ARTICLE IN PRESS

Journal of Psychiatric Research xxx (2009) xxxxxx

Contents lists available at ScienceDirect

Journal of Psychiatric Research

journal homepage: www.elsevier.com/locate/jpsychires

Review

Adjuvant use of nutritional and herbal medicines with antidepressants, mood

stabilizers and benzodiazepines
Jerome Sarris a,*, David J. Kavanagh b, Gerard Byrne a
a
b

School of Medicine, University of Queensland, Queensland, Australia

Institute of Health and Biomedical Innovation and School of Psychology and Counselling, Queensland University of Technology, Queensland, Australia

a r t i c l e

i n f o

Article history:
Received 6 February 2009
Received in revised form 31 May 2009
Accepted 15 June 2009
Available online xxxx
Keywords:
Adjuvant
Adjunctive
Herbal medicine
Antidepressants
Mood stabilizers
Benzodiazepines
Kava
St. Johns wort

a b s t r a c t
Adjuvant use of nutritional and herbal medicines has potential to increase the efcacy of synthetic pharmaceuticals, and perhaps also decrease their side-effects by allowing lower doses to be prescribed. We
evaluated current evidence for adjuvant use of nutritional and herbal medicines with antidepressants,
mood stabilizers and benzodiazepines; and explored novel future areas of research. The paper also critiques current evidence for co-administration of St. Johns wort with synthetic antidepressants. We performed a systematic search of MEDLINE, CINAHL, PsycINFO, The Cochrane database, China National
Knowledge Infrastructure and the Chinese Science Citation Database. Search results were supplemented
by a review of reference lists and a forward search using the Web of Science. Where possible we calculated effect sizes. Encouraging evidence exists for the use of omega-3 fatty acids, SAMe, folic acid and Ltryptophan adjuvantly with antidepressants to enhance response and improve efcacy. Various nutrients
also have emerging evidence as effective adjuncts with antipsychotics and mood stabilizers. While some
evidence supports nutritional adjuvancy with various psychopharmacotherapies, adjuvant use of herbal
therapies has not been sufciently studied to warrant standard clinical application. This remains a promising area of research via robust, safety-conscious studies.
2009 Elsevier Ltd. All rights reserved.

Contents
1.
2.
3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1.
Adjuvant use of pharmacotherapies for depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2.
Adjuvant use of nutritional and herbal medicines with antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.
Adjuvant use of pharmacotherapies for bipolar disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.
Adjuvant use of nutritional and herbal medicines with mood stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Anxiety disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.1.
Adjuvant use of pharmacotherapies for anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.2.
Adjuvant use of nutritional and herbal medicines with benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Novel adjuvant therapeutic uses of herbal medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Role of funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00
00

* Corresponding author. Address: School of Medicine, University of Queensland, K

Floor, Mental Health Centre, Royal Brisbane and Womens Hospital, Herston,
Brisbane, Queensland 4029, Australia.
E-mail address: j.sarris@uq.edu.au (J. Sarris).
0022-3956/$ - see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jpsychires.2009.06.003

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

ARTICLE IN PRESS
2

J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx

1. Introduction
Adjuvancy strategies of medicines are commonly classied
into augmentation and combination approaches (Fava and
Rush, 2006). Prescriptive augmentation in psychiatry involves
using psychotropic interventions that are not established
mono-therapies in conjunction with pharmaceutical psychotropics, in order to enhance response or limit side-effects. Combination strategies involve using two or more established
pharmaceutical psychotropics for the same purpose. Adjuvancy
can be initiated either at the start of the prescription, or later
if there is insufcient response to initial treatment. Most clinical
trials assessing adjuvancy apply the additional intervention after
absent or partial response to the initial prescription. Outcomes
that are commonly assessed in adjuvancy studies include enhanced response time and response rate (i.e. >50% reduction
on assessment scale used), and improved remission rate (absence of diagnosis or a score below at set level on an assessment
measure (Fava and Rush, 2006). Other outcomes that are less
commonly explored include reduction of side-effects (more common in studies using antipsychotics), remission of residual physiological or psychological symptoms, and subjective changes in
quality of life.
Surveys have shown that polypharmacy by general practitioners
and psychiatrists has increased signicantly over recent years (Davids et al., 2006; de la Gandara et al., 2005; Patten and Beck, 2004;
Tapp et al., 2003). Polypharmacy combinations commonly include
the use of multiple antidepressants in MDD, antidepressants with
benzodiazepines in anxious depression, combinations of atypical
antipsychotics in psychotic disorders, and mood stabilizers with
antidepressants in bipolar depression. However, such polypharmacy
is not always supported by evidence. Those data are briey reviewed
in later sections.
Many open or controlled clinical trials have been conducted
using adjuvant applications of nutritional and herbal medicines
with antipsychotics for amelioration of side-effects rather and increased efcacy. A major concern in using antipsychotics is tardive
dyskinesia, which over 20% of patients experience (Soares-Weiser
and Fernandez, 2007). Other side-effects of antipsychotics include
weight gain, somnolescence, constipation, cardiovascular and metabolic disorders (Haddad and Sharma, 2007; Henderson, 2008).
Traditional Chinese medicine formulas (Rathbone et al., 2005)
and Ginkgo biloba (Atmaca et al., 2005; Zhang et al., 2001b) have
demonstrated benecial effects in attenuating either extra-pyramidal side-effects or positive schizophrenic symptoms. An
antioxidation and anti-inammatory mechanism of action is
commonly posited as being responsible for attenuation of tardive
dyskinesia (Zhang et al., 2001a). Mixed results in respect to amelioration of positive or negative symptoms or tardive dyskinesia
have been revealed using omega-3 fatty acids (Berger et al.,
2007; Emsley et al., 2006; Fenton et al., 2001; Peet et al., 2001;
Vaddadi et al., 1989), and vitamin E (Dorfman-Etrog et al.,
1999; Shriqui et al., 1992; Zhang et al., 2004). A 2001 Cochrane
review concluded that while vitamin E may not effectively treat
tardive dyskinesia, it may have a role in its prevention (Soares
and McGrath, 2001). Controlled studies using vitamin B6 have
demonstrated benecial effects on the reduction of extra-pyramidal symptoms (Lerner et al., 2002, 2004, 2007; Miodownik et al.,
2003).
Other nutritional and herbal medicines hold potential in
adjuvant use with pharmaceutical medicines to increase their
efcacy via increased pharmacodynamic synergism (Williamson,
2001). Although this area is controversial because of the
potential for pharmacokinetic interactions, benecial interactions potentially may occur, leading to a reduction in the dos-

age
of the
pharmaceutical medication, or
increased
efcacy.
Despite an increased practice of synthetic polypharmacy (Preskorn, 2006), co-prescription of herbal medicines is often met with
alarm over concerns of potential drugherb interactions. While
caution is indicated in any case where multiple prescriptions have
potential for interactions, a differential concern over drugherb
interactions needs further examination. Rigorous study is needed
not only to determine the extent of any negative interactions,
but also to examine the potential for synergistic benets.
A previous review by Werneke et al. (2006), explored evidence
of herbal and nutritional psychotropic interventions and touched
upon their adjuvant use. Our intention is to provide a comprehensive and critical review of the literature, focusing specically 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.
2. Methods
The electronic databases MEDLINE (Pubmed), CINAHL, PsycINFO, Chinese Science Citation Database (via Web of Science)
and The Cochrane Library were accessed during late 2008. Pubmed
was searched using MeSH, with the terms, Medicine, Herbal,
Plants, Medicinal, Plant extracts, Phytotherapy and Drugs,
Chinese herbal, AND Adjuvant, Adjunctive, Augmentation.
Searches were conducted on a wide range of individual herbal
and nutritional medicines commonly trialed for psychotropic
activity (e.g. kava, St. Johns wort, folic acid, omega-3). A forward
search of the identied papers was performed using Web of Science cited reference search. 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, or inadequate methodological rigor. We reported the effect sizes in all placebo controlled studies where data was available. We calculated the (d) of
the clinical trials by (a) calculating the effect size separately within
the active and control group (taking the difference between baseline and post-treatment means, divided by the within-group standard deviation at baseline), and (b) subtracting the effect size of
the control group from that of the active group (Morris, 2008).
3. Results
A total of 4345 papers were identied 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.
As detailed below, most Western adjuvancy studies involved
nutritional medicines, while herbal medicine adjuvancy studies
were mostly of Asian origin, using traditional Chinese or Japanese formulations.
3.1. Depression
3.1.1. Adjuvant use of pharmacotherapies for depression
Only about a third of patients with MDD who are treated by a
rst-line antidepressant achieve complete remission (Rush et al.,
2006), with treatment trials typically focusing on a 50% reduction
in symptoms as a positive treatment response. Most adjuvancy
studies on antidepressants involve a range of synthetic agents,
including other antidepressants (e.g. TCAs or mirtazapine with
SSRIs), mood stabilizers (e.g. lithium, carbamazepine, or valproate),

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

ARTICLE IN PRESS
J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx

and noradrenergic or dopaminergic agents (e.g. bupropion, reboxetine, atomoxetine: Berlim et al., 2008; Nelson, 2000). Evidence for
pharmacological combinations primarily comprises open, uncontrolled studies, and results are mixed (Fava and Rush, 2006; Trivedi
et al., 2006). To date, the most advanced adjuvancy study is the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), a
multi-site, prospective, randomized, multi-step clinical trial comparing a series of adjunctive or alternative treatments for patients
who did not respond to citalopram (Warden et al., 2007). Results
conrmed that only a minority of people with MDD achieve remission via initial treatment with an SSRI. Switching, combining or
augmenting produced benets to some initial non-responders,
but a third of people with MDD did not achieve complete remission, even after multiple treatment strategies.
As detailed in Table 1, many studies have been conducted using
a variety of nutrients adjuvantly with antidepressants (omega-3, Sadenosyl-methionine, folic acid, tryptophan and inositol). Only one
herbal medicine mono-therapy study was revealed from our literature review, indicating that this is a relatively uncharted eld of
research.
3.1.2. Adjuvant use of nutritional and herbal medicines with
antidepressants
Omega-3 fatty acids have not yet demonstrated signicant results as a mono-therapy for Major Depressive Disorder (Marangell
et al., 2003; Parker et al., 2006). However, epidemiological studies
have demonstrated that a rise in depressive symptoms is correlated with lower dietary omega-3 sh oil intake (Appleton et al.,
2006, 2007; Lin and Su, 2007). Studies have also shown that people
with depression tend to have a lower serum level of essential fatty
acids (EPA and DHA: Appleton et al., 2006). A recent meta-analysis
conducted by Lin and Su (2007), included nine eligible RCTs of sufcient methodological rigor. The results revealed that omega-3
preparations demonstrated a positive standardized mean difference towards a benecial effect over placebo. Pooling of these results by the authors revealed a moderate effect size (d = 0.61). It
should be noted that not all studies had positive outcomes and that
longer clinical trials using a combination of both EPA/DHA are advised. A Cochrane review that included only one study, commented
that benecial effects may been found for depressive symptoms
but not for mania (Montgomery and Richardson, 2008).
Four adjuvancy trials have been conducted, all with positive
clinical outcomes and strong effect sizes. Randomized, doubleblind augmentation of 20 mg of uoxetine with 1 g of EPA over
8 weeks in 60 non-responsive depressed patients demonstrated a
signicantly better reduction on the Hamilton Depression Rating
Scale (HDRS; Hamilton, 1960) than uoxetine or EPA alone (Jazayeri et al., 2008). The response rate from the combination (P50% decrease on HDRS) was 81% compared with 56% and 50% for EPA and
uoxetine, respectively. A 4-week controlled study (n = 20) using
2 g daily of EPA in patients with non-response to stabilized antidepressants showed similar signicant benets (d = 2.92: Nemets
et al., 2002). One gram per day of ethyl-eicosapentaenoate was
effective as an adjuvant agent in a 12-week study of 70 subjects
with non-response to unspecied antidepressants (Peet and Horrobin, 2002). Curiously, the 4 g EPA arm only had a trend towards
improvement, and the group receiving 2 g/day did not experience
any statistically signicant benets. This may indicate either a curvilinear doseresponse effect or insufcient power to detect differential effects. An 8-week study using 6.6 g/day of omega-3 fatty
acids adjuvantly in 32 non-responders to antidepressants demonstrated a 13.6 point reduction on the HDRS, compared with 6.4
in the placebo group (d = 1.85: Su et al., 2003).
In evaluating effects of omega-3 on depressed mood, it should
be noted that there are issues in respect to the type of omega-3 formulation used in research and practice. Studies typically use differ-

ing formulations containing either eicosapentaenoic acid (EPA),

docosahexaenoic acid (DHA), a combination of EPA and DHA, or
puried ethyl esters. Currently there is not scientic consensus
on which preparation is preferential for depressive episodes.
Folate deciency (assessed via low dietary intake or low serum
level) has been consistently demonstrated in depressive populations and in poor responders to antidepressants (Morris et al.,
2008). Two controlled studies were located in our search. An RCT
used 500 lg of folic acid or placebo adjuvantly with 20 mg uoxetine in 127 subjects with HDRS of >20 (Coppen and Bailey, 2000). A
statistically signicant differential reduction after 10 weeks on
HDRS occurred only for women on completion of 6.8 4.1 in the
uoxetine plus folic acid condition, compared with 11.7 6.7 from
uoxetine plus placebo; d = 0.73. Over the same period, plasma
homocysteine decreased in women 20.6% more in the folate group
compared with control. Neither effect occurred in men. A recent
RCT involving 27 depressed subjects found that 20 mg of uoxetine
combined with 10 mg of folic acid was more effective in reducing
HDRS score compared to augmentation with placebo (7.43 1.65
vs. 11.43 1.31, respectively; p = 0.04: Resler et al., 2008). A significant reduction of homocysteine was also observed in the folic acid
group, compared to placebo. The researchers considered that a
mechanism of action may involve a reduced turnover rate of serotonin, and subsequent increased accumulation serotonin in the
cells, as the marker 5-Hydroxyindoleacetic acid was signicantly
lower in lymphocytes of patients receiving folate.
A UK-based RCT with 730 participants (FolATED) is being currently conducted to assess effects of folic acid augmentation (5 mg/
day: Roberts et al., 2007). The study will also evaluate the costeffectiveness of folic acid augmentation on antidepressant treatment, how genetic polymorphisms relevant to folate metabolism
affect antidepressant response, and whether baseline folate status
can predict response to antidepressant treatment.
Inositol has been studied as an antidepressant mono-therapy
and as an augmenting agent, and has mixed results (Taylor et al.,
2004). An early double-blind, controlled 4-week study with 28 participants demonstrated statistically signicant antidepressant
activity against placebo, using 12 g/day of inositol (Levine et al.,
1995). Subsequent double-blind, controlled studies (n = 27,
n = 42) were conducted using inositol as an augmenting agent with
SSRIs (Levine et al., 1999; Nemets et al., 1999). Neither study demonstrated a signicant difference between adjuvant use of inositol
or placebo.
S-Adenosyl-methionine (SAMe) has been studied for antidepressant activity for several decades. Most studies involve parenteral
or intramuscular injections of SAMe which subsequently crosses
the bloodbrain barrier (Williams et al., 2005). SAMe has consistently demonstrated an antidepressant mechanism of activity,
and comparable effects to synthetic antidepressants (Papakostas
et al., 2005). Several adjuvancy studies were found. A 6-week open
label study using 8001600 mg/day of SAMe with 30 non-responders to stabilized prescription of SSRIs or venlafaxine was conducted
by Alpert et al. (2004). Intention-to-treat analysis revealed that
adjuvant use of SAMe signicantly reduced depression from baseline to week 6 on HDRS (17 4.2 to 10.0 6.6). Intramuscular
administered SAMe (200 mg/day) demonstrated a signicant increase in the onset of response of imipramine (150 mg/day: Berlanga et al., 1992). A signicant effect became apparent by day 4
and remained until day 12, after which there was no difference between groups. Due to concerns over development of hypomania or
mania, SAMe should be used cautiously in patients with a history
of mania. Another caveat is cost. Therapeutic dosage of oral SAMe
may require up to 1600 mg, which costs approximately US$8/day.
Monoamine precursors are necessary for synthesis of serotonin,
dopamine and norepinephrine (Hood et al., 2005; Roiser et al.,
2005). L-tryptophan has been studied extensively as an antidepres-

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

Clinical evidence

Precautions

Conclusions

Omega-3

Four studies have demonstrated positive results after 2 or

more weeks of omega-3
(16.6 g/day) with SSRIs, TCAs, MAOIs (Jazayeri et al., 2008;
Nemets et al., 2002; Peet and Horrobin, 2002)

High dosage may " INR (caution with warfarin)

S-Adenosyl-methionine
(SAMe)

Intramuscular and oral augmentation of SAMe with

antidepressants has demonstrated " response and remission
rates (Berlanga et al., 1992). May enhance response in
antidepressant non-responders (Alpert et al., 2004)

May interact with serotonergic antidepressants; caution

in bipolar patients to avoid switching to mania

A potentially benecial antidepressant effect may occur, especially in

subjects with low EFA serum status. May also be benecial in subjects
with comorbid cardiovascular disease (which has increased risk in
depression)
Typical dosea: 39 g/day of omega-3 or 12 g/day EPA plus 12 g of
DHA
Expense may restrict applicability. Parenteral administration may be
more efcacious than oral administration
Typical dosea: 4001600 mg/day

L-tryptophan

L-tryptophan augmentation with MAOIs, SSRIs and some

TCAs is effective in increasing the antidepressant response:
phenezine sulphate (Glassman and Platman, 1969),
uoxetine (Levitan et al., 2000), clomipramine (Nardini et al.,
1983; Walinder et al., 1976). No difference occurred
compared to placebo with other tricyclics (Shaw et al., 1975)
Controlled studies have demonstrated inositol augmentation
with SSRIs does not improve depression in SSRI treatment
failures (Levine et al., 1999; Nemets et al., 1999)
Antidepressant augmentation with folic acid may increase
response rate increases and efcacy (Coppen and Bailey,
2000; Resler et al., 2008). Subjects with lower folate levels
are more likely to have a delayed response by on average
1.5 weeks (Papakostas et al., 2005)
4-week RCT (n = 45) 60 drops 1:5 lavender vs. 100 mg
imipramine. Lavender + imipramine was more effective than
imipramine alone in reducing depression (Akhondzadeh
et al., 2003)
Results of two studies using Xiaoyao and Sanpu Xinnao
herbal formulas with amitriptyline and uoxetine showed
signicantly ; adverse reactions and " remission rates
No increased efcacy however occurred (Yang et al., 2007;
Zhang et al., 2006)

High dosage may cause adverse reactions, e.g. GIT

complaints, nausea or serotonin syndrome (Byerley
et al., 1987)

May be of use in subjects taking antidepressants, in tryptophan

deciency, or in depression caused by serotonergic pathway
dysregulation
Typical dosea: 200 mg2 g/day

None noted

Inositol augmentation is currently not recommended

Caution should be observed in pernicious anaemia

(addition of B12 required); " doses may cause agitation
and anxiety

May increase response to antidepressants, perhaps especially in cases

of folate deciency, but further trials are required. May be more
efcacious in females than males
Typical dosea: 400 lg2 g/day

The only side-effect from lavender use was a slight

statistical increase in the occurrence of mild headaches

Larger studies are needed to conrm benecial synergistic

pharmacodynamic activity

None noted

Traditional Chinese herbal formulas may reduce side-effects and

increase compliance to antidepressants, but there is currently no
evidence of added antidepressant benet. Further studies are needed

Inositol

Folic acid

Lavender (Lavendula
angustifolia)

Traditional Chinese medicine

formulas

High dosage may also alter triglyceride levels

a
When prescribing nutritional and herbal medicines adjuvantly with pharmacotherapies, clinicians should be aware that many natural products vary in formulation design and chemical composition. Standardized results are
unlikely to uniformly occur where a decit of quality (manufacturing, storage, and standardization of active chemicals) is apparent. Caution in dosage is therefore required.

ARTICLE IN PRESS

Herbal/nutritional medicine

J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

Table 1
Adjuvant use of nutritional and herbal medicine with antidepressants.

ARTICLE IN PRESS
5

J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx

sant (Byerley et al., 1987). Although there are several positive studies, a rigorous systematic review and meta-analysis by Shaw et al.
(2002) concluded that due to small sample sizes, poor outcome
measures and publication bias, there were insufcient data to
inform clinical practice. Eight controlled adjuvancy studies were
located. L-tryptophan (or its biological intermediary, 5-hydroxytryptophan) augmentation was found to be effective in increasing the
antidepressant response with phenezine sulphate (Glassman and
Platman, 1969), clomipramine (Nardini et al., 1983; Walinder
et al., 1976), tranylcypromine (Coppen et al., 1963) and uoxetine
(Levitan et al., 2000). However, other clinical studies using tricyclics discovered no additional benet compared with placebo (Ayuso Gutierrez et al., 1973; Shaw et al., 1975; Thomson et al., 1982).
Many of the older studies were of weak methodological design, and
additional rigorous studies are needed to conrm these results.
Amino acids DL-phenylalanine and L-tyrosine, precursors to dopamine and norepinephrine, may provide augmenting antidepressant
activity however no studies were located assessing this.
Lavender (Lavendula angustifolia) is currently the only herbal
mono-therapy examined as an adjunct with other antidepressant
pharmacotherapy. A 4-week RCT using a combination of lavender
tincture (1:5 60 drops/day) and imipramine (100 mg/day) in 45
people with diagnosed MDD, was signicantly more effective than
imipramine alone on HDRS, indicating a synergistic effect
(Akhondzadeh et al., 2003). Two small studies testing traditional
oriental formulas Xiaoyao (Yang et al., 2007) and Sanpu Xinnao
(Zhang et al., 2006) adjuvantly with amitriptyline and uoxetine,
respectively, demonstrated no signicant increase in antidepressant activity. Adverse reactions were however reduced in both
combination groups, and relapse rates were also lower.
3.2. Bipolar disorder
3.2.1. Adjuvant use of pharmacotherapies for bipolar disorder
Mood stabilizers including lithium and valproic acid and
antipsychotics are commonly used as rst-line agents to treat the
presentation of the manic phase in Bipolar I Disorder (Miklowitz
and Johnson, 2006). Statistics vary regarding the effectiveness of
lithium in treating acute mania, with previous accounts of an effect
rate of 6080% perhaps being overestimated (Miklowitz and
Johnson, 2006). As Bipolar Disorder (BD) has serious consequences
(e.g. increased risk of suicide) and elicits signicant socio-economic cost, further pursuit of safe and efcacious treatments are
required (Oswald et al., 2007). Clinical research involving bipolar
pharmacotherapy adjuvancy is presently still in its infancy (Foun-

toulakis et al., 2005). In relation to synthetic agents, current evidence on adjuvancy strategies for mania gives tentative support
for use of carbamazepine with either haloperidol or lithium; and
olanzapine or risperidone with lithium or valproate (Zarate and
Quiroz, 2003). Mixed or negative results occurred in controlled
studies using gabapentine or lamotrigine with mood stabilizers,
although the small samples in these studies prohibit rm conclusions. Our review of research on treatment or prevention of BD
depression revealed few studies with robust methodology. No consistent benet in antidepressant augmentation was apparent,
while evidence indicated that tricyclic antidepressants such as
imipramine may also increase switching between depressive and
manic states.
The most comprehensive study of combination treatments in
BD I/II is the Sequenced Treatment Enhancement Program for Bipolar Depression (STEP-BD: Sachs et al., 2003). This complex naturalistic quasi-controlled program involving 4370 participants
explored the outcomes on depression and mania, involving standard care vs. various controlled interventions (e.g. mood stabilizers
in concert with buproprion, paroxetine, lamotrigine or inositol;
and psychological treatments). No benecial adjuvant effects on
depression were observed from bupropion or paroxetine over
those from mood stabilizers alone. Surprisingly, a trend occurred
in favor of the antidepressants over placebo in reducing the incidences of hypomania and mania (Thase, 2007). Results for adjunctive psychological intervention were more positive than adjunctive
pharmacotherapy. The study highlighted the difculty in managing
BD effectively, as demonstrated by poor compliance and response
to treatments.
Due to the intensity of neurochemical involvement and potentially harmful effects on mortality and morbidity in BD, standard
pharmaceutical interventions continue to be the required rst-line
treatment. Complementary medicines currently lack evidence in
addressing acute mania, and cannot be recommended as a rst-line
intervention. They may however have a potential role in augmenting the action of mood stabilizers or atypical antipsychotics, reducing side-effects, and in improving compliance. Treatment
adherence is a major problem of treating BD, with up to 60% of patients discontinuing treatment within the rst year of prescription
(Miklowitz and Johnson, 2006). The use of specic adjuvant nutritional or herbal medicines may allow for smaller doses of mood
stabilizers required. This could potentially ameliorate typical
side-effects, increasing adherence and overall outcomes. Papers
on the adjuvant use of herbal medicines and nutritional supplements with mood stabilizers are summarized in Table 2.

Table 2
Adjuvant use of herbal and nutritional medicine with mood stabilizers.
Herbal/
nutritional
medicine

Clinical evidence

Precautions

Conclusions

Omega-3

Augmentation with pre-prescribed mood stabilizers.

Limited evidence in beneting BD depression. Ineffective
in preventing or improving treatment of mania (Chiu
et al., 2005; Frangou et al., 2006; Keck et al., 2006)
An RCT using folic acid (200 lg) with lithium
demonstrated minor benet ; depression on BDI (Coppen
et al., 1986)
Inositol augmentation with lithium demonstrated no
signicant antidepressant or mood stabilizing effect on
HDRS. " response on HDRS in inositol group vs. placebo
(44% vs. 0%, respectively) (Eden Evins et al., 2006)
Jia-Wei-Xiao-Yao-San (Free and Easy Wanderer Plus) in
combination with carbamazepine increased response and
efcacy on depression outcomes. A statistically
signicant reduction in fatigue and dizziness also
occurred (Zhang et al., 2005)

High dosage may " INR (caution with

warfarin)
High dosage may also alter triglyceride
levels
None noted

Appears safe and is more benecial in addressing

the depression rather than mania. More studies
are required using EPA/DHA combinations

None noted

As with MDD, inositol may have little or no benet

in augmenting antidepressant or mood stabilizing
effects with lithium or valproate. A larger study is
required
Positive results of this research on the reduction of
depression and side-effects, encourages further
exploration of adjuvant use herbal medicines with
mood stabilizers

Folic acid

Inositol

Traditional
Chinese
medicine
formula

This formulation reduces serum level of

carbamazepine. Heavy metals and plant
substitutions have occurred in some
Chinese herbal medicines

Further studies using a higher dose of folic acid

may be of benet

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

ARTICLE IN PRESS
6

J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx

3.2.2. Adjuvant use of nutritional and herbal medicines with mood

stabilizers
Omega-3 fatty acids have been studied as a mono-therapy and as
an adjuvant intervention in bipolar depression. An RCT involving
44 participants using a combination of EPA and DHA (9.6 g/day)
as a mono-therapy revealed positive results on depression outcomes in terms of response and remission on HDRS (d = 1.15: Stoll
et al., 1999). No signicant effect on mania outcomes occurred. In
terms of adjuvant use of omega-3 in treating BD, three studies
were located. A 12 week, 3-arm controlled study involving 75 participants using 1 g or 2 g of EPA adjuvantly with unrestricted psychotropic medications revealed a small but signicantly greater
reduction on the HDRS from either dose, compared with placebo
(1 g: d = 0.90, 2 g: d = 0.50: Frangou et al., 2006). However, no signicant effect for mania was achieved on the Young Mania Rating
Scale (YMRS: Young et al., 1978). A larger study (n = 385) using 6 g
of EPA adjuvantly with at least one mood stabilizer in patients with
rapidly cycling bipolar disorder found no effect compared to placebo on reducing mania on YMRS (Keck et al., 2006) A small RCT
with 15 participants, using 4.4 g of EPA and 6.6 g of DHA/day adjuvantly with 20 mg/day of valproate also revealed no effect compared to placebo on reducing mania (Chiu et al., 2005). Current
evidence appears to weakly support omega-3 preparations adjuvantly in the depressive phase of bipolar. Omega-3 in the manic
phase appears to possess no clinical effect in attenuating mania.
Coppen et al. (1986) conducted a RCT using adjuvant folic acid
(200 lg) over a period of a year in 75 patients stabilized on lithium.
They found a small but signicant reduction on the Beck Depression Inventory (Beck et al., 1961) in the folic acid group, but not
in the placebo group. A comparison of the active and placebo
groups converts to a d of 0.22. It should be noted that the folic acid
dose was very low (200 lg), and that higher doses 5001000 lg
may yield a different response.
A pilot RCT was conducted, involving twenty-four participants
with DSM-IV bipolar depression (bipolar I = 21; bipolar II = 3) randomly assigned in addition to stable neuroleptic prescription with
12 g of inositol or D-glucose as placebo for 6 weeks (Chengappa
et al., 2000). The results revealed a non-signicant response between the groups on HDRS, MontgomeryAsberg Depression Rating Scale (MADRS: Montgomery and Asberg, 1979) and Clinical
Global Impression scales (CGI: Guy and Bonato, 1970). A small 6week RCT involving 17 participants using inositol or placebo adjuvantly in currently depressed bipolar patients with stabilized levels of lithium or valproate revealed mixed results (Eden Evins
et al., 2006). Although no differential reduction occurred in HDRS
or YMRS scores, four out of nine people achieved remission
(P50% reduction on HDRS) in the inositol group compared with
none out of eight in the placebo group. This is consistent with
the results of the STEP-BD inositol adjuvancy arm, where there
was only a 17% increase in remission rates (Thase, 2007).
The only located study that examined herbal medicine being
used adjuvantly with mood stabilizers involved the traditional Chinese medicine formulation Jia-Wei-Xiao-Yao-San (Free and Easy
Wanderer Plus: Zhang et al., 2005). A 12-week double-blind, randomized, controlled study involving 124 bipolar (depressed) and
111 bipolar (manic) participants was conducted. Response, efcacy
and side-effects were assessed using carbamazepine mono-therapy (CBZ), or carbamazepine adjuvantly with Free and Easy Wanderer Plus (CBZ + FEWP) or placebo. Results showed a
signicantly increased response rate on HDRS, MADRS and CGI
from CBZ + FEWP, compared with placebo or CBZ alone (84.8%,
63.8% and 34.8%, respectively). The combination also signicantly
reduced depression scores against placebo and carbamazepine at
weeks 8 and 12. Effect sizes on the HDRS at week 12 using intention-to-treat and completers analysis were d = 0.90 and d = 1.80,
respectively. No signicant effects were found on the mania out-

comes at endpoint between carbamazepine mono-therapy and

the combination. Interestingly, compared with carbamazepine, patients receiving CBZ + FEWP had a lower incidence of dizziness
(18.2% vs. 7.9%) and fatigue (9.1% vs. 1.1%). A follow-up study
(n = 188) continued treatment of CBZ and CBZ + FEWP to 26 weeks.
Results revealed no signicantly greater improvement at the endpoint, indicating that adjuvant FEWP administration may enhance
initial response and reduce some side-effects in the short term, but
that this benet is not maintained over time.
3.3. Anxiety disorders
3.3.1. Adjuvant use of pharmacotherapies for anxiety
Adjuvancy strategies to treat anxiety disorders are commonly
focused on integrating psychological interventions or benzodiazepines with antidepressants (Dunlop and Davis, 2008; Tyrer and
Baldwin, 2006). Benzodiazepines are commonly prescribed for a
range of anxiety disorders, or to attenuate anxious symptomatology occurring as a side effect from commencement of antidepressants (Dunlop and Davis, 2008). Aside from psychological
intervention, common adjuvant psychotropic interventions with
benzodiazepines include b-blockers (e.g. propanolol) to address somatic anxious symptoms, and sedating antipsychotics (e.g. olanzapine or risperidone: Rickels and Rynn, 2002). We located no
augmentation studies using nutritional or herbal medicines with
benzodiazepines.
Although benzodiazepines are effective anxiolytics, concerns
over dependence and tolerance caution their long-term use (Rickels and Rynn, 2002). Use of nutritional or herbal medicines in conjunction with benzodiazepines may also therefore focus on their
reduction or withdrawal, whereby they are given during dose
reduction, or as a substitute at benzodiazepine cessation. Because
the former involves adjuvant use, this application of nutritional
or herbal medicines is included here.
3.3.2. Adjuvant use of nutritional and herbal medicines with
benzodiazepines
One study using kava (Piper methysticum) in benzodiazepine
withdrawal was identied in the search. A 5-week RCT was conducted using a standardized kava extract (WS 1490) on 40 subjects with chronic anxiety and a long history of benzodiazepine
use (Malsch and Kieser, 2001). Subjects were tapered off their benzodiazepines over the rst 2 weeks, while the kava was titrated
from 50 mg up to 300 mg by the end of week one. Kava produced
a statistically signicant drop of 7.5 point decrease over placebo at
week 5 in anxiety on the Hamilton anxiety scale (Hamilton, 1959),
and a positive result on the BenndlichkeitsSkala subjective wellbeing scale (CIPS, 1996). Importantly, aside from some subjects
experiencing withdrawal symptoms, no negative reactions (e.g. increased sedation) occurred during the rst week of adjuvant kava
use. Furthermore, only ve subjects in the kava group displayed
adverse symptoms from benzodiazepine withdrawal compared
with 10 in the placebo group. During a follow-up study, 9 out of
14 subjects who were switched from kava to placebo experienced
re-occurrence of anxiety. Practitioners considering adjuvant use of
kava should however be aware that kava was withdrawn in 2002
from Europe, UK and Canadian markets over concerns over potential hepatotoxicity.
3.4. Novel adjuvant therapeutic uses of herbal medicines
Our review revealed that few clinical trials to date have studied
co-administered herbal preparations with pharmaceuticals. One
unexplored area of potential benet to sufferers of BD, MDD, or
anxiety disorders is the use of herbal medicines to reduce side-effects from psychopharmacotherapies, thereby subsequently

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

ARTICLE IN PRESS
J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx

improving compliance. A major problem with many synthetic

pharmaceutical antidepressants, is that compliance is often poor,
with fewer than 50% of patients continuing with their prescribed
medication after 3 months (Ellen et al., 2007). An illustration of this
attrition occurred in the STAR*D project, with approximately 1 in 4
patients at stage 1 (citalopram) discontinuing before remission
was achieved (Warden et al., 2007). 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 (Rathbone et al., 2005). Compared with those given only antipsychotics, signicantly 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. The authors of the Cochrane review concluded that CHM when combined with antipsychotic
drugs may be of benet in treating schizophrenia. As discussed
previously, a similar amelioration of side-effects (dizziness and fatigue) occurred in a bipolar disorder study using CHM with carbamazepine (Zhang et al., 2005).
Our review of the literature revealed that the only mono-preparations of HMs trialed adjuvantly with psychotropics are L.
angustifolia and G. biloba. As detailed above, these results were positive, encouraging further research into other HMs. Two phytotherapies that may provide novel adjuvant application with
synthetic antidepressants for enhancing efcacy in the treatment
of MDD are golden root (Rhodiola rosea), and saffron (Crocus sativus). Preliminary studies of moderate methodological rigor using
R. rosea have demonstrated potential antidepressant, anti-fatigue
and anxiolytic activity (Bystritsky et al., 2008; Darbinyan et al.,
2007; Kelly, 2001; Shevtsov et al., 2003). Before however adjuvancy studies are pursued, more substantive evidence of R. rosea as a
thymoleptic mono-therapy is required. In two studies with small
samples, the petals and stamen from C. sativus have demonstrated
against placebo signicant antidepressant activity (Akhondzadeh
et al., 2005; Moshiri et al., 2006), and in three trials have displayed
equivalent efcacy to imipramine (Akhondzadeh et al., 2004), and
uoxetine (Akhondzadeh et al., 2007; Noorbala et al., 2005). Additional studies by different research groups and with larger samples
are needed to validate these ndings. Regardless, the evidence currently encourages research into adjuvant use of saffron with
antidepressants.
A curious deciency uncovered in our review of the literature
was the absence of adjuvancy studies using St. Johns wort (Hypericum perfortum: SJW). A potential reason for the lack of trials
exploring co-prescription of SJW with antidepressants, may be a
concern over pharmacodynamic antagonism causing serotonin
syndrome and/or switching to hypomania or mania (Finfgeld,
2004). However, evidence to support such a concern is weak and
is currently based only on unsubstantiated case reports (Knuppel
and Linde, 2004; Rodriguez-Landa and Contreras, 2003; Schulz,
2006). The case studies typically also have concomitant use of
other medications and/or recreational drugs, and a background of
cyclothymia (Nierenberg et al., 1999; Raja and Azzoni, 2006; Schneck, 1998). In several cases, a clear temporal association appeared
to exist between SJW use and induction of hypomania or mania, so
caution is warranted in people with a personal or family history of
bipolar depression. Several case reports of serotonin syndrome
have been documented by drug surveillance agencies (Knuppel
and Linde, 2004). Currently however, it is not clear whether it is
a dose-dependent phenomenon or what its mechanisms may be,
and in particular, whether an interaction with antidepressants
causing hyperserotonergism actually occurs. We note that concerns over serotonin syndrome do not appear to be inhibiting research or off-label prescription of multiple synthetic
antidepressants (Davids et al., 2006; de la Gandara et al., 2005; Pat-

ten and Beck, 2004). Interestingly, an opposite concern is commonly raised in relation to pharmacokinetics, with SJW
documented to reduce plasma levels of antidepressants via P-glycoprotein (PgP) pump up-regulation and CYP450 3A4 induction
(Izzo, 2004; Madabushi et al., 2006). These metabolic pathways
are used in the metabolism of many antidepressants (Zhou,
2008), suggesting that caution should be observed in co-prescription. Regardless, SJW preparations low in hyperforin (constituent
responsible for pharmacokinetic alterations) are less likely to have
this effect on PgP and CYP450 3A4, and hence may be safer (Madabushi et al., 2006; Zanoli, 2004). The counter side of using low
hyperforin extracts is that in vitro and animal models demonstrate
that hyperforin exerts greater antidepressant activity than other
isolates such as hypericin. Furthermore, it also crosses the blood
brain barrier, whereas hypericin does not appear to do so.
There are several potential advantages of SJW adjuvancy. SJW
exerts a broad range of psychopharmacological activity, including
decreased degradation and non-selective re-uptake of serotonin,
dopamine and norepinephrine, modulation of neurotransmitter
transport systems, and possible neuro-endocrinological effects
(Butterweck, 2003; Zanoli, 2004). 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 antidepressants to increase response, or potentially to lower the risk of
side-effects from the synthetic antidepressant by reducing the dose
required for efcacy. Clinical trials employing rigorous methodology and appropriate safety protocols would be required to assess
any SJW adjuvancy strategies.

4. Discussion
Review of the literature revealed that encouraging evidence exists for the use of omega-3 fatty acids, SAMe, folic acid and L-tryptophan adjuvantly with antidepressants to enhance response and
improve efcacy. Folic acid, omega-3 and some Chinese herbal
medicines also have emerging evidence as effective adjuncts with
antipsychotics and mood stabilizers. In respect to the treatment
of BD, these interventions appear only to benet the depressive
phase of the disorder. Current evidence does not rmly support
the adjuvant use of nutritional or herbal medicines in limitation
or withdrawal of benzodiazepines, but this remains an area worthy
of exploration. As detailed above, only one study trialing a herbal
medicine (kava) with concomitant benzodiazepines was identied.
Although these results were promising, further trials examining
safety would need to be employed before human use could be ethically recommended.
The evidence tells us that in psychiatric conditions such as
MDD, the person needs to be treated early and aggressively to minimize the chance of relapse (Rush, 2007). From a clinical perspective the issue may not be whether the adjuvant intervention
possesses statistically signicant therapeutic properties in a chosen sample. It is whether the chosen treatment is effective in the
individual prescribed the treatment, given the unique and complex
causation/s of their illness (Antonijevic, 2006). In the case of MDD,
many complex neuro-endocrinological pathways are involved
(Belmaker and Agam, 2008). Adjuvancy strategies should ideally
therefore be tailored to the individual. Examples include noradrenergic or dopaminergic modulation in non-responders to SSRIs, or
for the management of persistent lassitude, amotivation or hyperphagia (Nestler and Carlezon, 2006; Ressler and Nemeroff, 2000),
administration of sex hormones in cases of hormonal insufciency
(Belmaker and Agam, 2008), anxiolytics or hypnotic prescription in
co-thymic presentations, or buffering of initial anxiogenic sideeffects from antidepressants (Tyrer and Baldwin, 2006). Common-

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

ARTICLE IN PRESS
8

J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx

sense suggests that a one-size ts all approach often adopted in

clinical trials may have less success than tailored prescriptions
treating the cause/s of the individuals depression; although this
contention requires further evidence. The difculty both clinicians
and researchers face is how to provide evidence-based adjuvant
strategies when a paucity of data exists on clear prescriptive protocols (Antonijevic, 2006). Research needs to be advanced in identifying which treatments combinations (synthetic or natural) are
more benecial for which manifestations of MDD.
In the case of nutritional adjuvancy, a benecial effect may
more likely occur when specic deciencies or neurological dysregulations are apparent. For example, a patient who does not eat
any omega-3 containing foods may potentially benet more from
adjuvant omega-3 prescription than a patient who regularly eats
deep sea sh. Common deciencies affecting mental health outcomes may involve amino acids (e.g. tryptophan, phenylalanine,
tyrosine), which provide the precursors to neurochemicals (Byerley et al., 1987); B vitamins in particular B6, B12 and folate, which
are involved in methylating pathways (Morris et al., 2008; Papakostas et al., 2005); and omega-3, which encourages neuronal communication (Appleton et al., 2006; Lin and Su, 2007).
In conclusion, while some positive evidence supports nutritional adjuvancy with various psychopharmacotherapies, adjuvant
use of herbal therapies has not been sufciently studied to warrant
standard clinical application. This remains a promising area of research via robust, safety-conscious studies.

Conict of interest
None.
Role of funding
None.
Acknowledgements
Sincere thanks are extended to Professor Qiu Xiaochun for his
assistance in searching the Chinese databases, and to Dr. Gary Deed
for his critique of the paper.
References
Akhondzadeh B, Moshiri E, Noorbala A, Jamshidi A, Abbasi S, Akhondzadeh S.
Comparison of petal of Crocus sativus L. and uoxetine in the treatment of
depressed outpatients: a pilot double-blind randomized trial. Progress in
Neuropsychopharmacology and Biological Psychiatry 2007;30:43942.
Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroudi F.
Comparison of Crocus sativus L. and imipramine in the treatment of mild to
moderate depression: a pilot double-blind randomized trial [ISRCTN45683816].
BMC Complementary and Alternative Medicine 2004;4:12.
Akhondzadeh S, Kashani L, Fotouhi A, Jarvandi S, Mobaseri M, Moin M, et al.
Comparison of Lavandula angustifolia Mill. tincture and imipramine in the
treatment of mild to moderate depression: a double-blind, randomized trial.
Progress
in
Neuropsychopharmacology
and
Biological
Psychiatry
2003;27:1237.
Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, Amini H, Fallah-Pour H, Jamshidi
AH, et al. Crocus sativus L. in the treatment of mild to moderate depression: a
double-blind, randomized and placebo-controlled trial. Phytotherapy Research
2005;19:14851.
Alpert JE, Papakostas G, Mischoulon D, Worthington III JJ, Petersen T, Mahal Y, et al.
S-Adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive
disorder: an open trial following partial or nonresponse to selective serotonin
reuptake inhibitors or venlafaxine. Journal of Clinical Psychopharmacology
2004;24:6614.
Antonijevic IA. Depressive disorders is it time to endorse different
pathophysiologies? Psychoneuroendocrinology 2006;31:115.
Appleton KM, Hayward RC, Gunnell D, Peters TJ, Rogers PJ, Kessler D, et al. Effects of
n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic
review of published trials. American Journal of Clinical Nutrition
2006;84:130816.

Appleton KM, Peters TJ, Hayward RC, Heatherley SV, McNaughton SA, Rogers PJ,
et al. Depressed mood and n-3 polyunsaturated fatty acid intake from sh: nonlinear or confounded association? Social Psychiatry and Psychiatric
Epidemiology 2007;42:1004.
Atmaca M, Tezcan E, Kuloglu M, Ustundag B, Kirtas O. The effect of extract of Ginkgo
biloba addition to olanzapine on therapeutic effect and antioxidant enzyme
levels in patients with schizophrenia. Psychiatry and Clinical Neurosciences
2005;59:6526.
Ayuso Gutierrez JL, Lopez-Ibor Alino JJ, Montejo Iglesias L. Tryptophan and
amitriptyline in the treatment of depression (double blind study). Actas Luso
Esp Neurol Psiquiatr Cienc Anes 1973;1:4716.
Beck AT, Ward C, Mendelson M. Beck Depression Inventory (BDI). Archives of
General Psychiatry 1961;4:56171.
Belmaker RH, Agam G. Major depressive disorder. New England Journal of Medicine
2008;358:5568.
Berger GE, Proftt TM, McConchie M, Yuen H, Wood SJ, Amminger GP, et al. Ethyleicosapentaenoic acid in rst-episode psychosis: a randomized, placebocontrolled trial. Journal of Clinical Psychiatry 2007;68:186775.
Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H. Efcacy of S-adenosyl-Lmethionine in speeding the onset of action of imipramine. Psychiatry Research
1992;44:25762.
Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic
treatment of resistant/refractory major depression: an overview. Annals of
Medicine 2008;40:14959.
Butterweck V. Mechanism of action of St. Johns wort in depression: what is known?
CNS Drugs 2003;17:53962.
Byerley WF, Judd LL, Reimherr FW, Grosser BI. 5-Hydroxytryptophan: a review of its
antidepressant efcacy and adverse effects. Journal of Clinical
Psychopharmacology 1987;7:12737.
Bystritsky A, Kerwin L, Feusner JD. A pilot study of Rhodiola rosea (Rhodax) for
generalized anxiety disorder (GAD). Journal of Alternative and Complementary
Medicine 2008;14:17580.
Chengappa K, Levine J, Gershon S, Mallinger A, Hardan A, Vagnucci A, et al. Inositol
as an add-on treatment for bipolar depression. Bipolar Disorder 2000;2:4755.
Chiu CC, Huang SY, Chen CC, Su KP. Omega-3 fatty acids are more benecial in the
depressive phase than in the manic phase in patients with bipolar I disorder.
Journal of Clinical Psychiatry 2005;66:16134.
CIPS. Internationale skalen fur die psychiatrie. Gottingen: Beltz; 1996.
Coppen A, Bailey J. Enhancement of the antidepressant action of uoxetine by folic
acid: a randomised, placebo controlled trial. Journal of Affective Disorders
2000;60:12130.
Coppen A, Chaudhry S, Swade C. Folic acid enhances lithium prophylaxis. Journal of
Affective Disorders 1986;10:913.
Coppen A, Shaw DM, Farrell JP. Potentiation of the antidepressive effect of a
monoamine-oxidase inhibitor by tryptophan. Lancet 1963;1:7981.
Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmstrom C, Panossian A.
Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to
moderate depression. Nordic Journal of Psychiatry 2007;61:3438.
Davids E, Bunk C, Specka M, Gastpar M. Psychotropic drug prescription in a
psychiatric
university
hospital
in
Germany.
Progress
in
Neuropsychopharmacology and Biological Psychiatry 2006;30:110916.
de la Gandara J, Aguera L, Rojo JE, Ros S, de Pedro JM. Use of antidepressant
combinations: which, when and why? Results of a Spanish survey. Acta
Psychiatrica Scandinavica Supplemental 2005:326.
Dorfman-Etrog P, Hermesh H, Prilipko L, Weizman A, Munitz H. The effect of
vitamin E addition to acute neuroleptic treatment on the emergence of
extrapyramidal side effects in schizophrenic patients: an open label study.
European Neuropsychopharmacology 1999;9:4757.
Dunlop BW, Davis PG. Combination treatment with benzodiazepines and SSRIs for
comorbid anxiety and depression: a review. Primary Care Companion to the
Journal of Clinical Psychiatry 2008;10:2228.
Eden Evins A, Demopulos C, Yovel I, Culhane M, Ogutha J, Grandin LD, et al. Inositol
augmentation of lithium or valproate for bipolar depression. Bipolar Disorder
2006;8:16874.
Ellen S, Selzer R, Norman T, Blashki G. Depression and anxiety:
pharmacological treatment in general practice. Australian Family Physician
2007;36:2228.
Emsley R, Niehaus DJ, Koen L, Oosthuizen PP, Turner HJ, Carey P, et al. The effects of
eicosapentaenoic acid in tardive dyskinesia: a randomized, placebo-controlled
trial. Schizophrenia Research 2006;84:11220.
Fava M, Rush AJ. Current status of augmentation and combination treatments for
major depressive disorder: a literature review and a proposal for a novel
approach to improve practice. Psychotherapy and Psychosomatics
2006;75:13953.
Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M. A placebo-controlled trial
of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for
residual symptoms and cognitive impairment in schizophrenia. American
Journal of Psychiatry 2001;158:20714.
Finfgeld DL. Serotonin syndrome and the use of SSRIs. Journal of Psychosocial
Nursing and Mental Health Services 2004;42:1620.
Fountoulakis KN, Vieta E, Sanchez-Moreno J, Kaprinis SG, Goikolea JM, Kaprinis GS.
Treatment guidelines for bipolar disorder: a critical review. Journal of Affective
Disorders 2005;86:110.
Frangou S, Lewis M, McCrone P. Efcacy of ethyl-eicosapentaenoic acid in bipolar
depression: randomised double-blind placebo-controlled study. British Journal
of Psychiatry 2006;188:4650.

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

ARTICLE IN PRESS
J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx
Glassman AH, Platman SR. Potentiation of a monoamine oxidase inhibitor by
tryptophan. Journal of Psychiatric Research 1969;7:838.
Guy W, Bonato RE. CGI: Clinical Global Impressions. Manual for the ECDEU
assessment battery, 2nd revised ed.. Chevy Chase, MD: National Institute of
Mental Health; 1970.
Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics: differential risk
and clinical implications. CNS Drugs 2007;21:91136.
Hamilton M. The assessment of anxiety states by rating. British Journal of Medical
Psychology 1959;32:505.
Hamilton M. A rating scale for depression. Journal of Neurology and Neurosurgery
in Psychiatry 1960;23:5662.
Henderson DC. Managing weight gain and metabolic issues in patients treated with
atypical antipsychotics. Journal of Clinical Psychiatry 2008;69:e04.
Hood SD, Bell CJ, Nutt DJ. Acute tryptophan depletion. Part I: Rationale and
methodology. Australian and New Zealand Journal of Psychiatry
2005;39:55864.
Izzo AA. Drug interactions with St. Johns wort (Hypericum perforatum): a review of
the clinical evidence. International Journal of Clinical Pharmacology and
Therapeutics 2004;42:13948.
Jazayeri S, Tehrani-Doost T, Keshavarz A, Hosseini M, Djazayery A, Amini H.
Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid
and uoxetine, separately and in combination, in major depressive disorder.
Australian and New Zealand Journal of Psychiatry 2008;42:1928.
Keck Jr PE, Mintz J, McElroy SL, Freeman MP, Suppes T, Frye MA, et al. Double-blind,
randomized, placebo-controlled trials of ethyl-eicosapentaenoate in the
treatment of bipolar depression and rapid cycling bipolar disorder. Biological
Psychiatry 2006;60:10202.
Kelly GS. Rhodiola rosea: a possible plant adaptogen. Alternative Medicine Review
2001;6:293302.
Knuppel L, Linde K. Adverse effects of St. Johns wort: a systematic review. Journal of
Clinical Psychiatry 2004;65:14709.
Lerner V, Bergman J, Statsenko N, Miodownik C. Vitamin B6 treatment in acute
neuroleptic-induced akathisia: a randomised, double-blind, placebo-controlled
study. Journal of Clinical Psychiatry 2004;65:15504.
Lerner V, Miodownik C, Kaptsan A, Bersudsky Y, Libov I, Sela BA, et al. Vitamin B6
treatment for tardive dyskinesia: a randomized, double-blind, placebocontrolled, crossover study. Journal of Clinical Psychiatry 2007;68:164854.
Lerner V, Miodownik C, Kaptsan A, Cohen H, Loewenthal U, Kotler M. Vitamin B6 as
add-on treatment in chronic schizophrenic and schizoaffective patients: a
double-blind, placebo-controlled study. Journal of Clinical Psychiatry
2002;63:548.
Levine J, Barak Y, Gonzalves M, Szor H, Elizur A, Kofman O, et al. Double-blind,
controlled trial of inositol treatment of depression. American Journal of
Psychiatry 1995;152:7924.
Levine J, Mishori A, Susnosky M, Martin M, Belmaker RH. Combination of inositol
and serotonin reuptake inhibitors in the treatment of depression. Biological
Psychiatry 1999;45:2703.
Levitan RD, Shen JH, Jindal R, Driver HS, Kennedy SH, Shapiro CM. Preliminary
randomized double-blind placebo-controlled trial of tryptophan combined with
uoxetine to treat major depressive disorder: antidepressant and hypnotic
effects. Journal of Psychiatry and Neuroscience 2000;25:33746.
Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of
antidepressant efcacy of omega-3 fatty acids. Journal of Clinical Psychiatry
2007;68:105661.
Madabushi R, Frank B, Drewelow B, Derendorf H, Butterweck V. Hyperforin in St.
Johns wort drug interactions. European Journal of Clinical Pharmacology
2006;62:22533.
Malsch U, Kieser M. Efcacy of kavakava in the treatment of non-psychotic
anxiety, following pretreatment with benzodiazepines. Psychopharmacology
(Berlin) 2001;157:27783.
Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ. A double- blind,
placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the
treatment of major depression. American Journal of Psychiatry
2003;160:9968.
Miklowitz DJ, Johnson SL. The psychopathology and treatment of bipolar disorder.
Annual Reviews in Clinical Psychology 2006;2:199235.
Miodownik C, Cohen H, Kotler M, Lerner V. Vitamin B6 add-on therapy in treatment
of schizophrenic patients with psychotic symptoms and movement disorders.
Harefuah 2003;142:5926. 647.
Montgomery P, Richardson AJ. Omega-3 fatty acids for bipolar disorder. Cochrane
Database Systematic Reviews 2008 [CD005169].
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to
change. British Journal of Psychiatry 1979;134:3829.
Morris DW, Trivedi MH, Rush AJ. Folate and unipolar depression. Journal of
Alternative Complementary Medicine 2008;14:27785.
Morris S. Estimating effect sizes from pretestposttest-control group designs.
Organizational Research Methods 2008;11:36486.
Moshiri E, Basti AA, Noorbala AA, Jamshidi AH, Hesameddin Abbasi S, Akhondzadeh
S. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: a
double-blind, randomized and placebo-controlled trial. Phytomedicine 2006.
Nardini M, De Stefano R, Iannuccelli M, Borghesi R, Battistini N. Treatment of
depression with L-5-hydroxytryptophan combined with chlorimipramine, a
double-blind study. International Journal Clinical Pharmacology Research
1983;3:23950.
Nelson JC. Augmentation strategies in depression 2000. Journal of Clinical
Psychiatry 2000;61(Suppl. 2):139.

Nemets B, Mishory A, Levine J, Belmaker RH. Inositol addition does not improve
depression in SSRI treatment failures. Journal of Neural Transmission
1999;106:7958.
Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance
medication treatment for recurrent unipolar depressive disorder. American
Journal of Psychiatry 2002;159:4779.
Nestler EJ, Carlezon Jr WA. The mesolimbic dopamine reward circuit in depression.
Biological Psychiatry 2006;59:11519.
Nierenberg AA, Burt T, Matthews J, Weiss AP. Mania associated with St. Johns wort.
Biological Psychiatry 1999;46:17078.
Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi AH. Hydro-alcoholic
extract of Crocus sativus L. versus uoxetine in the treatment of mild to
moderate depression: a double-blind, randomized pilot trial. Journal of
Ethnopharmacology 2005;97:2814.
Oswald P, Souery D, Kasper S, Lecrubier Y, Montgomery S, Wyckaert S, et al. Current
issues
in
bipolar
disorder:
a
critical
review.
European
Neuropsychopharmacology 2007;17:68795.
Papakostas GI, Petersen T, Lebowitz BD, Mischoulon D, Ryan JL, Nierenberg AA, et al.
The relationship between serum folate, vitamin B12, and homocysteine levels in
major depressive disorder and the timing of improvement with uoxetine.
International Journal of Neuropsychopharmacology 2005;8:5238.
Parker G, Gibson N, Heruc G, Rees A, Hadzi-Pavlovic D. Omega-3 fatty acids and
mood disorders. American Journal of Psychiatry 2006;163:96978.
Patten SB, Beck C. Major depression and mental health care utilization in Canada:
1994 to 2000. Canadian Journal of Psychiatry 2004;49:3039.
Peet M, Brind J, Ramchand CN, Shah S, Vankar GK. Two double-blind placebocontrolled pilot studies of eicosapentaenoic acid in the treatment of
schizophrenia. Schizophrenia Research 2001;49:24351.
Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate
in patients with ongoing depression despite apparently adequate treatment
with standard drugs. Archives of General Psychiatry 2002;59:9139.
Preskorn SH. Pharmacogenomics, informatics, and individual drug therapy in
psychiatry: past, present and future. Journal Psychopharmacology
2006;20:8594.
Raja M, Azzoni A. Hypericum-induced mood disorders: switch from depression to
mixed episodes in two patients. International Journal of Psychiatry in Clinical
Practice 2006;10:1468.
Rathbone J, Zhang L, Zhang M, Xia J, Liu X, Yang Y. Chinese herbal medicine for
schizophrenia. Cochrane Database Systematic Reviews 2005 [CD003444].
Resler G, Lavie R, Campos J, Mata S, Urbina M, Garca A, et al. Effect of folic acid
combined with uoxetine in patients with major depression on plasma
homocysteine and vitamin B12, and serotonin levels in lymphocytes.
Neuroimmunomodulation 2008;15:14552.
Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the
pathophysiology of depression and anxiety disorders. Depression and Anxiety
2000;12(Suppl. 1):219.
Rickels K, Rynn M. Pharmacotherapy of generalized anxiety disorder. Journal of
Clinical Psychiatry 2002;63(Suppl. 14):916.
Roberts SH, Bedson E, Hughes D, Lloyd K, Moat S, Pirmohamed M, et al. Folate
augmentation of treatment evaluation for depression (FolATED): protocol of a
randomised controlled trial. BMC Psychiatry 2007;7:65.
Rodriguez-Landa JF, Contreras CM. A review of clinical and experimental
observations about antidepressant actions and side effects produced by
Hypericum perforatum extracts. Phytomedicine 2003;10:68899.
Roiser J, McLean A, Ogilvie A, Blackwell A, Bamber D, Goodyer I, et al. The subjective
and cognitive effects of acute phenylalanine and tyrosine depletion in patients
recovered from depression. Neuropsychopharmacology 2005;30:77585.
Rush AJ. STAR*D: what have we learned? American Journal of Psychiatry
2007;164:2014.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al.
Acute and longer-term outcomes in depressed outpatients requiring one or
several treatment steps: a STAR*D report. American Journal of Psychiatry
2006;163:190517.
Sachs GS, Thase ME, Otto MW, Bauer M, Miklowitz D, Wisniewski SR, et al.
Rationale, design, and methods of the systematic treatment enhancement
program
for
bipolar
disorder
(STEP-BD).
Biological
Psychiatry
2003;53:102842.
Schneck C. St. Johns wort and hypomania. Journal of Clinical Psychiatry
1998;59:689.
Schulz V. Safety of St. Johns wort extract compared to synthetic antidepressants.
Phytomedicine 2006;13:199204.
Shaw DM, Macsweeney DA, Hewland R, Johnson AL. Tricyclic antidepressants and
tryptophan in unipolar depression. Psychological Medicine 1975;5:2768.
Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression.
Cochrane Database Systematic Reviews 2002 [CD003198].
Shevtsov VA, Zholus BI, Shervarly VI, Volskij VB, Korovin YP, Khristich MP, et al. A
randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus
placebo and control of capacity for mental work. Phytomedicine
2003;10:95105.
Shriqui C, Bradwejn J, Annable L, Jones B. Vitamin E in the treatment of tardive
dyskinesia: a double-blind placebo-controlled study. American Journal of
Psychiatry 1992;149:3913.
Soares-Weiser K, Fernandez HH. Tardive dyskinesia. Seminars in Neurology
2007;27:15969.
Soares K, McGrath J. Vitamin E for neuroleptic-induced tardive dyskinesia. Cochrane
Database Systematic Reviews 2001(4) [CD000209].

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003

ARTICLE IN PRESS
10

J. Sarris et al. / Journal of Psychiatric Research xxx (2009) xxxxxx

Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, et al. Omega 3
fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled
trial. Archives of General Psychiatry 1999;56:40712.
Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive
disorder. A preliminary double-blind, placebo-controlled trial. European
Neuropsychopharmacology 2003;13:26771.
Tapp A, Wood AE, Secrest L, Erdmann J, Cubberley L, Kilzieh N. Combination
antipsychotic therapy in clinical practice. Psychiatric Services 2003;54:559.
Taylor MJ, Wilder H, Bhagwagar Z, Geddes J. Inositol for depressive disorders.
Cochrane Database Systematic Reviews 2004 [CD004049].
Thase ME. STEP-BD and bipolar depression: what have we learned? Current
Psychiatry Reports 2007;9:497503.
Thomson J, Rankin H, Ashcroft GW, Yates CM, McQueen JK, Cummings SW. The
treatment of depression in general practice: a comparison of L-tryptophan,
amitriptyline, and a combination of L-tryptophan and amitriptyline with
placebo. Psychological Medicine 1982;12:74151.
Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, et al.
Medication augmentation after the failure of SSRIs for depression. New England
Journal of Medicine 2006;354:124352.
Tyrer P, Baldwin D. Generalised anxiety disorder. Lancet 2006;368:215666.
Vaddadi KS, Courtney P, Gilleard CJ, Manku MS, Horrobin DF. A double-blind trial of
essential fatty acid supplementation in patients with tardive dyskinesia.
Psychiatric Research 1989;27:31323.
Walinder J, Skott A, Carlsson A, Nagy A, Bjorn-Erik R. Potentiation of the
antidepressant action of clomipramine by tryptophan. Archives in General
Psychiatry 1976;33:13849.
Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results:
a comprehensive review of ndings. Current Psychiatry Reports
2007;9:44959.
Werneke U, Taylor T, Priebe S. Complementary medicines in psychiatry: review of
effectiveness and safety. British Journal of Psychiatry 2006;188:10921.
Williams AL, Girard C, Jui D, Sabina A, Katz DL. S-Adenosylmethionine (SAMe) as
treatment for depression: a systematic review. Clinical and Investigative
Medicine 2005;28:1329.

Williamson EM. Synergy and other interactions in phytomedicines. Phytomedicine

2001;8:4019.
Yang ZY, Zhang WB, Liu JL. Comparative study of modied xiaoyao pill combining
amitriptyline on therapeutic effect and compliance in treating patients with
depression. Zhongguo Zhong Xi Yi Jie He Za Zhi 2007;27:6424.
Young R, Biggs J, Ziegler V, Meyer D. A rating scale for mania: reliability, validity and
sensitivity. British Journal of Psychiatry 1978:42935.
Zanoli P. Role of hyperforin in the pharmacological activities of St. Johns wort. CNS
Drug Reviews 2004;10:20318.
Zarate Jr CA, Quiroz JA. Combination treatment in bipolar disorder: a review of
controlled trials. Bipolar Disorder 2003;5:21725.
Zhang HW, Wang CY, Xu HN, Zhao X, Dai Q, Li J, et al. Clinical study on effect of
uoxetine combined with Chinese medicine or tibetan drugs in treating senile
depression in plateau district. Zhongguo Zhong Xi Yi Jie He Za Zhi
2006;26:2024.
Zhang XY, Zhou DF, Cao LY, Xu CQ, Chen DC, Wu GY. The effect of vitamin E
treatment on tardive dyskinesia and blood superoxide dismutase: a doubleblind placebo-controlled trial. Journal of Clinical Psychopharmacology
2004;24:836.
Zhang XY, Zhou DF, Su JM, Zhang PY. The effect of extract of Ginkgo biloba added to
haloperidol on superoxide dismutase in inpatients with chronic schizophrenia.
Journal of Clinical Psychopharmacology 2001a;21:858.
Zhang XY, Zhou DF, Zhang PY, Wu GY, Su JM, Cao LY. A double-blind, placebocontrolled trial of extract of Ginkgo biloba added to haloperidol in treatmentresistant patients with schizophrenia. Journal of Clinical Psychiatry
2001b;62:87883.
Zhang ZJ, Kang WH, Tan QR, Li Q, Gao CG, Zhang FG, et al. Adjunctive herbal
medicine with carbamazepine for bipolar disorders: a double-blind,
randomized, placebo-controlled study. Journal of Psychiatric Research 2005.
Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome
P450 3A4. Current Drug Metabolism 2008;9:31022.

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06.003