document22

Journal of Psychiatric Research xxx (2009) xxx–xxx

ARTICLE IN PRESS

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Journal of Psychiatric Research

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

Review

Adjuvant use of nutritional and herbal medicines with antidepressants, moodstabilizers and benzodiazepines

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

a School of Medicine, University of Queensland, Queensland, Australiab 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 2009Received in revised form 31 May 2009Accepted 15 June 2009Available online xxxx

Keywords:AdjuvantAdjunctiveHerbal medicineAntidepressantsMood stabilizersBenzodiazepinesKavaSt. John’s wort

0022-3956/$ - see front matter � 2009 Elsevier Ltd. Adoi:10.1016/j.jpsychires.2009.06.003

* Corresponding author. Address: School of MedicinFloor, Mental Health Centre, Royal Brisbane andBrisbane, Queensland 4029, Australia.

E-mail address: [email protected] (J. Sarris).

Please cite this article in press as: Sarris J et al.pines. Journal of Psychiatric Research (2009), d

a b s t r a c t

Adjuvant use of nutritional and herbal medicines has potential to increase the efficacy of synthetic phar-maceuticals, and perhaps also decrease their side-effects by allowing lower doses to be prescribed. Weevaluated 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 cri-tiques current evidence for co-administration of St. John’s wort with synthetic antidepressants. We per-formed a systematic search of MEDLINE, CINAHL, PsycINFO, The Cochrane database, China NationalKnowledge Infrastructure and the Chinese Science Citation Database. Search results were supplementedby a review of reference lists and a forward search using the Web of Science. Where possible we calcu-lated effect sizes. 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 efficacy. Various nutrientsalso have emerging evidence as effective adjuncts with antipsychotics and mood stabilizers. While someevidence supports nutritional adjuvancy with various psychopharmacotherapies, adjuvant use of herbaltherapies has not been sufficiently studied to warrant standard clinical application. This remains a prom-ising area of research via robust, safety-conscious studies.

� 2009 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.1. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.1. Adjuvant use of pharmacotherapies for depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1.2. Adjuvant use of nutritional and herbal medicines with antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.1. Adjuvant use of pharmacotherapies for bipolar disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2.2. Adjuvant use of nutritional and herbal medicines with mood stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Anxiety disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3.1. Adjuvant use of pharmacotherapies for anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.3.2. Adjuvant use of nutritional and herbal medicines with benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.4. Novel adjuvant therapeutic uses of herbal medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Role of funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

ll rights reserved.

e, University of Queensland, KWomens Hospital, Herston,

Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiaze-oi:10.1016/j.jpsychires.2009.06.003

http://dx.doi.org/10.1016/j.jpsychires.2009.06.003

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

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1. Introduction

Adjuvancy strategies of medicines are commonly classifiedinto ‘‘augmentation” and ‘‘combination” approaches (Fava andRush, 2006). Prescriptive augmentation in psychiatry involvesusing psychotropic interventions that are not establishedmono-therapies in conjunction with pharmaceutical psychotrop-ics, in order to enhance response or limit side-effects. Combina-tion strategies involve using two or more establishedpharmaceutical psychotropics for the same purpose. Adjuvancycan be initiated either at the start of the prescription, or laterif there is insufficient response to initial treatment. Most clinicaltrials assessing adjuvancy apply the additional intervention afterabsent or partial response to the initial prescription. Outcomesthat are commonly assessed in adjuvancy studies include en-hanced response time and response rate (i.e. >50% reductionon assessment scale used), and improved remission rate (ab-sence of diagnosis or a score below at set level on an assessmentmeasure (Fava and Rush, 2006). Other outcomes that are lesscommonly explored include reduction of side-effects (more com-mon in studies using antipsychotics), remission of residual phys-iological or psychological symptoms, and subjective changes inquality of life.

Surveys have shown that polypharmacy by general practitionersand psychiatrists has increased significantly over recent years (Da-vids et al., 2006; de la Gandara et al., 2005; Patten and Beck, 2004;Tapp et al., 2003). Polypharmacy combinations commonly includethe use of multiple antidepressants in MDD, antidepressants withbenzodiazepines in ‘‘anxious” depression, combinations of atypicalantipsychotics in psychotic disorders, and mood stabilizers withantidepressants in bipolar depression. However, such polypharmacyis not always supported by evidence. Those data are briefly reviewedin later sections.

Many open or controlled clinical trials have been conductedusing adjuvant applications of nutritional and herbal medicineswith antipsychotics for amelioration of side-effects rather and in-creased efficacy. A major concern in using antipsychotics is tardivedyskinesia, which over 20% of patients experience (Soares-Weiserand Fernandez, 2007). Other side-effects of antipsychotics includeweight gain, somnolescence, constipation, cardiovascular and met-abolic 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) havedemonstrated beneficial effects in attenuating either extra-pyra-midal side-effects or positive schizophrenic symptoms. Anantioxidation and anti-inflammatory mechanism of action iscommonly posited as being responsible for attenuation of tardivedyskinesia (Zhang et al., 2001a). Mixed results in respect to ame-lioration of positive or negative symptoms or tardive dyskinesiahave 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 Cochranereview concluded that while vitamin E may not effectively treattardive dyskinesia, it may have a role in its prevention (Soaresand McGrath, 2001). Controlled studies using vitamin B6 havedemonstrated beneficial effects on the reduction of extra-pyrami-dal symptoms (Lerner et al., 2002, 2004, 2007; Miodownik et al.,2003).

Other nutritional and herbal medicines hold potential inadjuvant use with pharmaceutical medicines to increase theirefficacy via increased pharmacodynamic synergism (Williamson,2001). Although this area is controversial because of thepotential for pharmacokinetic interactions, beneficial interac-tions potentially may occur, leading to a reduction in the dos-

Please cite this article in press as: Sarris J et al. Adjuvant use of nutritional andpines. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.06

age of the pharmaceutical medication, or increasedefficacy.

Despite an increased practice of synthetic polypharmacy (Presk-orn, 2006), co-prescription of herbal medicines is often met withalarm over concerns of potential drug–herb interactions. Whilecaution is indicated in any case where multiple prescriptions havepotential for interactions, a differential concern over drug–herbinteractions needs further examination. Rigorous study is needednot only to determine the extent of any negative interactions,but also to examine the potential for synergistic benefits.

A previous review by Werneke et al. (2006), explored evidenceof herbal and nutritional psychotropic interventions and touchedupon their adjuvant use. Our intention is to provide a comprehen-sive and critical review of the literature, focusing specifically onthe current evidence of adjuvant use of herbal and nutritionalmedicines with commonly used pharmacotherapies for moodand anxiety disorders. A secondary aim is to provide a perspectiveon future research and integrative clinical applications of naturaland synthetic medicines.

2. Methods

The electronic databases MEDLINE (Pubmed), CINAHL, Psy-cINFO, Chinese Science Citation Database (via Web of Science)and The Cochrane Library were accessed during late 2008. Pubmedwas 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 herbaland nutritional medicines commonly trialed for psychotropicactivity (e.g. kava, St. John’s wort, folic acid, omega-3). A forwardsearch of the identified papers was performed using Web of Sci-ence cited reference search. We reviewed papers that describedcontrolled, uncontrolled or quasi-experimental human studies.Reasons for exclusion included: a higher level of evidence beingavailable, use of isolated herbal constituents, or inadequate meth-odological rigor. We reported the effect sizes in all placebo con-trolled studies where data was available. We calculated the (d) ofthe clinical trials by (a) calculating the effect size separately withinthe active and control group (taking the difference between base-line and post-treatment means, divided by the within-group stan-dard deviation at baseline), and (b) subtracting the effect size ofthe control group from that of the active group (Morris, 2008).

3. Results

A total of 4345 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 medicinewith ‘‘Antidepressants”, ‘‘Mood Stabilizers” and ‘‘Benzodiazepines”.As detailed below, most ‘‘Western” adjuvancy studies involvednutritional medicines, while herbal medicine adjuvancy studieswere mostly of ‘‘Asian” origin, using traditional Chinese or Japa-nese formulations.

3.1. Depression

3.1.1. Adjuvant use of pharmacotherapies for depressionOnly about a third of patients with MDD who are treated by a

first-line antidepressant achieve complete remission (Rush et al.,2006), with treatment trials typically focusing on a 50% reductionin symptoms as a positive treatment response. Most adjuvancystudies on antidepressants involve a range of synthetic agents,including other antidepressants (e.g. TCAs or mirtazapine withSSRIs), mood stabilizers (e.g. lithium, carbamazepine, or valproate),

herbal medicines with antidepressants, mood stabilizers and benzodiaze-.003


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and noradrenergic or dopaminergic agents (e.g. bupropion, reboxe-tine, atomoxetine: Berlim et al., 2008; Nelson, 2000). Evidence forpharmacological combinations primarily comprises open, uncon-trolled studies, and results are mixed (Fava and Rush, 2006; Trivediet al., 2006). To date, the most advanced adjuvancy study is the Se-quenced Treatment Alternatives to Relieve Depression (STAR*D), amulti-site, prospective, randomized, multi-step clinical trial com-paring a series of adjunctive or alternative treatments for patientswho did not respond to citalopram (Warden et al., 2007). Resultsconfirmed that only a minority of people with MDD achieve remis-sion via initial treatment with an SSRI. Switching, combining oraugmenting produced benefits to some initial non-responders,but a third of people with MDD did not achieve complete remis-sion, even after multiple treatment strategies.

As detailed in Table 1, many studies have been conducted usinga variety of nutrients adjuvantly with antidepressants (omega-3, S-adenosyl-methionine, folic acid, tryptophan and inositol). Only oneherbal medicine mono-therapy study was revealed from our liter-ature review, indicating that this is a relatively uncharted field ofresearch.

3.1.2. Adjuvant use of nutritional and herbal medicines withantidepressants

Omega-3 fatty acids have not yet demonstrated significant re-sults as a mono-therapy for Major Depressive Disorder (Marangellet al., 2003; Parker et al., 2006). However, epidemiological studieshave demonstrated that a rise in depressive symptoms is corre-lated with lower dietary omega-3 fish oil intake (Appleton et al.,2006, 2007; Lin and Su, 2007). Studies have also shown that peoplewith depression tend to have a lower serum level of essential fattyacids (EPA and DHA: Appleton et al., 2006). A recent meta-analysisconducted by Lin and Su (2007), included nine eligible RCTs of suf-ficient methodological rigor. The results revealed that omega-3preparations demonstrated a positive standardized mean differ-ence towards a beneficial effect over placebo. Pooling of these re-sults by the authors revealed a moderate effect size (d = 0.61). Itshould be noted that not all studies had positive outcomes and thatlonger clinical trials using a combination of both EPA/DHA are ad-vised. A Cochrane review that included only one study, commentedthat beneficial effects may been found for depressive symptomsbut not for mania (Montgomery and Richardson, 2008).

Four adjuvancy trials have been conducted, all with positiveclinical outcomes and strong effect sizes. Randomized, double-blind augmentation of 20 mg of fluoxetine with 1 g of EPA over8 weeks in 60 non-responsive depressed patients demonstrated asignificantly better reduction on the Hamilton Depression RatingScale (HDRS; Hamilton, 1960) than fluoxetine or EPA alone (Jazay-eri et al., 2008). The response rate from the combination (P50% de-crease on HDRS) was 81% compared with 56% and 50% for EPA andfluoxetine, respectively. A 4-week controlled study (n = 20) using2 g daily of EPA in patients with non-response to stabilized antide-pressants showed similar significant benefits (d = 2.92: Nemetset al., 2002). One gram per day of ethyl-eicosapentaenoate waseffective as an adjuvant agent in a 12-week study of 70 subjectswith non-response to unspecified antidepressants (Peet and Hor-robin, 2002). Curiously, the 4 g EPA arm only had a trend towardsimprovement, and the group receiving 2 g/day did not experienceany statistically significant benefits. This may indicate either a cur-vilinear dose–response effect or insufficient power to detect differ-ential effects. An 8-week study using 6.6 g/day of omega-3 fattyacids adjuvantly in 32 non-responders to antidepressants demon-strated a 13.6 point reduction on the HDRS, compared with 6.4in the placebo group (d = 1.85: Su et al., 2003).

In evaluating effects of omega-3 on depressed mood, it shouldbe noted that there are issues in respect to the type of omega-3 for-mulation 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, orpurified ethyl esters. Currently there is not scientific consensuson which preparation is preferential for depressive episodes.

Folate deficiency (assessed via low dietary intake or low serumlevel) has been consistently demonstrated in depressive popula-tions and in poor responders to antidepressants (Morris et al.,2008). Two controlled studies were located in our search. An RCTused 500 lg of folic acid or placebo adjuvantly with 20 mg fluoxe-tine in 127 subjects with HDRS of >20 (Coppen and Bailey, 2000). Astatistically significant differential reduction after 10 weeks onHDRS occurred only for women on completion of 6.8 ± 4.1 in thefluoxetine plus folic acid condition, compared with 11.7 ± 6.7 fromfluoxetine plus placebo; d = 0.73. Over the same period, plasmahomocysteine decreased in women 20.6% more in the folate groupcompared with control. Neither effect occurred in men. A recentRCT involving 27 depressed subjects found that 20 mg of fluoxetinecombined with 10 mg of folic acid was more effective in reducingHDRS score compared to augmentation with placebo (7.43 ± 1.65vs. 11.43 ± 1.31, respectively; p = 0.04: Resler et al., 2008). A signif-icant reduction of homocysteine was also observed in the folic acidgroup, compared to placebo. The researchers considered that amechanism of action may involve a reduced turnover rate of sero-tonin, and subsequent increased accumulation serotonin in thecells, as the marker 5-Hydroxyindoleacetic acid was significantlylower in lymphocytes of patients receiving folate.

A UK-based RCT with 730 participants (‘‘FolATED”) is being cur-rently conducted to assess effects of folic acid augmentation (5 mg/day: Roberts et al., 2007). The study will also evaluate the cost-effectiveness of folic acid augmentation on antidepressant treat-ment, how genetic polymorphisms relevant to folate metabolismaffect antidepressant response, and whether baseline folate statuscan predict response to antidepressant treatment.

Inositol has been studied as an antidepressant mono-therapyand as an augmenting agent, and has mixed results (Taylor et al.,2004). An early double-blind, controlled 4-week study with 28 par-ticipants demonstrated statistically significant antidepressantactivity 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 withSSRIs (Levine et al., 1999; Nemets et al., 1999). Neither study dem-onstrated a significant difference between adjuvant use of inositolor placebo.

S-Adenosyl-methionine (SAMe) has been studied for antidepres-sant activity for several decades. Most studies involve parenteralor intramuscular injections of SAMe which subsequently crossesthe blood–brain barrier (Williams et al., 2005). SAMe has consis-tently demonstrated an antidepressant mechanism of activity,and comparable effects to synthetic antidepressants (Papakostaset al., 2005). Several adjuvancy studies were found. A 6-week openlabel study using 800–1600 mg/day of SAMe with 30 non-respond-ers to stabilized prescription of SSRIs or venlafaxine was conductedby Alpert et al. (2004). Intention-to-treat analysis revealed thatadjuvant use of SAMe significantly reduced depression from base-line to week 6 on HDRS (17 ± 4.2 to 10.0 ± 6.6). Intramuscularadministered SAMe (200 mg/day) demonstrated a significant in-crease in the onset of response of imipramine (150 mg/day: Ber-langa et al., 1992). A significant effect became apparent by day 4and remained until day 12, after which there was no difference be-tween groups. Due to concerns over development of hypomania ormania, SAMe should be used cautiously in patients with a historyof mania. Another caveat is cost. Therapeutic dosage of oral SAMemay 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-



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

Herbal/nutritional medicine Clinical evidence Precautions Conclusions

Omega-3 Four studies have demonstrated positive results after 2 ormore weeks of omega-3

High dosage may " INR (caution with warfarin) A potentially beneficial antidepressant effect may occur, especially insubjects with low EFA serum status. May also be beneficial in subjectswith comorbid cardiovascular disease (which has increased risk indepression)

(1–6.6 g/day) with SSRIs, TCAs, MAOIs (Jazayeri et al., 2008;Nemets et al., 2002; Peet and Horrobin, 2002)

High dosage may also alter triglyceride levels

Typical dosea: 3–9 g/day of omega-3 or 1–2 g/day EPA plus 1–2 g ofDHA

S-Adenosyl-methionine(SAMe)

Intramuscular and oral augmentation of SAMe withantidepressants has demonstrated " response and remissionrates (Berlanga et al., 1992). May enhance response inantidepressant non-responders (Alpert et al., 2004)

May interact with serotonergic antidepressants; cautionin bipolar patients to avoid switching to mania

Expense may restrict applicability. Parenteral administration may bemore efficacious than oral administrationTypical dosea: 400–1600 mg/day

L-tryptophan L-tryptophan augmentation with MAOIs, SSRIs and someTCAs is effective in increasing the antidepressant response:phenezine sulphate (Glassman and Platman, 1969),fluoxetine (Levitan et al., 2000), clomipramine (Nardini et al.,1983; Walinder et al., 1976). No difference occurredcompared to placebo with other tricyclics (Shaw et al., 1975)

High dosage may cause adverse reactions, e.g. GITcomplaints, nausea or serotonin syndrome (Byerleyet al., 1987)

May be of use in subjects taking antidepressants, in tryptophandeficiency, or in depression caused by serotonergic pathwaydysregulationTypical dosea: 200 mg–2 g/day

Inositol Controlled studies have demonstrated inositol augmentationwith SSRIs does not improve depression in SSRI treatmentfailures (Levine et al., 1999; Nemets et al., 1999)

None noted Inositol augmentation is currently not recommended

Folic acid Antidepressant augmentation with folic acid may increaseresponse rate increases and efficacy (Coppen and Bailey,2000; Resler et al., 2008). Subjects with lower folate levelsare more likely to have a delayed response by on average1.5 weeks (Papakostas et al., 2005)

Caution should be observed in pernicious anaemia(addition of B12 required); " doses may cause agitationand anxiety

May increase response to antidepressants, perhaps especially in casesof folate deficiency, but further trials are required. May be moreefficacious in females than malesTypical dosea: 400 lg–2 g/day

Lavender (Lavendulaangustifolia)

4-week RCT (n = 45) 60 drops 1:5 lavender vs. 100 mgimipramine. Lavender + imipramine was more effective thanimipramine alone in reducing depression (Akhondzadehet al., 2003)

The only side-effect from lavender use was a slightstatistical increase in the occurrence of mild headaches

Larger studies are needed to confirm beneficial synergisticpharmacodynamic activity

Traditional Chinese medicineformulas

Results of two studies using Xiaoyao and Sanpu Xinnaoherbal formulas with amitriptyline and fluoxetine showedsignificantly ; adverse reactions and " remission rates

None noted Traditional Chinese herbal formulas may reduce side-effects andincrease compliance to antidepressants, but there is currently noevidence of added antidepressant benefit. Further studies are needed

No increased efficacy however occurred (Yang et al., 2007;Zhang et al., 2006)

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 areunlikely to uniformly occur where a deficit of quality (manufacturing, storage, and standardization of active chemicals) is apparent. Caution in dosage is therefore required.

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sant (Byerley et al., 1987). Although there are several positive stud-ies, a rigorous systematic review and meta-analysis by Shaw et al.(2002) concluded that due to small sample sizes, poor outcomemeasures and publication bias, there were insufficient data toinform clinical practice. Eight controlled adjuvancy studies werelocated. L-tryptophan (or its biological intermediary, 5-hydroxytry-ptophan) augmentation was found to be effective in increasing theantidepressant response with phenezine sulphate (Glassman andPlatman, 1969), clomipramine (Nardini et al., 1983; Walinderet al., 1976), tranylcypromine (Coppen et al., 1963) and fluoxetine(Levitan et al., 2000). However, other clinical studies using tricyc-lics discovered no additional benefit compared with placebo (Ayu-so Gutierrez et al., 1973; Shaw et al., 1975; Thomson et al., 1982).Many of the older studies were of weak methodological design, andadditional rigorous studies are needed to confirm these results.Amino acids DL-phenylalanine and L-tyrosine, precursors to dopa-mine and norepinephrine, may provide augmenting antidepressantactivity however no studies were located assessing this.

Lavender (Lavendula angustifolia) is currently the only herbalmono-therapy examined as an adjunct with other antidepressantpharmacotherapy. A 4-week RCT using a combination of lavendertincture (1:5 60 drops/day) and imipramine (100 mg/day) in 45people with diagnosed MDD, was significantly more effective thanimipramine alone on HDRS, indicating a synergistic effect(Akhondzadeh et al., 2003). Two small studies testing traditionaloriental formulas Xiaoyao (Yang et al., 2007) and Sanpu Xinnao(Zhang et al., 2006) adjuvantly with amitriptyline and fluoxetine,respectively, demonstrated no significant increase in antidepres-sant activity. Adverse reactions were however reduced in bothcombination groups, and relapse rates were also lower.

3.2. Bipolar disorder

3.2.1. Adjuvant use of pharmacotherapies for bipolar disorderMood stabilizers including lithium and valproic acid and

antipsychotics are commonly used as first-line agents to treat thepresentation of the manic phase in Bipolar I Disorder (Miklowitzand Johnson, 2006). Statistics vary regarding the effectiveness oflithium in treating acute mania, with previous accounts of an effectrate of 60–80% perhaps being overestimated (Miklowitz andJohnson, 2006). As Bipolar Disorder (BD) has serious consequences(e.g. increased risk of suicide) and elicits significant socio-eco-nomic cost, further pursuit of safe and efficacious treatments arerequired (Oswald et al., 2007). Clinical research involving bipolarpharmacotherapy adjuvancy is presently still in its infancy (Foun-

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

Herbal/nutritionalmedicine

Clinical evidence Precautions

Omega-3 Augmentation with pre-prescribed mood stabilizers.Limited evidence in benefiting BD depression. Ineffectivein preventing or improving treatment of mania (Chiuet al., 2005; Frangou et al., 2006; Keck et al., 2006)

High dosagewarfarin)High dosagelevels

Folic acid An RCT using folic acid (200 lg) with lithiumdemonstrated minor benefit ; depression on BDI (Coppenet al., 1986)

None noted

Inositol Inositol augmentation with lithium demonstrated nosignificant antidepressant or mood stabilizing effect onHDRS. " response on HDRS in inositol group vs. placebo(44% vs. 0%, respectively) (Eden Evins et al., 2006)

None noted

TraditionalChinesemedicineformula

Jia-Wei-Xiao-Yao-San (Free and Easy Wanderer Plus) incombination with carbamazepine increased response andefficacy on depression outcomes. A statisticallysignificant reduction in fatigue and dizziness alsooccurred (Zhang et al., 2005)

This formulacarbamazepisubstitutionsChinese herb


toulakis et al., 2005). In relation to synthetic agents, current evi-dence on adjuvancy strategies for mania gives tentative supportfor use of carbamazepine with either haloperidol or lithium; andolanzapine or risperidone with lithium or valproate (Zarate andQuiroz, 2003). Mixed or negative results occurred in controlledstudies using gabapentine or lamotrigine with mood stabilizers,although the small samples in these studies prohibit firm conclu-sions. Our review of research on treatment or prevention of BDdepression revealed few studies with robust methodology. No con-sistent benefit in antidepressant augmentation was apparent,while evidence indicated that tricyclic antidepressants such asimipramine may also increase switching between depressive andmanic states.

The most comprehensive study of combination treatments inBD I/II is the Sequenced Treatment Enhancement Program for Bipo-lar Depression (STEP-BD: Sachs et al., 2003). This complex natural-istic quasi-controlled program involving 4370 participantsexplored the outcomes on depression and mania, involving stan-dard care vs. various controlled interventions (e.g. mood stabilizersin concert with buproprion, paroxetine, lamotrigine or inositol;and psychological treatments). No beneficial adjuvant effects ondepression were observed from bupropion or paroxetine overthose from mood stabilizers alone. Surprisingly, a trend occurredin favor of the antidepressants over placebo in reducing the inci-dences of hypomania and mania (Thase, 2007). Results for adjunc-tive psychological intervention were more positive than adjunctivepharmacotherapy. The study highlighted the difficulty in managingBD effectively, as demonstrated by poor compliance and responseto treatments.

Due to the intensity of neurochemical involvement and poten-tially harmful effects on mortality and morbidity in BD, standardpharmaceutical interventions continue to be the required first-linetreatment. Complementary medicines currently lack evidence inaddressing acute mania, and cannot be recommended as a first-lineintervention. They may however have a potential role in augment-ing the action of mood stabilizers or atypical antipsychotics, reduc-ing side-effects, and in improving compliance. Treatmentadherence is a major problem of treating BD, with up to 60% of pa-tients discontinuing treatment within the first year of prescription(Miklowitz and Johnson, 2006). The use of specific adjuvant nutri-tional or herbal medicines may allow for smaller doses of moodstabilizers required. This could potentially ameliorate typicalside-effects, increasing adherence and overall outcomes. Paperson the adjuvant use of herbal medicines and nutritional supple-ments with mood stabilizers are summarized in Table 2.

Conclusions

may " INR (caution with Appears safe and is more beneficial in addressingthe depression rather than mania. More studiesare required using EPA/DHA combinationsmay also alter triglyceride

Further studies using a higher dose of folic acidmay be of benefit

As with MDD, inositol may have little or no benefitin augmenting antidepressant or mood stabilizingeffects with lithium or valproate. A larger study isrequired

tion reduces serum level ofne. Heavy metals and planthave occurred in some

al medicines

Positive results of this research on the reduction ofdepression and side-effects, encourages furtherexploration of adjuvant use herbal medicines withmood stabilizers




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3.2.2. Adjuvant use of nutritional and herbal medicines with moodstabilizers

Omega-3 fatty acids have been studied as a mono-therapy and asan adjuvant intervention in bipolar depression. An RCT involving44 participants using a combination of EPA and DHA (9.6 g/day)as a mono-therapy revealed positive results on depression out-comes in terms of response and remission on HDRS (d = 1.15: Stollet al., 1999). No significant effect on mania outcomes occurred. Interms of adjuvant use of omega-3 in treating BD, three studieswere located. A 12 week, 3-arm controlled study involving 75 par-ticipants using 1 g or 2 g of EPA adjuvantly with unrestricted psy-chotropic medications revealed a small but significantly greaterreduction 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 sig-nificant effect for mania was achieved on the Young Mania RatingScale (YMRS: Young et al., 1978). A larger study (n = 385) using 6 gof EPA adjuvantly with at least one mood stabilizer in patients withrapidly cycling bipolar disorder found no effect compared to pla-cebo on reducing mania on YMRS (Keck et al., 2006) A small RCTwith 15 participants, using 4.4 g of EPA and 6.6 g of DHA/day adju-vantly with 20 mg/day of valproate also revealed no effect com-pared to placebo on reducing mania (Chiu et al., 2005). Currentevidence appears to weakly support omega-3 preparations adju-vantly in the depressive phase of bipolar. Omega-3 in the manicphase 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 significant reduction on the Beck Depres-sion Inventory (Beck et al., 1961) in the folic acid group, but notin the placebo group. A comparison of the active and placebogroups converts to a d of 0.22. It should be noted that the folic aciddose was very low (200 lg), and that higher doses 500–1000 lgmay yield a different response.

A pilot RCT was conducted, involving twenty-four participantswith DSM-IV bipolar depression (bipolar I = 21; bipolar II = 3) ran-domly assigned in addition to stable neuroleptic prescription with12 g of inositol or D-glucose as placebo for 6 weeks (Chengappaet al., 2000). The results revealed a non-significant response be-tween the groups on HDRS, Montgomery–Asberg Depression Rat-ing Scale (MADRS: Montgomery and Asberg, 1979) and ClinicalGlobal Impression scales (CGI: Guy and Bonato, 1970). A small 6-week RCT involving 17 participants using inositol or placebo adju-vantly in currently depressed bipolar patients with stabilized lev-els of lithium or valproate revealed mixed results (Eden Evinset al., 2006). Although no differential reduction occurred in HDRSor YMRS scores, four out of nine people achieved remission(P50% reduction on HDRS) in the inositol group compared withnone out of eight in the placebo group. This is consistent withthe results of the STEP-BD inositol adjuvancy arm, where therewas only a 17% increase in remission rates (Thase, 2007).

The only located study that examined herbal medicine beingused adjuvantly with mood stabilizers involved the traditional Chi-nese medicine formulation Jia-Wei-Xiao-Yao-San (Free and EasyWanderer Plus: Zhang et al., 2005). A 12-week double-blind, ran-domized, controlled study involving 124 bipolar (depressed) and111 bipolar (manic) participants was conducted. Response, efficacyand side-effects were assessed using carbamazepine mono-ther-apy (CBZ), or carbamazepine adjuvantly with Free and Easy Wan-derer Plus (CBZ + FEWP) or placebo. Results showed asignificantly increased response rate on HDRS, MADRS and CGIfrom CBZ + FEWP, compared with placebo or CBZ alone (84.8%,63.8% and 34.8%, respectively). The combination also significantlyreduced depression scores against placebo and carbamazepine atweeks 8 and 12. Effect sizes on the HDRS at week 12 using inten-tion-to-treat and completers analysis were d = 0.90 and d = 1.80,respectively. No significant effects were found on the mania out-


comes at endpoint between carbamazepine mono-therapy andthe combination. Interestingly, compared with carbamazepine, pa-tients 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 significantly greater improvement at the end-point, indicating that adjuvant FEWP administration may enhanceinitial response and reduce some side-effects in the short term, butthat this benefit is not maintained over time.

3.3. Anxiety disorders

3.3.1. Adjuvant use of pharmacotherapies for anxietyAdjuvancy strategies to treat anxiety disorders are commonly

focused on integrating psychological interventions or benzodiaze-pines with antidepressants (Dunlop and Davis, 2008; Tyrer andBaldwin, 2006). Benzodiazepines are commonly prescribed for arange of anxiety disorders, or to attenuate anxious symptomatol-ogy occurring as a side effect from commencement of antidepres-sants (Dunlop and Davis, 2008). Aside from psychologicalintervention, common adjuvant psychotropic interventions withbenzodiazepines include b-blockers (e.g. propanolol) to address so-matic anxious symptoms, and sedating antipsychotics (e.g. olanza-pine or risperidone: Rickels and Rynn, 2002). We located noaugmentation studies using nutritional or herbal medicines withbenzodiazepines.

Although benzodiazepines are effective anxiolytics, concernsover dependence and tolerance caution their long-term use (Ric-kels and Rynn, 2002). Use of nutritional or herbal medicines in con-junction with benzodiazepines may also therefore focus on theirreduction or withdrawal, whereby they are given during dosereduction, or as a substitute at benzodiazepine cessation. Becausethe former involves adjuvant use, this application of nutritionalor herbal medicines is included here.

3.3.2. Adjuvant use of nutritional and herbal medicines withbenzodiazepines

One study using kava (Piper methysticum) in benzodiazepinewithdrawal was identified in the search. A 5-week RCT was con-ducted using a standardized kava extract (WS� 1490) on 40 sub-jects with chronic anxiety and a long history of benzodiazepineuse (Malsch and Kieser, 2001). Subjects were tapered off their ben-zodiazepines over the first 2 weeks, while the kava was titratedfrom 50 mg up to 300 mg by the end of week one. Kava produceda statistically significant drop of 7.5 point decrease over placebo atweek 5 in anxiety on the Hamilton anxiety scale (Hamilton, 1959),and a positive result on the Benfindlichkeits–Skala subjective well-being scale (CIPS, 1996). Importantly, aside from some subjectsexperiencing withdrawal symptoms, no negative reactions (e.g. in-creased sedation) occurred during the first week of adjuvant kavause. Furthermore, only five subjects in the kava group displayedadverse symptoms from benzodiazepine withdrawal comparedwith 10 in the placebo group. During a follow-up study, 9 out of14 subjects who were switched from kava to placebo experiencedre-occurrence of anxiety. Practitioners considering adjuvant use ofkava should however be aware that kava was withdrawn in 2002from Europe, UK and Canadian markets over concerns over poten-tial hepatotoxicity.

3.4. Novel adjuvant therapeutic uses of herbal medicines

Our review revealed that few clinical trials to date have studiedco-administered herbal preparations with pharmaceuticals. Oneunexplored area of potential benefit to sufferers of BD, MDD, oranxiety disorders is the use of herbal medicines to reduce side-ef-fects from psychopharmacotherapies, thereby subsequently




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improving compliance. A major problem with many syntheticpharmaceutical antidepressants, is that compliance is often poor,with fewer than 50% of patients continuing with their prescribedmedication after 3 months (Ellen et al., 2007). An illustration of thisattrition occurred in the STAR*D project, with approximately 1 in 4patients at stage 1 (citalopram) discontinuing before remissionwas achieved (Warden et al., 2007). An example of the potentialof herbal medicines to reduce side-effects and improve compliancewith synthetic psychotropics is detailed in a Cochrane databasesystematic review of Chinese herbal medicine (CHM) preparationsfor schizophrenia (Rathbone et al., 2005). Compared with those gi-ven only antipsychotics, significantly fewer patients withdrewfrom treatment in the CHM plus antipsychotic groups than fromthe antipsychotic mono-therapy groups. Subjects also displayedfewer side-effects such as constipation. The authors of the Cochra-ne review concluded that CHM when combined with antipsychoticdrugs may be of benefit in treating schizophrenia. As discussedpreviously, a similar amelioration of side-effects (dizziness and fa-tigue) occurred in a bipolar disorder study using CHM with car-bamazepine (Zhang et al., 2005).

Our review of the literature revealed that the only mono-prep-arations of HMs trialed adjuvantly with psychotropics are L.angustifolia and G. biloba. As detailed above, these results were po-sitive, encouraging further research into other HMs. Two phyto-therapies that may provide novel adjuvant application withsynthetic antidepressants for enhancing efficacy in the treatmentof MDD are golden root (Rhodiola rosea), and saffron (Crocus sati-vus). Preliminary studies of moderate methodological rigor usingR. rosea have demonstrated potential antidepressant, anti-fatigueand anxiolytic activity (Bystritsky et al., 2008; Darbinyan et al.,2007; Kelly, 2001; Shevtsov et al., 2003). Before however adjuvan-cy studies are pursued, more substantive evidence of R. rosea as athymoleptic mono-therapy is required. In two studies with smallsamples, the petals and stamen from C. sativus have demonstratedagainst placebo significant antidepressant activity (Akhondzadehet al., 2005; Moshiri et al., 2006), and in three trials have displayedequivalent efficacy to imipramine (Akhondzadeh et al., 2004), andfluoxetine (Akhondzadeh et al., 2007; Noorbala et al., 2005). Addi-tional studies by different research groups and with larger samplesare needed to validate these findings. Regardless, the evidence cur-rently encourages research into adjuvant use of saffron withantidepressants.

A curious deficiency uncovered in our review of the literaturewas the absence of adjuvancy studies using St. John’s wort (Hyper-icum perfortum: SJW). A potential reason for the lack of trialsexploring co-prescription of SJW with antidepressants, may be aconcern over pharmacodynamic antagonism causing serotoninsyndrome and/or switching to hypomania or mania (Finfgeld,2004). However, evidence to support such a concern is weak andis currently based only on unsubstantiated case reports (Knuppeland Linde, 2004; Rodriguez-Landa and Contreras, 2003; Schulz,2006). The case studies typically also have concomitant use ofother medications and/or recreational drugs, and a background ofcyclothymia (Nierenberg et al., 1999; Raja and Azzoni, 2006; Sch-neck, 1998). In several cases, a clear temporal association appearedto exist between SJW use and induction of hypomania or mania, socaution is warranted in people with a personal or family history ofbipolar depression. Several case reports of serotonin syndromehave been documented by drug surveillance agencies (Knuppeland Linde, 2004). Currently however, it is not clear whether it isa dose-dependent phenomenon or what its mechanisms may be,and in particular, whether an interaction with antidepressantscausing hyperserotonergism actually occurs. We note that con-cerns over serotonin syndrome do not appear to be inhibiting re-search or off-label prescription of multiple syntheticantidepressants (Davids et al., 2006; de la Gandara et al., 2005; Pat-


ten and Beck, 2004). Interestingly, an opposite concern is com-monly raised in relation to pharmacokinetics, with SJWdocumented to reduce plasma levels of antidepressants via P-gly-coprotein (PgP) pump up-regulation and CYP450 3A4 induction(Izzo, 2004; Madabushi et al., 2006). These metabolic pathwaysare used in the metabolism of many antidepressants (Zhou,2008), suggesting that caution should be observed in co-prescrip-tion. Regardless, SJW preparations low in hyperforin (constituentresponsible for pharmacokinetic alterations) are less likely to havethis effect on PgP and CYP450 3A4, and hence may be safer (Mad-abushi et al., 2006; Zanoli, 2004). The counter side of using lowhyperforin extracts is that in vitro and animal models demonstratethat hyperforin exerts greater antidepressant activity than otherisolates 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. SJWexerts a broad range of psychopharmacological activity, includingdecreased degradation and non-selective re-uptake of serotonin,dopamine and norepinephrine, modulation of neurotransmittertransport systems, and possible neuro-endocrinological effects(Butterweck, 2003; Zanoli, 2004). This broad range of activitymay potentially provide an increased therapeutic effect from otherantidepressants. A balanced approach to adjuvant prescriptioncould involve low-dose administration of SJW with antidepres-sants to increase response, or potentially to lower the risk ofside-effects from the synthetic antidepressant by reducing the doserequired for efficacy. Clinical trials employing rigorous methodol-ogy and appropriate safety protocols would be required to assessany SJW adjuvancy strategies.

4. Discussion

Review of the literature revealed that encouraging evidence ex-ists for the use of omega-3 fatty acids, SAMe, folic acid and L-tryp-tophan adjuvantly with antidepressants to enhance response andimprove efficacy. Folic acid, omega-3 and some Chinese herbalmedicines also have emerging evidence as effective adjuncts withantipsychotics and mood stabilizers. In respect to the treatmentof BD, these interventions appear only to benefit the depressivephase of the disorder. Current evidence does not firmly supportthe adjuvant use of nutritional or herbal medicines in limitationor withdrawal of benzodiazepines, but this remains an area worthyof exploration. As detailed above, only one study trialing a herbalmedicine (kava) with concomitant benzodiazepines was identified.Although these results were promising, further trials examiningsafety would need to be employed before human use could be eth-ically recommended.

The evidence tells us that in psychiatric conditions such asMDD, the person needs to be treated early and aggressively to min-imize the chance of relapse (Rush, 2007). From a clinical perspec-tive the issue may not be whether the adjuvant interventionpossesses statistically significant therapeutic properties in a cho-sen sample. It is whether the chosen treatment is effective in theindividual prescribed the treatment, given the unique and complexcausation/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 ideallytherefore be tailored to the individual. Examples include noradren-ergic or dopaminergic modulation in non-responders to SSRIs, orfor the management of persistent lassitude, amotivation or hyper-phagia (Nestler and Carlezon, 2006; Ressler and Nemeroff, 2000),administration of sex hormones in cases of hormonal insufficiency(Belmaker and Agam, 2008), anxiolytics or hypnotic prescription in‘‘co-thymic” presentations, or buffering of initial anxiogenic side-effects from antidepressants (Tyrer and Baldwin, 2006). Common-




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sense suggests that a ‘‘one-size fits all” approach often adopted inclinical trials may have less success than tailored prescriptionstreating the cause/s of the individual’s depression; although thiscontention requires further evidence. The difficulty both cliniciansand researchers face is how to provide evidence-based adjuvantstrategies when a paucity of data exists on clear prescriptive proto-cols (Antonijevic, 2006). Research needs to be advanced in identi-fying which treatments combinations (synthetic or natural) aremore beneficial for which manifestations of MDD.

In the case of nutritional adjuvancy, a beneficial effect maymore likely occur when specific deficiencies or neurological dysre-gulations are apparent. For example, a patient who does not eatany omega-3 containing foods may potentially benefit more fromadjuvant omega-3 prescription than a patient who regularly eatsdeep sea fish. Common deficiencies affecting mental health out-comes may involve amino acids (e.g. tryptophan, phenylalanine,tyrosine), which provide the precursors to neurochemicals (Byer-ley et al., 1987); B vitamins in particular B6, B12 and folate, whichare involved in methylating pathways (Morris et al., 2008; Papa-kostas et al., 2005); and omega-3, which encourages neuronal com-munication (Appleton et al., 2006; Lin and Su, 2007).

In conclusion, while some positive evidence supports nutri-tional adjuvancy with various psychopharmacotherapies, adjuvantuse of herbal therapies has not been sufficiently studied to warrantstandard clinical application. This remains a promising area of re-search via robust, safety-conscious studies.

Conflict of interest

None.

Role of funding

None.

Acknowledgements

Sincere thanks are extended to Professor Qiu Xiaochun for hisassistance in searching the Chinese databases, and to Dr. Gary Deedfor his critique of the paper.

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