation
Database 5-Cochrane
Library
Methods
Terms were Medicine, Herbal, Plants, Medicinal,
Plant extracts, Phytotherapy and Drugs, Chinese
herbal, Adjuvant, Adjunctive,
Augmentation
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• We reviewed papers that described:controlled, uncontrolled or quasi-experimental human studies. Reasons for exclusion
included: a higher level of evidence
being available use of isolated herbal
constituents inadequate methodological rigor.
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Results• 4
345 papers were identified from our search criteria and 35 clinical trials were judged to be relevant to the review
These studies are reviewed under nutritional and herbal medicine with Antidepressants, Mood Stabilizers and Benzodiazepines
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Depression
Adjuvant use of pharmacotherapies for depress
ion
adjuvancy studies
on antidepressants involve
synthetic agents
including:
antidepressants (TCAs or mirtazapine with SSRIs), mood
stabilizers
(lithium, carbamazepine,
or valproate), and
noradrenergic or dopamin
ergic agents
(bupropion,
reboxetine,
atomoxetine)
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Only one herbal medicine mono-therapy study was revealed from our literature
review, indicating that this is a relatively uncharted field of
research
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Adjuvant use of nutritional and herbal medicines with antidepressants
Omega-3 fatty acids have not yet demonstrated significant results
as a mono-therapy for Major Depressive Disorder
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A recent meta-analysisincluded nine eligible RCTs:
omega-3 preparations demonstrated a positive standardized mean difference
towards a beneficial effect over placebo
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Folate deficiency: has been consistently
demonstrated in depressive populations
and in poor responders to antidepressants
Two controlled studies were located:
folic acid was more effective in reducing
HDRS score compared to augmentation with placebo
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Inositol has been studied as an antidepressant mono-therapyand as an augmenting agent:
it has mixed results
• no significant difference between adjuvant use of inositol or placebo
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S-Adenosyl-methionine has been studied for antidepressant activity for several decades
parenteral or intramuscular injections (crosses the blood–brain barrier) it demonstrated an antidepressant mechanism of activity, and comparable
effects to synthetic antidepressants
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Another caveat is cost. Therapeutic oral dose may require up to 1600 mg, which costs approximately US$8/day
S-adenosyl methionine should
be used cautiously in patients
with a history of mania.
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L-tryptophan has been studied as an antidepressant
L-tryptophan augmentation was found to be effective in increasing the antidepressant response with:
phenezine sulphate, clomipramine tranylcypromine
and fluoxetineBut not for all the TCAs
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Amino acids DL-phenylalanine and L-tyrosine, precursors to dopamine and norepinephrine, may provide augmenting antidepressantactivity
• however no studies were located assessing this
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Mood stabilizers including lithium and valproic acid andantipsychotics are commonly
used as first-line agents to treat the presentation of the manic phase in Bipolar I Disorder
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• Omega-3 Augmentation with
pre-prescribed mood stabilizers.
Limited evidence in benefiting BD
depression. Ineffectivein preventing or
improving treatment of mania
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Omega3:Appears safe and is more beneficial in addressing the depression rather than mania. More studies are required using EPA/DHA combinations
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Folic acid:
An RCT using folic acid (200
microgram) with lithium
demonstrated minor benefit in reducing depression on BDI
Further studies using a higher dose of folic acid may be
of benefit
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Inositol: Inositol augmentation with lithium demonstrated no significant antidepressant or mood stabilizing effect on HDRS
• As with MDD, inositol may have little or no benefit in augmenting antidepressant or mood stabilizing effects with lithium or valproate. A larger study is required
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A statistically significant reduction in fatigue and dizziness also occurred
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This formulation
reduces serum level of
carbamazepine. Heavy metals
and plant substitutions
have occurred in some
Chinese herbal medicines
• Positive results of this research on the
reduction of depression and side effects,
encourages further exploration of adjuvant use herbal medicines
withmood stabilizers
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Anxiety disorders
Adjuvant use of pharmacotherapies for anxiety Adjuvancy
strategies to treat anxiety disorders are commonly
focused on integrating psychological interventions or benzodiazepines with
antidepressants
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Aside from psychologicalintervention, common adjuvant psychotropic interventions withbenzodiazepines include b-blockers (propanolol) to address
somaticanxious symptoms, and sedating antipsychotics (olanzapine or
risperidone)
no augmentation studies using nutritional or herbal medicines with
benzodiazepines
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Although BDZs are effective anxiolytics, concerns over dependence and tolerance caution their long-term
use
nutritional or herbal medicines with BDZs may also focus on their reduction or withdrawal, so they
are given during dose reduction, or as a substitute at BDZs cessation
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Adjuvant use of nutritional and herbal medicines with benzodiazepines
One study using kava (Piper methysticum) in benzodiazepine
withdrawal was identified in the search
Kava produced a statistically significant drop of 7.5 point decrease over placebo at week 5 in anxiety on the Hamilton anxiety scale
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Novel adjuvant therapeutic uses of herbal medicines
• review revealed that few clinical trials to date have studied co-administered
herbal preparations with pharmaceuticals
• An example of the potential of herbal medicines to reduce side-effects and improve compliance with synthetic
psychotropics is detailed in a Cochrane database systematic review of Chinese herbal medicine (CHM) preparations for
schizophrenia
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A major problem with many syntheticpharmaceutical antidepressants, is that compliance is often poor
• systematic review of Chinese herbal medicine showed that fewer patients withdrew from treatment in the CHM plus antipsychotic groups than from the antipsychotic mono-therapy groups
• Subjects also displayed fewer side-effects such as constipation
• amelioration of side-effects (dizziness and fatigue)occurred in a bipolar disorder study using CHM with carbamazepine
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only mono-preparations of HMs trialed adjuvantly with psychotropics are
L. angustifolia and G. bilobaresults were positive
Two phytotherapies that may provide novel adjuvant application with synthetic antidepressants for enhancing
efficacy in the treatment of MDD are: golden root (Rhodiola rosea)
saffron (Crocus sativus)
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• In two studies the petals and stamen from C. sativus have demonstratedagainst placebo significant antidepressant activity
• in three trials have displayed equivalent efficacy to imipramine and fluoxetine
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A curious deficiency
uncovered in our review is:
St. John’s wort (Hypericum
perfortum: SJW)
potential reason:
may be a concern over
pharmacodynamic antagonism causing
serotonin syndrome and/or
switching to hypomania or mania
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1-decreased degradatio
n
3-
modulation of
neurotransmitter
transport systems
2-non selective re-uptake
of serotonin, dopamine
and norepineph
rine
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This broad range of activity may potentially provide an increased therapeutic effect from other antidepressants
A balanced approach to adjuvant prescription could involve low-dose administration of SJW with antidepressantsto increase response, or potentially to lower the risk of side-effects from the synthetic antidepressant by reducing the dose required for efficacy
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Discussion
• Review of the literature revealed that encouraging evidence exists for the use of omega-3 fatty acids, s-adenosyl methionin, folic acid and L-tryptophan adjuvantly with antidepressants to enhance response and
improve efficacy
• Folic acid, omega-3 and some Chinese herbal medicines also have emerging evidence as effective adjuncts with antipsychotics and mood stabilizers
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Current evidence does not firmly support the adjuvant use of nutritional or herbal
medicines in limitation or withdrawal of BDZs, but this remains an area worthy of exploration. As
detailed above, only one study trialing a herbal medicine (kava) with concomitant BDZs was
identified
In respect to the treatment
of BD, these interventions appear only to benefit the
depressive phase of the disorder
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In the case of nutritional adjuvancy, a beneficial effect ma more likely occur
when specific deficiencies or neurological dysregulations are apparent
a patient who does not eat any omega-3 containing foods may potentially benefit
more fromadjuvant omega-3 prescription than a
patient who regularly eats deep sea fish
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Common deficiencies affecting mental health outcomes may involve: amino acids (tryptophan,phenylalanine,tyrosine) which provide the precursors to neurochemicals B vitamins in particular B6, B12 and folate which are involved in methylating pathways omega-3 which encourages neuronal communication
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In conclusion
• While some positive evidence supports nutritional adjuvancy with various psychopharmacotherapies, adjuvant use of herbal therapies has
not been sufficiently studied to warrant standard clinical application. This remains a promising area of research via robust, safety-conscious
studies
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Many thanks